Multiple Myeloma

The development of MM is commonly preceded by MGUS, a premalignant condition that results when plasma cells undergo mutations that restore their capacity for proliferation. In MGUS, these clonal plasma cells take up less than 10% of bone marrow. The serum protein value is less than 3 g/dL and myeloma-related end-organ damage is absent. An intermediate disease stage between MGUS and MM, termed smoldering MM, is characterized by an M protein level of  3 g/dL or more and over 10% clonal plasma cells in bone marrow, but no symptoms of myeloma-related end-organ damage.[6]   .

A variety of cytogenetic abnormalities are found in MGUS and MM. Approximately half of cases are hyperdiploid, usually with extra copies of the odd-numbered chromosomes. Most of the remainder are nonhyperdiploid and are characterized by a primary translocation involving the Ig heavy-chain gene at 14q32.[6] In addition, virtually all cases involve dysregulation of the cyclin D/retinoblastoma (cyclin D/RB) pathway.  This genetic heterogeneity contributes to the rapid emergence of drug resistance in MM.[7]  

Increasing evidence suggests that the bone marrow microenvironment of tumor cells plays a pivotal role in the pathogenesis of myelomas.[8] This discovery has resulted in the expansion of treatment options.

The role of cytokines in the pathogenesis of MM is an important area of research. Interleukin (IL)-6 is also an important factor promoting the in vitro growth of myeloma cells. Other cytokines are tumor necrosis factor and IL-1b.

The pathophysiologic basis for the clinical sequelae of MM involves the skeletal, hematologic, renal, and nervous systems, as well as general processes (see below).

Skeletal processes

Plasma-cell proliferation causes extensive skeletal destruction with osteolytic lesions, anemia, and hypercalcemia. Mechanisms for hypercalcemia include bony involvement and, possibly, humoral mechanisms. Isolated plasmacytomas (which affect 2-10% of patients) lead to hypercalcemia through production of the osteoclast-activating factor.

Destruction of bone and its replacement by tumor may lead to pain, spinal cord compression, and pathologic fracture. The mechanism of spinal cord compression symptoms may be the development of an epidural mass with compression, a compression fracture of a vertebral body destroyed by multiple myeloma, or, rarely, an extradural mass. With pathologic fracture, bony involvement is typically lytic in nature.

Hematologic processes

Bone marrow infiltration by plasma cells results in neutropenia, anemia, and thrombocytopenia. M components may interact specifically with clotting factors, leading to defective aggregation.

Renal processes

The most common mechanisms of renal injury in MM are direct tubular injury, amyloidosis, or involvement by plasmacytoma.[9, 10] Renal conditions that may be observed include hypercalcemic nephropathy, hyperuricemia due to renal infiltration of plasma cells resulting in myeloma, light-chain nephropathy, amyloidosis, and glomerulosclerosis.

Neurologic processes

The nervous system may be involved as a result of radiculopathy and/or cord compression due to nerve compression and skeletal destruction (amyloid infiltration of nerves).

General processes

General pathophysiologic processes include hyperviscosity syndrome. This syndrome is infrequent in MM and occurs with overproduction of IgG1, IgG3, or IgA. Sludging in the capillaries can result in purpura, retinal hemorrhage, papilledema, coronary ischemia, or central nervous system (CNS) symptoms (eg, confusion, vertigo, seizure). Cryoglobulinemia causes Raynaud phenomenon, thrombosis, and gangrene in the extremities.

The precise etiology of MM has not yet been established. Roles have been suggested for a variety of factors, including genetic causes, environmental or occupational causes, MGUS, radiation, chronic inflammation, and infection.

Genetic causes

MM has been reported in two or more first-degree relatives and in identical twins, although no evidence suggests a hereditary basis for the disease. A study by the Mayo Clinic found MM in eight siblings from a group of 440 patients; these eight siblings had different heavy chains but the same light chains.

Some studies have shown that abnormalities of certain oncogenes, such as c-myc, are associated with development early in the course of plasma cell tumors and that abnormalities of oncogenes such as N-ras and K-ras are associated with development after bone marrow relapse. Abnormalities of tumor suppressor genes, such as TP53, have been shown to be associated with spread to other organs.[11]

Ongoing research is investigating whether human leukocyte antigen (HLA)-Cw5 or HLA-Cw2 may play a role in the pathogenesis of multiple myeloma.

Environmental or occupational causes

Case-controlled studies have suggested a significant risk of developing MM in individuals with significant occupational exposures in the agriculture, food, and petrochemical industries. An increased risk has been reported in farmers, especially in those who use herbicides and insecticides (eg, chlordane), and in people exposed to benzene and other organic solvents. There is conflicting evidence regarding long-term (>20 y) exposure to hair dyes and possible increased risk of developing MM.[12]

MGUS/Smoldering Multiple Myeloma (SMM)

Monoclonal gammopathy of undetermined significance (MGUS) is defined by the presence of three criteria:

• Serum monoclonal M protein (M-protein) concentration < 3 g/dL
• Bone marrow plasma cell concentration < 10%
• No evidence of end organ damage

MGUS is seen in 2-3% of the elderly Caucasian population. It is divided into the following three subtypes:

• Non IgM MGUS
• IgM MGUS
• Light chain MGUS

Patients with non-IgM MGUS have a risk of progression to MM at rate of 1% per year. For these patients, risk factors for progression to MM are as follows:

• M protein concentration > 1.5 g/dL
• Non-IgG isotype
• An abnormal free light chain (FLC) ratio

Patients with IgM MGUS have a risk of progression to Waldenstrom macroglobulinemia and less frequently lymphoma or amyloid light chain (AL) amyloidosis. IgM MGUS rarely progresses into MM. Light chain MGUS has a tendency to progress to light chain MM, AL amyloidosis, or light chain deposition disease.

A study by Wadhera et al examined secondary MGUS that developed in patients with MM. Of 1942 patients with MM, 128 (6.6%) developed a secondary MGUS at a median of 12 months from the diagnosis of MM. Overall survival was superior in patients with MM who developed secondary MGUS compared with the rest of the cohort.[13]

Smoldering MM is present when the serum M protein concentration is > 3 g/dL or the bone marrow plasma cell concentration is > 10% but there is no evidence of end-organ damage. Risk factors for progression of SMM to MM include any of the following:

• M protein concentration >3 g/dL
• Abnormal FLC ratio
• Bone marrow plasma cell concentration >10%

The time to progression decreases with increasing numbers of risk factors, as follows:

• One factor: 10 years
• Two factors: 5.1 years
• Three factors: 1.9 years

Radiation

Radiation may play a role in some patients. An increased risk has been reported in atomic-bomb survivors exposed to more than 50 Gy: In 109,000 survivors of the atomic bombing of Nagasaki during World War II, 29 died from multiple myeloma between 1950 and 1976. Some more recent studies, however, do not confirm that these survivors have an increased risk of developing multiple myeloma.

A study of workers at the Oak Ridge Diffusion Plant in eastern Tennessee showed only a weak correlation of risk of multiple myeloma to uranium exposure.[14]

Chronic inflammation

A relationship between MM and preexisting chronic inflammatory diseases has been suggested. However, a case-control study provides no support for the role of chronic antigenic stimulation.

Infection

Human herpesvirus 8 (HH8) infection of bone marrow dendritic cells has been found in patients with multiple myeloma and in some patients with MGUS.

MM accounts for 10% of all hematologic cancers.[15, 16]  The American Cancer Society estimates that in the United States, approximately 35,730 new cases of MM (19,860 in men and 15,870 in women) will be diagnosed in 2023.[17]  The lifetime risk of getting MM is approximately one in 125 (0.8%).[18] Approximately 12,590 deaths from MM (7000 in men and 5590 in women) are expected to occur in the US in 2023.[17] Rates for new MM cases rose slightly over the last decade, from 6.6 per 100,000 persons in 2010 to 7.1 per 100,000 persons in 2020, while death rates declined slightly, from 3.3 to 3.0 per 100,000 from 2010 to 2020.[18]

In the US, the annual incidence of MM per 100,000 persons is 8.1 cases in white men, 5.0 cases in White women, 17.0 cases in Black men, and 12.9 cases in Black women. For Hispanics, the rates are 8.1 in men and 5.9 in women. Rates are lowest for Asians/Pacific Islanders, at 5.1 in men and 3.2 in women.[18]  According to a study of the ethnic disparities among patients with MM, Hispanics had the youngest median age at diagnosis (65 years) and Whites had the oldest (71 years). Asians had the best overall survival rates, while Hispanics had the worst.[19]

The median age at diagnosis of MM is 69 years. Less than 14% of patients are younger than 55 years, and only about 3% are younger than 45 years.[18]

MM is a heterogeneous disease, with survival ranging from 1 year to more than 10 years. Median survival in unselected patients with MM is 3 years. The 5-year relative survival rate is 46.6%.[18] Survival is higher in younger people and lower in the elderly.[11, 20]

The tumor burden and the proliferation rate are the two key indicators for the prognosis in patients with MM. Many schemas have been published to aid in determining the prognosis. One schema uses C-reactive protein (CRP) and beta-2 microglobulin (which is an expression of tumor burden) to predict survival, as follows[21] :

• If levels of both proteins are less than 6 mg/L, the median survival is 54 months.
• If the level of only one component is less than 6 mg/L, the median survival is 27 months.
• If levels of both protein values are greater than 6 mg/L, the median survival is 6 months.

Poor prognostic factors include the following:

• Tumor mass
• Hypercalcemia
• Bence Jones proteinemia
• Kidney impairment (ie, stage B disease or creatinine level > 2 mg/dL at diagnosis)

The prognosis by treatment is as follows:

• Conventional therapy: Overall survival is approximately 3 years, and event-free survival is less than 2 years.
• High-dose chemotherapy with stem-cell transplantation: The overall survival rate is greater than 50% at 5 years.

Infections are an important cause of early death in MM. In a United Kingdom study, 10% of patients died within 60 days after diagnosis of MM, and 45% of those deaths were due to infection.[22] In a Swedish study, 22% of patients died of infection within the first year after diagnosis. The risk of both bacterial infections (eg, meningitis, septicemia, pneumonia) and viral infections (eg, herpes zoster, influenza) was seven times higher in patients with MM than in matched controls. The Swedish investigators also found that the risk of infections has increased in recent decades, and they argue that the use of more intensive treatment measures for MM (ie, newer drugs and high-dose chemotherapy with transplantation) has contributed to the increased risk.[23]

Patient education is very important in the management of MM. The International Myeloma Foundation (IMF) offers educational resources, a quarterly newsletter, and conferences. Patients or physicians can contact the IMF by phone at (800) 452-CURE (800-452-2873) in the United States and Canada or on the Web at International Myeloma Foundation.

Patient education should address, at a minimum, the following questions:

• What is MM, and how does it affect the body?
• What are the causes of MM?
• What is the treatment for MM?
• What are the adverse effects of medicine? (As an example, patients should be informed of the risk of osteonecrosis of the jaw, which has been associated with bisphosphonate therapy in MM.)
• What are some of the complications of MM?
• Where can additional information be found?

For patient education information, see Multiple Myeloma.

Presenting signs and symptoms of multiple myeloma (MM) include bone pain, pathologic fractures, weakness, anemia, infection (often pneumococcal), hypercalcemia, spinal cord compression, and renal failure. In approximately 30% of cases, MM is discovered through routine blood screening when patients are being evaluated for unrelated problems. Typically, a large gap between the total protein and the albumin levels observed on an automated chemistry panel suggests a problem (ie, protein minus albumin equals globulin).

In one third of patients, MM is diagnosed after a pathologic fracture occurs; such fractures commonly involve the axial skeleton. Two thirds of patients complain of bone pain, commonly with lower back pain. This bone pain is frequently located in the back, long bones, skull, and/or pelvis.

Patients may also complain of nonspecific constitutional symptoms related to hyperviscosity and hypercalcemia.

Bone pain

Bone pain is the most common presenting symptom in MM. Most case series report that 70% of patients have bone pain at presentation. The lumbar spine is one of the most common sites of pain.

Pathologic fractures and bone lesions

Pathologic fractures are very common in MM; 93% of patients have more than one site of bony involvement. A severe bony event is a common presenting issue.

Spinal cord compression

The symptoms that should alert physicians to consider spinal cord compression are back pain, weakness, numbness, or dysesthesias in the extremities. Because spinal cord compressions in MM occur at multiple levels, comprehensive evaluation of the spine is warranted. Patients who are ambulatory at the start of therapy have the best likelihood of preserving function and avoiding paralysis.

Bleeding

Occasionally, a patient may come to medical attention for bleeding resulting from thrombocytopenia. Rarely, monoclonal protein may absorb clotting factors and lead to bleeding.

Hypercalcemia

Confusion, somnolence, bone pain, constipation, nausea, and thirst are the presenting symptoms of hypercalcemia. This complication may be present in as many as 30% of patients with MM at presentation. In most solid malignancies, hypercalcemia carries an ominous prognosis, but in MM, its occurrence does not adversely affect survival.

Infection

Abnormal humoral immunity and leukopenia may lead to infection. Pneumococcal organisms are commonly involved, but shingles (ie, herpes zoster) and Haemophilus infections are also more common in patients with MM.

Hyperviscosity

Hyperviscosity may be associated with a number of symptoms, including generalized malaise, infection, fever, paresthesia, sluggish mentation, and sensory loss. Patients may report headaches and somnolence, and they may bruise easily and have hazy vision. Patients with MM typically experience these symptoms when their serum viscosity is greater than 4 times that of normal serum.

Epistaxis may be a presenting symptom of MM with a high tumor volume. Occasionally, patients may have such a high volume of monoclonal protein that their blood viscosity increases, resulting in complications such as stroke, myocardial ischemia, or infarction.

Neurologic symptoms

Carpal tunnel syndrome is a common complication of myeloma. Meningitis (especially that resulting from pneumococcal or meningococcal infection) is more common in patients with MM. Some peripheral neuropathies have been attributed to MM. Long-term neurologic function is directly related to the rapidity of the diagnosis and the institution of appropriate therapy for MM.

Anemia

Anemia, which may be quite severe, is the most common cause of weakness in patients with MM.

On head, ears, eyes, nose, and throat (HEENT) examination, the eyes may show exudative macular detachment, retinal hemorrhage, or cotton-wool spots. Pallor from anemia may be present. Ecchymoses or purpura from thrombocytopenia may be evident.

Bony tenderness is not uncommon in MM, resulting from focal lytic destructive bone lesions or pathologic fracture. Pain without tenderness is typical. Pathologic fractures may be observed. In general, painful lesions that involve at least 50% of the cortical diameter of a long bone or lesions that involve the femoral neck or calcar femorale are at high (50%) risk for a pathologic fracture. The risk of fracture is lower in upper-extremity lesions than in lower-extremity lesions. Even a small cortical defect can decrease torsional strength by as much as 60% (stress riser effect).

Neurologic findings may include a sensory level change (ie, loss of sensation below a dermatome corresponding to a spinal cord compression), neuropathy, myopathy, a Tinel sign, or a Phalen sign due to carpel tunnel compression secondary to amyloid deposition.

Extramedullary plasmacytomas, which consist of soft-tissue masses of plasma cells, are not uncommon. Plasmacytomas have been described in almost every site in the body. Although the aerodigestive tract is the most common location, reports also describe orbital, ear canal, cutaneous, gastric, rectal, prostatic, and retroperitoneal lesions.

On evaluation of the abdomen, hepatosplenomegaly may be discovered. Cardiovascular system examination may reveal cardiomegaly secondary to immunoglobulin deposition.

Amyloidosis may develop in some patients with MM. The characteristic physical examination findings that suggest amyloidosis include the following:

• Shoulder pad sign
• Macroglossia
• Typical skin lesions
• Post-proctoscopic peripalpebral purpura 

The shoulder pad sign is defined by bilateral swelling of the shoulder joints secondary to amyloid deposition. Physicians describe the swelling as hard and rubbery. Amyloidosis may also be associated with carpal tunnel syndrome and subcutaneous nodules.

Macroglossia may occur secondary to amyloid deposition in the tongue and is a common finding in patients with amyloidosis (see the image below).

Skin lesions that have been described as waxy papules or nodules may occur on the torso, ears, or lips.

Post-proctoscopic peripalpebral purpura strongly suggests amyloidosis. The term originated in the time when rectal biopsy was the initial procedure of choice for diagnosing amyloidosis, and the hemodynamic effect of the procedure—comparable to a prolonged Valsalva maneuver—would lead to burst capillaries in patients with amyloid infiltration of the vessels around the eyes, Patients also may develop these raccoonlike dark circles around their eyes as a result of coughing, vomiting, or forced expiration during spirometric testing).

Renal failure and insufficiency are seen in 25% of patients with MM,[24]  and may reflect any of the following:

• Myeloma kidney syndrome with multiple etiologies
• Amyloidosis with light chains
• Nephrocalcinosis due to hypercalcemia

Anemia, neutropenia, or thrombocytopenia is due to bone marrow infiltration of plasma cells. Thrombosis and Raynaud phenomenon due to cryoglobulinemia may be present.

Bone disease may result in the following:

• Severe bone pain, pathologic fracture due to lytic lesions: Lytic disease or fracture may be observed on plain radiographs.
• Increased bone resorption leading to hypercalcemia
• Spinal cord compression: This is one of the most severe adverse effects of MM. Reports indicate that as many as 20% of patients develop spinal cord compression at some point during the course of their disease. Symptoms typically include back pain, weakness or paralysis in the legs, numbness, or dysesthesias in the lower extremities. However, depending on the level of involvement, patients may present with upper-extremity symptoms.

Radiculopathy and/or cord compression may occur because of skeletal destruction and nerve compression.

Bacterial infection may develop; it is the leading cause of death in patients with myeloma. The highest risk is in the first 2-3 months of chemotherapy.

Purpura, retinal hemorrhage, papilledema, coronary ischemia, seizures, and confusion may occur as a result of hyperviscosity syndrome.

Hypercalcemia may cause polyuria and polydipsia, muscle cramps, constipation, and a change in the patient’s mental status.

The International Myeloma Workshop developed guidelines for standard investigative workup in patients suspected to have multiple myeloma. These guidelines include the following:[1]

• Serum and urine assessment for monoclonal protein (densitometer tracing and nephelometric quantitation; immunofixation for confirmation)
• Serum-free light chain assay (in all patients with newly diagnosed plasma cell dyscrasias)
• Bone marrow aspiration and/or biopsy
• Serum beta-2 microglobulin, albumin, and lactate dehydrogenase measurement
• Standard metaphase cytogenetics
• Fluorescent in situ hybridization
• Skeletal survey
• Magnetic resonance imaging

Consider the risk of acute kidney injury, especially in the setting of contrast medium injection for imaging studies. Take care to limit patients’ exposure and maintain hydration.

Perform a complete blood count (CBC) to determine if the patient has anemia, thrombocytopenia, or leukopenia. The CBC and differential may show pancytopenia. The reticulocyte count is typically low. Peripheral blood smears may show rouleau formation.

The erythrocyte sedimentation rate (ESR) is typically increased. Coagulation studies may yield abnormal results.

Obtain a comprehensive metabolic panel to assess levels of the following:

• Total protein, albumin, and globulin
• Blood urea nitrogen (BUN) and creatinine
• Uric acid (will be elevated if the patient has high cell turnover or is dehydrated)

Obtain a 24-hour urine collection for quantification of the Bence Jones protein (ie, lambda light chains), protein, and creatinine clearance. Quantification of proteinuria is useful for the diagnosis of MM (>1 g of protein in 24 h is a major criterion) and for monitoring the response to therapy. Creatinine clearance can be useful for defining the severity of the patient’s renal impairment.

Serum protein electrophoresis (SPEP) is used to determine the type of each protein present and may indicate a characteristic curve (ie, where the spike is observed). Urine protein electrophoresis (UPEP) is used to identify the presence of the Bence Jones protein in urine. Immunofixation is used to identify the subtype of protein (ie, IgA lambda).

National Comprehensive Cancer Network (NCCN) guidelines also recommend the use of serum free light chain assay and plasma cell fluorescence in situ hybridization (FISH) for del 13, del 17p13, t(4;14), t(11;14), 1q21 amplification as part of the initial diagnostic workup.[2]

Chemical screening, including calcium and creatinine SPEP, immunofixation, and immunoglobulin quantitation, may show azotemia, hypercalcemia, an elevated alkaline phosphatase level, and hypoalbuminemia. A high lactate dehydrogenase (LDH) level is predictive of an aggressive lymphomalike course.

SPEP is a useful screening test for detecting M proteins. An M component is usually detected by means of high-resolution SPEP. The kappa-to-lambda ratio has been recommended as a screening tool for detecting M-component abnormalities. An M-component serum concentration of 30 g/L is a minimal diagnostic criterion for MM. In about 25% of patients, M protein cannot be detected by using SPEP.

Routine urinalysis may not indicate the presence of Bence Jones proteinuria. Therefore, a 24-hour urinalysis by means of UPEP or immunoelectrophoresis may be required. UPEP or immunoelectrophoresis can also be used to detect an M component and kappa or lambda light chains. The most important means of detecting MM is electrophoretic measurement of immunoglobulins in both serum and urine.

Suppression of nonmyelomatous immunoglobulin is a minor diagnostic criterion for MM. The level of MM protein (ie, M protein level), as documented by the immunoglobulin level, can be useful as a marker to assess the response to therapy.

Beta-2 microglobulin is a surrogate marker for the overall body tumor burden. The level of beta-2 microglobulin is increased in patients with renal insufficiency without MM, which is one reason that it is a useful prognosticator in MM.[21] (See Prognosis.) Patients with MM and impaired renal function have a worse prognosis.

C-reactive protein (CRP) is a surrogate marker of interleukin (IL)-6 activity. IL-6 is often referred to as the plasma cell growth factor. Like beta-2 microglobulin, CRP is useful for prognostication.[21] (See Prognosis.)

Check the serum viscosity in patients with central nervous system (CNS) symptoms, nosebleeds, or very high M protein levels. These findings may indicate hyperviscosity syndrome.

Simple radiography is indicated for the evaluation of skeleton lesions, and a skeletal survey is performed when myeloma is in the differential diagnosis. Plain radiography remains the gold standard imaging procedure for staging newly diagnosed and relapsed myeloma, according to an International Myeloma Working Group consensus statement.[25]

Perform a complete skeletal series at diagnosis of MM, including the skull (a very common site of bone lesions in persons with MM; see the image below), the long bones (to look for impending fractures), and the spine.

Conventional plain radiography can usually depict lytic lesions. Such lesions appear as multiple, rounded, punched-out areas, most often in the skull, vertebral column, ribs, and/or pelvis. Less common but not rare sites of involvement include the long bones. Plain radiographs can be supplemented by computed tomography (CT) scanning to assess cortical involvement and risk of fracture. Diffuse osteopenia may suggest myelomatous involvement before discrete lytic lesions are apparent.

Findings from this evaluation may be used to identify impending pathologic fractures, allowing physicians the opportunity to repair debilities and prevent further morbidity.

Also see the topic Imaging Multiple Myeloma.

Magnetic resonance imaging (MRI) is useful in detecting thoracic and lumbar spine lesions, paraspinal involvement, and early cord compression. Findings from MRI of the vertebrae are often positive when plain radiographs are not. MRI can depict as many as 40% of spinal abnormalities in patients with asymptomatic gammopathies in whom radiographic studies are normal. For this reason, evaluate symptomatic patients with MRI to obtain a clear view of the spinal column and to assess the integrity of the spinal cord.

Also see the topic Imaging Multiple Myeloma.

Comparative studies have suggested the possible utility of positron emission tomography (PET) scanning in the evaluation of MM.[26, 27] For example, a comparison study of PET scanning and whole-body MRI in patients with bone marrow biopsy-proven multiple myeloma found that although MRI had higher sensitivity and specificity than PET in the assessment of disease activity, when used in combination and with concordant findings, the 2 modalities had a specificity and positive predictive value of 100%.

These researchers suggest that the combination of modalities may be valuable for assessing the effectiveness of treatment, when aggressive and expensive regimens are used.[27] However, PET scanning has not yet been integrated into standard practice. The International Myeloma Working Group notes the potential usefulness of PET scanning in selected patients but suggests that such studies ideally should be performed in the context of a clinical trial.[25]

A study by Zamagni et al found that 18-F fluorodeoxyglucose (FDG) PET/CT scan findings were reliable predictors of prognosis among patients with multiple myeloma who had undergone thalidomide-dexamethasone induction therapy and double autotransplantation.[28]

Also see the topic Imaging Multiple Myeloma.

Do not use bone scans to evaluate MM. Cytokines secreted by MM cells suppress osteoblast activity; therefore, typically, no increased uptake is observed. On technetium bone scanning, more than 50% of lesions can be missed.

MM is characterized by an increased number of bone marrow plasma cells. Plasma cells show low proliferative activity, as measured by using the labeling index. This index is a reliable parameter for the diagnosis of MM. High values are strongly correlated with progression of the disease.

Obtain bone marrow aspirate and biopsy samples from patients with MM to calculate the percentage of plasma cells in the aspirate (reference range, up to 3%) and to look for sheets or clusters of plasma cells in the biopsy specimen. Bone marrow biopsy enables a more accurate evaluation of malignancies than does bone marrow aspiration.

Plasma cells are 2-3 times larger than typical lymphocytes; they have eccentric nuclei that are smooth (round or oval) in contour with clumped chromatin and have a perinuclear halo or pale zone (see the image below). The cytoplasm is basophilic.

Many MM cells have characteristic, but not diagnostic, cytoplasmic inclusions, usually containing immunoglobulin. The variants include Mott cells, Russell bodies, grape cells, and morula cells. Bone marrow examination reveals plasma cell infiltration, often in sheets or clumps (see the image below). This infiltration is different from the lymphoplasmacytic infiltration observed in patients with Waldenstrom macroglobulinemia.

Analysis of bone biopsy specimens may reveal plasmacytic, mixed cellular, or plasmablastic histologic findings. Approximate median survival by histologic type is as follows:

• Plasmacytic - 39.7 months
• Mixed cellular - 16.1 months
• Plasmablastic - 9.8 months

Cytogenetic analysis of the bone marrow may contribute significant prognostic information in multiple myeloma. The most significant cytogenetic abnormality appears to be deletion of 17p13. This abnormality is associated with shorter survival, more extramedullary disease, and hypercalcemia. This locus is the site of the TP53 tumor suppressor gene. Chromosome 1 abnormalities and c-myc defects are also significant prognostic factors in multiple myeloma.

Although not as well defined as in other hematologic malignancies, such as acute leukemia, risk-adapted therapy based on cytogenetic abnormalities is at the forefront of myeloma research.

Staging is a cumulative evaluation of all of the diagnostic information garnered and is a useful tool for stratifying the severity of patients’ disease. Currently, two staging systems for multiple myeloma are in use: the Salmon-Durie system, which has been widely used since 1975; and the International Staging System, developed by the International Myeloma Working Group and introduced in 2005.[29, 30]  A revision of the International Staging System, published in 2015, added genetic information to the standard laboratory tests.[31]  See also Multiple Myeloma Staging.

Salmon-Durie staging system

The Salmon-Durie classification of MM is based on three stages and additional subclassifications.

In stage I, the MM cell mass is less than 0.6 × 1012 cells/m2, and all of the following are present:

• Hemoglobin value >10 g/dL
• Serum calcium value < 12 mg/dL (normal)
• Normal bone structure (scale 0) or only a solitary bone plasmacytoma on radiographs
• Low M-component production rates (IgG value < 5 g/dL, IgA value < 3 g/dL, urine light-chain M component on electrophoresis < 4 g/24 h)

In stage II, the MM cell mass is 0.6-1.2 × 1012 cells/m2 or more. The other values fit neither those of stage I nor those of stage III.

In stage III, the MM cell mass is >1.2 × 1012 cells/m2, and all of the following are present:

• Hemoglobin value < 8.5 g/dL
• Serum calcium value >12 mg/dL
• Advanced lytic bone lesions (scale 3) on radiographs
• High M-component production rates (IgG value greater than 7 g/dL, IgA value greater than 5 g/dL, urine light-chain M component on electrophoresis greater than 12 g/24 h)

Subclassification A includes relatively normal renal function (serum creatinine value < 2 mg/dL), whereas subclassification B includes abnormal renal function (serum creatinine value > 2 mg/dL)

Median survival is as follows:

• Stage I, >60 months
• Stage II, 41 months
• Stage III, 23 months

Disease in subclassification B has a significantly worse outcome (eg, 2-12 mo survival in 4 separate series).

International Staging System

The International Staging System of the International Myeloma Working Group is also based on three stages.

Stage I consists of the following:

• Beta-2 microglobulin ≤3.5 g/dL and albumin ≥3.5 g/dL
• CRP ≥4.0 mg/dL
• Plasma cell labeling index < 1%
• Absence of chromosome 13 deletion
• Low serum IL-6 receptor
• Long duration of initial plateau phase

Stage II consists of the following:

• Beta-2 microglobulin level ≥3.5 to < 5.5 g/dL, or
• Beta-2 microglobulin < 3.5 g/dL and albumin < 3.5 g/dL

Stage III consists of the following:

• Beta-2 microglobulin of 5.5 g/dL or more

Median survival is as follows:

• Stage I, 62 months
• Stage II, 44 months
• Stage III, 29 months

Revised International Staging System

In the 2015 revision of the International Staging System (ISS) , stage I comprises all of the following:

• ISS stage I  
• Standard-risk chromosomal abnormalities by fluorescence in situ hybridization (FISH)(ie, no high-risk)
• Serum lactate dehydrogenase (LDH) level at or below the upper limit of normal

Stage II consists of all other possible combinations of ISS criteria, chromosomal abnormalities, and LDH other than those of stage I or III.

Stage III consists of the following:

• ISS stage III and 
• High-risk chromosomal abnormalities by FISH (ie, presence of del(17p) and/or translocation t(4;14) and/or translocation t(14;16)) or
• Serum LDH level above the upper limit of normal          

Physicians must understand both the natural history of multiple myeloma (MM) and the limitations of current therapy in the treatment of the disease. The objective in therapy is to obtain the deepest response in the first round by choosing the appropriate regimen; this should lead to better overall survival in both transplant and non-transplant patients. In situations with no definite data on therapeutic choices, participation in clinical trials should be encouraged. For a summary of treatment approaches to MM, see Multiple Myeloma Treatment Protocols.

Progression of disease and timing of treatment

An important study by Dimopoulos and associates evaluated the risk of disease progression in asymptomatic subjects with MM.[32] This study evaluated 638 consecutive untreated subjects with MM. Of these subjects, 95 were asymptomatic and were not treated until their M protein value rose to greater than 5 g/dL or they developed new lytic bone lesions or symptoms of bone disease.

The 638 individuals were designated as either low risk (ie, no bone disease, M protein level < 3 g/dL, or Bence Jones protein level < 5 g/24 h) or high risk (ie, lytic bone disease and serum M protein level >3 g/dL or Bence Jones protein level > 5 g/24 h). Intermediate-risk subjects did not have bone disease or an M protein level greater than 3 g/dL or a Bence Jones protein level greater than 5 g/24 h. The patients were evaluated every 2 months.

The median time for disease progression was 10 months in the high-risk group, 25 months in the intermediate-risk group, and 61 months in the low-risk group.[32] At the time of progression, subjects were treated with standard chemotherapy. Their response rates did not significantly differ from those of unselected populations. Median survival time from the institution of chemotherapy did not differ among the groups. Thus, asymptomatic subjects did not benefit from early treatment, and delayed treatment did not affect treatment efficacy (ie, survival).

A systematic review by He et al demonstrated a reduction in vertebral compressions and time to progression with early systemic treatment for asymptomatic patients, but this study also revealed an increase in acute leukemia in the early treatment group.[33] The failure to demonstrate improved survival may be due to the small number of patients studied.

The 2009 International Myeloma Workshop concluded that detection of any cytogenic abnormality suggests higher-risk disease, including chromosomal 13 or 13q deletion, t(4;14), and del17p and fluorescence in situ hybridization detection of t(4;14), t(14;16), and del17p.[34] Fluorescence in situ hybridization detection of 13q deletion alone is not considered a high-risk feature. International Staging System stages II and II and high serum beta(2)-microglobulin levels are suggestive of higher risk disease.

A study by Klein et al determined that the prognostic significance of t(4;14) may be eliminated or lessened among patients who receive lenalidomide and dexamethasone; however, del(17p13) and +1q21 are still associated with a dismal overall survival.[35] A study by Neben et al concludes that long-term administration of bortezomib in patients with del(17p13) may result in better overall and progression-free survival.[36]

Current therapeutic approaches

Overall, the care of patients with MM is complex and should focus on treatment of the disease process and any associated complications.[3, 5] Although MM remains incurable, several drug therapies are valuable in the treatment of patients with MM, as are autologous stem cell transplantation, radiation, and surgical care in certain cases.

Several studies are evaluating the role of treatment in patients with high-risk smoldering multiple myeloma (SMM). Previous smaller studies evaluating thalidomide did not show a clear evidence of benefit with treatment in patients with SMM; however, these included patients with all risk levels of SMM.

In a phase III trial that was restricted to patients with high-risk SMM, the PETHEMA group found evidence of benefit from treatment with lenalidomide versus observation. After a median follow-up of 40 months, study patients who were randomized to lenalidomide and dexamethasone induction followed by lenalidomide maintenance demonstrated significantly prolonged median time to progression (median not reached vs 21 months) and higher 3-year survival rate (94% vs. 80%).[37]

Lenalidomide as single-agent therapy (without dexamethasone induction) may also slow progression of SMM to MM. A phase III trial in 182 patients found that after 3 years, SMM had not progressed to MM in 91% of patients receiving lenalidomide, compared with 66% of those who underwent observation only.  Many patients stopped taking lenalidomide early due to adverse effects (eg, fatigue, neutropenia); however, preliminary results suggest that even a short course of treatment may be beneficial.[38]

In addition, the success of three-drug combinations for MM has led to trials of their use in SMM. Triplets currently under study for SMM include carfilzomib, lenalidomide, and dexamethasone and daratumumab, lenalidomide, and dexamethasone.

Longer follow-up will be necessary, however. Concern for second primary malignancies (SPMs) with the use of lenalidomide is also a significant issue. Consequently, watchful observation and frequent monitoring remains the standard of care for patients with SMM. 

Patients with MM for whom therapy is indicated typically receive chemotherapy. Greater understanding of the cell biology of MM and the ability to identify prognostic factors has led to the increasing individualization of treatment for affected patients. Physicians treat many patients with high-dose therapy or hematopoietic stem cell transplantation.

For primary induction therapy in patients with MM who are candidates for transplantation, National Comprehensive Cancer Network (NCCN) guidelines recommend the following combinations as preferred regimens[2] :

• Bortezomib/lenalidomide/dexamethasone (category 1)
• Bortezomib/cyclophosphamide/dexamethasone (preferred initial treatment in patients with acute kidney injury)

Other recommended regimens, according to the NCCN, are as follows:

• Carfilzomib/lenalidomide/dexamethasone
• Daratumumab/lenalidomide/bortezomib/dexamethasone
• Ixazomib/lenalidomide/dexamethasone (category 2B)

The NCCN considers the following regimens useful in certain circumstances (although triplet regimens should be used as the standard, patients not considered candidates for a 3-drug regimen can be started on a 2-drug regimen, with the third drug added once performance status improves):

• Bortezomib/doxorubicin/dexamethasone
• Carfilzomib/cyclophosphamide/dexamethasone
• Ixazomib/cyclophosphide/dexamethasone
• Bortezomib/thalidomide/dexamethasone (category 1)
• Cyclophosphamide/lenalidomide/dexamethasone
• Daratumumab/cyclophosphamide/bortezomib/dexamethasone
• Daratumumab/bortezomib/thalidomide/dexamethasone
• Dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide/bortezomib (VTD-PACE)

Patients should be assessed for response after two cycles of one of the above regimens.

Patients with MM who are treated with lenalidomide or thalidomide are at significantly increased risk for thrombotic events, and many physicians incorporate anticoagulation strategies in their management. A study by Palumbo et al determined that aspirin and low-dose warfarin had similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths in patients with myeloma receiving thalidomide-based regimens compared with low-molecular weight heparin, except in elderly patients.[35] In addition, the NCCN recommends that clinicians consider harvesting peripheral blood stem cells before patients have prolonged exposure to lenalidomide.[2]

As monotherapy or in combination, interferon alfa-2b and prednisone modestly prolong the disease-free interval.

A study by the Southwest Oncology Group compared lenalidomide plus dexamethasone to placebo plus dexamethasone in patients with newly diagnosed MM.[39] The study determined that lenalidomide plus dexamethasone had superior 1-year progression-free survival, overall response rate, and very good partial response rate, suggesting that it is safe and effective as initial therapy for patients with newly diagnosed MM. In 2015, the US Food and Drug Administration (FDA) expanded the approval of lenalidomide, in combination with dexamethasone, to include newly diagnosed MM. The original indication was for patients who had received at least 1 prior therapy.

A phase III randomized, open-label trial of 119 patients with high-risk SMM found that early treatment with lenalidomide plus dexamethasone, followed by maintenance therapy with lenalidomide, delayed progression to symptomatic disease and increased overall survival.[40, 41]

Adjunctive therapy for MM includes radiation therapy to target areas of pain, impending pathologic fracture, or existing pathologic fracture. Bisphosphonate therapy serves as prophylaxis (ie, primary, secondary) against skeletal events (eg, hypercalcemia, spinal cord compression, pathologic fracture, need for surgery, need for radiation). Evidence suggests that it may be effective in treating bone pain and in decreasing the likelihood of lesion recurrence.[42, 43, 44]

Adjunctive therapy may also include any of the following, as appropriate:

• Erythropoietin
• Corticosteroids
• Surgical intervention
• Plasmapheresis

Studies of chimeric antigen receptor (CAR) T-cell therapy using B-cell maturation antigen (BCMA) have reported objective in responses in patients with relapsed and/or refractory MM; in most patients, however, disease remission does not last longer than 18 months. Attempts to improve results are in progress.[45, 46]

Bone disease guidelines

Bisphosphonates (eg, zoledronic acid, pamidronate) or denosumab for prevention of skeletal related events (SREs) should be considered for all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions.[44, 47]  See Guidelines/Management of Multiple Myeloma–related Bone Disease

In patients with symptomatic MM, chemotherapy is required. In asymptomatic patients with MM, treatment is delayed until disease clinically progresses or until serum or urine levels of M protein substantially increase.

The M-component level in serum and/or urine is an indicator of the tumor burden; its reduction after chemotherapy is used as a sign of response. A 50% reduction in M-component is considered a good clinical response (according to the Chronic Leukemia-Myeloma Task Force). The historical standard regimen of melphalan plus prednisone induces a response in 50-60% of patients with MM. Disappearance of the M component on electrophoresis occurs in only 3% of patients, and cure is extraordinarily rare.

The first step before starting therapy in MM is to determine whether a patient is a candidate for an autologous stem cell transplant. Eligibility depends primarily on the patient’s age and comorbidities. Typically, age of 65 years is used as a cut-off point for transplant eligibility. Thus, treatment for MM is best looked at in terms of the following three categories of patients:

• Young, newly diagnosed patients who are potential transplant candidates
• High-risk patients who are potential transplant candidates
• Newly diagnosed elderly patients who are not transplant candidates

Young, newly diagnosed patients who are potential transplant candidates

Conventionally, VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone) chemotherapy has been used to decrease the tumor burden in MM as preparation for transplantation. VAD is administered as a 4-day continuous intravenous infusion of vincristine and doxorubicin, with 4 daily oral doses of dexamethasone. Patients require a central venous catheter for delivery of the infusion. In selected patients, this therapy can be performed in an outpatient setting.

Many researchers feel that the high-dose steroid component of VAD accounts for much of its efficacy. In some patients, high-dose dexamethasone alone may produce significant clinical responses.

Significant concerns with the use of infusion therapy include the risk of soft-tissue injury if the chemotherapy agent infiltrates, the risk of cardiac injury from the doxorubicin, and the risk of infection or hyperglycemia from the high-dose steroids. Some patients also experience adverse central nervous system (CNS) effects from the high-dose steroids. Given these risks, and the higher response rates of new agents (thalidomide, lenalidomide, and bortezomib), VAD is now considered suboptimal treatment. Overall, data on these novel agents are very encouraging and promising. Nevertheless, oncologists will need further studies to help define the exact timing and role of novel agents in the treatment of MM.

Regimens with thalidomide 

Thalidomide has proved effective against MM. The superiority of induction regimens containing thalidomide was demonstrated in randomized trials that compared VAD with thalidomide plus dexamethasone[48] ; thalidomide and doxorubicin plus dexamethasone[49] ; and thalidomide plus VAD.[50]

Thalidomide has a well-established role as first-line therapy, either as a single agent or in combination with steroids in patients with MM. The toxicity of this drug is predominantly sensory neuropathy, and because of the drug’s teratogenicity, close monitoring is required to avoid inadvertent administration during pregnancy.

Regimens with lenalidomide

An analogue of thalidomide, lenalidomide (Revlimid) is now a standard component of MM therapy. In 2013, Celgene Corp announced that a phase III trial of lenalidomide met the main goal of improving progression-free survival (PFS) in patients with newly diagnosed MM.[51] The drug was already approved for use in previously-treated MM, mantle cell lymphoma, and transfusion-dependent anemia caused by myelodysplastic syndromes.

In the late-stage study, treatment with lenalidomide combined with dexamethasone in patients with newly diagnosed MM resulted in significantly longer survival without the cancer worsening, than did treatment with a regimen consisting of melphalan, prednisone, and thalidomide (MPT).[51]

In a randomized, double-blind, placebo-controlled trial, lenalidomide plus high-dose dexamethasone proved superior to high-dose dexamethasone alone as treatment for newly diagnosed MM.[48] The overall response rate was 84% in the lenalidomide plus high-dose dexamethasone group versus 53% in the high-dose dexamethasone group, with 22% of patients achieving complete remission in the lenalidomide plus high-dose dexamethasone arm.

PFS and overall survival favored lenalidomide plus high-dose dexamethasone, but 12-month survival for both arms was > 90%. A very important observation, however, was the high incidence of deep venous thrombosis in the lenalidomide plus high-dose dexamethasone arm.[48]

In another randomized trial of lenalidomide plus high-dose dexamethasone (LD) versus lenalidomide plus low-dose dexamethasone (Ld) in newly diagnosed MM, Rajkumar found that although the overall response rate within the first 4 months favored LD, analysis at 1 year, overall survival was 96% in the Ld arm compared with 87% in the LD arm (P=0.0002). As a result, the trial was stopped, and patients on high-dose therapy were crossed over to low-dose therapy.[52]

Another trial assessed the safety and efficacy of the combination regimen clarithromycin (Biaxin), lenalidomide (Revlimid), and dexamethasone (BiRD) as first-line therapy for MM.[53] Of the 72 patients enrolled, 65 had an objective response (90.3%). A combined stringent and conventional complete response rate of 38.9% was achieved, and 73.6% of the patients achieved at least a 90% decrease in M-protein levels. BiRD was found to be an effective regimen with manageable side effects in the treatment of symptomatic, newly diagnosed MM.

Patients tolerate lenalidomide therapy well, and nausea is usually minimal. Patients typically experience total alopecia, but other adverse effects (eg, peripheral neurotoxicity, constipation) are usually mild. Pancytopenia is expected, but is not severe enough to require hospitalization for infection or transfusion unless the patient also has some other cause of bone marrow suppression.

Regimens with bortezomib

Bortezomib (Velcade), a proteosome inhibitor, has shown striking activity against MM. Objective responses as high as 27.7% in patients with relapsed and heavily pretreated MM[54] led to its approval by the FDA in 2003. Subsequent studies reported response rates as high as 80% when bortezomib is combined with melphalan.

A randomized trial that compared bortezomib plus dexamethasone with VAD for induction showed response rates of 80% for the bortezomib plus dexamethasone arm versus 62.8% for the VAD arm.[55] This regimen has been shown to be active not only before but also after transplantation. Following high-dose therapy and autologous transplantation, the rate of very good partial response or better continued to favor bortezomib plus dexamethasone. This benefit was observed independent of beta-2 microglobulin or adverse cytogenetic risk groups.

Similarly, a superior response rate was seen when the combination of bortezomib, thalidomide, and dexamethasone (VTd) was compared with thalidomide plus dexamethasone in a large phase III study: 93% in the VTd arm versus 80% in the thalidomide-dexamethasone arm, in which patients went on to receive tandem autologous stem cell transplantation.[56] As in other studies, response was independent of adverse prognostic risk factors.

The phase III Velcade as Initial Standard Therapy in MM (VISTA) trial found that the combined treatment of bortezomib, melphalan, and prednisone (VMP) significantly prolongs overall survival compared with melphalan and prednisone (MP) after lengthy follow-up and extensive subsequent antimyeloma therapy. A notable outcome of this study was that first-line bortezomib use did not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib-based and other novel-agent–based treatment until relapse.[57]

A study by Harousseau et al confirms the role of bortezomib in the initial nonintensive management of MM.[58]

A study by Sher et al found that a combination of bortezomib, pegylated liposomal doxorubicin, and thalidomide, known as the VDT regimen, had overall response rate and complete plus near-complete response rates of 78% and 35%, respectively.[57] The study concluded that VDT was a tolerable and effective regimen that may induce high response rates in patients considered to be poor candidates for steroid-based treatments.

Bortezomib appears to be of especial benefit in patients with plasma cell leukemia and kidney failure. The predominant adverse effects were neuropathy, hypotension, and thrombocytopenia. Despite these results, the exact timing of bortezomib administration in the treatment plan of patients with newly diagnosed MM is still evolving through ongoing research.

The FDA approved administration of bortezomib by the subcutaneous (SC) route in 2012. A study by Moreau et al found that the efficacy of SC bortezomib is not inferior to that of standard IV administration. Moreau also observed a better safety profile with SC administration: in particular, the incidence of grade 2 or greater peripheral neuropathy was 24% for SC compared with 41% for IV; grade 3 or higher peripheral neuropathy occurred in 6% of patients with SC administration vs 16% for IV administration.[59] Starting therapy with SC administration may be considered for patients with pre-existing peripheral neuropathy and those at high risk for it.

A study by Mateos et al found that patients with cytogenetic abnormalities had similar response to bortezomib therapy but shorter survival. The authors concluded that the present treatment schema does not overcome the negative prognosis associated with high-risk cytogenetic abnormalities.[60]

Daratumumab

In 2019, the FDA approved daratumumab with VTD for newly diagnosed patients with MM who are eligible for autologous stem cell transplantation (ASCT). Approval was based on results from the phase III CASSIOPEIA study (n=1085) that evaluated whether adding daratumumab to VTD before and after ASCT would improve the complete response rates in newly diagnosed patients. Results from the first part of the trial showed complete response rate post-consolidation was significantly higher with VTD plus daratumumab compared with VTD alone (29% vs 20%). At a median follow-up of 18.8 months, the addition of daratumumab resulted in a 53% reduction in the risk of disease progression or death compared with VTD alone.[61]

Two phase III trials, CASTOR and POLLUX, have demonstrated an overall survival (OS) benefit with daratumumab-containing regimens in relapsed/refractory MM. In CASTOR, on median follow-up of 72.6 months, median OS was 49.6 months with daratumumab, bortezomib, and dexamethasone versus 38.5 months with bortezomib and dexamethasone (P = 0.0075).[62] In POLLUX, on median follow-up of 79.7 months, median OS was was 67.6 months with daratumumab, lenalidomide, and dexamethasone versus 51.8 months with lenalidomide and dexamethasone (P = 0.0044).[63]

High-risk patients who are potential transplant candidates

Patients are considered at high risk if their MM meets any of the following criteria:

• Advanced-stage disease (stage III according to the International Staging System)
• Poor cytogenetics, such as t (4:14), t (14:16), and t (14:20), deletion of chromosome 13, inactivation of TP53
• Complex karyotype
• Very high proliferative rates 

This group represents about 25% of those with newly diagnosed MM, with an expected median survival of 2 years or less. Although they respond to traditional therapies for induction, these individuals tend to relapse rapidly. Therefore, novel agents should be considered up front for these patients.

The advent of thalidomide, lenalidomide, and bortezomib has substantially improved outcomes in these high-risk groups. In fact, these novel agents appear to overcome the influence contributed by high-risk cytogenetics.[64, 65] Once a response has been achieved, then patients can be brought to ASCT.

Newly diagnosed elderly patients who are not transplant candidates

All of the regimens used in transplant candidates may be used in patients who are not being considered for transplantation. Other regimens, however, can only be used in patients who will not be undergoing transplantation, as they impair stem cell reserve.

The gold standard has been the MP regimen since as far back as the 1950s. This regimen typically consists of melphalan 9 mg/m2 and prednisone 100 mg given on days 1-4, with courses repeated at 4- to 6-week intervals for at least 1 year. A meta-analysis of 4930 patients from 20 randomized trials compared MP with other drug combinations and showed a significantly higher response rate (60%) with this combination, with a response duration of 18 months; however, no evidence of any difference in mortality was found between MP and other drug combinations.[66]

Subsequent research examined the use of regimens that combine MP with other agents. A randomized three-arm study compared MP, MP plus thalidomide, and reduced-intensity ASCT using melphalan 100 mg/m2 in 447 previously untreated patients between ages 65 and 75 years. After a median follow-up of 51.5 months, median overall survival (the primary endpoint) was significantly better in the MPT arm than in the other two arms: 51.6 months for MP plus thalidomide versus 33.2 months for MP and 38.3 months for transplantation arm. The authors recommended MPT as first-line treatment for previously untreated elderly patients with multiple myeloma.[67]  

Hulin et al conducted a randomized, placebo-controlled, phase III trial to investigate the efficacy of adding thalidomide to MP in 229 elderly patients (>75 y) newly diagnosed with MM.[68] During each 6-week cycle, melphalan 0.2 mg/kg/d plus prednisone 2 mg/kg/d was given to all patients on days 1-4 for 12 cycles. In addition, patients were randomly assigned to receive thalidomide 100 mg/d PO (n = 113) or placebo (n = 116), continuously for 72 weeks.

Overall survival was significantly longer in the group that received thalidomide (median, 44 mo) compared with placebo (median, 29.1 mo).[68] PFS was also significantly prolonged in the thalidomide group (median, 24.1 mo) relative to the placebo group (median, 18.5 mo). However, the investigators noted peripheral neuropathy and neutropenia were significantly increased in the thalidomide group.[68]

A randomized, controlled trial evaluated the addition of thalidomide to standard MP chemotherapy in elderly patients with previously untreated MM. Although no impact on survival was observed, more patients in the thalidomide group achieved an objective response. Of note, thromboembolic events were not more frequent in the thalidomide group.[69]  A separate study by Fayers et al concluded that thalidomide added to MP therapy improved overall survival and PFS in previously untreated elderly patients with MM, extending the mean survival time by an average of 20%.[70]  

MP plus lenalidomide has also shown promise.[71]  A study by Gay et al assessed the addition of thalidomide and/or bortezomib to standard oral MP treatment in 1175 elderly patients with newly diagnosed myeloma.[72] The study found that these novel agents helped achieve maximal response in these patients.

A phase III study by the ALCYONE Trial Investigators found that the addition of daratumumab to the combination of bortezomib, melphalan, and prednisone in patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation resulted in a lower risk of disease progression or death.[73] At a median follow-up of 16.5 months, results of treatment with and without daratumumab were as follows:

• 18-month PFS rate: 71.6% vs 50.2% 
• Overall response rate: 90.9% vs 73.9% (P< 0.001)
• Rate of complete response or better (including stringent complete response): 42.6% 24.4% (P< 0.001)

However, the rate of grade 3 or 4 infections was 23.1% in the daratumumab group and 14.7% in the control group.

The MAIA trial was an open-label, randomized, phase 3 study comparing lenalidomide with low-dose dexamethasone with or without daratumumab in patients with newly diagnosed MM who were ineligible for ASCT. The study demonstrated an improvement in PFS in the daratumumab combination arm compared with the control arm. Patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group. A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells).[74]

Current National Comprehensive Cancer Network (NCCN) guidelines recommend MP in combination with daratumumab and bortezomib as a category 1 regimen. However, the NCCN lists the following as preferred primary therapy regimens (category 1)  for non-transplant candidates[2] :

• Bortezomib/lenalidomide/dexamethasone
• Daratumumab/lenalidomide/dexamethasone

Maintenance therapy

In spite of advances in treatment, MM remains an incurable disease. To improve overall survival (OS) in these patients, a number of trials have evaluated the role of maintenance therapy in both transplant-eligible and transplant-ineligible patients.

Five large phase III studies have looked at role of thalidomide maintenance after ASCT. Three initial studies showed an improvement in both PFS and OS.[75] However, two subsequent studies—including one large study with 1970 patients—did not show an improvement in OS with thalidomide maintenance.[76, 77] Long-term use of thalidomide is also associated with significant neuropathy, thus limiting its use in maintenance therapy.

Given its favorable toxicity profile and efficacy at low doses, lenalidomide has also been studied for maintenance therapy. Two large trials, CALGB 100104 and IFM 05-02, have evaluated the role of lenalidomide in maintenance therapy, using slightly different protocols and having somewhat different outcomes.[78, 79] Patients in both studies received induction treatment followed by ASCT. In the IFM 05-02 study, however, all patients received 2 months of consolidation treatment with lenalidomide before being randomized to lenalidomide or placebo.

Both studies showed a significant improvement in time to progression (46 vs 27 months in CALGB study and 41 vs 23 months in IFM study). However, CALGB 100104 study showed significant improvement in OS (85 % vs 77 %), whereas IFM 05-02 did not show an improvement in OS. Both studies showed an increased incidence of hematologic toxicity and second primary malignancies (SPMs), particularly acute myelogenous leukemia/myelodysplastic syndrome in the lenalidomide arm.

The reason for the difference in the two studies in terms of OS benefit is not very clear. Since all the patients in the IFM trial received 2 months of consolidation treatment with lenalidomide following ASCT, it is possible that only short period of maintenance therapy, rather than continuous maintenance therapy, is required to achieve all the OS benefit seen in the CALGB trial.

A meta-analysis shows the benefit of maintenance lenalidomide, with a 51% reduction in the risk of recurrence.[80] This benefit outweighs the risk of SPM seen in the trials of lenalidomide maintenance.

Bortezomib has also been shown to be effective for maintenance therapy in the HOVON-65/GMMG-HD4 trial.[81] In this trial, patients were randomized to either PAD (bortezomib, doxorubicin [Adriamycin], and dexamethasone) induction followed by bortezomib maintenance or to VAD induction followed by thalidomide maintenance. PFS in the PAD arm was significantly better than in the VAD arm (35 vs 28 months). Patients with high-risk cytogenetics, especially del(17p13) and t(4;14) abnormalities, seemed to benefit more with bortezomib maintenance.

Although several trials have shown the benefit of maintenance therapy after ASCT, the risk of SPM and the need for continuous treatment should be kept in mind. Individual patient characteristics should be taken in consideration before recommending maintenance therapy.

Maintenance therapy has also been evaluated in non–transplant eligible patients. Thalidomide has been studied as maintenance in a number of trials; most of the trials have shown only advantage in PFS, with no advantage in OS. The main problem with thalidomide has been the high incidence of neuropathy in these patients.

A trial of lenalidomide as maintenance therapy after induction with melphalan, prednisone, and lenalidomide showed a significant improvement in PFS (26 vs 7 months) but similar 4-year OS. Patients in the lenalidomide arm had more hematologic toxicity, including neutropenia, thrombocytopenia, and higher risk of second primary malignancy. However, given its overall tolerability, lenalidomide is a good option for induction and maintenance therapy in transplant-ineligible patients.[82]

A number of trials have also evaluated bortezomib in maintenance therapy. All of them have showed benefit in PFS but no clear OS benefit. Bortezomib given once a week in maintenance seems to be better tolerated and associated with lesser neuropathy.[83]

Patients with refractory disease or relapse

Patients who have a relapse after initial disease control may be treated with any of the agents not already utilized. If the relapse occurs longer than 6 months after the initial therapy, then the initial regimen can be used again.

In addition, National Comprehensive Cancer Network guidelines list the following as preferred regimens for previously treated (1-3 previous therapies) multiple myeloma[2] :

• Bortezomib/lenalidomide/dexamethasone
• Carfilzomib/lenalidomide/dexamethasone (category 1)
• Daratumumab/bortezomib/dexamethasone (category 1)
• Daratumumab/lenalidomide/dexamethasone (category 1)
• Ixazomib/lenalidomide/dexamethasone (category 1)
• Isatuximab-irfc/carfilzomib/dexamethasone (category 1)

Triplet regimens are the standard, but patients who are considered unable to tolerate three drugs can be started with a 2-drug regimen, with a third drug added once their performance status improves.[2]

In 2020, the FDA approved carfilzomib/daratumumab/dexamethasone for treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy. Approval was based on data from two open-label studies: in CANDOR, median PFS was not reached for the carfilzomib/daratumumab/dexamethasone arm and was 15.8 months for the carfilzomib/dexamethasone arm; in EQUULEUS, which evaluated carfilzomib/daratumumab/dexamethasone in 85 patients, the overall response rate was 81%, with a duration of response of 27.5 months.[84]  

Bortezomib

Bortezomib has a well-established role as salvage therapy, based on a phase III randomized trial showing a response rate of 38% versus 18% in patients receiving dexamethasone only.[54] Median PFS was 6.22 months in the bortezomib arm versus 3.49 months in the dexamethasone-only group.

Panobinostat

Panobinostat (Farydak) is a histone deacetylase (HDAc) inhibitor approved in 2015. It is indicated in combination with bortezomib and dexamethasone for treatment of MM in patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent. The FDA approval was based on efficacy and safety data in a prespecified subgroup analysis of the phase III PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA) trial, in which patients treated with panobinostat (n = 94) had a median PFS of 10.6 months, compared with 5.8 months for patients in the placebo arm (n= 99) (hazard ratio= 0.52 [95% confidence interval: 0.36, 0.76]).[85]

Carfizomib

In 2012, the FDA approved carfilzomib (Kyprolis) for the treatment of patients with MM who have received at least two prior therapies including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of therapy completion. The approval was based on a phase 2b, single-arm, multicenter clinical study of 266 patients with relapsed MM with other therapies. The study assessed for overall response rate (ORR), which was 22.9% over a median duration of 7.8 months.[86]

In 2015, the FDA expanded carfilzomib’s indication for MM based on data from the ASPIRE study, conducted in patients with relapsed MM who had received 1-3 prior lines of therapy. In ASPIRE, median PFS for patients treated with carfilzomib combined with lenalidomide and dexamethasone was 26.3 months, compared with 17.6 months in those treated with lenalidomide and low-dose dexamethasone alone.[87]

In 2016, the FDA approved carfilzomib in combination with dexamethasone for relapsed or refractory MM in patients who have received 1-3 prior lines of therapy. Approval was based on the ENDEAVOR study (n=929) where a statistically significant improvement in median PFS was observed with carfilzomib plus dexamethasone compared with bortezomib plus dexamethasone in patients with relapsed MM (26.3 mo vs 17.6 mo; P=0.0001).[88] On interim analysis, median overall survival was 47.6 months in the carfilzomib group versus 40.0 months in the bortezomib group (hazard ratio 0.791, one-sided P=0.010).[89]

Daratumumab

Daratumumab (Darzalex) gained approval from the FDA in 2015 for patients with MM who had received at least three prior treatments, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or whose disease is refractory to both a PI and an IMiD. The approval was based on the phase II MMY2002 (SIRIUS) study that showed treatment with single-agent daratumumab resulted in an ORR of 29.2% in patients who received a median of five prior lines of therapy, including a PI and an IMiD.[90]

Stringent complete response (sCR) was reported in 2.8%, very good partial response (VGPR) was reported in 9.4%, and partial response (PR) was reported in 17% of patients. For responders, the median duration of response was 7.4 months. At baseline, 97% of patients were refractory to their last line of therapy, 95% were refractory to both a PI and an IMiD, and 77% were refractory to alkylating agents.[90] These data are supported by similar results from a phase I/II trial.[91]

Ixazomib

Ixazomib (Ninlaro) is a reversible proteasome inhibitor. It preferentially binds and inhibits the chymotrypsinlike activity of the beta 5 subunit of the 20S proteasome. Ixazomib is indicated in combination with lenalidomide and dexamethasone for patients with multiple myeloma who have received at least 1 prior therapy. Approval was based on data from the phase 3 TOURMALINE-MM1 trial, an international, randomized, double-blind clinical trial of 722 patients with treatment-refractory or recurrent multiple myeloma. It compared ixazomib with placebo the patients who also received lenalidomide and dexamethasone. Median progression-free survival was improved by 35% with ixazomib compared with placebo (20.6 vs 14.7 months; P = 0.012).[92]

Elotuzumab

Elotuzumab (Empliciti) is a humanized IgG1 monoclonal antibody that specifically targets the SLAMF7 (signaling lymphocytic activation molecule family member 7) protein. SLAMF7 is expressed on myeloma cells and natural killer cells and plasma cells. Elotuzumab facilitates the interaction with natural killer cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity. It is indicated for use in combination with lenalidomide and dexamethasone for MM in patients who have received 1-3 prior therapies.

Approval was based on the ELOQUENT-2 trial, a randomized, open-label clinical study that included 646 participants with multiple myeloma who had experienced relapse or who had not responded to previous treatment. The addition of elotuzumab to the combination of lenalidomide and dexamethasone extended PFS to 19.4 months, as compared with 14.9 months in patients treated with lenalidomide and dexamethasone (P< 0.001). Additionally, the overall response rate (including complete and partial responses) was 78.5%, compared with 60.1% in patients receiving lenalidomide and dexamethasone (P< 0.001).[93]

The ELOQUENT-3 trial studies 117 patients with MM that was refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor. Patients received elotuzumab plus pomalidomide and dexamethasone or pomalidomide and dexamethasone alone (control group). Median PFS was 10.3 months in the elotuzumab group and 4.7 months in the control group. The overall response rate was 53% in the elotuzumab group compared with 26% in the control group.[94]

Isatuximab

The FDA approved the anti-CD38 monoclonal antibody isatuximab (Sarclisa) in 2020 for relapsed or refractory MM in combination with pomalidomide and dexamethasone in patients who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor. Approval was based on the ICARIA-MM clinical trial (n = 307). The median PFS was 11.5 months in the isatuximab/pomalidomide/dexamethasone group compared with 6.5 months in the pomalidomide/dexamethasone group (P = 0.001).[95]  

In 2021, the FDA also approved isatuximab, in combination with carfilzomib and dexamethasone, for the treatment of relapsed or refractory MM in adults who have received one to three prior lines of therapy. Approval was based on the phase III IKEMA trial (n=302), in which the addition of isatuximab to carfilzomib/dexamethasone resulted in a 45% reduction in the risk of disease progression or death. Median PFS was not reached in the isatuximab/carfilzomib/dexamethasone arm, compared with 20.27 months in the carfilzomib/dexamethasone arm (P = 0.0032).[96]  

Thalidomide

Thalidomide is useful in the treatment of patients with relapsing and refractory MM. Its antiangiogenic properties have become increasingly apparent as a critical step in the proliferation and spread of malignant neoplasm.[97]

Lenalidomide

An important prospective placebo-controlled trial of the addition of lenalidomide to dexamethasone in relapsed MM demonstrated spectacular results.[98] The major response rate with lenalidomide was 61% compared with 19.9% in the placebo arm. There was a significant improvement in time to progression (11.1 months in the lenalidomide plus dexamethasone group vs 4.7 months in the placebo group). Overall survival was significantly improved.[98]

Pomalidomide

A study by Lacy et al found that pomalidomide overcame resistance in MM that was refractory to both lenalidomide and bortezomib.[99] In 2013, pomalidomide was approved by the FDA for use in patients with MM who have received at least two previous therapies (including lenalidomide and bortezomib) and have disease progression on or within 60 days of completion of the last therapy.[100, 101]

This approval was supported by a phase II study comparing pomalidomide plus low-dose dexamethasone with pomalidomide alone in patients with relapsed MM refractory to their last therapy who had received lenalidomide and bortezomib. Of the 221 patients who were evaluable for response, 29.2% in the pomalidomide plus low-dose dexamethasone arm achieved a partial response or better, compared with 7.4% in the pomalidomide-alone arm.[100] The median duration of response for the former was 7.4 months; the median had not been reached for the latter.

In another study, Miguel et al found that the combination of pomalidomide with low-dose dexamethasone yielded a longer median PFS in 455 patients with refractory or relapsed and refractory MM than high-dose dexamethasone alone.[102] In the open-label, randomized study patients received 28-day cycles of either pomalidomide (4 mg/day on days 1-21) plus low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22) or only high-dose dexamethasone (40 mg/day on days 1-4, 9-12, and 17-20). At follow-up (median, 10 months), median PFS was 4.0 months for the combination therapy group, compared with 1.9 months for the monotherapy group, for a hazard ratio of 0.48. Rates of most adverse events were similar in the two groups.[102]

Selinexor

The first selective inhibitor of nuclear export (SINE), selinexor, was approved by the FDA in 2019. Selinexor acts on tumor suppressor proteins (TSPs), growth regulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). Inhibition of XPO1 leads to accumulation of TSPs in the nucleus, reductions in several oncoproteins (eg, c‐myc, cyclin D1), cell cycle arrest, and apoptosis of cancer cells. Selinexor is indicated in combination with dexamethasone for adults with relapsed or refractory MM who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody.

The multicenter, single-arm, open-label STORM trial analyzed selinexor plus dexamethasone. STORM part 2 included 122 patients with relapsed/refractory MM who previously had 3 or more treatments. FDA approval was based on results from the 83 patients from the STORM trial whose disease was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab. This group had a 25.4% overall response rate, 1% stringent complete response rate, 5% very good partial response, and 19% partial response rate.[103, 104]  

Belantamab mafodotin-blmf 

In 2020, the FDA granted accelerated approval to the antibody-drug conjugate belantamab mafodotin-blmf (Blenrep) for adult patients with relapsed or refractory MM who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. Approval was based on the open-label DREAMM-2 trial, in which the overall response rate (ORR) was 31% (97.5% CI: 21%, 43%) in patients receiving the recommended dose of 2.5 mg/kg intravenously, once every 3 weeks until disease progression or unacceptable toxicity, with response duration ≥6 months in 73% of responders. Because of the risks of ocular toxicity (changes in the corneal epithelium), belantamab mafodotin-blmf is available only through a restricted program under a Risk Evaluation and Mitigation Strategy.[105, 106]

Teclistamab

In 2022, the FDA granted accelerated approval to teclistamab (Tecvayli) for adults with relapsed or refractory MM who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Teclistamab is the first of a new class of agents: it is a bispecific T-cell engaging antibody that binds to CD3 receptors on the surface of T-cells and to B-cell maturation antigen (BCMA) expressed on the surface of MM cells and some healthy B-lineage cells.

Efficacy was based on a single-arm, multicohort, open-label, multicenter study, MajesTEC-1. Patients (n=165) had previously received at least 3 prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, and had not received prior BCMA-targeted therapy. Patients received weekly SC teclistamab (at a dose of 1.5 mg/kg) after receiving step-up doses of 0.06 mg and 0.3 mg/kg. The overall response rate was 63%, with 39.4% having a complete response or better. The median duration of response was 18.4 and the median duration of progression-free survival was 11.3 months.[107]

Elranatamab

In August 2023, the FDA granted accelerated approval to elranatamab (Elrexfio) for relapsed or refractory MM in adults who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Like teclistamab, elranatamab is a bispecific BCMA-directed CD3 T-cell engager.

Approval was based on MagnetisMM-3, an open-label, single-arm, multicenter study in which the objective response rate in treated patients receiving the recommended dose was 57.7%. On median follow-up of 11.1 months in responders, the median duration of response (DOR) was not reached and the DOR rate at 6 months was 90.4% and at 9 months was 82.3%[108]

Talquetamab

Also in August 2023, the FDA granted accelerated approval to talquetamab (Talvey) for relapsed or refractory MM in adults who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Talquetamab is a bispecific antibody against CD3 and GPRC5D; it redirects T cells to mediate killing of myeloma cells that express GPRC5D.

Efficacy was evaluated in MMY1001 (MonumenTAL-1), a single-arm, open-label, multicenter study that included 187 patients who had previously received at least four prior systemic therapies. Overall response rate (ORR) in patients receiving 0.4 mg/kg weekly was 73% and median duration of response (DOR)  was 9.5 months. ORR in 87 patients receiving 0.8 mg/kg biweekly was 73.6% and median DOR was not estimable. An estimated 85% of responders maintained response for at least 9 months.[109]

Using the patient’s own (ie, autologous) bone marrow or peripheral blood stem cells facilitates more intense therapy for MM. After harvesting the stem cells from the patient, physicians can use otherwise lethal doses of total body irradiation and chemotherapy and then “rescue” the patient by reinfusing the harvested cells. This process of myeloablative therapy, followed by the reinfusion of stem cells, is termed autologous stem cell transplantation.

This sequence of therapy allows physicians to use melphalan at an approximately 10-20 times higher dose than is used in standard therapy.[49] In autologous transplantation, the reinfused stem cells or bone marrow act as a support to the patient but do not offer additional anticancer effects.

Tandem autologous transplantation has been proposed as a way of overcoming the incomplete response to a single transplant. A 2-arm trial of single versus tandem transplantation revealed no difference in overall survival at 54 months.[110]

Another two-arm study that compared single versus tandem transplants for newly diagnosed MM showed that whereas double autologous stem cell transplantation effected superior complete or near-complete response rates, relapse-free survival, and event-free survival (EFS), it failed to significantly prolong overall survival.[111] Benefits offered by double autologous stem cell transplantation were particularly evident among patients who failed to achieve at least a near-complete response after one autotransplantation.

A review of long-term outcomes of several autotransplantation trials for MM found that tandem transplantations were superior to both single transplantations and standard therapies and that tandem transplantations with thalidomide were superior to trials without thalidomide.[112] However, postrelapse survival (PRS) was superior when initial EFS exceeded 1280 days and when tandem transplantations had been administered, whereas PRS was shorter when EFS lasted 803 days or less and when trials had included thalidomide and bortezomib.[112]

Two randomized prospective studies compared standard chemotherapy with high-dose autologous transplantation. In the first study of 200 subjects, researchers observed better response rates (ie, 81% for the transplantation group vs 57% for the conventionally treated group) and better 5-year event-free survival rates (ie, 28% vs 10%).[113] The second study also showed a significant improvement in event-free survival rates and superior quality of life for subjects treated with the high-dose approach.

In highly selected patients with MM, physicians may use allogeneic (ie, from someone else) transplantation. In this approach, physicians administer myeloablative therapy and infuse stem cells (ie, peripheral blood or bone marrow) obtained from a donor, preferably a human leukocyte antigen (HLA)-identical sibling.

The advantage of this approach over autologous transplantation is that the patient is not at risk of being reinfused with MM cells. In addition, the donor’s immune system may fight the recipient’s cancer (ie, graft vs myeloma effect). Unfortunately, the donor’s immune system may also attack the recipient’s body (ie, graft vs host effect).

Physicians use allogeneic transplantation less often than autologous transplantation in MM patients, for several reasons. First, the risks of complications and death from allogeneic transplantation increase with age, and most patients with MM are older than the ideal age for allogeneic transplantation. 

Second, the transplantation-related mortality rate is quite high in patients with MM who undergo allogeneic transplantation. The death rate within 100 days of transplantation ranges from 10% to 56% in different case series.

Third, although some survivors experience long-term disease-free results after allogeneic transplantation, a retrospective case-matched analysis of allogeneic versus autologous transplantation showed a median survival of 34 months for the autologous transplantation group and 18 months for the allogeneic group.

The exception to this rule is the rare patient with a twin donor. In a limited study of 25 transplantations involving twins, outcomes with syngeneic transplantations were superior, with reduced transplantation-related mortality.

The development of a nonmyeloablative preparative regimen for MM allogeneic transplantation is changing the equation. A republished report of 52 high-risk patients who underwent nonmyeloablative transplants described a 17% mortality rate.[114] Progression-free survival at 18 months was roughly 30%.

A phase II trial of autologous stem cell transplantation followed by a nonmyeloablative matched sibling related donor transplant demonstrated this approach to be feasible, with low treatment-related mortality.[115] Further studies are needed to evaluate relative efficacy.

Allotransplants have markedly reduced activity; therefore, the use of nonmyeloablative regimens (mini-allotransplantation) may hold promise for more widely exploiting this feature.[116, 117]

A study by Moreau et al determined that achievement of very good partial response (VGPR) after induction therapy is an important prognostic factor in patients undergoing autologous stem cell transplantation.[118] VGPR was significantly improved with bortezomib-dexamethasone induction therapy.

A study by Harousseau et al also concluded that this combination significantly improved postinduction and posttransplantation complete response/near response rate at at least VGPR rates compared with VAD.[119] Cavo et al also concluded that this combination represents a new standard of care for patients with multiple myeloma who are eligible for transplant.[120]

In MM patients with progressive or relapsing disease following autologous stem-cell transplantation, treatment with the combination of bortezomib, thalidomide and dexamethasone is more effective than treatment with thalidomide and dexamethasone alone, although triple therapy is associated with a greater risk of grade 3 neurotoxicity.[121]

Idecabtagene vicleucel (Abecma) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous CAR T-cell therapy. In March 2021, the therapy was approved for relapsed or refractory MM after ≥4 prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.[122]

Approval was based on the KarMMA study, a multicenter, open-label study of idecabtagene vicleucel in patients with relapsed or refractory MM who had received at least 3 prior lines of therapy. At a median follow-up of 13.3 months, 94 of the 128 patients (73%) had a response; 42 of the 128 (33%) had a complete response or better, and 79% of those had minimal residual disease (MRD)–negative status. The median progression-free survival was 8.8 months. Common adverse effects included neutropenia, anemia, thrombocytopenia, and cytokine release syndrome.[123]

In March 2022, the FDA approved ciltacabtagene autoleucel (Carvykti), a CAR-T cell therapy featuring two BCMA-targeting single domain antibodies, for relapsed or refractory MM in adults who were previously treated with ≥4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.[124]

Approval was based on the findings from the open-label, single-arm, phase 1b/2 CARTITUDE-1 study, which enrolled patients who had received a median of 6 prior treatment regimens. Treated patients had 98% overall response rate. Stringent complete responses rates were 78% (95 % CI, 68.8-86.1) at 18-month follow-up and 83% at 22-month follow-up. At a median of 18 months follow-up, median duration of response was 21.8 months.[124, 125]

Intense research has focused on the use of interferon alfa to treat MM. This drug does not appear to be effective for inducing remission, and a randomized controlled trial showed that patients do not benefit from the addition of interferon to melphalan and prednisone.[126] Interferon alfa does appear to prolong remission in selected patients with MM. For this use, it may be administered after conventional chemotherapy or bone marrow (ie, stem cell) transplantation has been completed.

The toxicity of interferon and the availability of alternate interventions have significantly limited the role of interferon alfa.

MM is extremely sensitive to radiation. Physicians use radiation to treat symptomatic lesions and to stabilize bones at risk for fracture. Physicians also use radiation to treat spinal cord compression. Low-dose, double-hemibody irradiation has been studied as systemic therapy for refractory or relapsed MM, but without dramatic success.

If the pain is mild and if less than 50% of the bone is involved, a course of irradiation can be initiated. Radiation treatment can result in additional early bone loss due to inflammation, and weight bearing should be limited for the first 4-6 weeks.

Bisphosphonates

Bisphosphonates are specific inhibitors of osteoclastic activity and are used to treat bone resorption. They also have a role in the secondary prevention of bony complications in MM, including hypercalcemia, pathologic fracture, and spinal cord compression. Intravenous (IV) pamidronate (Aredia) has been shown to be effective in preventing skeletal complications; zoledronic acid (Zometa) may be significantly more potent than pamidronate. A study by Morgan et al found that the early use of zoledronic acid was superior to clodronic acid in preventing skeletal-related events among patients with newly diagnosed MM, irrespective of bone disease status at baseline.[42]

A randomized placebo-controlled trial of pamidronate in subjects with MM who had experienced one skeletal event demonstrated that the medication reduced the likelihood of a second skeletal event from 41% to 24% after 9 months of therapy.[43] The investigators also noted improvements in pain, narcotic usage, and quality of life scores.

A 2007 systematic review of the use of bisphosphonates in MM confirmed a number-needed-to-treat (NNT) of 10 for the prevention of vertebral fractures, although no impact on mortality was seen.[44]

The American Society of Clinical Oncology (ASCO) issued a clinical practice guideline governing bisphosphonate therapy for MM patients who have lytic destruction of bone or compression fracture of the spine from osteopenia.[44]

Zoledronic acid doses should be reduced in patients with preexisting mild to moderate renal impairment (estimated creatinine clearance, 30-60 mL/min); the drug is not recommended for use in patients with severe renal impairment.[44] All patients receiving pamidronate or zoledronic acid therapy should be screened every 3-6 months for albuminuria. If unexplained albuminuria (>500 mg/24 hours) is found, ASCO recommends discontinuation of the drug until the renal problems resolve.[44]

A study by Morgan et al revealed the anticancer properties of zoledronic acid in addition to its ability to reduce skeletal-related events in MM.[127]

Denosumab

In January 2018, denosumab was approved by the FDA for prevention of skeletal-related events (SREs) in patients with MM. It was originally indicated for SREs in patients with solid tumors. Denosumab is a human monoclonal antibody targeting and binding to receptor activator of nuclear factor kappa-Β ligand (RANKL). Osteoclast-activating factors, such as RANKL, are implicated in an increased risk for SREs with MM.

In a phase III trial of denosumab compared with zoledronic acid in patients (n=1718) with bone metastases, denosumab was noninferior and showed an advantage in significantly reducing the risk for renal adverse events. A post hoc analysis at 15 months was also conducted, since many of the skeletal-related events (60%) occurred early, within 3 months, which led the authors to speculate that the data reflected events occurring before the treatment had enough time to take effect. Results did show superiority of denosumab (n = 450) over zoledronic acid (n = 459) in terms of the endpoint of time to the first SRE (hazard ratio [HR], 0.66; P = 0.039). Median progression-free survival showed difference of more than 10 months was observed between the denosumab (46.09 months) and zoledronic acid (35.38 months) groups (HR, 0.82; P = 0.036). No difference in overall survival was noted between the treatment groups.[128]

Osteonecrosis of the jaw

Osteonecrosis of the jaw is a rare but severe adverse effect of bisphosphonate therapy. Level 1 evidence (ie, systematic reviews or randomized controlled trials) indicate that approximately 1% of cancer patients exposed to zolendronic acid develop osteonecrosis of the jaw.[129] Dental extractions appear to be a risk factor, and guidelines recommend avoiding this where possible.

A position paper by the American Association of Oral and Maxillofacial Surgeons describes the differential diagnosis, prevention, and treatment of medication-related osteonecrosis of the jaw. Consultation with an appropriate dental professional is advised before prescribing a bisphosphonate.[129]

Potential complications of MM include the following:

• Skeletal complications (eg, pain, hypercalcemia, pathologic fracture, spinal cord compression)
• Infection
• Anemia
• Kidney failure
• Amyloidosis

Treatment for myeloma-induced hypercalcemia is the same as that for other malignancy-associated hypercalcemia; however, the dismal outcome observed with hypercalcemia in solid tumors is not observed in MM.

To treat pathologic fractures, physicians should orthopedically stabilize (ie, typically pin) and irradiate these lesions. Careful attention to a patient’s bony symptoms, intermittent radiographic surveys, and the use of bisphosphonates may be useful to prevent fractures.[44, 130, 131] (See Surgical Care and Bisphosphonate Therapy.)

Spinal cord compression is one of the most severe adverse effects of MM. The dysfunction may be reversible, depending on the duration of the cord compression; however, once established, the dysfunction is only rarely fully reversed. Patients who may have spinal cord compression need a rapid evaluation, which may necessitate urgent transfer to a center equipped with MRI for diagnosis or a center with a radiation oncologist for urgent therapy.

Patients with spinal cord compression due to MM should begin corticosteroid therapy immediately to reduce swelling. Urgent arrangements must be made for radiation therapy in order to restore or stabilize neurologic function. Surgery may be indicated. (See Surgical Care.)

Erythropoietin may ameliorate anemia resulting from either MM alone or from chemotherapy and has been shown to improve quality of life.[132] A systematic review failed to demonstrate a survival advantage for the use of erythropoietin agents in the treatment of patients with cancer-related anemia.[133]

Acute kidney injury related to MM is typically managed with plasmapheresis to rapidly lower circulating abnormal proteins. Data about this approach are limited, but a small randomized study showed a survival advantage with the use of apheresis.[10] Hydration (to maintain a urine output of > 3 L/d), management of hypercalcemia, and avoidance of nephrotoxins (eg, intravenous contrast media, antibiotics) are also key factors. Conventional therapy may take weeks to months to show a benefit.

Kidney impairment resulting from MM is associated with a very poor prognosis. A case series demonstrated that patients with kidney failure from myeloma may benefit from autologous stem cell transplants, and as many as one third may demonstrate improvement in their kidney function with this approach.[134] A report by Ludwig et suggests that bortezomib-based therapy may restore kidney function in MM patients with kidney failure.[9]

Guidelines on the management of MM complications by the European Myeloma Network include the following recommendations[135] :

• Whole-body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus is recommended as the novel standard for the detection of lytic lesions.
• Myeloma patients with adequate kidney function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate.
• Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid, but its advantage is not clear for patien ts with no bone involvement on computed tomography or magnetic resonance imaging.
• In asymptomatic patients, bisphosphonates are not recommended.
• Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use.
• Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin < 10 g/dL) in whom other causes of anemia have been excluded.
• Erythropoietic agents should be stopped after 6-8 wk if no adequate hemoglobin response is achieved.
• For kidney impairment, bortezomib-based regimens are the current standard of care.
• For the management of treatment-induced peripheral neuropathy, drug modification is needed.
• Vaccination against influenza is recommended; vaccination against Streptococcus pneumoniae and Haemophilus influenzae is appropriate, but efficacy is not guaranteed due to suboptimal immune response. ^[136]
• Prophylactic acyclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, or autologous or allogeneic transplantation

Surgical therapy for MM is limited to adjunctive therapy. It consists of prophylactic fixation of pending fractures, decompression of the spinal cord when indicated, and treatment of pathologic fractures.

Prophylactic treatment of impending fractures and the treatment of pathologic fractures may involve bracing. In general, bracing is not effective for the long bones, though it may be effective for treating spinal involvement without neurologic compromise.

Intramedullary fixation is the procedure of choice when surgery is necessary. If the metaphysis or joint surface is involved, resection of the diseased bone and reconstruction with a total joint or, more typically, a hemiarthroplasty is indicated. Modular implants may be required. Severe destruction of the diaphysis may require reconstruction with combinations of methylmethacrylate, intramedullary nails, or resection and prosthetic replacement.

Although surgical decompression of the spinal cord is sometimes appropriate, posterior laminectomy in this population has been reported to have a mortality rate of 6-10% and to not be superior to radiation. This surgical approach is probably best reserved for cases of MM in which radiation fails. Newer surgical interventions, such as kyphoplasty, in which cement is injected into compressed vertebrae, have been shown to improve function with few complications, although the studies reported have been small.

Patients with MM who are receiving bisphosphonate therapy should include adequate calcium in their diet.

The dietary supplement curcumin may slow the progression of smoldering multiple myeloma.[137]

Patients with MM should be encouraged to be physically active to the extent appropriate for their individual bone status. Physical activity may help maintain bone strength.

In general, patients with activity-related pain in either the femur or the tibia should be given a walker or crutches until a radiographic workup has been completed. Radiation therapy elicits an inflammatory response, and for the first 6 weeks or so, bony resorption may actually weaken the target bone. Given that prophylactic treatment of an impending fracture is usually easier than reconstruction of a pathologic fracture, one should have a low threshold for initiating protected weight bearing.

No preventive measures for MM are known. A study by Chang et al found that routine residential ultraviolet radiation exposure may have a protective effect against lymphomagenesis through mechanisms that may be independent of vitamin D.[138]

Patients with MM often benefit from the expertise of an orthopedic surgeon who is versed in oncologic management because prophylactic fixation of impending pathologic fractures is occasionally warranted.

From the orthopedic perspective, because patients with MM have significant systemic comorbidities—including potentially severe hematologic, infectious, and metabolic diseases—the orthopedic surgeon treating the skeletal disease in a patient with myeloma should work in conjunction with the radiation oncologists and the medical oncologists.

Patients with MM may require hospitalization for the treatment of pain or bony pathology.

Patients with MM are at high risk of infection, especially from encapsulated organisms. Vaccinations against pneumococcal organisms and influenza are recommended. Consider vaccinating patients against Haemophilus influenzae type b. Use of the herpes zoster vaccine should be considered.

The following laboratory results are helpful in the follow-up care of patients with MM:

• Complete blood count (CBC), chemical profile 7 (especially blood urea nitrogen [BUN] and serum creatinine), serum calcium, and serum uric acid, and serum protein electrophoresis (SPEP) findings.
• M-component level in the serum and/or urine. (This is an indicator of tumor burden; a reduction with chemotherapy is used as a sign of a treatment response.)
• Serum beta-2 microglobin. (An elevated level indicates a large malignant cell mass, renal impairment, or both.)
• Serum lactate dehydrogenase (LDH) level. (A high level is predictive of an aggressive lymphomalike course.)

Diagnosis

Similar recommendations for the standard investigational workup for suspected myeloma have been issued by the following organizations:

• International Myeloma Working Group ^[139]
• National Comprehensive Cancer Network (NCCN) ^[2]
• European Hematology Association and European Society for Medical Oncology (EHA-ESMO) ^[140]

The International Myeloma Working Group guidelines recommend the following diagnostic studies[139] :

• Serum and urine assessment for monoclonal protein (densitometer tracing and nephelometric quantitation; immunofixation for confirmation)
• Serum free light chain (FLC) assay (in all patients with newly diagnosed plasma cell dyscrasias)
• Bone marrow aspiration and/or biopsy
• Serum beta2-microglobulin, albumin, serum immunoglobulins, and lactate dehydrogenase (LDH) measurement
• Standard metaphase cytogenetics
• Fluorescence in situ hybridization (FISH)
• Skeletal survey
• Magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET), or low-dose whole-body CT for better detection of bone and extramedullary disease

The NCCN guidelines recommend the following diagnostic studies[2] :

• Complete blood count (CBC), differential, platelet count
• Serum blood urea nitrogen (BUN), creatinine, electrolytes, albumin, calcium, uric acid levels
• Serum LDH and beta-2 microglobulin
• Creatinine clearance (calculated or measured)
• Serum quantitative immunoglobulins, serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (SIFE)
• 24-h urine for total protein, urine protein electrophoresis (UPEP), urine immunofixation electrophoresis (UIFE)
• Serum FLC assay
• Whole-body low-dose CT scan or FDG PET/CT
• Unilateral bone marrow aspirate and biopsy, including bone marrow immunohistochemistry and/or multi-parameter flow cytometry
• Metaphase cytogenetics on bone marrow
• Plasma cell FISH on bone marrow: del 13, del 17p13, t(4;14), t(11;14), t(14;16), t(14;20), 1q21 amplification, 1p deletion

The EHA-ESMO guidelines consider the following tests obligatory for the diagnosis of multiple myeloma[140] :

• Blood count and smear
• Serum electrophoresis and immunofixation
• Serum FLC assay
• Serum immunoglobulin levels
• Kidney and liver function tests
• Serum calcium
• Serum LDH and beta-2 microglobulin
• 24-hr urine for assessment of proteinuria and light--chain proteinuria
• Urine electrophoresis and immunofixation
• Bone marrow cytology and biopsy to confirm plasmacytosis and monoclonality
• Bone marrow next-generation flow cytometry or next-generation sequencing to detect clonal plasma cells
• Bone marrow karyotype and FISH for detection of del17p, t(4;14), t(14;16), ampl 1q/gain 1q, t(11;14)
• Whole-body low-dose CT; whole-body MRI if CT is negative

Diagnostic criteria

Multiple myeloma is defined as smoldering (asymptomatic) or active (symptomatic). The International Myeloma Working Group criteria for smoldering multiple myeloma are as follows[139] :

• Serum monoclonal protein ≥3 g/dL or  urinary monoclonal protein (Bence Jones protein) ≥500 mg/24 h  and/or clonal bone marrow plasma cells 10%–60%
• Absence of myeloma-defining events or amyloidosis

The NCCN also recommends that a patient whose bone survey is negative be assessed for bone disease with whole-body skeletal MRI, FDG PET/CT, or low-dose CT to differentiate active from smoldering MM.[2]

The current diagnostic criteria for symptomatic multiple myeloma are as follows[139] :

• Clonal bone marrow plasma cells ≥10% or bony or extramedullary plasmacytoma (confirmed by biopsy)
• One or more myeloma-defining events.

Myeloma-defining events include the following [139] :

• Hypercalcemia: Serum calcium level > 1 mg/dL (> 0.25 mmol/L) higher than the upper limit of normal or > 2.75 mmol/L (> 11 mg/dL)
• Abnormal kidney function: Serum creatinine > 2 mg/dL (> 177 μmol/L) or creatinine clearance < 40 mL/min
• Anemia: Hemoglobin < 10 g/dL, or  > 2 g/dL below the lower limit of normal
• Bone lesions: One or more osteolytic lesions on skeletal radiography, CT, or PET-CT
• Biomarkers of malignancy: Clonal bone marrow plasma cells ≥60% and/or  involved/uninvolved serum FLC ratio ≥100 (involved kappa) or < 0.01 (involved lambda) and/or one or more focal ≥5 mm lesions on MRI scans

Staging

In 2015, the  International Myeloma Working Group published the Revised International Staging System for Multiple Myeloma.[141] The revised system was subsequently recommended by the NCCN.[2]  The Revised International Staging System (R-ISS) was created by combining the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase FISH (iFISH) after CD138 plasma cell purification, plus serum LDH assay results .[141]

Like the ISS, the R-ISS is based on three stages. Stage I criteria are as follows:

• Beta-2 microglobulin ≤3.5 g/dL and albumin ≥3.5 g/dL
• Standard risk for CA
• Normal LDH

Stage II comprises patients who do not meet criteria for stage I or stage III

Stage III consists of the following:

• Beta-2 microglobulin of 5.5 g/dL or more, and either
• High risk for CA  or high LDH

Median progression-free survival is as follows:

• Stage I : 66 months
• Stage II: 42 months
• Stage III: 29 months

 National Comprehensive Cancer Network (NCCN) general treatment recommendations for symptomatic multiple myeloma (MM) include the following[2] :

• A single autologous stem cell transplant is the preferred approach in transplant-eligible patients
• A second (tandem) autologous stem cell transplant is recommended for patients who relapse more than 12 mo after the first transplant

The NCCN guidelines recommend combining induction therapy for MM with bone-targeted treatment (bisphosphonates or denosumab) and supportive care as necessary. For primary induction therapy in patients with MM who are candidates for transplantation, NCCN guidelines recommend the following as the preferred regimens[2] :

• Bortezomib/lenalidomide/dexamethasone (category 1)

Other recommended regimens, according to the NCCN, are as follows:

• Carfilzomib/lenalidomide/dexamethasone
• Daratumumab/lenalidomide/bortezomib/dexamethasone
• Ixazomib/lenalidomide/dexamethasone (category 2B)

The NCCN considers the following regimens useful in certain circumstances (although triplet regimens should be used as the standard, patients not considered candidates for a 3-drug regimen can be started on a 2-drug regimen, with the third drug added once performance status improves):

• Bortezomib/cyclophosphamide/dexamethasone (preferred primarily for patients with acute kidney insufficiency)
• Bortezomib/doxorubicin/dexamethasone
• Carfilzomib/cyclophosphamide/dexamethasone
• Ixazomib/cyclophosphide/dexamethasone
• Bortezomib/thalidomide/dexamethasone (category 1)
• Cyclophosphamide/lenalidomide/dexamethasone
• Daratumumab/cyclophosphamide/bortezomib/dexamethasone
• Daratumumab/bortezomib/thalidomide/dexamethasone
• Dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide/bortezomib (VTD-PACE)

For primary induction therapy in patients who are not transplant candidates, the NCCN guidelines list the following as preferred regimens[2] :

• Bortezomib/lenalidomide/dexamethasone (category 1)
• Daratumumab/lenalidomide/dexamethasone (category 1)

Other NCCN-recommended regimens for these cases include the following:

• Carfilzomib/lenalidomide/dexamethasone
• Ixazomib/lenalidomide/dexamethasone
• Daratumumab/bortezomib/melphalan/prednisone (category 1)
• Daratumumab/cyclophosphamide/bortezomib/dexamethasone

For maintenance therapy, the NCCN recommends lenalidomide. Although lenalidomide is a category 1 recommendation, the NCCN notes that lenalidomide maintenance appears to be associated with increased risk of secondary cancers, especially after transplant; this should be discussed with patients. The other recommended agent is bortezomib; bortezomib/lenalidomide is useful in certain circumstances.

For treatment of early relapses (1-3 prior therapies), the regimen used for primary induction can be repeated if relapse occurs after more than 6 months. Otherwise, category 1 preferred regimens for early relapse include the following[2] :

• Carfilzomib/lenalidomide/dexamethasone
• Daratumumab/bortezomib/dexamethasone
• Daratumumab/carfilzomib/dexamethasone
• Daratumumab/lenalidomide/dexamethasone
• Isatuximab-irfc/pomalidomide/dexamethasone
• Ixazomib/pomalidomide/dexamethasone

Preferred regimens after two prior therapies that included an immunomodulatory drug and a proteasome inhibitor, and with disease progression on/within 60 days of completion of last therapy, are as follows:

• Ixazomib/pomalidomide/dexamethasone
• Pomalidomide/bortezomib/dexamethasone (category 1)

Preferred regimens after two prior therapies including lenalidomide and a proteasome inhibitor as as follows:

• Isatuximab-irfc/pomalidomide/dexamethasone (category 1)
• Daratumumab/pomalidomide/dexamethasone (category 1)

Preferred regimens after at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory drug are as follows:

• Elranatamab-bcmm
• Talquetamab-tgvs

European Hematology Association and European Society for Medical Oncology (EHA-ESMO)

EHA-ESMO guideline recommendations for front-line therapy of MM include the following[140] :

• For fit patients < 70 years without comorbidities, induction therapy (4-6 cycles) followed by conditioning with high-dose melphalan (200 mg/m ²) and autologous stem cell transplantation (ASCT) is the recommended approach.
• For pre-ASCT induction therapy, daratumumab/bortezomib/thalidomide/dexamethasone (DaraVTD) is the new standard of care. If DaraVTD is not available, bortezomib/thalidomide/dexamethasone (which probably offers the best risk-benefit profile among bortezomib-based triplet regimens) or bortezomib/cyclophosphamide/dexamethasone may be used. Daratumumab/bortezomib/lenalidomide/dexamethasone and isatuximab/bortezomib/lenalidomide/dexamethasone are under clinical investigation and may be standards of care in the near future.
• Consolidation therapy post-ASCT has not been established to date as standard therapy; 2 cycles of bortezomib/lenalidomide/dexamethasone consolidation has to be considered in patients who received bortezomib/cyclophosphamide/dexamethasone induction, while a tandem ASCT is recommended for patients with genetically defined high-risk disease or in all overall survival benefit, even in high-risk disease, compared with tandem ASCT.
• Maintenance with lenalidomide is considered the standard of care for all MM patients post-ASCT; bortezomib may be considered for patients with high-risk disease. Ixazomib maintenance offers progression-free survival (PFS) benefit over placebo, but has not been approved by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA).
• For patients who are not eligible for ASCT, there are 3 new standards of care: bortezomib/lenalidomide/dexamethasone, daratumumab/bortezomib/melphalan/prednisone and daratumumab/lenalidomide/dexamethasone; if those are not available, bortezomib/lenalidomide/dexamethasone is the preferred option in fit patients; otherwise, lenalidomide/dexamethasone and bortezomib/melphalan/prednisone may be considered.

EHA-ESMO guideline recommendations for second-line therapy of MM include the following[140] :

• Second-line ASCT is an option for patients who received primary therapy that included an ASCT followed by lenalidomide maintenance and whose initial remission lasted for ≥36 months.
• Patients who received bortezomib-based therapy upfront without lenalidomide or daratumumab should receive lenalidomide/dexamethasone plus carfilzomib, daratumumab, ixazomib, or elotuzumab. Daratumumab/lenalidomide/dexamethasone provides the best PFS for these patients, while only carfilzomib/lenalidomide/dexamethasone and elotuzumab/lenalidomide/dexamethasone have shown an OS benefit over lenalidomide/dexamethasone to date.
• Patients with MM refractory to upfront lenalidomide could receive pomalidomide/bortezomib/dexamethasone, daratumumab/carfilzomib/dexamethasone, ixazomib/carfilzomib/dexamethasone, or daratumumab/bortezomib/dexamethasone. Of those regimens, only pomalidomide/bortezomib/dexamethasone has been approved yet by the EMA.
• Venetoclax/bortezomib/dexamethasone is a suitable option for patients with t(11;14) MM that has failed to respond to lenalidomide and is sensitive to proteasome inhibitors, if available.

EHA-ESMO guideline recommendations for third-line and subsequent therapy of MM include the following[140] :

• For patients who have been exposed to, or whose MM is refractory to, both bortezomib and lenalidomide, recommended regimens are daratumumab/carfilzomib/dexamethasone, isatuximab/pomalidomide/dexamethasone, isatuximab/carfilzomib/dexamethasone, and elotuzumab/pomalidomide/dexamethasone.
• Patients with t(11;14) MM that is refractory to lenalidomide and sensitive to proteasome inhibitors may be treated with venetoclax/bortezomib/dexamethasone, if available.
• For triple-refractory patients, selinexor/dexamethasone or belantamab mafodotin monotherapy is recommended, if available.

In 2021, the International Myeloma Working Group (IMWG) released updated practice guidelines for the management of multiple myeloma–related bone disease.[47]  The recommendations include the following:

• Zoledronic acid is the preferred bone-targeted agent for patients with newly diagnosed multiple myeloma, whether or not they have multiple myeloma–related bone disease. Once patients achieve a very good partial response or better, after at least 12 months, consideration can be given to decreasing the frequency of zoledronic acid treatment or discontinuing it.
• Denosumab can be considered for the treatment of multiple myeloma–related bone disease, particularly in patients with renal impairment. Denosumab might prolong progression-free survival in patients with newly diagnosed multiple myeloma who have multiple myeloma-related bone disease and who are eligible for autologous stem cell transplantation. Denosumab discontinuation is challenging due to the rebound effect.
• Cement augmentation is effective for painful vertebral compression fractures.
• Radiotherapy is recommended for uncontrolled pain, impending or symptomatic spinal cord compression, or pathologic fractures.
• Surgery should be used for the prevention and restoration of long-bone pathologic fractures, vertebral column instability, and spinal cord compression with bone fragments within the spinal route.

In 2017, the American Society of Clinical Oncology (ASCO) issued an update to its clinical practice guideline on the role of bone-modifying agents in multiple myeloma.[44] ASCO recommendations include the following:

• For patients with multiple myeloma in whom imaging studies show lytic destruction of bone or compression fracture of the spine from osteopenia, intravenous (IV) pamidronate (90 mg delivered over at least 2 hours) or zoledronic acid (4 mg delivered over at least 15 minutes every 3 to 4 weeks) is recommended. Denosumab is an alternative.
• In patients with solitary plasmacytoma or smoldering (asymptomatic) or indolent myeloma who have osteopenia but no lytic disease, starting bisphosphonates is not recommended.
• In patients with monoclonal gammopathy of undetermined significance, starting bisphosphonate therapy is not recommended unless they have osteopenia or osteoporosis.
• In patients receiving radiation therapy, analgesics, or surgical intervention for fractures or impending fractures, IV pamidronate or zoledronic acid is recommended as an adjunctive treatment. Denosumab is an additional option.
• In patients with multiple myeloma who have osteopenia (osteoporosis) but no radiographic evidence of lytic bone disease, IV bisphosphonates may be started.

ASCO recommendations for patients with renal impairment include the following:

• Patients with preexisting mild-to-moderate renal impairment (estimated creatinine clearance, 30 to 60 mL/min) should receive a reduced dosage of zoledronic acid. No changes in infusion time or interval are required.
• Zoledronic acid is not recommended for use in patients with severe renal impairment. Denosumab may be preferred over zoledronic acid in patients with compromised renal function.
• Pamidronate 90 mg administered over 4 to 6 hours, is recommended for patients with extensive bone disease and existing severe renal impairment (serum creatinine level > 3.0 mg/dL [265 µmol/L] or an estimated creatinine clearance < 30 mL/min). In patients with preexisting renal impairment, consider reducing the initial pamidronate dose. Infusion times less than 2 hours with pamidronate or less than 15 minutes with zoledronic acid should be avoided.

ASCO recommendations regarding duration of therapy include the following:

• Continuing bone-targeted treatment for up to 2 years is suggested. Consider less frequent dosing \in patients with responsive or stable disease.
• In patients who do not have active myeloma and are on maintenance therapy, consider a 3-month interval of bisphosphonate administration.
• For patients in whom bisphosphonates were withdrawn after 2 years and relapse with new-onset skeletal-related events occurs, the drug should be resumed.
• Denosumab should not be stopped abruptly, given its reversible mechanism of action.

The NCCN, American Society of Clinical Oncology (ASCO), and International Myeloma Workshop clinical guidelines for prevention of venous thromboembolism agree that patients with multiple myeloma who are receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should receive prophylactic anticoagulation therapy with either aspirin or low molecular weight heparin (LMWH) for lower-risk patients and LMWH for higher-risk patients.[142, 143, 144]

A joint American Society of Hematology (ASH) and ASCO clinical practice guideline on the use of erythropoiesis-stimulating agents (ESAs) in cancer was updated in 2019. The specific recommendations for patients with multiple myeloma receiving concurrent chemotherapy include the following[142] :

• Depending on clinical circumstances, ESAs may be offered to patients with chemotherapy-associated anemia whose cancer treatment is not curative in intent and whose hemoglobin (HgB) has declined to < 10 g/dL; red blood cell (RBC) transfusion is also an option, depending on the severity of the anemia or clinical circumstances.
• ESAs should not be offered to patients with chemotherapy-associated anemia whose cancer treatment is curative in intent.
• In patients with myeloma, clinicians should observe the hematologic response to cancer treatment before considering an ESA. Particular caution should be exercised in the use of ESAs concomitant with treatment strategies and diseases where risk of thromboembolic complications is increased. In all cases, blood transfusion is a treatment option that should be considered.
• In patients who do not respond to ESA treatment within 6 to 8 weeks, the ESA should be discontinued and the patient should be reevaluated for underlying tumor progression, iron deficiency, or other etiologies for anemia.
• Iron replacement may be used to improve HgB response and reduce RBC transfusions for patients receiving ESA with or without iron deficiency.

Guidelines on the management of multiple myeloma complications by the European Myeloma Network include the following recommendations[135] :

• Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus is recommended as the novel standard for the detection of lytic lesions in myeloma.
• Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate.
• Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid, but its advantage is not clear for patien ts with no bone involvement on computed tomography or magnetic resonance imaging.
• In asymptomatic myeloma, bisphosphonates are not recommended.
• Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use.
• Treatment with ESAs may be initiated in patients with persistent symptomatic anemia (hemoglobin < 10g/dL) in whom other causes of anemia have been excluded.
• Erythropoietic agents should be stopped after 6-8 wk if no adequate hemoglobin response is achieved.
• For renal impairment, bortezomib-based regimens are the current standard of care.
• For the management of treatment-induced peripheral neuropathy, drug modification is needed.
• Vaccination against influenza is recommended; vaccination against  Streptococcus pneumoniae and  Haemophilus influenzae is appropriate, but efficacy is not guaranteed due to suboptimal immune response.
• Prophylactic acyclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, or autologous or allogeneic transplantation.

A guideline from the European Myeloma Network includes the following recommendations for vaccination in multiple myeloma[136] :

• Influenza - All patients, nonimmune family members, close contacts and healthcare workers
• Hepatitis A -  Patients traveling to areas of high endemicity
• Hepatitis B - Patients traveling to areas of high endemicity, behavioral/occupational exposure, hemodialysis
• Pneumococci -  PCV13, all patients; PPV23, > 2 months, or 6–12 months, after PCV13
• Haemophilus influenzae – All patients
• Meningococci - Patients with asplenia, complement deficiency, recurrent episodes of bacterial infections
• Diptheria/tetanus/acellular pertussis (DTaP) - Patients who did not receive a primary vaccination for DTaP, or a booster dose of tetanus and diphtheria toxoid vaccine. May be limited to tetanus only, based on epidemiological prevalence
• Herpes zoster – All patients

Multiple myeloma (MM) is treated with several categories of medications. Chemotherapeutic agents, corticosteroids, and monoclonal antibodies are used to reduce the disease burden, and bisphosphonates are used to promote bone healing and to provide secondary prophylaxis against skeletal-related events (eg, hypercalcemia, bone fracture, spinal cord compression, need for radiation, and need for surgery). In addition, erythropoietin is used to treat anemia, either alone or in conjunction with chemotherapy.

Class Summary

The choice of chemotherapy depends on several factors, including the patient’s performance status, age, renal function, desire for inpatient or outpatient therapy, and likelihood of receiving future autologous stem cell transplantation.

In patients with renal failure or highly aggressive disease, therapy with vincristine, Adriamycin (doxorubicin), and dexamethasone (VAD) may be preferred. In elderly patients or patients in whom autologous transplantation is not possible in the future, melphalan and prednisone (MP) therapy is preferred because of its ease of administration and low toxicity. 

Cyclophosphamide (Cytoxan, Neosar)

Cyclophosphamide is chemically related to nitrogen mustards. It is an alkylating agent, and its mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Melphalan (Alkeran)

The most widely used regimen is MP. Melphalan is an alkylating agent and a derivative of mechlorethamine that inhibits mitosis by cross-linking DNA strands. It is indicated for the palliative treatment of multiple myeloma.

Doxorubicin (Adriamycin, Rubex)

Doxorubicin is part of VAD therapy. It inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA; these 2 events, in turn, can inhibit growth of neoplastic cells.

Doxorubicin liposomal (Doxil)

Doxorubicin liposomal is a pegylated formulation that protects the liposomes and, thereby, increases blood circulation time. The drug inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA; these 2 events can, in turn, inhibit growth of neoplastic cells.

Vincristine (Oncovin)

Vincristine inhibits cellular mitosis by inhibition of intracellular tubulin function, binding to microtubules, and synthesis of spindle proteins in the S phase. Vincristine is part of VAD therapy. Its mechanism of action is complex and includes depolymerization of microtubules.

Bortezomib (Velcade)

Bortezomib is the first drug approved in the group of anticancer agents known as proteasome inhibitors. The proteasome pathway is an enzyme complex existing in all cells, which degrades ubiquitinated proteins that control the cell cycle and cellular processes and maintains cellular homeostasis. Reversible proteasome inhibition disrupts pathways supporting cell growth, thus decreasing cancer cell survival. Bortezomib is indicated for patients with multiple myeloma. Development of peripheral neuropathy is a limiting factor. A decreased incidence of peripheral neuropathy has been observed with SC administration compared with the IV route.

Carfilzomib (Kyprolis)

Proteasome inhibitor; elicits antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. It is indicated as monotherapy, in combination with dexamethasone, or in combination with lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma in patients who have received at least 1 prior line of therapy.  

Ixazomib (Ninlaro)

Reversible proteasome inhibitor. It preferentially binds and inhibits the chymotrypsinlike activity of the beta 5 subunit of the 20S proteasome. It is indicated in combination with lenalidomide and dexamethasone for patients with multiple myeloma who have received at least 1 prior therapy.

Panobinostat (Farydak)

Panobinostat is a histone deacetylase (HDAc) inhibitor. HDAc catalyzes the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins. Inhibition of HDAc activity results in increased acetylation of histone proteins and an epigenetic alteration that results in a relaxing of chromatin, leading to transcriptional activation. It is indicated in combination with bortezomib and dexamethasone for treatment of multiple myeloma in patients who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent.

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body’s immune response to diverse stimuli. 

Prednisone (Deltasone, Orasone, Meticorten)

The most widely used regimen is MP. Prednisone stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

Dexamethasone (Decadron)

Dexamethasone is part of many treatment regimens for multiple myeloma. Dexamethasone stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

Class Summary

Monoclonal antibodies that target proteins expressed on multiple myeloma cells (eg, CD38, SLAMF7) have been approved.

Denosumab (Xgeva)

Monoclonal antibody that specifically targets RANKL. It binds to RANKL and inhibits its binding to RANK receptor, thereby preventing osteoclast formation. This results in decreased bone resorption and increases bone mass in osteoporosis. RANKL inhibition decreases tumor-induced bone destruction and SREs. Denosumab is indicated for prevention of SREs in patients with multiple myeloma.

Daratumumab (Darzalex)

Monoclonal antibody that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is indicated for patients with multiple myeloma who have received at least 3 prior treatments, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are double-refractory to a PI and IMiD. Other regimens for relapsed/refractory MM are approved for daratumumab in combination with dexamethasone plus bortezomib or lenalidomide or pomalidomide. It is also indicated for newly diagnosed MM in patients ineligible for ASCT as part of various combination regimens. May also be considered in newly diagnosed MM in patients who are eligible for ASCT in combination with bortezomib, thalidomide, and dexamethasone.

Elotuzumab (Empliciti)

Humanized IgG1 monoclonal antibody that specifically targets the SLAMF7 (signaling lymphocytic activation molecule family member 7) protein. SLAMF7 is expressed on myeloma cells and natural killer cells and plasma cells. Facilitates the interaction with natural killer cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity. It is indicated in combination with lenalidomide and dexamethasone for multiple myeloma in patients who have received 1-3 prior therapies. Elotuzumab is also indicated in combination with pomalidomide and dexamethasone for patients with multiple myeloma who have received 2 or more prior therapies including lenalidomide and a proteasome inhibitor.

Isatuximab (Sarclisa, isatuximab-irfc)

Anti-CD38 monoclonal antibody indicated for relapsed or resistant multiple myeloma in combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor, and in combination with carfilzomib and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.

Elranatamab (Elrexfio)

Elranatamab is a humanized BCMA-CD3 bispecific antibody. FDA granted accelerated approval for adults with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Talquetamab (Talquetamab-tgvs, Talvey)

Talquetamab is a potential first-in-class, investigational T-cell redirecting bispecific antibody targeting both GPRC5D, a novel multiple myeloma target that does not shed over time, and CD3, a component of the T-cell receptor. It was granted accelerated approval to talquetamab (Talvey) for relapsed or refractory multiple myeloma in adults who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Class Summary

Interferons are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alfa-, beta-, and gamma-interferons may be administered topically, systemically, and intralesionally. 

Interferon alfa-2B (Intron A)

Interferon alfa-2B is a protein product manufactured by recombinant DNA technology. The mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.

Class Summary

Immunosuppressant agents inhibit key factors in the immune system that are responsible for immune reactions.

Thalidomide (Thalomid)

Thalidomide, when used in combination with dexamethasone, is indicated for the treatment of patients with newly diagnosed multiple myeloma. Thalidomide is an immunomodulatory agent that may suppress excessive production of tumor necrosis factor (TNF)-alpha and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration. Because of concerns regarding teratogenicity, thalidomide can only be prescribed by registered physicians and is dispensed by registered pharmacists. Patients must participate in ongoing surveys to receive therapy, and only a 28-d supply can be prescribed at a time.

Lenalidomide (Revlimid)

Lenalidomide is indicated in combination with dexamethasone for multiple myeloma. It is structurally similar to thalidomide. Lenalidomide elicits immunomodulatory and antiangiogenic properties. It inhibits proinflammatory cytokine secretion and increases anti-inflammatory cytokines from peripheral blood mononuclear cells.

Pomalidomide (Pomalyst)

Thalidomide analogue indicated in combination with dexamethasone for patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor. Also used in combination with elotuzumab and dexamethasone.

Class Summary

Agents in this drug class are antibody-drug conjugates. The antibody component is an afucosylated IgG1 directed against B-cell maturation agent (BCMA), a protein expressed on normal B lymphocytes and multiple myeloma cells. The small molecule component is MMAF, a microtubule inhibitor.

Belantamab mafodotin (Belantamab mafodotin-blmf, Blenrep)

Upon binding to BCMA, belantamab mafodotin-blmf is internalized followed by release of MMAF via proteolytic cleavage. The released MMAF intracellularly disrupts the microtubule network, leading to cell cycle arrest and apoptosis. It also has antitumor activity in multiple myeloma cells and mediated killing of tumor cells through MMAF-induced apoptosis, as well as by tumor cell lysis through antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). It is indicated for relapsed or refractory MM in patients who were previously treated with 4 or more prior therapies.

Teclistamab (Tecvayli)

Teclistamab is a bispecific T-cell engaging antibody binds to CD3 receptor surface of T-cells and B-cell maturation antigen (BCMA) expressed on the surface of multiple myeloma cells and some healthy B-lineage cells. In October 2022, the FDA granted accelerated approval for adults with relapsed or refractory MM who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Idecabtagene vicleucel (Abecma)

B-cell maturation antigen (BCMA)-directed genetically modified autologous CAR T-cell therapy is indicated for relapsed or refractory MM after ≥4 prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Each idecabtagene vicleucel dose is customized using a patient’s own T-cells to help fight the myeloma. These T-cells are collected and genetically modified to include a new gene that facilitates targeting and killing myeloma cells. Once modified, the cells are infused back into the patient. 

Ciltacabtagene autoleucel (Carvykti)

CAR-T cell therapy featuring 2 BCMA-targeting single domain antibodies is indicated for relapsed or refractory MM in adults who were previously treated with ≥4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

Class Summary

A selective inhibitor of nuclear export (SINE) acts on tumor suppressor proteins (TSPs), growth regulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). Inhibition of XPO1 leads to accumulation of TSPs in the nucleus, reductions in several oncoproteins (eg, c‐myc, cyclin D1), cell cycle arrest, and apoptosis of cancer cells.

Selinexor (Xpovio)

Indicated in combination with dexamethasone for adults with relapsed or refractory multiple myeloma (RRMM) who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody.

Class Summary

Bisphosphonates inhibit bone resorption via action on osteoclasts or osteoclast precursors.

Pamidronate (Aredia)

Pamidronate inhibits normal and abnormal bone resorption. It appears to inhibit bone resorption without inhibiting bone formation and mineralization. The optimal timing and duration of therapy are being studied. Pamidronate is administered intravenously (IV) over 2 hours. Newer drugs similar in structure and function are being studied and may have improved efficacy and greater convenience.

Zoledronic acid (Zometa)

Zoledronic acid inhibits bone resorption, possibly by acting on osteoclasts or osteoclast precursors. It is effective in treating the hypercalcemia of malignancy.

Class Summary

Colony-stimulating factors induce erythropoiesis.

Epoetin alfa, erythropoietin (Epogen, Procrit)

Erythropoietin stimulates the division and differentiation of committed erythroid progenitor cells and induces the release of reticulocytes from bone marrow into the blood stream.

Erythropoietin is a naturally occurring hormone produced by the kidneys to stimulate bone marrow production of red blood cells. In patients with MM, administration of exogenous erythropoietin may correct anemia, leading to a significant improvement in performance status and quality of life.

Class Summary

These drugs inhibit the C-X-C motif chemokine receptor 4 (CXCR4) and block binding of its cognate ligand, stromal-derived factor-1α (SDF-1α)/CXCL12. SDF-1α and CXCR4 play a role in trafficking and homing of hematopoietic stem cells to the marrow compartment.

Motixafortide (Aphexda)

Indicated in combination with filgrastim to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with multiple myeloma. 

Plerixafor (Mozobil)

Indicated in combination with filgrastim to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with multiple myeloma and non-Hodgkin lymphoma.