Multiple Myeloma

Updated: Sep 13, 2023
  • Author: Dhaval Shah, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Practice Essentials

Multiple myeloma (MM) is a plasma cell malignancy in which monoclonal plasma cells proliferate in bone marrow, resulting in an overabundance of monoclonal paraprotein (M protein), destruction of bone, and displacement of other hematopoietic cell lines. [1] First described in 1848, MM is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. See the image below.

Bone marrow aspirate demonstrating plasma cells of Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo). All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.

Signs and symptoms

MM can range from asymptomatic to severely symptomatic with complications requiring emergent treatment. Presenting signs and symptoms of MM include the following:

  • Bone pain
  • Pathologic fractures
  • Spinal cord compression (from pathologic fracture)
  • Weakness, malaise
  • Bleeding, anemia
  • Infection (often pneumococcal)
  • Hypercalcemia
  • Kidney failure
  • Neuropathies

See Presentation for more detail.


MM is often discovered through routine blood screening when patients are being evaluated for unrelated problems. In one third of patients, the condition is diagnosed after a pathologic fracture occurs, usually involving the axial skeleton.

Examination for MM may reveal the following:

  • HEENT examination: Exudative macular detachment, retinal hemorrhage, or cotton-wool spots
  • Dermatologic evaluation: Pallor from anemia, ecchymoses or purpura from thrombocytopenia; extramedullary plasmacytomas (most commonly in aerodigestive tract but also orbital, ear canal, cutaneous, gastric, rectal, prostatic, retroperitoneal areas)
  • Musculoskeletal examination: Bony tenderness or pain without tenderness
  • Neurologic assessment: Sensory level change (ie, loss of sensation below a dermatome corresponding to a spinal cord compression), neuropathy, myopathy, positive Tinel sign, or positive Phalen sign
  • Abdominal examination: Hepatosplenomegaly
  • Cardiovascular evaluation: Cardiomegaly

In patients with MM and amyloidosis, the characteristic examination findings include the following:

  • Shoulder pad sign
  • Macroglossia
  • Typical skin lesions
  • Post-proctoscopic peripalpebral purpura (eyelid purpura may also follow coughing, vomiting, the Valsalva maneuver, or forced expiration during spirometric testing)
  • Carpal tunnel syndrome
  • Subcutaneous nodules


The International Myeloma Workshop guidelines for standard investigative workup in patients with suspected MM 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 beta2-microglobulin, albumin, and lactate dehydrogenase measurement
  • Standard metaphase cytogenetics
  • Fluorescence in situ hybridization
  • Skeletal survey
  • MRI

Routine laboratory tests include the following:

  • Complete blood count and differential
  • Erythrocyte sedimentation rate
  • Comprehensive metabolic panel (eg, levels of total protein, albumin and globulin, BUN, creatinine, uric acid)
  • 24-hour urine collection for quantification of the Bence Jones protein (ie, lambda light chains), protein, and creatinine clearance; proteinuria greater than 1 g/24 hr is a major criterion
  • C-reactive protein
  • Serum viscosity in patients with CNS symptoms, nosebleeds, or very high M protein levels

National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines also recommend the use of serum free light chain assay and plasma cell fluorescence in situ hybridization (FISH) on bone marrow: del 13, del 17p13, t(4;14), t(11;14), t(14;16), t(14;20), 1q21 amplification, 1p deletion as part of the initial diagnostic workup. [2]

Imaging studies

  • Simple radiography for the evaluation of skeleton lesions; skeletal survey, including the skull, long bones, and spine
  • MRI for detecting thoracic and lumbar spine lesions, paraspinal involvement, and early cord compression
  • PET scanning in conjunction with MRI potentially useful

See Workup for more detail.


Treatment choices are guided by the results of the diagnostic workup, which determine the initial classification of the patient's illness into one of the following disorders in the spectrum of MM:

Radiation therapy is the primary therapy for solitary plasmacytoma with or without marrow involvement. Surgery may be required if the lesion causes structural instability or neurologic compromise. [2]

Active surveillance or watchful waiting is recommended for patient with SMM or asymptomatic MM. However, patients at high risk of progression to active MM may benefit from early intervention.

Newly diagnosed patients with MM should be referred to a hematopoietic cell transplant (HCT) center to assess whether they are eligible for HCT and/or high-dose therapy. Transplant-eligible patients are initially treated with primary therapy (induction) followed by high-dose chemotherapy with autologous HCT. [3, 4, 5]

Treatment regimens

Treatment regimens for symptomatic MM are generally based on the following patient categories:

  • 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

Triplet regimens are the standard. All contain dexamethasone and many include lenalidomide. Clinicians treat many patients with high-dose therapy and peripheral blood or bone marrow stem cell transplantation. Maintenance therapy is typically with lenalidomide; bortezomib may also be used.

For MM that relapses after more than 6 months, the regimen used for primary induction therapy can be repeated. For relapses that occur sooner,  a number of regimens are available. Regimen selection varies with early relapse (1-3 prior therapies) versus late relapse (> 3 prior therapies). Newer agents for relapses after ≥4 prior therapies include belantamab mafodotin, an antibody-drug conjugate that contains a monoclonal antibody directed against the B-cell maturation antigen, and the chimeric antigen receptor (CAR) T-cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel

See Treatment and Medication for more detail.



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 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.


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

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.