eMedicine Specialties > Hematology > Plasma Cell Disorders

Multiple Myeloma: Treatment & Medication

Author: Sara J Grethlein, MD, Associate Dean for Graduate Medical Education, Professor, Department of Internal Medicine, Division of Hematology and Oncology, State University of New York Upstate Medical University
Coauthor(s): Lilian M Thomas, MD, Fellow, Department of Hematology/Oncology, State University of New York Upstate Medical University
Contributor Information and Disclosures

Updated: Nov 19, 2009

Treatment

Medical Care

Physicians must understand both the natural history of multiple myeloma and the limitations of current therapy in the treatment of the disease.

An important study by Dimopoulos and associates evaluated the risk of disease progression in asymptomatic subjects with multiple myeloma.¹⁴ This study evaluated 638 consecutive untreated subjects with multiple myeloma. Of these subjects, 95 were asymptomatic and were not treated until their M protein value rose to greater than 5 g/dL. These subjects developed increased bone disease or symptoms of bone disease. The individuals in this group 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.¹⁴ At the time of progression, subjects were treated with standard chemotherapy. The subjects' response rates did not significantly differ from those of unselected populations. The median survival time from the institution of chemotherapy did not differ among the groups. To summarize, asymptomatic subjects did not benefit from early treatment, and delayed treatment did not affect the efficacy of the treatment (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.¹⁵ The failure to demonstrate improved survival may be due to the small number of patients studied.

Patients with multiple myeloma for whom therapy is indicated typically receive chemotherapy. Our understanding of the cell biology of multiple myeloma 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 and peripheral blood or bone marrow stem cell transplantation. A randomized prospective study showed that this approach results in higher response rates and better disease-free survival rates. Recent advances in treatment include establishment of thalidomide, lenalidomide, and bortezomib as active agents in multiple myeloma. Patients with myeloma who are treated with lenalidomide or thalidomide are at significantly increased risk of thrombotic events, and many physicians incorporate anticoagulation strategies in their management.

Adjunctive therapy for multiple myeloma 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). Erythropoietin may ameliorate anemia resulting from either multiple myeloma alone or from chemotherapy and has been shown to improve quality of life.¹⁶ A systematic review failed to demonstrate a survival advantage for the use of erythropoietin agents in the treatment of patients with cancer-related anemia.¹⁷

Patients with spinal cord compression due to multiple myeloma should begin corticosteroid therapy immediately to reduce swelling. Urgent arrangements must be made for radiation therapy in order to restore or stabilize neurologic function. Although surgical decompression 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 multiple myeloma 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 multiple myeloma who present with acute renal failure may benefit from plasmapheresis. 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. A report by Ludwig et suggests that bortezomib-based therapy may restore renal function in multiple myeloma patients with renal failure.¹

• Transplantation
  • Using the patient's own (ie, autologous) bone marrow or peripheral blood stem cells facilitates more intense therapy for multiple myeloma. 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 an 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.¹⁸ 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.¹⁹
  • In another 2-arm study that compared single versus tandem transplants for newly diagnosed multiple myeloma, Cavo et al showed that double autologous stem cell transplantation effected superior complete response or near complete response rates, relapse-free survival, and event-free survival, but it failed to significantly prolong overall survival.²⁰ 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.
  • In highly selected patients with multiple myeloma, 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 an HLA-identical sibling. The advantage of this approach over autologous transplantation is that the patient is not at risk of being reinfused with multiple myeloma cells. Also, 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).
  • 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%).²¹ 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.
  • Physicians use allogeneic transplantation less often than autologous transplantation in multiple myeloma patients, for several reasons.
    • First, the risks of complications and death from allogeneic transplantation increase with age, and most patients with multiple myeloma are older than the ideal age for allogeneic transplantation.
    • Second, the transplantation-related mortality rate is quite high in patients with multiple myeloma 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 multiple myeloma allogeneic transplantation is changing the equation. A republished report of 52 high-risk patients who underwent nonmyeloablative transplants described a 17% mortality rate.²²  Progression-free survival at 18 months was roughly 30%. A recently reported 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. Further studies are needed to evaluate relative efficacy.²³
• Radiation
  • Multiple myeloma 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 multiple myeloma, but without dramatic success.

Surgical Care

Surgical therapy for multiple myeloma is limited to adjunctive therapy.

Consultations

Patients with multiple myeloma 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.

Diet

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

Activity

Encourage patients with multiple myeloma to be physically active, as appropriate to their individual bone status. Physical activity may help maintain bone strength.

Medication

Treatment for multiple myeloma is best categorized on the basis of the patient's age and prognostic factors. We will look at 3 separate categories: (1) the young, newly diagnosed patient, who is potentially a transplant candidate; (2) high-risk patients who are potentially transplant candidates; and (3) newly diagnosed elderly patients who are not transplant candidates.

The young, newly diagnosed patient, who is potentially a transplant candidate

Conventionally, VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone) chemotherapy has been used to decrease the tumor burden in multiple myeloma 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 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.

Thalidomide has proved effective against multiple myeloma. The superiority of induction regimens containing thalidomide was demonstrated in randomized trials that compared VAD with thalidomide plus dexamethasone²⁴ ; thalidomide and doxorubicin plus dexamethasone¹⁸ ; and thalidomide plus VAD.²⁵

Thalidomide has a well-established role as first-line therapy, either as a single agent or in combination with steroids in patients with multiple myeloma. 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.

Bortezomib, a proteosome inhibitor, has shown striking activity against multiple myeloma. Objective responses as high as 27.7% in patients with relapsed and heavily pretreated multiple myeloma²⁶ led to its approval by the Food and Drug Administration (FDA) in 2003. Subsequent studies reported response rates as high as 80% when bortezomib is combined with melphalan.

A randomized trial compared bortezomib plus dexamethasone with VAD for induction, showing response rates of 80% for the bortezomib plus dexamethasone arm versus 62.8% for the VAD arm (P < .001).²⁷ This regimen has been shown to be active not only in the pretransplantation setting but also posttransplantation. Following high-dose therapy and autologous transplantation, the rate of very good partial response or better continued to favor bortezomib plus dexamethasone (61.7% vs. 41.7%, P < .001). 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 was compared with thalidomide plus dexamethasone in a large phase 3 study: 93% in the bortezomib-thalidomide-dexamethasone arm versus 80% in the thalidomide-dexamethasone arm, in which patients went on to receive tandem autologous stem cell transplantation.²⁸ As in other studies, response was independent of adverse prognostic risk factors.

Bortezomib appears to be of especial benefit in patients with plasma cell leukemia and renal 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 multiple myeloma is still evolving through ongoing research. Varicella-zoster virus reactivation occurs in 10%-60% of patients with multiple myeloma treated with bortezomib. Antiviral prophylaxis (eg, acyclovir, 400 mg daily) has been found effective for preventing these reactivations.²⁹

An analogue of thalidomide, lenalidomide (Revlimid) is now a standard component of multiple myeloma therapy. 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 multiple myeloma.²⁴ 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.²⁴ Progression-free survival 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.

In another randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide (LD) plus low-dose dexamethasone (Ld) in newly diagnosed multiple myeloma, the overall response rate for LD was superior (82%) to that for Ld (70%), with an improvement in the VGPR-or-better rate for LD (44% vs 26%) evaluated after 4 months.³⁰ When best overall response was compared, LD again was superior, with an overall response rate of 82% compared with 71% for Ld. However, there was no difference in progression-free survival between the 2 arms. Overall survival continued to favor the Ld arm; however, for patients younger than 65 years, there was no benefit in survival for Ld over LD.³⁰

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.

High-risk patients who are potentially transplant candidates

High-risk multiple myeloma patients are those with advanced-stage disease, according to the International Staging System stage III; those with poor cytogenetics, such as t (4:14), t (14:16), and t (14:20), deletion of chromosome 13, inactivation of P53; and those with a complex karyotype. Patients with very high proliferative rates are also included in this classification. This group represents about 25% of those with newly diagnosed multiple myeloma, 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.^31,32 Once a response has been achieved, then these patients can be brought to autologous stem cell transplantation.

Newly diagnosed elderly patients who are not transplant candidates

All of the above regimens may be used in patients who are not being considered for autologous stem cell transplantation. The following, however, can only be used in patients not going for transplantation, as they impair stem cell reserve. The gold standard has been melphalan and prednisone (M and P) as far back as the 1950’s. A meta-analysis of 4930 patients from 20 randomized trials compared melphalan and prednisone to other drug combinations and showed a significantly higher response rate (60%) with this combination, with a response duration of 18 months and overall survival of 24 to 36 months.³³

A 3-arm study looked at melphalan and prednisone plus thalidomide versus melphalan and prednisone versus VAD induction, followed by high-dose melphalan and autologous stem cell transplantation in 447 patients between ages 65 and 75 years.³⁴ The patients were randomized, with overall survival as the primary endpoint. The response rate in the melphalan and prednisone plus thalidomide arm and transplantation arm was similar; the complete response rate was significantly better in the melphalan and prednisone plus thalidomide and the transplantation arms than in the melphalan and prednisone arm.³⁴ Melphalan and prednisone plus thalidomide is now recommended as first-line treatment. Melphalan and prednisone plus lenalidomide has also shown promise.³⁵

Hulin et al conducted a randomized, placebo-controlled, phase III trial to investigate the efficacy of adding thalidomide to a regimen of melphalan and prednisone in 229 elderly patients (> 75 y) newly diagnosed with multiple myeloma.³⁶ 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; P = 0.028).³⁶ Progression-free survival was also significantly prolonged in the thalidomide group (median, 24.1 mo) relative to the placebo group (median, 18.5 mo; P = 0.001). However, the investigators noted peripheral neuropathy and neutropenia were significantly increased in the thalidomide group.³⁶

Interferon alfa

Intense research has focused on the use of interferon alfa to treat multiple myeloma. 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.³⁷ Interferon alfa appears to prolong remission in selected patients with multiple myeloma. For this use, interferon alfa 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 has significantly limited the role of interferon alfa.

Bisphosphonates

Bisphosphonates have a role in the secondary prevention of bony complications in multiple myeloma, including hypercalcemia, pathologic fracture, and spinal cord compression. A randomized placebo-controlled trial of pamidronate (eg, Aredia) in subjects with multiple myeloma 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.³⁸ The investigators also noted improvements in pain, narcotic usage, and quality of life scores. A 2007 systematic review of the use of bisphosphonates in multiple myeloma confirmed a number-needed-to-treat (NNT) of 10 for the prevention of vertebral fractures, although no impact on mortality was seen.⁴

Zoledronic acid (Zometa) may be significantly more potent than pamidronate. Recent evidence suggests that osteonecrosis of the jaw may occur in some patients receiving bisphosphonate therapy.³⁹ The management of osteonecrosis of the jaw is evolving, and no definitive data have yet been published. Collaboration with knowledgeable dentists and oral surgeons is essential. Dental extractions appear to be a risk factor, and guidelines recommend avoiding this where possible.

Patients who have a relapse after initial disease control may be treated with any of the agents not already utilized. If the multiple myeloma relapse occurs longer than 6 months after the initial therapy, then the initial regimen can be used again. Bortezomib has a well-established role as salvage therapy based on a phase III randomized trial showing a response rate of 38% relative to 18% in patients receiving dexamethasone only.²⁶ Median progression-free survival was 6.22 months in the bortezomib arm versus 3.49 months in the dexamethasone-only group.

An important prospective placebo controlled trial of the addition of lenalidomide to dexamethasone in relapsed cases of multiple myeloma demonstrated spectacular results.⁴¹ 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 in the lenalidomide plus dexamethasone group vs 4.7% in the placebo group). Overall survival was significantly improved.⁴¹

Chemotherapeutic Agents

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, VAD may be preferred. In elderly patients or patients in whom autologous transplantation is not possible in the future, M and P is preferred because of its ease of administration and low toxicity.

Melphalan (Alkeran)

Most widely used regimen is M and P. Melphalan inhibits mitosis by cross-linking DNA strands.

Doxorubicin (Adriamycin, Rubex)

Part of VAD. 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)

Part of VAD therapy. Mechanism of action is complex and includes depolymerization of microtubules.

Bortezomib (Velcade)

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.

Corticosteroids

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

Prednisone (Deltasone, Orasone, Meticorten)

Most widely used regimen is M and P. Stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

Dexamethasone (Decadron)

Part of VAD therapy. Many believe 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. Stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

Interferons

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-2A (Roferon A, Intron A)

Protein product manufactured by recombinant DNA technology. The mechanism of the antitumor activity not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.

Bisphosphonates

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

Pamidronate (Aredia)

Inhibits normal and abnormal bone resorption. Appears to inhibit bone resorption without inhibiting bone formation and mineralization. The optimal timing and duration of therapy is being studied. Administered IV over 2 h. Newer drugs similar in structure and function are being studied and may have improved efficacy and greater convenience.

Zoledronic acid (Zometa)

Inhibits bone resorption, possibly by acting on osteoclasts or osteoclast precursors. Effective in treating the hypercalcemia of malignancy.

Colony-stimulating Factors

Colony-stimulating factors induce erythropoiesis.

Epoetin alfa, erythropoietin (Epogen, Procrit)

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

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

Antibiotics

Therapy with antibiotic agents must cover all the likely pathogens in the context of the multiple myeloma clinical setting.

Trimethoprim-sulfamethoxazole (Bactrim DS, Septra DS)

Inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid.

Immunosuppressant Agents

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

Thalidomide (Thalomid)

Immunomodulatory agent that may suppress excessive production of TNF-alpha and may downregulate 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)

Indicated for the transfusion-dependent myelodysplastic syndrome subtype of deletion 5q cytogenetic abnormality. Structurally similar to thalidomide. Elicits immunomodulatory and antiangiogenic properties. Inhibits proinflammatory cytokine secretion and increases anti-inflammatory cytokines from peripheral blood mononuclear cells.

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