Multiple Myeloma Treatment Information for Healthcare Professionals

Multiple Myeloma

Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information.

Idiotypic myeloma cells can be found in the blood of myeloma patients in all stages of the disease.^1,2 For this reason, when treatment is indicated, systemic chemotherapy must be considered for all patients with symptomatic plasma cell neoplasms. Patients with monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic, smoldering myeloma do not require immediate treatment, but must be followed carefully for signs of disease progression.

Patients with an M-protein in the serum and/or urine are evaluated as follows:

1. Measure and follow the serum M-protein by serum electrophoresis. The M-protein can also be followed by specific nephelometry immunoglobulin assays, however, these assays always overestimate the M-protein because normal immunoglobulins are included in the result. For this reason, baseline and follow-up measurements of the M-protein should be done by the same method.³
   
2. Measure and follow the amount of M-protein light chains excreted in the urine per 24 hours. First, measure the total amount of protein excreted per 24 hours and multiply this value by the percentage of urine protein that is M-protein, as determined by electrophoresis of concentrated urine protein.
   
3. Identify the heavy- and light-chain of the M-protein by immunoelectrophoresis or immunofixation.
   
4. Measure the hemoglobin, leukocyte, platelet, and differential counts.
   
5. Determine the percentage of marrow plasma cells. More than one site may need to be sampled because marrow plasma cell distribution tends to be spotty.
   
6. Take needle aspirates of a solitary lytic bone lesion, extramedullary tumor(s), or enlarged lymph node(s) to determine whether these are plasmacytomas.
   
7. Evaluate renal function with serum creatinine and a creatinine clearance. Electrophoresis of concentrated urine protein is very helpful in differentiating glomerular lesions from tubular lesions. Glomerular lesions, such as those resulting from glomerular deposits of amyloid or light chain deposition disease, result in the non-selective leakage of all serum proteins into the urine; the electrophoresis pattern of this urine resembles the serum pattern. In most myeloma patients the glomeruli function normally, allowing only the small molecular weight proteins, such as albumin and light chains, to filter into the urine. In the tubules the concentration of protein increases as water is reabsorbed. This leads to precipitation of proteins and the formation of tubular casts, which may injure the tubular cells. With tubular lesions, the typical electrophoresis pattern shows a small albumin peak and a larger light chain peak in the globulin region; this tubular pattern is the usual pattern found in myeloma patients.
   
8. Measure serum levels of calcium, alkaline phosphatase, lactic dehydrogenase, and, when indicated by clinical symptoms, cryoglobulins and serum viscosity.
   
9. Obtain radiographs of the skull, ribs, vertebrae, pelvis, shoulder girdle, and long bones.
   
10. Perform magnetic resonance imaging (MRI) if a paraspinal mass is detected, or if symptoms suggest spinal cord or nerve root compression.
    
11. If amyloidosis is suspected, do a needle aspiration of subcutaneous abdominal fat and stain the bone marrow biopsy for amyloid as the easiest and safest way to confirm the diagnosis.⁴
    
12. Measure serum albumin and beta-2 microglobulin as useful, independent prognostic factors.^5,6
    
13. The marrow plasma cell labeling index, the serum soluble IL-6 receptor, and the number of circulating myeloma cells are under evaluation as prognostic factors.⁷

These initial studies should be compared with subsequent values at a later time, when it is necessary to decide whether the disease is stable or progressive, responding to treatment or getting worse. The major challenge is to separate the stable asymptomatic group of patients, who do not require treatment, from patients with progressive, symptomatic myeloma who should be treated immediately.

Patients with MGUS have an M-protein in the serum and/or urine and fewer than 10% plasma cells in the marrow, but no other signs or symptoms of disease. Those with smoldering myeloma have similar characteristics, but may have more than 10% marrow plasma cells. Since from 1% to 2% of MGUS patients will progress per year to develop myeloma (most commonly), amyloidosis, a lymphoma, or chronic lymphocytic leukemia, these patients must be followed carefully.⁸ Treatment is delayed until the disease progresses to the stage that symptoms or signs appear. Patients with MGUS or smoldering myeloma do not respond more frequently, achieve longer remissions or improved survival if chemotherapy is started early, while they are still asymptomatic, as opposed to waiting for progression before treatment is initiated.⁹

Treatment options for patients with symptomatic myeloma range from relatively simple conventional chemotherapy to high-dose chemotherapy and peripheral stem cell or allogeneic bone marrow transplantation. Treatment choice is determined largely by the age and general health of the patient and should be finely attuned to the preferences of patients and their families.

Conventional chemotherapy treatment options

Chemotherapy prolongs the survival of patients with symptomatic myeloma to a median of 40 to 46 months for patients with stage I disease, 35 to 40 months for patients with stage II disease, and 24 to 30 months for patients with stage III disease.

A well-tolerated chemotherapy regimen producing consistent results is melphalan and prednisone (MP).^10,11

Other regimens appear to produce similar survival outcomes. They are:

1. VAD: vincristine + doxorubicin + dexamethasone ^12,13
   
2. High-dose dexamethasone ¹⁴
   
3. Cyclophosphamide + prednisone ¹⁵
   
4. VBMCP (the M2 protocol): vincristine + carmustine + melphalan + cyclophosphamide + prednisone ^11,16
   
5. VMCP/VBAP: vincristine + melphalan + cyclophosphamide + prednisone alternating with vincristine + carmustine + doxorubicin + prednisone^11,17

A randomized, double-blind study of patients with stage III myeloma showed that monthly intravenous pamidronate significantly reduces pathologic fractures, bone pain, spinal cord compression, and the need for bone irradiation (there were 38% skeletal-related events in the treated group versus 51% in the placebo group after 21 months of therapy, p=.015).¹⁸[Level of evidence: 1iDii] In addition, survival was increased (median survival was 21 months versus 14 months) in the patients receiving pamidronate and second line or greater chemotherapy.

There is no strong evidence that any alkylating agent is superior to another. All standard doses and schedules produce equivalent results. However, the absorption and metabolism of some alkylating agents require special attention. Melphalan is absorbed erratically from the gastrointestinal tract, and food interferes with this absorption. For this reason, melphalan should be administered on an empty stomach, e.g., 1 hour before breakfast. (Food does not interfere with the absorption of prednisone, which is often given with breakfast.) The clearance of melphalan from the blood stream is delayed in patients with renal failure, leading to increased toxic effects; the initial dose of melphalan should be reduced in patients with a serum creatinine greater than 2.0 milligrams per deciliter. Cumulative hematologic toxic effects tends to develop with repeated courses of melphalan. If slow hematologic recovery prevents repeating a course of melphalan at 6 to 7 week intervals, consideration should be given to switching to cyclophosphamide, which allows more rapid marrow recovery.

Because melphalan is absorbed so erratically, the dose should be increased until mild hematologic toxic effects, or a response, is observed. In patients with normal renal function, the usual starting dose is 0.25 milligrams per kilogram per day for 4 days, repeated at 4 to 6 weeks. If no hematologic toxic effects or response is observed, the dose should be increased by 2 to 4 milligrams per day for 4 days, and blood counts should be repeated weekly. The dose of melphalan is increased in subsequent courses until mild leukopenia or thrombocytopenia is observed, with recovery in 4 to 6 weeks.

Cyclophosphamide, in contrast to melphalan, is absorbed well, and clearance from the blood stream does not influence its toxic effects. Also, the dose of cyclophosphamide does not have to be reduced in patients with renal insufficiency. Cyclophosphamide is less toxic to thrombopoiesis than melphalan, and may be preferred in the treatment of thrombocytopenic patients.

Combinations of alkylating agents and prednisone, given simultaneously or alternately, have not proven to be superior to therapy with MP.^10,19-21;²²[Level of evidence: 1iiA] A meta-analysis of studies comparing melphalan plus prednisone with drug combinations concluded that both forms of treatment were equally effective.²³[Level of evidence: 1iiA] Patients who relapsed after initial therapy with cyclophosphamide and prednisone had no difference in overall survival (median 17 months) when randomized to VBMCP or VAD.²⁴

Myeloma patients who respond to treatment show a progressive fall in the M- protein until a plateau is reached; subsequent treatment with conventional doses does not result in any further improvement. This has led investigators to question how long treatment should be continued. Three clinical trials considered the role of maintenance therapy;^25-27 all found no improvement in survival. In a single study,²⁷ it was observed that maintenance therapy with MP prolonged the initial remission duration (31 months) compared to no maintenance treatment (23 months). There was no effect on overall survival, however, because the majority of patients who relapsed in the no maintenance arm responded again to MP, while those on maintenance MP did not respond to further treatment. Most therapists recommend continuing induction therapy for at least 12 months. The Canadian group ²⁷ suggests that induction chemotherapy be continued as long as the M-protein continues to fall; therapy can be discontinued after the M-protein reaches a plateau that remains stable for 4 months.

Maintenance interferon alfa therapy has been reported in several studies to prolong initial remission duration.^28-31 The slight improvement in overall survival initially reported for the Italian study ²⁸ disappeared on further follow-up. Five other randomized studies of interferon maintenance in responders to alkylator-based chemotherapy have been performed. Doses of interferon have ranged from 2 to 5 million units 3 times per week. Response duration was improved in 3 out of 6 studies; however, overall survival was improved in only a single study (with borderline significance).^28-33 Interferon maintenance should not be considered standard therapy for myeloma. In this population, toxic effects may be substantial and must be balanced against the potential benefits in response duration.³⁴

Lytic lesions of the spine should be irradiated if they are associated with an extramedullary (paraspinal) plasmacytoma, if there is painful destruction of a vertebral body, or if there is computed tomography or MRI evidence of spinal cord compression.

Back pain caused by osteoporosis and small compression fractures of the vertebrae responds best to chemotherapy. Extensive radiation of the spine or long bones for diffuse osteoporosis may lead to prolonged suppression of hemopoiesis, and is rarely indicated.³⁵ Bisphosphonates ¹⁸ or gallium nitrate ³⁶ may be useful for slowing or reversing the osteopenia that is so common in myeloma patients.

High-dose chemotherapy options for symptomatic myeloma

The failure of conventional chemotherapy to cure the disease has led investigators to test the effectiveness of much higher doses of drugs such as melphalan. The development of techniques for harvesting hemopoietic stem cells, from marrow aspirates or the peripheral blood of the patient, and infusing these cells to promote hemopoietic recovery, made it possible for investigators to test very large doses of melphalan. From the experience with thousands of patients treated in this way, it is possible to draw a few conclusions:

1. The risk of early death due to treatment-related toxic effects have been reduced to less than 5%.³⁷ Patients can now be treated as outpatients.
   
2. High-dose therapy should be reserved for myeloma patients who are still responsive to chemotherapy. Patients with refractory myeloma rarely achieve a complete response to high-dose treatment, and responses are usually brief.³⁸
   
3. Extensive prior chemotherapy, especially with alkylating agents, compromises marrow hemapoieses and may make the harvesting of adequate numbers of hemopoietic stem cells impossible.
   
4. After autologous bone marrow transplantation, 84 patients were randomized to receive maintenance interferon or no treatment.³⁹[Level of evidence: 1iiA] The interferon group had longer progression-free survival (46 months versus 27 months, p<0.025) and overall survival (75% versus 50%, p<0.01). These results have not been confirmed after peripheral stem cell transplantation.
   
5. Newly diagnosed patients with progressive disease should be considered candidates for clinical trials of new approaches to treatment.⁴⁰
   
6. Younger patients in good health tolerate high-dose therapy better than patients with poor performance status.³⁷

The Intergroupe Francais du Myelome randomized 200 previously untreated myeloma patients under 65 years of age to treatment with conventional chemotherapy (alternating courses of VMCP/VBAP) versus high-dose therapy (140 milligrams melphalan per meter squared and total body irradiation, 8 Gy delivered in 4 fractions over 4 days with no lung shielding, followed by autologous bone marrow rescue). Survival and disease-free survival were significantly improved in the high-dose arm (the estimated 5-year survival was 52% versus 12%; the estimated 5-year event-free survival was 28% versus 10%).⁴¹[Level of evidence: 1iiA] Relapses, however, continue to occur at a constant rate, so that at 5 years, only 28% of those receiving high-dose therapy, and 10% of those on conventional chemotherapy have not relapsed. Event-free survival is significantly better for the high-dose group (p=0.01), but there is no sign of a slowing in the relapse rate, or a plateau, to suggest that any of these patients have been cured.⁴¹ While this study suggests that myeloablative therapy with autologous transplant may prolong survival for patients with multiple myeloma, the finding requires confirmation by the current ongoing intergroup study comparing standard therapy to high-dose options. Appropriate patients should consider enrolling in this important trial.⁴⁰

In a registry of 162 patients who underwent allogeneic matched sibling-donor transplants, the actuarial overall survival rate was 28% at 7 years.⁴²[Level of evidence: 3iiiA] Favorable prognostic features included low tumor burden, responsive disease before transplant, and application of transplantation after first-line therapy. Many patients are not young enough or healthy enough to undergo these intensive approaches. A definite graft-versus-myeloma effect has been demonstrated, including regression of myeloma relapses following the infusion of donor lymphocytes.^43-45 Allogeneic marrow transplants are too risky to be considered by most patients, but the possibility of a potent, and possibly curative graft-versus-myeloma reaction makes this procedure attractive. Further research is required to make allogeneic transplants less dangerous, and also, perhaps, to find methods for initiating an autoimmune response to the myeloma cells.

References:

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2. Billadeau D, Van Ness B, Kimlinger T, et al.: Clonal circulating cells are common in plasma cell proliferative disorders: a comparison of monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma. Blood 88(1): 289-296, 1996.
3. Riches PG, Sheldon J, Smith AM, et al.: Overestimation of monoclonal immunoglobulin by immunochemical methods. Annals of Clinical Biochemistry 28(Pt. 3): 253-259, 1991.
4. Gertz MA, Li CY, Shirahama T, et al.: Utility of subcutaneous fat aspiration for the diagnosis of systemic amyloidosis (immunoglobulin light chain). Archives of Internal Medicine 148(4): 929-933, 1988.
5. Greipp PR: Advances in the diagnosis and management of myeloma. Seminars in Hematology 29(3, Suppl 2): 24-45, 1992.
6. Durie BG, Stock-Novack DL, Salmon SE, et al: Prognostic value of pretreatment serum beta-2 microglobulin in myeloma: A Southwest Oncology Group Study. Blood 75(4): 823-830, 1990.
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9. Hjorth M, Hellquist L, Holmberg E, et al.: Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I: a randomized study. European Journal of Haematology 50(2): 95-102, 1993.
10. Peest D, Deicher H, Coldewey R, et al.: Induction and maintenance therapy in multiple myeloma: a multicenter trial of MP versus VCMP. European Journal of Cancer and Clinical Oncology 24(6): 1061-1067, 1988.
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13. Segeren CM, Sonneveld P, Van Der Holt B, et al.: Vincristine, doxorubicin, and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. British Journal of Haematology 105(1): 127-130, 1999.
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16. Case DC, Lee BJ, Clarkson BD: Improved survival times in multiple myeloma treated with melphalan, prednisone, cyclophosphamide, vincristine and BCNU: M-2 protocol. American Journal of Medicine 63(6): 897-903, 1977.
17. Durie BG, Dixon DO, Carter S, et al.: Improved survival duration with combination chemotherapy induction for multiple myeloma: a Southwest Oncology Group Study. Journal of Clinical Oncology 4(8): 1227-1237, 1986.
18. Berenson JR, Lichtenstein A, Porter L, et al.: Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Journal of Clinical Oncology 16(2): 593-602, 1998.
19. Pavlovsky S, Corrado C, Santarelli MT, et al.: An update of two randomized trials in previously untreated multiple myeloma comparing melphalan and prednisone versus three- and five-drug combinations: an Argentine Group for the Treatment of Acute Leukemia study. Journal of Clinical Oncology 6(5): 769-775, 1988.
20. Blade J, San Miguel JF, Alcala A, et al.: Alternating combination VCMP/VBAP chemotherapy versus melphalan/prednisone in the treatment of multiple myeloma: a randomized multicentric study of 487 patients. Journal of Clinical Oncology 11(6): 1165-1171, 1993.
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28. Mandelli F, Avvisati G, Amadori S, et al.: Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy. New England Journal of Medicine 322(20): 1430-1434, 1990.
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30. Osterborg A, Bjorkholm M, Bjoreman M, et al.: Natural interferon-alpha in combination with melphalan/prednisone versus melphalan/prednisone in the treatment of multiple myeloma stages II and III: a randomized study from the Myeloma Group of Central Sweden. Blood 81(6): 1428-1434, 1993.
31. Browman GP, Bergsagel D, Sicheri D, et al.: Randomized trial of interferon maintenance in multiple myeloma: a study of the National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology 13(9): 2354-2360, 1995.
32. Nordic Myeloma Study Group: Interferon-alpha 2b added to melphalan-prednisone for initial and maintenance therapy in multiple myeloma: a randomized, controlled trial. Annals of Internal Medicine 124(2): 212-222, 1996.
33. Drayson MT, Dunn JA, Olujohungbe AB, et al.: Alpha 2B-interferon treatment used in plateau phase of multiple myeloma increases relapse free interval but not overall survival. Blood 88(suppl 10): A-2332, 586a, 1996.
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35. Catell D, Kogen Z, Donahue B, et al.: Multiple myeloma of an extremity: must the entire bone be treated? International Journal of Radiation Oncology, Biology, Physics 40(1): 117-119, 1998.
36. Warrell RP, Lovett D, Dilmanian FA, et al.: Low-dose gallium nitrate for prevention of osteolysis in myeloma: results of a pilot randomized study. Journal of Clinical Oncology 11(12): 2443-2450, 1993.
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43. Alyea EP, Schlossman RL, Canning C, et al.: CD8-depleted donor lymphocyte infusions mediate graft-versus multiple myeloma (MM) effect. Blood 88(suppl 10): A-1021, 258a, 1996.
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45. Verdonck LF, Lokhorst HM, Dekker AW, et al.: Graft-versus-myeloma effect in two cases. Lancet 347(9004): 800-801, 1996.

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