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Multiple Myeloma

Treatment Recommendations

  • Practical Therapeutics
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Summary

Multiple myeloma is a relatively common B cell neoplasm seen more frequently in older patients. Most patients require treatment at the time of diagnosis; however, asymptomatic patients with good prognostic factors may be safely observed, sometimes for extended periods, without chemotherapy. Several recently developed prognostic factors, in particular β2-microglobulin, have improved our ability to predict clinical outcome.

Traditional chemotherapy with intermittent oral melphalan plus prednisone can induce remissions in approximately 50% of patients. More aggressive multi-agent combination chemotherapy regimens can produce higher response rates compared with oral melphalan/prednisone, but whether this results in a survival benefit remains controversial.

All patients treated with conventional dose chemotherapy will eventually relapse. Maintenance therapy with interferon-α can prolong the duration of remissions. Relapse is associated with more aggressive, less responsive, disease. Conventional salvage therapies are effective in the minority of patients, and responses are short lived. High dose chemotherapy, with or without total body irradiation, followed by autologous bone marrow or peripheral stem cell transplantation can induce remissions in some patients who have relapsed or whose disease is refractory to conventional salvage chemotherapy. Unfortunately, these responses are usually not durable.

The results of autologous transplantation in a more favourable group of previously untreated or minimally treated patients have been encouraging. Increased response rates, more durable remissions and, probably, improved survival compared with conventional dose chemotherapy have been demonstrated. Further study is needed to determine if autologous transplantation will cure patients with myeloma. Allogeneic bone marrow transplantation, although of limited applicability and associated with high treatment-related mortality, has the greatest potential to provide patients with long term survival.

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References

  1. Berenson J, Wong R, Kim K, et al. Evidence for peripheral blood B lymphocyte but not T lymphocyte involvement in multiple myeloma. Blood 1987; 70: 1550–3

    PubMed  CAS  Google Scholar 

  2. Mellstedt H, Holm G, Pettersson D, et al. Idiotype-bearing lymphoid cells in plasma cell neoplasia. Clin Haematol 1982; 11: 65–85

    PubMed  CAS  Google Scholar 

  3. Wingo PA, Tong T, Bolden S. Cancer statistics, 1995. CA Cancer J Clin 1995; 45: 8–30

    Article  PubMed  CAS  Google Scholar 

  4. Michaeli J, Durie BGM. Plasma cell disorders. In: Kelley WN, editor. Textbook of internal medicine. 2nd ed. Philadelphia: JB Lippincott, 1991: 1087–96

    Google Scholar 

  5. Niesvizky R, Siegel D, Michaeli J. Biology and treatment of multiple myeloma. Blood Rev 1993; 7: 24–33

    Article  PubMed  CAS  Google Scholar 

  6. Salmon SE, Cassady JR. Plasma cell neoplasms. In: De Vita Jr VT, Hellman S, Rosenberg SA, editors. Cancer principles and practice of oncology. Philadelphia: JB Lippincott, 1993: 1984–2025

    Google Scholar 

  7. Dimopoulos MA, Moulopoulos A, Smith T, et al. Risk of disease progression in asymptomatic multiple myeloma. Am J Med 1993; 94: 57–61

    Article  PubMed  CAS  Google Scholar 

  8. Hjorth M, Helquist L, Holmberg E, et al. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I — a randomized study. Eur J Haematol 1993; 50: 95–102

    Article  PubMed  CAS  Google Scholar 

  9. Moulopoulos LA, Dimopoulos MA, Smith TL, et al. Prognostic significance of magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 1995; 13: 251–6

    PubMed  CAS  Google Scholar 

  10. Durie BGM, Slock-Novack D, Salmon SE, et al. Prognostic value of pretreatment serum β2 microglobulin in myeloma: a Southwest Oncology Group study. Blood 1990; 75: 823–30

    PubMed  CAS  Google Scholar 

  11. Boccadoro M, Omede P, Roberto F, et al. Multiple myeloma: beta-2-microglobulin is not a useful follow-up parameter. Acta Haematol 1989; 82: 122–5

    Article  PubMed  CAS  Google Scholar 

  12. Greipp PR. Prognosis in myeloma. Mayo Clin Proc 1994; 69: 895–902

    Article  PubMed  CAS  Google Scholar 

  13. Dimopoulos M, Barlogie B, Smith T, et al. High serum lactate dehydrogenase level as a marker for drug resistance and short survival in multiple myeloma. Ann Intern Med 1991; 115: 931–5

    PubMed  CAS  Google Scholar 

  14. Ludwig H, Nachbaur DM, Fritz E, et al. IL-6 is a prognostic factor in multiple myeloma [letter]. Blood 1991; 77: 2794–5

    PubMed  CAS  Google Scholar 

  15. Bataille R, Jourdan M, Zhang XG, et al. Serum levels of interleukin-6, a potent myeloma cell growth factor, as a reflect of disease severity in plasma cell dyscrasias. J Clin Invest 1989; 84: 2008–11

    Article  PubMed  CAS  Google Scholar 

  16. Bataille R, Boccadoro M, Klein B, et al. C-reactive protein and β-2 microglobulin produce a simple and powerful myeloma staging system. Blood 1992; 80: 733–7

    PubMed  CAS  Google Scholar 

  17. Greipp PR, Gaillard JP, Klein B, et al. Independent prognostic value for plasma cell labeling index (PCLI), immunofluorescence microscopy plasma cell percent (IMPCP), beta 2 microglobulin (B2M), soluble interleukin-6 receptor (sIL-6R), and C-reactive protein in myeloma [abstract]. Blood 1994; 84 Suppl. 1: 385a

    Google Scholar 

  18. Kyrtsonis M-L, Dedousis GVZ, Papanastasiou C, et al. Soluble interleukin-6 receptor (sIL-6R) levels in serum of patients with multiple myeloma (MM) at diagnosis and during the course of the disease [abstract]. Blood 1995; 84 Suppl. 1: 178a

    Google Scholar 

  19. Cimino G, Avvisati G, Amadori S, et al. High serum IL-2 levels are predictive of prolonged survival in multiple myeloma. Br J Haematol 1990; 75: 373–7

    Article  PubMed  CAS  Google Scholar 

  20. Medical Research Council’s Working Party on Leukaemia in Adults. Report on the second myelomatosis trial after five years follow-up. Br J Cancer 1980; 42: 813–22

    Article  Google Scholar 

  21. Belch A, Shelley W, Bersagel D, et al. A randomized trial of maintenance versus no maintenance melphalan and prednisone in responding multiple myeloma patients. Br J Cancer 1988; 57: 94–9

    Article  PubMed  CAS  Google Scholar 

  22. Baccarani M, Fanin R, Fasola G, et al. Maintenance treatment of multiple myeloma. Eur J Haematol 1989; 43 Suppl. 51: 145–51

    Google Scholar 

  23. Bergsagel DE, Bailey AJ, Langley GR, et al. The chemotherapy of plasma-cell myeloma and the incidence of acute leukemia. N Engl J Med 1979; 301: 743–8

    Article  PubMed  CAS  Google Scholar 

  24. Salmon SE, Haut A, Bonnet JD, et al. Alternating combination chemotherapy and levamisole improves survival in multiple myeloma: a Southwest Oncology Group study. J Clin Oncol 1983; 1: 453–61

    PubMed  CAS  Google Scholar 

  25. Durie BGM, Dixon DO, Carter S, et al. Improved survival duration with combination chemotherapy induction for multiple myeloma: a Southwest Oncology Group study. J Clin Oncol 1986; 4: 1227–37

    PubMed  CAS  Google Scholar 

  26. Boccadoro M, Marmont F, Tribatto M, et al. Multiple myeloma: VMCP/VBAP alternating combination chemotherapy is not superior to melphalan and prednisone even in high-risk patients. J Clin Oncol 1991; 9: 444–8

    PubMed  CAS  Google Scholar 

  27. Case, DC, Lee BJ III, Clarkson BD. Improved survival times in multiple myeloma treated with melphalan, prednisone, cyclophosphamide, vincristine and BCNU: M-2 protocol. Am J Med 1977; 63: 897–903

    Article  PubMed  Google Scholar 

  28. MacLennan ICM, Chapman C, Dunn J, et al. Combined chemotherapy with ABCM versus melphalan for treatment of myelomatosis. Lancet 1992; 339: 200–5

    Article  PubMed  CAS  Google Scholar 

  29. Alexanian R, Barlogie B, Tucker S, et al. VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol 1990; 33: 86–9

    Article  PubMed  CAS  Google Scholar 

  30. Alexanian R, Dimopoulos MA, Delasalle K, et al. Primary dexamethasone treatment of multiple myeloma. Blood 1992; 80: 887–90

    PubMed  CAS  Google Scholar 

  31. Cooper MR, Mclntyre OR, Propert KJ, et al. Single, sequential, and multiple alkylating agent therapy for multiple myeloma: a CALGB study. J Clin Oncol 1986; 4: 1331–9

    PubMed  CAS  Google Scholar 

  32. Peest D, Deicher H, Coldeway R, et al. Induction and maintenance therapy in multiple myeloma: a multicenter trial of MP versus VCMP. Eur J Cancer Clin Oncol 1988; 24: 1061–7

    Article  PubMed  CAS  Google Scholar 

  33. Pavlovsky S, Saslavsky J, Tezanos M, et al. A randomized trial of melphalan and prednisone versus melphalan, prednisone, cyclophosphamide, MeCCNU, and vincristine in untreated multiple myeloma. J Clin Oncol 1984; 2: 836–40

    PubMed  CAS  Google Scholar 

  34. Blade J, San Miguel JF, Alvala A, et al. Alternating combination VCMP/VBAP chemotherapy versus melphalan/prednisone in the treatment of multiple myeloma: a randomized multicentric study of 487 patients. J Clin Oncol 1993; 11: 1165–71

    PubMed  CAS  Google Scholar 

  35. Oken MM, Tsiastis A, Abramson N, et al. Comparison of standard (MP) with intensive (VBMCP) therapy for the treatment of multiple myeloma [abstract]. Proc Am Soc Clin Oncol 1984; 3: 270

    Google Scholar 

  36. Hjorth M, Hellquist L, Holmberg E, et al. Initial treatment in multiple myeloma: no advantage of multidrug chemotherapy over melphalan-prednisone. Br J Haematol 1990; 74: 185–91

    Article  PubMed  CAS  Google Scholar 

  37. Gregory WM, Richards MA, Malpas JS. Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: an overview of published trials. J Clin Oncol 1992; 10: 334–42

    PubMed  CAS  Google Scholar 

  38. Oken MM. Standard treatment of multiple myeloma. Mayo Clin Proc 1994; 69: 781–6

    Article  PubMed  CAS  Google Scholar 

  39. Barlogie B, Smith, Alexanian R. Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med 1984; 310: 1353–6

    Article  PubMed  CAS  Google Scholar 

  40. Alexanian R, Barlogie B, Dixon D. High-dose glucocorticoid treatment of resistant myeloma. Ann Intern Med 1986; 105: 8–11

    PubMed  CAS  Google Scholar 

  41. Barlogie B, Velasquez WS, Alexanian R, et al. Etoposide, dexamethasone, cytarabine and cisplatin in vincristine, doxorubicin and dexamethasone-refractory myeloma. J Clin Oncol 1989; 7: 1514–7

    PubMed  CAS  Google Scholar 

  42. Ohrling M, Bjorkholm M, Osterborg A, et al. Etoposide, doxorubicin, cyclophosphamide and high-dose betamethasone (EACB) as outpatient salvage therapy for multiple myeloma. Eur J Haematol 1993; 51: 45–9

    Article  PubMed  CAS  Google Scholar 

  43. Blade J, San Miguel J, Sanz-Sanz MA, et al. Treatment of melphalan-resistant multiple myeloma with vincristine, BCNU, doxorubicin and high-dose dexamethasone (VBAD). Eur J Cancer 1992; 29A: 57–60

    PubMed  CAS  Google Scholar 

  44. McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukemia and myeloma. Lancet 1983; ii: 822–4

    Article  Google Scholar 

  45. Jagannath S, Barlogie B. Autologous bone marrow transplantation for multiple myeloma. Hematol Oncol Clin North Am 1992; 6: 437–49

    PubMed  CAS  Google Scholar 

  46. Harousseau JL, Milpied N, Jouet JP, et al. Intensive therapy for high grade myltiple myeloma (MM) [abstract]. Bone Marrow Transplant 1991; 7 Suppl. 2: 28–32

    PubMed  Google Scholar 

  47. Vesole DH, Barlogie B, Jagannath S, et al. High-dose therapy for refractory multiple myeloma: improved prognosis with better supportive care and double transplants. Blood 1994; 84: 950–6

    PubMed  CAS  Google Scholar 

  48. Barlogie B, Hall R, Zander A, et al. High-dose melphalan with autologous bone marrow transplantation for multiple myeloma. Blood 1986; 67: 1298–301

    PubMed  CAS  Google Scholar 

  49. Gore ME, Selby PJ, Viner C, et al. Intensive treatment of multiple myeloma and criteria for complete remission. Lancet 1989; ii: 879–81

    Article  Google Scholar 

  50. Ventura GJ, Barlogie B, Hester JP, et al. High dose cyclophosphamide, BCNU and VP-16 with autologous blood stem cell support for refractory multiple myeloma. Bone Marrow Transplant 1990; 5: 265–8

    PubMed  CAS  Google Scholar 

  51. Gahrton G, Tura S, Ljungman P, et al. Allogeneic bone marrow transplantation in multiple myeloma. N Engl J Med 1991; 325: 1267–73

    Article  PubMed  CAS  Google Scholar 

  52. Gahrton G, Tura S, Ljungman P, et al. Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol 1995; 13: 1312–22

    PubMed  CAS  Google Scholar 

  53. Lokhorst HM, Menwissen OJ, Verdonek LF, et al. High-risk multiple myeloma treated with high-dose melphalan. J Clin Oncol 1992; 10: 47–51

    PubMed  CAS  Google Scholar 

  54. Jagannath S, Barlogie B, Dicke K, et al. Autologous bone marrow transplantation in multiple myeloma: identification of prognostic factors. Blood 1990; 76: 1860–6

    PubMed  CAS  Google Scholar 

  55. Alexanian R, Dimopoulos M, Smith T, et al. Limited value of myeloablative therapy for late multiple myeloma. Blood 1994; 83: 512–6

    PubMed  CAS  Google Scholar 

  56. Alexanian R, Dimopoulos MA, Hester J, et al. Early myeloablative therapy for multiple myeloma. Blood 1994; 84: 4278–82

    PubMed  CAS  Google Scholar 

  57. Gianni AM, Tarella C, Bregni M, et al. High-dose sequential chemoradiotherapy, a widely applicable regimen, confers survival benefit to patients with high-risk multiple myeloma. J Clin Oncol 1994; 12: 503–9

    PubMed  CAS  Google Scholar 

  58. Attal M, Huguet F, Schlaifer D, et al. Intensive combined therapy for previously untreated aggressive myeloma. Blood 1992; 79: 1130–6

    PubMed  CAS  Google Scholar 

  59. Cunningham D, Paz-Aves L, Milan S, et al. High-dose melphalan and autologous bone marrow transplantation as consolidation in previously untreated myeloma. J Clin Oncol 1994; 12: 759–63

    PubMed  CAS  Google Scholar 

  60. Marit G, Boiron JM, Pico JL, et al. Autologous blood stem cell transplantation (ABSCT) in high-risk myeloma (MM) [abstract]. Bone Marrow Transplant 1991; 7 Suppl. 2: 29

    PubMed  Google Scholar 

  61. Fermand J-P, Chevret S, Ravand P, et al. High-dose chemoradiotherapy and autologous blood stem cell transplantation in multiple myeloma: results of a phase II trial involving 63 patients. Blood 1993; 82: 2005–9

    PubMed  CAS  Google Scholar 

  62. Attal M, Harousseau JL, Stoppa AM, et al. High dose therapy in multiple myeloma: a prospective randomized study of the ‘Intergroupe Francais du Myelome’ [abstract]. Blood 1994; 84: 3869

    Google Scholar 

  63. Barlogie B, Jagannath S, Vesole D, et al. Total therapy (TT) for newly diagnosed myltiple myeloma (MM) [abstract]. Blood 1993; 82 Suppl.: 198a

    Google Scholar 

  64. Sullivan PW, Salmon SE. Kinetics of tumor growth and regression in IgG multiple myeloma. J Clin Invest 1972; 51: 1697–708

    Article  PubMed  CAS  Google Scholar 

  65. Cunningham D, Paz-Aves L, Gore ME, et al. High-dose melphalan for multiple myeloma: long-term follow-up data. J Clin Oncol 1994; 12: 764–8

    PubMed  CAS  Google Scholar 

  66. Jagannath S, Vesole DH, Tricot G, et al. Hemopoietic stem cell transplants for multiple myeloma. Oncology 1994; 8: 89–103

    PubMed  CAS  Google Scholar 

  67. Anderson KC, Anderson J, Soiffer R, et al. Monoclonal antibody-purged bone marrow transplantation therapy for multiple myeloma. Blood 1993; 82: 2568–76

    PubMed  CAS  Google Scholar 

  68. Reece DE, Barnett MJ, Conners JM, et al. Treatment of multiple myeloma with intensive chemotherapy followed by autologous BMT using marrow purged with 4-hydroperoxycyclo-phosphamide. Bone Marrow Transplant 1993; 11: 139–46

    PubMed  CAS  Google Scholar 

  69. Barlogie B, Gahrton G. Bone marrow transplantation in multiple myeloma. Bone Marrow Transplant 1991; 7: 71–9

    PubMed  CAS  Google Scholar 

  70. Cavo M, Tura S, Rosti G, et al. Allogeneic BMT for multiple myeloma (MM): the Italian experience. Bone Marrow Transplant 1991; 7 Suppl. 2: 31

    PubMed  Google Scholar 

  71. Bensinger CD, Buckner RA, Clift FB, et al. Phase I study of busulfan and cyclophosphamide in preparation for allogeneic marrow transplant for patients with multiple myeloma. J Clin Oncol 1992; 10: 1492–7

    PubMed  CAS  Google Scholar 

  72. Avvisati G, Mandelli F. The role of interferon-α in the management of myelomatosis. Hematol Oncol Clin North Am 1992; 6: 395–405

    PubMed  CAS  Google Scholar 

  73. Cooper MR, Dear K, McIntyre OR, et al. A randomized clinical trial comparing melphalan/prednisone with or without interferon alfa-2b in newly diagnosed patients with multiple myeloma: a Cancer and Leukemia Group B study. J Clin Oncol 1993; 11: 155–60

    PubMed  CAS  Google Scholar 

  74. Osterborg A, Bjorkholm M, Bjoreman M, et al. Natural inter-feron-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 1993; 81: 1428–34

    PubMed  CAS  Google Scholar 

  75. Ludwig H, Cohen AM, Huber H, et al. Interferon alfa-2b with VMCP compared to VMCP alone for induction and interferon alfa-2b compared to controls for remission maintenance in multiple myeloma: interim results. Eur J Cancer 1991; 27 Suppl. 4: S40–S45

    PubMed  Google Scholar 

  76. Ludwig H, Cohen AM, Huber H, et al. Interferon (IFN) with VMCP compared to VMCP for induction and IFN compared to control for remission maintenance in multiple myeloma (MM) [abstract]. Proc Am Soc Clin Oncol 1994; 13: 408

    Google Scholar 

  77. Montuoro A, De Rosa L, De Blasio A, et al. Alpha-2a-interferon/melphalan/prednisone versus melphalan/prednisone in previously untreated patients with multiple myeloma. Br J Haematol 1990; 76: 365–8

    Article  PubMed  CAS  Google Scholar 

  78. Corrado C, Pavlovsky S, Saslasky J, et al. Randomized trial comparing melphalan-prednisone with or without recombinant alfa 2 interferon (r alpha2 INF) in multiple myeloma [abstract]. Proc Am Soc Clin Oncol 1989; 8: 258

    Google Scholar 

  79. Preis P, Scheithauer W, Fritz E, et al. VMCP chemotherapy with or without interferon-alpha-2 in newly diagnosed patients with multiple myeloma. Onkologie 1989; 12: 27–9

    Article  PubMed  CAS  Google Scholar 

  80. Westin J. Interferon therapy during the plateau phase of multiple myeloma: an update of a Swedish multicenter study. Semin Oncol 1991; 18: 37–40

    PubMed  CAS  Google Scholar 

  81. 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. N Engl J Med 1990; 322: 1430–4

    Article  PubMed  CAS  Google Scholar 

  82. Browman GP, Rubin S, Walker I, et al. Interferon α-2b (IFN) maintenance therapy prolongs progression-free and overall survival in plasma cell myeloma (PCM): results of a randomized trial [abstract]. Proc Am Soc Clin Oncol 1994; 13: 408

    Google Scholar 

  83. Weinstein RS. Bone involvement in multiple myeloma [editorial]. Am J Med 1992; 93: 591–4

    Article  PubMed  CAS  Google Scholar 

  84. Lantinen R, Laakso M, Palva I, et al. Randomized, placebo-controlled multicentre trial of clodronate in multiple myeloma. Lancet 1992; 340: 1049–52

    Article  Google Scholar 

  85. Clemens MR, Fessele K, Heim ME. Multiple myeloma: effect of daily dichloromethylene bisphosphonate on skeletal complications. Ann Hematol 1993; 66: 141–6

    Article  PubMed  CAS  Google Scholar 

  86. Thiebaud D, Leyvraz S, von Fliedner V, et al. Treatment of bone metastasis from breast cancer and myeloma with Pamidronate. Eur J Cancer 1991; 27: 37–41

    Article  PubMed  CAS  Google Scholar 

  87. van Breukelen FJM, Bijvoet OLM, van Oosterom AT, et al. Inhibition of osteolytic bone lesions by (3-amino-l-hydroxy-propylidene)-1, 1-bisphosphonate (A.P.D.). Lancet 1979; i: 803–5

    Article  Google Scholar 

  88. Warrell RP, Lovett D, Dilmanian A, et al. Low-dose gallium nitrate for prevention of osteolysis in myeloma: results of a pilot randomized study. J Clin Oncol 1993; 11: 2443–50

    PubMed  Google Scholar 

  89. Ludwig H, Fritz E, Kotzmann H, et al. Erythropoietin treatment of anemia associated with multiple myeloma. N Engl J Med 1990; 322: 1693–9

    Article  PubMed  CAS  Google Scholar 

  90. Sonneveld P, Schoester M, de Leeuw K. Clinical modulation of multidrug resistance in multiple myeloma: effect of cyclosporin on resistant tumor cells. J Clin Oncol 1994; 12: 1584–91

    PubMed  CAS  Google Scholar 

  91. Salmon SE, Dalton WS, Grogan TM, et al. Multidrug-resistant myeloma: laboratory and clinical effects of verapamil as a chemosensitizer. Blood 1991; 78: 44–50

    PubMed  CAS  Google Scholar 

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  1. Department of Medicine, Division of Hematologic/Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    C. Galen Choy, Ruben Niesvizky &  Joseph Michaeli

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Choy, C.G., Niesvizky, R. & Michaeli, J. Multiple Myeloma. Clin Immunother 4, 346–360 (1995). https://doi.org/10.1007/BF03259298

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