Current Therapy for Multiple Myeloma
2002; Elsevier BV; Volume: 77; Issue: 8 Linguagem: Inglês
10.4065/77.8.813
ISSN1942-5546
AutoresS. Vincent Rajkumar, Morie A. Gertz, Robert A. Kyle, Philip R. Greipp,
Tópico(s)Cancer therapeutics and mechanisms
ResumoMultiple myeloma is an incurable plasma cell malignancy that accounts for 10% of all hematologic cancers. For decades the mainstay of therapy has been the use of melphalan and prednisone; with this regimen, the median survival is approximately 3 years. Recently, important advances were made that have substantially altered the manner in which patients with myeloma are treated. Newly diagnosed patients with good performance status are now treated with autologous stem cell transplantation, resulting in improved survival. Because of the increasing use of transplantation as initial therapy, several therapeutic issues have emerged: the role of tandem transplantation, early vs delayed transplantation, and the role of allogeneic transplantation. The pronounced activity of thalidomide in patients with refractory myeloma represents another important advance. This has prompted the study of several novel agents in the treatment of myeloma, at least 2 of which appear promising. Supportive care measures also have improved, including the use of bisphosphonates to prevent osteolytic lesions. The purpose of this review is to summarize recent advances and provide an evidence-based approach to the treatment of multiple myeloma. Multiple myeloma is an incurable plasma cell malignancy that accounts for 10% of all hematologic cancers. For decades the mainstay of therapy has been the use of melphalan and prednisone; with this regimen, the median survival is approximately 3 years. Recently, important advances were made that have substantially altered the manner in which patients with myeloma are treated. Newly diagnosed patients with good performance status are now treated with autologous stem cell transplantation, resulting in improved survival. Because of the increasing use of transplantation as initial therapy, several therapeutic issues have emerged: the role of tandem transplantation, early vs delayed transplantation, and the role of allogeneic transplantation. The pronounced activity of thalidomide in patients with refractory myeloma represents another important advance. This has prompted the study of several novel agents in the treatment of myeloma, at least 2 of which appear promising. Supportive care measures also have improved, including the use of bisphosphonates to prevent osteolytic lesions. The purpose of this review is to summarize recent advances and provide an evidence-based approach to the treatment of multiple myeloma. Multiple myeloma is a clonal plasma cell disorder characterized by the presence of a monoclonal protein in the serum or urine, osteolytic lesions, increased plasma cells in the bone marrow, anemia, and hypercalcemia.1Bataille R Harousseau JL Multiple myeloma.N Engl J Med. 1997; 336: 1657-1664Crossref PubMed Scopus (498) Google Scholar It accounts for 1% of all malignancies and 10% of malignant hematologic neoplasms.1Bataille R Harousseau JL Multiple myeloma.N Engl J Med. 1997; 336: 1657-1664Crossref PubMed Scopus (498) Google Scholar, 2Jemal A Thomas A Murray T Thun M Cancer statistics, 2002 [published correction appears in CA Cancer J Clin. 2002;52:119].CA Cancer J Clin. 2002; 52: 23-47Crossref PubMed Scopus (2924) Google Scholar In 2002, approximately 14,600 new patients in the United States will be diagnosed as having myeloma, and more than 10,800 will die of the disease.2Jemal A Thomas A Murray T Thun M Cancer statistics, 2002 [published correction appears in CA Cancer J Clin. 2002;52:119].CA Cancer J Clin. 2002; 52: 23-47Crossref PubMed Scopus (2924) Google Scholar The annual incidence is approximately 4 per 100,000 population. The incidence rates in Europe are slightly lower: approximately 3 per 100,000 in the United Kingdom, Sweden, and the Netherlands and 2.5 per 100,000 in Denmark, France, and Spain.3Herrinton LJ Weiss NS Olshan AF The epidemiology of myeloma.in: Malpas JS Bergsagel DE Kyle RA Myeloma: Biology and Management. Oxford University Press, Oxford, England1995: 127-168Google Scholar The incidence is lower in Asian countries: less than 1 per 100,000 in China and the Philippines.3Herrinton LJ Weiss NS Olshan AF The epidemiology of myeloma.in: Malpas JS Bergsagel DE Kyle RA Myeloma: Biology and Management. Oxford University Press, Oxford, England1995: 127-168Google Scholar The incidence in black persons is almost twice that of white persons. At present, there is no cure for myeloma, and median survival with standard therapy is approximately 3 years. A state-of-the-art, evidence-based approach to the treatment of symptomatic, newly diagnosed multiple myeloma is presented in this review. Symptomatic multiple myeloma is defined by the presence of increased monoclonal plasma cells in the bone marrow, presence of a serum or urinary monoclonal protein, and symptoms related to 1 or more of the following features: osteolytic lesions, anemia, hypercalcemia, or renal failure. Other causes of anemia, renal failure, and hypercalcemia must be considered and excluded. A schematic approach to the management of patients with newly diagnosed, symptomatic multiple myeloma is shown in Figure 1. Of importance, a subset of patients may have mild anemia or small osteolytic lesions on skeletal survey, with minimal or no symptoms. These patients can be observed without therapy until definite evidence of progression, based on the results of 2 randomized trials that showed no significant improvement in overall survival in patients who received immediate treatment with melphalan plus prednisone compared with those who received treatment at progression.4Hjorth M Hellquist L Holmberg E Magnusson B Rodjer S Westin J Myeloma Group of Western Sweden Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I—a randomized study.Eur J Haematol. 1993; 50: 95-102Crossref PubMed Scopus (175) Google Scholar, 5Grignani G Gobbi PG Formisano R et al.A prognostic index for multiple myeloma.Br J Cancer. 1996; 73: 1101-1107Crossref PubMed Scopus (65) Google Scholar It is also based on the toxic effects of therapy and the fact that some patients may not experience disease progression for many months with no therapy.6Greipp PR Kyle RA Staging, kinetics, and prognosis of multiple myeloma.in: Wiernik PH Canellos GP Dutcher JP Kyle RA Neoplastic Diseases of the Blood. 3rd ed. Churchill Livingstone, New York, NY1996: 537-559Google Scholar, 7Kyle RA Greipp PR Smoldering multiple myeloma.N Engl J Med. 1980; 302: 1347-1349Crossref PubMed Scopus (329) Google Scholar Once a decision is made that therapy is indicated, the next issue is to determine whether the patient is a candidate for autologous stem cell transplantation because survival is superior with this strategy.8Attal M Harousseau J-L Stoppa A-M Intergroupe Français du Myélome et al.A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma.N Engl J Med. 1996; 335: 91-97Crossref PubMed Scopus (2589) Google Scholar Patients who are not candidates for autologous stem cell transplantation because of advanced age, poor performance status, pronounced renal failure, or comorbidity should receive standard-dose alkylator-based therapy with melphalan (an alkylating agent) and prednisone or a suitable alternative therapeutic regimen. The rest of the patients are treated with early or delayed autologous stem cell transplantation. For decades, the simple oral regimen of melphalan plus prednisone has remained the cornerstone of therapy for myeloma. The overall response rate with this regimen is about 50%.9Myeloma Trialists' Collaborative GroupCombination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials.J Clin Oncol. 1998; 16: 3832-3842Crossref PubMed Scopus (537) Google Scholar Melphalan is administered orally at a dose of 0.15 mg/kg daily for 7 days. Prednisone is administered orally at a dose of 60 mg/d during the same 7 days. The treatment is repeated every 6 weeks. An alternative schedule is to administer melphalan, 9 mg/m2 per day, for 4 days in combination with prednisone, 100 mg/d, on the same 4 days, with the treatment repeated every 4 weeks. The white blood cell count and platelet count must be obtained 2 to 3 weeks after initiation of therapy and before re-treatment. Based on these counts, the dose of melphalan for subsequent cycles is adjusted to produce mild cytopenia at mid cycle. Patients are treated in this manner for 1 year or up to 6 months after a plateau phase has been achieved. The complete response (CR) rate with this strategy is less than 10%, and the median survival is about 3 years.10Kovacsovics TJ Delaly A Intensive treatment strategies in multiple myeloma.Semin Hematol. 1997; 34: 49-60PubMed Google Scholar The 5-year survival rate is approximately 25%.9Myeloma Trialists' Collaborative GroupCombination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials.J Clin Oncol. 1998; 16: 3832-3842Crossref PubMed Scopus (537) Google Scholar Many investigators have sought to improve the results obtained with melphalan plus prednisone by using more complex multiagent chemotherapy. Unfortunately, these more aggressive combination chemotherapeutic regimens such as vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone (VBMCP) result in superior response rates (60%-70%) but no substantial survival benefit.9Myeloma Trialists' Collaborative GroupCombination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials.J Clin Oncol. 1998; 16: 3832-3842Crossref PubMed Scopus (537) Google Scholar, 11Alexanian R Dimopoulos M The treatment of multiple myeloma.N Engl J Med. 1994; 330: 484-489Crossref PubMed Scopus (367) Google Scholar, 12Oken MM Harrington DP Abramson N Kyle RA Knospe W Glick JH Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and pred-nisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479.Cancer. 1997; 79: 1561-1567Crossref PubMed Scopus (83) Google Scholar Similarly, the addition of interferon to initial therapy produces slightly better response rates with no clinically meaningful improvement in survival.13Myeloma Trialists' Collaborative GroupInterferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients.Br J Haematol. 2001; 113: 1020-1034Crossref PubMed Scopus (216) Google Scholar As a result, melphalan and prednisone remain the best choice for initial therapy for patients who are not candidates for stem cell transplantation. Alternatives to melphalan and prednisone are useful when a more rapid reduction of tumor burden is needed or when melphalan and prednisone are ineffective. A good alternative is VBMCP, as is the regimen of vincristine, doxorubicin (Adriamycin), and dexamethasone (VAD).14Alexanian R Barlogie B Tucker S VAD-based regimens as primary treatment for multiple myeloma.Am J Hematol. 1990; 33: 86-89Crossref PubMed Scopus (266) Google Scholar High-dose dexamethasone alone produces a response in 45% of patients with myeloma.15Alexanian R Dimopoulos MA Delasalle K Barlogie B Primary dexamethasone treatment of multiple myeloma.Blood. 1992; 80: 887-890Crossref PubMed Google Scholar It is thought that highdose dexamethasone accounts for most of the activity of the VAD regimen, with much less toxicity. Dexamethasone is administered at a dose of 40 mg/d orally on days 1 through 4, 9 through 12, and 17 through 20 every 5 weeks. Dexamethasone has the advantage over melphalan of not causing alky lator-mediated stem cell damage. However, toxicity may be higher, including severe proximal muscle weakness and increased risk of opportunistic infections. High-dose therapy followed by autologous stem cell transplantation improves response rate and survival in patients with myeloma, but the strategy is not curative.16Harousseau JL Attal M The role of autologous hematopoietic stem cell transplantation in multiple myeloma.Semin Hematol. 1997; 34: 61-66PubMed Google Scholar, 17Barlogie B Jagannath S Epstein J et al.Biology and therapy of multiple myeloma in 1996.Semin Hematol. 1997; 34: 67-72PubMed Google Scholar, 18Gertz MA Pineda AA Chen MG et al.Refractory and relapsing multiple myeloma treated by blood stem cell transplantation.Am J Med Sci. 1995; 309: 152-161Crossref PubMed Scopus (17) Google Scholar Response rates exceed 75% to 90%,10Kovacsovics TJ Delaly A Intensive treatment strategies in multiple myeloma.Semin Hematol. 1997; 34: 49-60PubMed Google Scholar, 11Alexanian R Dimopoulos M The treatment of multiple myeloma.N Engl J Med. 1994; 330: 484-489Crossref PubMed Scopus (367) Google Scholar and CR rates range from 20% to 40%.8Attal M Harousseau J-L Stoppa A-M Intergroupe Français du Myélome et al.A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma.N Engl J Med. 1996; 335: 91-97Crossref PubMed Scopus (2589) Google Scholar, 17Barlogie B Jagannath S Epstein J et al.Biology and therapy of multiple myeloma in 1996.Semin Hematol. 1997; 34: 67-72PubMed Google Scholar A French randomized trial in 200 previously untreated patients with myeloma showed improved survival with autologous bone marrow transplantation compared with conventional chemotherapy, with 5-year survival rates of 52% and 12%, respectively.8Attal M Harousseau J-L Stoppa A-M Intergroupe Français du Myélome et al.A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma.N Engl J Med. 1996; 335: 91-97Crossref PubMed Scopus (2589) Google Scholar Thus, the current standard of care is autologous stem cell transplantation for eligible patients younger than 65 years with good performance status and adequate renal function. Preliminary data from a recent randomized trial by the Spanish Cooperative Group have not yet confirmed a similar difference in overall survival.19Blade J Sureda A Ribera JM et al.High-dose therapy autotransplantation/intensification vs continued conventional chemotherapy in multiple myeloma patients responding to initial treatment chemotherapy: results of a prospective randomized trial from the Spanish Cooperative Group PETHEMA [abstract].Blood. 2001; 98 (Abstract 3386.): 815aGoogle Scholar Based on this study and others, there are concerns regarding the true efficacy of stem cell transplantation, especially with the emergence of novel active agents such as thalidomide and the proteasome inhibitor PS-341. Age older than 65 years alone is not a contraindication for transplantation.20Siegel DS Desikan KR Mehta J et al.Age is not a prognostic variable with autotransplants for multiple myeloma.Blood. 1999; 93: 51-54PubMed Google Scholar Such patients are candidates for transplantation if they have good functional status and limited comorbidity. The process of transplantation involves 3 to 4 cycles of induction therapy to minimize tumor burden, then peripheral blood stem cell collection using apheresis techniques (harvest), followed by high-dose myeloablative therapy (conditioning regimen), and finally reinfusion of stem cells (rescue). Peripheral blood stem cells are preferred over bone marrow because they result in more rapid engraftment and minimize discomfort to the patient compared with that from bone marrow collection. The standard conditioning regimen is melphalan, 200 mg/m2. Total body irradiation is not used, based on the results of a French randomized trial showing increased toxicity with no significant survival benefit.21Moreau P Facon T Attal M Intergroupe Francophone du Myélome et al.Comparison of 200 mg/m2 melphalan and 8 Gy total body irradiation plus 140 mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial.Blood. 2002; 99: 731-735Crossref PubMed Scopus (453) Google Scholar Similarly, stem cells are not purged of contaminating myeloma cells or enriched for CD34+ cells, based on the results of a large randomized trial that showed no clinical benefit.22Stewart AK Vescio R Schiller G et al.Purging of autologous peripheral-blood stem cells using CD34 selection does not improve overall or progression-free survival after high-dose chemotherapy for multiple myeloma: results of a multicenter randomized controlled trial.J Clin Oncol. 2001; 19: 3771-3779Crossref PubMed Scopus (173) Google Scholar Controversial issues in the treatment of myeloma with stem cell transplantation are discussed subsequently. Optimum Pretransplantation Induction Regimen.—Although infusional VAD is considered the standard pretransplantation induction therapy, it is cumbersome to administer and is associated with substantial toxicity. Lack of response to initial VAD (primary refractory disease) does not portend poor survival after transplantation, and patients are treated with transplantation regardless of response status to VAD.23Rajkumar SV Fonseca R Lacy MQ et al.Autologous stem cell transplantation for relapsed and primary refractory myeloma.Bone Marrow Transplant. 1999; 23: 1267-1272Crossref PubMed Scopus (58) Google Scholar, 24Singhal S Powles R Sirohi B Treleaven J Mehta J Response to induction chemotherapy is not essential to obtain survival benefit from high-dose melphalan and autotransplantation in myeloma [abstract].Blood. 2001; 98 (Abstract 3390.): 816aGoogle Scholar The best strategy for managing patients who have progressive disease with induction therapy is unclear. Alternative induction regimens with new agents may be an option and need to be studied. It is clear that dexamethasone accounts for a significant proportion of the activity of VAD, and although the response rate may be lower, there is no effect on overall survival.15Alexanian R Dimopoulos MA Delasalle K Barlogie B Primary dexamethasone treatment of multiple myeloma.Blood. 1992; 80: 887-890Crossref PubMed Google Scholar There is no difference in engraftment or stem cell collection with dexamethasone alone compared with VAD.25Anagnostopoulos A Aleman A Williams P et al.Autologous stem cell transplantation (ASCT) after nonmyelosuppressive induction therapy with dexamethasone alone is safe and effective for newly diagnosed multiple myeloma (MM) pts who receive high dose chemotherapy (HDC) [abstract].Blood. 2001; 98 (Abstract 2858.): 683aGoogle Scholar Therefore, dexamethasone is an appropriate alternative to VAD as pretransplantation induction therapy. Recently, there was interest in thalidomide as induction therapy. A Mayo Clinic study of 50 patients with previously untreated myeloma showed a response rate of 64% with use of the combination of low-dose thalidomide (200 mg/d) and pulsed dexamethasone.26Rajkumar SV Hayman SR Gertz MA et al.Combination therapy with thalidomide plus dexamethasone (Thal/Dex) for newly diagnosed myeloma (MM) [abstract].Blood. 2001; 98 (Abstract 3525.): 849aGoogle Scholar This regimen may be a suitable oral alternative to infusional chemotherapy with VAD as initial treatment of myeloma in preparation for stem cell transplantation. An Eastern Cooperative Oncology Group randomized phase 3 trial of thalidomide plus dexamethasone vs dexamethasone alone as induction therapy for newly diagnosed myeloma is ongoing in the United States (P.R.G., oral communication, June 2002). Prolonged alkylator therapy before transplantation results in poor engraftment. Hence, alkylating agents should be avoided in patients who are candidates for stem cell transplantation.27Goldschmidt H Hegenbart U Wallmeier M Hohaus S Haas R Factors influencing collection of peripheral blood progenitor cells following high-dose cyclophosphamide and granulocyte colony-stimulating factor in patients with multiple myeloma.Br J Haematol. 1997; 98: 736-744Crossref PubMed Scopus (105) Google Scholar, 28Kroger N Zeller W Hassan HT et al.Successful mobilization of peripheral blood stem cells in heavily pretreated myeloma patients with G-CSF alone.Ann Hematol. 1998; 76: 257-262Crossref PubMed Scopus (34) Google Scholar Early vs Delayed Transplantation.—Autologous stem cell transplantation for myeloma is often performed early in the course of the disease, after 3 to 4 cycles of induction chemotherapy. However, it is possible to delay transplantation until relapse without compromising survival, provided hematopoietic stem cells are harvested and cryopreserved early in the course of disease before alkylator therapy. Data from 2 French randomized trials that compared early vs delayed transplantation indicate no significant difference in outcome between the 2 strategies.29Fermand JP Ravaud P Chevret S et al.High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? results of a multicenter sequential randomized clinical trial.Blood. 1998; 92: 3131-3136PubMed Google Scholar, 30Facon T Mary JY Harousseau JL et al.Front-line or rescue autologous bone marrow transplantation (ABMT) following a first course of high dose melphalan (HDM) in multiple myeloma (MM): preliminary results of a prospective randomized trial (CIAM protocol) [abstract].Blood. 1996; 88 (Abstract 2729.): 685aGoogle Scholar The results of another large US multicenter randomized trial addressing this issue were recently obtained, analysis of which is awaited (P.R.G., oral communication, June 2002). The choice between the 2 options currently is based on patient preference and other clinical conditions and risk factors. Single vs Tandem Transplantation.—At present the role of tandem (double) transplantation in myeloma is unclear. With tandem transplantation, patients receive a second planned transplant after recovery from the first procedure. Barlogie et al31Barlogie B Jagannath S Vesole DH et al.Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma.Blood. 1997; 89: 789-793PubMed Google Scholar, 32Vesole 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: 950-956PubMed Google Scholar, 33Tricot G Jagannath S Vesole DH et al.Hematopoietic stem cell transplants for multiple myeloma.Leuk Lymphoma. 1996; 22: 25-36Crossref PubMed Scopus (20) Google Scholar, 34Desikan R Barlogie B Sawyer J et al.Results of high-dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities.Blood. 2000; 95: 4008-4010PubMed Google Scholar at the University of Arkansas advocate tandem autologous stem cell transplantation to improve CR rates and survival. In a study of 231 patients with newly diagnosed myeloma, they showed that more than 70% of patients are able to go through induction therapy and both transplantations successfully.35Barlogie B Jagannath S Desikan KR et al.Total therapy with tandem transplants for newly diagnosed multiple myeloma.Blood. 1999; 93: 55-65PubMed Google Scholar The mortality rates were 3% during induction, 1% with the first transplant, and 4% with the second transplant. With use of an intent-to-treat analysis, the CR rate was 26% with the first transplant and 41% after the second transplantation. Overall survival with this approach was 68 months. These results have prompted several studies of tandem stem cell transplantation in myeloma. Preliminary data from 4 different randomized trials on this treatment strategy were presented recently.36Dalton WS Bergsagel PL Kuehl WM Anderson KC Harousseau JL Multiple myeloma.Hematology (Am Soc Hematol Educ Program). 2001; : 157-177Crossref PubMed Scopus (49) Google Scholar These trials indicate a slight increase in response rates and possibly event-free survival with tandem transplantation. However, only 1 of the 4 trials has thus far shown any improvement in overall survival with tandem transplantation.36Dalton WS Bergsagel PL Kuehl WM Anderson KC Harousseau JL Multiple myeloma.Hematology (Am Soc Hematol Educ Program). 2001; : 157-177Crossref PubMed Scopus (49) Google Scholar The final results of these trials will clarify this important issue. Because the role of tandem transplantation is not settled, it is wise to harvest enough stem cells for 2 transplantations. At Mayo Clinic, Rochester, Minn, a single transplantation is done with half of the stem cells collected, and the other half are cryopreserved for transplantation at relapse. A recent study by Sirohi et al37Sirohi B Powles R Singhal S et al.High-dose melphalan and second autografts for myeloma relapsing after one autograft: results equivalent to tandem autotransplantation [abstract].Blood. 2001; 98 (Abstract 1690.): 402aGoogle Scholar suggests that this strategy produces results equivalent to those reported with tandem transplantation. Role of Allogeneic Transplantation.—Autologous stem cell transplantation has 2 drawbacks. First, the harvested stem cells are inevitably contaminated by tumor cells. Second, there is no possibility of an immunologically mediated graft-vs-myeloma effect. Allogeneic transplantation eliminates the problem of tumor cell contamination of the stem cells. Furthermore, using donor lymphocyte infusions, several investigators found a graft-vs-myeloma effect in myeloma with allografting.38Cavo M Benni M Cirio TM Gozzetti A Tura S Allogeneic bone marrow transplantation for the treatment of multiple myeloma: an overview of published reports.Stem Cells. 1995; 13: 126-131PubMed Google Scholar, 39Tura S Cavo M Allogeneic bone marrow transplantation in multiple myeloma.Hematol Oncol Clin North Am. 1992; 6: 425-435PubMed Google Scholar, 40Lokhorst HM Schattenberg A Cornelissen JJ Thomas LL Verdonck LF Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation.Blood. 1997; 90: 4206-4211PubMed Google Scholar Studies show that allogeneic transplantation leads to prolonged disease-free survival in a relatively small percentage of patients.41Bensinger WI Buckner CD Anasetti C et al.Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome.Blood. 1996; 88: 2787-2793PubMed Google Scholar, 42Cavo M Bandini G Benni M et al.High-dose busulfan and cyclophosphamide are an effective conditioning regimen for allogeneic bone marrow transplantation in chemosensitive multiple myeloma.Bone Marrow Transplant. 1998; 22: 27-32Crossref PubMed Scopus (55) Google Scholar However, the high treatment-related mortality rate (approximately 30%) and significant toxicity from graft-vs-host disease (GVHD) have limited the role of this procedure in the treatment of myeloma. As a result, we rarely recommend conventional allogeneic bone marrow transplantation for the treatment of myeloma. There is interest in studying nonmyeloablative ("mini") allogeneic transplantation for selected patients with myeloma, either immediately after autologous stem cell transplantation43Molina A Sahebi F Maloney DG et al.Non-myeloablative peripheral blood stem cell (PBSC) allografts following cytoreductive autotransplants for treatment of multiple myeloma (MM) [abstract].Blood. 2000; 96 (Abstract 2063.): 480aGoogle Scholar or at relapse. Maloney et al44Maloney DG Sahebi F Stockerl-Goldstein KE et al.Combining an allogeneic graft-vs-myeloma effect with high-dose autologous stem cell rescue in the treatment of multiple myeloma [abstract].Blood. 2001; 98 (Abstract 1822.): 435aGoogle Scholar recently reported results in 32 patients treated with autologous stem cell transplantation followed by a nonmyeloablative allogeneic transplantation. They used melphalan, 200 mg/m2, as the conditioning regimen for autologous transplantation and mycophenolate, cyclosporine, and total body irradiation (200 cGy) as conditioning agents for the nonmyeloablative allogeneic transplantation. All allografts were from HLA-identical sibling donors. The response rate to therapy was 84%, with a relatively low day-100 treatment-related mortality rate of 6%. However, the high incidences of acute (45%) and chronic (55%) GVHD tempered enthusiasm for this approach. A recent study by Badros et al45Badros A Barlogie B Siegel E et al.Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning.J Clin Oncol. 2002; 20: 1295-1303Crossref PubMed Scopus (172) Google Scholar also confirmed the high incidence of GVHD with this approach, with rates of 58% for acute GVHD and 29% for chronic GVHD. Treatment-related mortality was 29%. Until further refinements are made and additional confirmatory studies are completed, the role of allogeneic stem cell transplantation as initial therapy for myeloma must be considered investigational. The role of maintenance therapy after either conventional-dose melphalan plus prednisone therapy or stem cell transplantation is investigational. Several studies show that interferon alfa as maintenance therapy prolongs the plateau phase in patients with myeloma.46Shustik C Interferon in the treatment of multiple myeloma.Cancer Control. 1998; 5: 226-234PubMed Google Scholar, 47Mandelli 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: 1430-1434Crossref PubMed Scopus (331) Google Scholar, 48Browman 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.J Clin Oncol. 1995; 13: 2354-2360Crossref PubMed Scopus (93) Google Scholar, 49Westin J
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