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Multiple Myeloma Updates 
  Submitted By: Mohamad Hussein, M.D.

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Article by:
Mohamad Hussein, M.D.
Director, Cleveland Clinic Myeloma Research Program

Bone marrow transplantation in the management of myeloma; where to next?

The psychology involved in utilizing stem cell transplant in the management of multiple myeloma is a two part process; physicians view the procedure as an aggressive proactive approach to a non curable disease, and thus the sense of disappointment when the procedure fails is not associate with a guilt feeling. On the other hand for patients and their families, the emotions are high, and such a procedure despite the outcome is viewed as resilience. The low morbidity, and the improved results with selected patients as well as the psychology described above are resulting in single bone marrow transplantation to be increasingly utilized in the management of MM. In a report of 77 patients with MM who fulfilled the criteria for transplant (age less than 66 years, stage II or III, good performance status, and disease responsive to initial chemotherapy) but who were treated with conventional chemotherapy, median survival was five years, which is similar to that seen for autologous stem cell transplantation [1]. A randomized trial by the French Myeloma Group compared high-dose chemotherapy and autologous bone marrow transplantation with conventional chemotherapy in 200 previously untreated myeloma patients under the age of 65 years [2]. Data were analyzed on an intention-to-treat basis in which 25% of the patients who were randomized to transplantation did not receive a transplant. The response rate (81% versus 57%) and complete responses (22% versus 5%) were superior in the transplant group. The five-year event free survival (28% versus 10% and overall survival 52% versus 12%) were superior in the transplant group. In the multivariate analysis of all 200 patients, event-free survival was significantly related to the level of 2-microglobulin in serum (P<0.001) and the treatment assignment (P =0.01). Overall survival was related only to the level of 2-microglobulin (P<0.001) suggesting that patient selection plays an important role in response and survival. Another issue in the use of autologous bone marrow transplantation is the timing of the transplant, i.e., early versus late. In a multicenter, sequential, randomized trial designed to assess the optimal timing of high dose therapy (HDT); 185 were randomly assigned to receive HDT and peripheral blood stem cell (PBSC), (early HDT group, n = 91) or a conventional-dose chemotherapy (CCT) regimen (late HDT group, n = 94). In the late HDT group, HDT and transplantation were performed as rescue treatment, in case of primary resistance to CCT or at relapse in responders. PBSC were collected before randomization, after mobilization by chemotherapy, and in the two groups, HDT was preceded by three or four treatments with vincristine, doxorubicin, and methylprednisolone. Data were analyzed on an intent-to-treat basis. Within a median follow-up of 58 months, estimated median overall survival was 64.6 months in the early HDT group and 64 months in the late group. Early HDT may be preferred because it is associated with a shorter period of chemotherapy [3]. More recently, two randomized trials by Joan Blade, and Christine M. Segeren, confirmed the absence of any advantage to progression free or over all survival to be offered by single high dose therapy as compared to standard chemotherapy [4, 5]. Tandem transplant became an attractive therapeutic tool because of the low morbidity and mortality associated with the procedure. Tandem transplant even though carries a slightly higher risk when compared to single autotransplant, appears to probably offer a survival advantage specially in the group of patients that receive their second transplant in a timely fashion and did not express chromosome 13 abnormalities [6]. This could be a function of changing the tumor biology or a treatment selectivity allowing patients with the best performance status, and prognostic criteria to receive the second transplant. The French group has updated the data of the IFM 94 of single versus double transplant in an abstract format, where double transplant was not found to improve the median event free or overall all survival [7]. With this information the South West Oncology Group (SWOG) is initiating a frontline study to investigate the concept of non chemotherapy induction followed by timely tandem transplant. The working hypothesis is that induction chemotherapy, and high dose pre-harvest chemotherapy taxes the patient with significant morbidity preventing the timeliness of the second procedure. Longer follow up, and further research in this area is under way. Until this data is available the use of this procedure should be within the confinements of well designed studies.
Allogeneic bone marrow transplantation
The major advantage with allogeneic bone marrow transplantation is that the graft contains no tumor cells that can lead to a relapse in addition to the theoretical benefit of graft versus myeloma effect. Unfortunately, over 90%s of patients with MM are ineligible because of their age, lack of an HLA-matched sibling donor, or inadequate renal, pulmonary, or cardiac function. Furthermore, there is presently a mortality rate of at least 25%. In a report of 266 patients from the European Blood and Bone Marrow Transplantation registry, 51% obtained a complete response. The overall treatment mortality rate was approximately 40%. The actuarial survival was 30% at 4 years and 20% at 10 years [8]. As noted in the previous paragraph, standard allogeneic stem cell transplant regimens have been associated with a high transplant-related mortality in multiple myeloma. Nonmyeloablative therapy can establish stable engraftment after allo-SCT and maintain the antitumor effect with less toxicity, which is important in heavily pretreated and elderly patients. Badros et al reported on 16 poor-risk myeloma patients receiving allo-SCT from an HLA-matched (n = 14) or mismatched (n = 2) sibling following conditioning with melphalan 100 mg/m2 (MEL-100). Ten patients had refractory relapse, 4 responsive relapse, and 2 patients were in near complete remission (nCR) with poor-prognosis disease. Patients had received 1 (n = 9) or 2 (n = 7) prior autotransplants. Donor lymphocyte infusions were given to 14 patients with no clinical evidence of graft versus host disease either to attain full donor chimerism (n = 4) or to eradicate residual disease (n = 10). Fifteen patients showed myeloid engraftment, and 12 patients were full donor chimeras at day +21. No transplant related mortality was observed during the first 100 days. Acute GVHD developed in 10 patients; 1 had fatal grade IV GVHD. Seven progressed to chronic GVHD, limited in 3 and extensive in 4 patients. At a median follow-up of 1 year, 5 patients achieved and sustained CR, 3 nCR, and 4 partial remission. Of 4 patients progressing after transplantation, 3 achieved a remission following further chemotherapy and donor lymphocyte infusion. Remarkable graft versus myeloma responses were seen in chemotherapy-refractory patients. Two patients died of progressive disease, and 3 died of GVHD complications without active disease. GVHD remains a major problem with this procedure. This treatment modality should be used within the boundaries of research studies.


Additional Authors:  

Works Cited:  
  1. Blade J, San Miguel JF, Fontanillas M et al: Survival of multiple myeloma patients who are potential candidates for early high-dose therapy intensification/autotransplantation and who were conventionally treated. J CI in Onco1 1996, 14:2167-2173.
2. Attal M, Herousseau JL, Stoppa AM et al: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 1996, 335:91-97.
3. Fermand 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(9): 3131-3136
4. Joan Blade, Anna Sureda, Josep M. Ribera, et al: High-Dose Therapy Autotrasplantation/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. Blood, V 97, No 11 , Abs 3386, 2001
5. Christine M. Segeren, Pieter Sonneveld, Bronno Van der Holt et al: Myeloablative Treatment Following Intensified Chemotherapy in Untreated Multiple Myeloma: A Prospective, Randomized Phase III Study. Blood, V 97, No 11 , Abs 3388, 2001
6. Desikan R, Barlogie B, Sawyer J et al. Results of high-dose therapy for 1,000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities. Blood. 2000, 95:4008-4010.
7. Jean-Paul Fermand, Jean-Pierre Marolleau, Corinne Alberti, et al. In Single Versus Tandem High Dose Therapy (HDT) Supported with Autologous Blood Stem Cell (ABSC) Transplantation Using Unselected or CD34 Enriched ABSC: Preliminary Results of a Two by Two Designed Randomized Trial in 230 Young Patients with Multiple Myeloma (MM). Blood, V 97, No 11 , 2001
8. Gharton G, Tura S, Svcnsson H et al. Allogeneic bone marrow transplantation in multiple myeloma: an update of the EBMT registry. Boston: Harvard Medical School. Sixth International Workshop on Multiple Myeloma. Syllabus, Boston, MA, 1997, June 14 to 18

Article Links:  
  • Cleveland Clinic Myeloma Research Program
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