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Bone Marrow Transplantation In Multiple Myeloma


Why is High Dose Therapy and Bone Marrow Transplantation Considered in Multiple Myeloma


For the last 30 years, conventional dose melphalan and prednisone or corticosteroids alone at various dose levels have been the mainstay of treatment for patients with multiple myeloma. Complete remissions are unusual, and few if any are cured with conventional therapy.

 This has prompted the interest in studying high dose therapy which has demonstrated a higher incidence of complete remissions. The use of stem cell or bone marrow salvage, does allow the administration of high doses of chemotherapy in a relatively safe fashion. Although complete remission rates range from 25 to 80%, the median duration of these responses, unfortunately, has been only 24 to 36 months, at best.


What are the different types of bone marrow transplantation?


Pros and cons for different types of transplant and conventional therapy


 Syngeneic (identical twin) or Allogeneic (Related or unrelated) Bone Marrow Transplant

The advantage of this procedure is the use of uncontaminated bone marrow to salvage the recipient. Moreover, the use of allogeneic bone marrow transplants may be associated with a graft-versus-myeloma effect, but there have not been enough syngeneic transplants reported in patients with multiple myeloma to make meaningful comparisons of relapse rates to clarify this issue.

 The median age at diagnosis for patients with multiple myeloma is 70 years, while 55 is the usual upper age limit for allogeneic bone marrow transplantation in most transplant centers. In addition, most patients do not have syngeneic or suitable allogeneic donors. For these reasons, syngeneic/allogeneic bone marrow transplantation has not been as popular as autologous transplant.

 If an appropriate donor is available, several pretransplant prognostic factors could define the group of patients that would do better. Favorable pretransplant prognostic factors for survival are female gender, Stage I disease at diagnosis, one line of previous treatment and being in remission before transplantation. The subtype immunoglobulin A "IgA" and a low b2 microglobulin level also tend to have a favorable prognostic impact.

 At this stage, however, there are no randomized trials available to justify the 30-40% transplant related deaths associated with this procedure.


Autologous Bone Marrow (ABMT) or Peripheral Stem Cell Transplant (APSCT)

 The low complication profile, as well as the potential of performing the procedure safely up to the age of 70 years, make this a very attractive treatment method and, hence, heavily studied. Unfortunately, only one prospective randomized trial by the French Group has been reported in the literature.

 Transplantation of APSC alone or as a supplement to ABM has been reported. Engraftment of all lineages is more rapidly achieved with APSCT than after autologous bone marrow grafting. Also, a theoretical advantage of APSCT is less contamination with myeloma cells compared with ABMT.

 Who Should Receive Autologous Transplantation?

 Autologous PSC or bone marrow transplantation are more likely to be associated with adverse outcomes if patients have b2 microglobulin levels more than 2.5 mg/ml, received more than two regimens of prior therapy, time to transplant longer that 3 years from diagnosis, and history of prior radiation therapy.

 The criteria to chose the patient who could potentially benefit from ABMT or APSCT are far from clear. In a recent publication, the outcome of patients with multiple myeloma who were potential candidates for early high dose therapy followed by APSCT or ABMT was evaluated. The median survival time of patients who were less than 65 years of age and who responded to initial chemotherapy was 5 years. This survival duration is similar to that reported in selected series of patients given early high dose therapy. To confuse matters further, a study from MD Anderson suggested that the subpopulation of patients with primary resistant myeloma is the most likely to benefit from transplantation.

 The only published trial that has randomized patients between conventional chemotherapy and high dose therapy followed by ABMT has shown that the conventional therapy group achieved a median event-free survival of 18 months with a median overall survival of 37.4 months. In the high dose group, the median event-free survival was 27 months and the median survival was not reached at the time of the publication. When prognostic factors for overall survival were analyzed with multivariant analysis, only b2-microglobulin level stood out as a statistically significant factor.

 The estimated (not actual) probabilities of event-free survival and overall survival 5 Years after the diagnosis in the conventional dose group was 10% and 12%, respectively, versus 28% and 52% in the high dose therapy group.

 These results are encouraging, but need to be confirmed by other studies.

 In summary bone marrow transplantation appears to be a promising procedure, however, at this time, it should not be recommended outside of study boundaries. It would be reasonable to consider harvesting stem cells from responding patients for future use, especially given that repeated regimens or large dosages of melphalan could impair future stem cell collection.


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