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Michigan Oncology Journal Summer 1999

Stem Cell Transplantation for Multiple Myeloma

Chris Reynolds, M.D.,
Instructor of Medicine

Joseph Uberti, M.D., Ph.D.,
Associate Professor of Internal Medicine
Clinical Director, Adult BMT Program

Despite advances in the treatment, diagnosis and supportive care aspects of multiple myeloma, it remains a disease that is incurable through standard chemotherapy. With chemotherapy, the median duration of survival is three years. Twenty-five percent of patients survive longer than five years and only 5% survive longer than 10 years. Initial chemotherapy for the disease often consists of more complicated and intense regimens, such as VAD, VMCP or VBAP, which often result in high complete and objective response rates. However, there is controversy over whether these more complex regimens substantially improve the overall survival rates in multiple myeloma when compared to the more traditional and better-tolerated standard regimens such as melphalan and prednisone (1). Although conventional chemotherapy does prolong survival when compared with no treatment, it ultimately represents palliation for patients due to the lack of evidence of any curative potential.

High-Dose Chemotherapy and Autologous Transplant
To date there is no convincing evidence that increasing the complexity and intensity of non-transplant doses of chemotherapy increases the overall survival in multiple myeloma patients. However, there is emerging evidence that high-dose chemotherapy with stem cell support does offer a survival advantage over standard chemotherapy. A number of phase II studies have shown that autologous stem cell transplantation is safe and effective therapy for multiple myeloma with a low transplant-related toxicity. Thirty to 40% of patients in these trials achieve complete remissions with overall survivals of 2.7 to 6.7 years (2).

In a recently published trial, patients with myeloma were randomized to receive either standard chemotherapy or chemotherapy followed by autologous transplant ( 3). All patients in the trial received induction chemotherapy with four cycles of alternating VMCP/VBAP. Patients were then randomized to receive either further conventional chemotherapy of VMCP/VBAP or high-dose therapy of melphalan and TBI followed by autologous stem cell transplant. The study showed a dramatic advantage of transplant compared to standard chemotherapy. The five-year, event-free survival (EFS) and overall survival (OS) were 28% and 52% in the transplant arm compared to 10% and 12% in the chemotherapy arm.

In spite of transplant's advantage over standard chemotherapy, it is still unclear if autologous BMT is curative for myeloma. Newer approaches have evolved to enhance the activity of transplants in an attempt to cure these patients. Approaches include the use of "tandem transplants" followed by maintenance interferon (4), as well as "purging" myeloma cells from the autologous stem cell harvest (5). Although both approaches offer theoretical advantages over standard transplants, neither has yet proven to be superior in controlled randomized trials. Based on the data presented, we believe all patients who undergo treatment for myeloma should be considered for high-dose therapy with stem cell rescue. In the absence of HLA-matched donors and in older patients, we recommend an autologous peripheral blood stem cell (PBSC) transplant after four courses of induction therapy with VAD. An interim analysis of 27 consecutive patients showed that 15 patients were in complete remission, two had stable disease and 10 had progressed or expired from their disease. In an attempt to preserve hematopoietic stem cell function it is helpful to treat patients with regimens that do not contain alkylating agents. The use of agents such as melphalan, which is known to be quite toxic to stem cells, makes collection and use of stem cells difficult.

Allogeneic Transplant for Myeloma
Although most evidence indicates the advantage of high-dose therapy over conventional therapy, there is little evidence that this approach will cure a high number of patients. This limitation has prompted a number of centers to initiate the use of allogeneic transplantation for patients who have an HLA-matched donor. Currently we are recommending allogeneic BMT to patients with myeloma who are young (age < 55) and have aggressive disease. If an HLA-identical sibling or unrelated donor is found, we do recommend proceeding to transplant. A recent interim analysis of 23 patients who have undergone allogeneic transplant at the University of Michigan demonstrated an overall survival of 60% (see Figure 1). Fifteen of these patients entered complete remission after the transplant. The use of peripheral blood stem cells, as well as better control of graft-vs.-host disease (GVHD), has contributed to the initial success of this treatment. Further follow-up will be needed to assess the relapse rate in these patients.

Despite the high mortality often associated with allogeneic transplants, there are several potential advantages. The first is that the allograft provides a stem cell source that is free from contamination of myeloma cells. The second and perhaps most promising advantage is the recently documented evidence of a potent anti-myeloma effect with an allogeneic BMT. Several centers have shown that myeloma patients who have relapsed after an allogeneic transplant respond to donor lymphocyte infusions (6,7). These infusions result in complete or partial responses in a number of patients who have relapsed after an allogeneic BMT.

Future Directions
Our current efforts are directed at lessening the transplant-related toxicity associated with an allogeneic transplant. This includes the use of allogeneic stem cells instead of marrow as a donor source (8), the use of new agents for the prevention of GVHD, such as tacrolimus (9), and the use of a new low-intensity regimen specifically targeted at older patients with myeloma (see article on page 6). We feel these new initiatives will substantially lessen the toxicity of allogeneic transplantation, which in turn will allow us to harness the potent anti-myeloma activity of an allogeneic transplant, thus increasing the cure rate for patients with this otherwise fatal malignancy.

References

  1. 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. 10:334,1992.
  2. Barlogie B. Advances in therapy of multiple myeloma: lessons from acute leukemia. Clinical Cancer Research. 3:2605, 1997.
  3. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. NEJM. 335:91, 1996.
  4. Barlogie B, Jagannath S, Desikan K.R., et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 93:55 1999.
  5. Vescio R, Schiller G, Keith Stewart A, et al. Multicenter phase III trial to evaluate CD34+ selected versus unselected autologous peripheral blood progenitor cell transplantation in multiple myeloma. Blood. 93:1858, 1999.
  6. Tricot G, Vesole DH, Jagannath S, et al. Graft-vs-myeloma effect: proof of principle. Blood. 87:1196, 1996.
  7. Lokhorst HM, Schattenberg A, Cornelissen JJ, et al. Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation. Blood. 90:4206, 1997.
  8. Uberti JP, Adams PT, Silver SM, et al. Allogeneic peripheral blood stem cell transplantation (APBSCT) for high-risk hematologic malignancies: the efficacy of tacrolimus for the prevention of acute graft-versus-host disease (AGVHD). Blood. 90:393a, 1997.
  9. Uberti JP, Cronin S, Ratanatharathorn V. Optimum use of tacrolimus in the prophylaxis of graft- versus-host disease. BioDrugs. 11:5, 1999.

Figure 1. Kaplan-Meier estimate of overall survival following related, allogeneic one marrow (n=8) or peripheral stem cell (n=15) transplant.

 

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Please note: The articles listed in the Cancer Center's News Archive are here for historical purposes. The information and links may no longer be up-to-date.