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Comments on Bone Marrow Transplantation for Multiple Myeloma

Comments on Bone Marrow Transplantation for Multiple Myeloma

Multiple myeloma is a malignant disease characterized by excess proliferation of monoclonal plasma cells. Its progression leads to bone marrow failure, increased risk of infection, and painful osteolytic bony lesions. Although patients are most often responsive to multidrug chemotherapy, the median survival of myeloma patients is only 3 years and conventional treatment is not curative. Advanced myeloma, especially if complicated by hypercalcemia or renal failure, results in a median survival of less than 2 years.

Recent clinical studies suggest that autologous bone marrow or peripheral stem-cell transplantation offers the potential to intensify, and thus, improve the effectiveness of chemotherapy and radiation used for treatment of patients' myeloma. Drug intensification, as well as combined-modality radiation and chemotherapy, can result in 50% to 70% of patients achieving a significant partial response to therapy and, most encouragingly, nearly 50% of patients achieving a complete response--well above response rates expected with any conventional-dose chemotherapy.

Experience from multiple centers, including the University of Minnesota, and a large randomized trial suggest that this high complete response rate has great promise in extending survival for patients with myeloma. Transplantation within 1 year from diagnosis--and before extensive chemotherapy has compromised marrow reserve and induced multidrug resistance--may be critical in treatment planning. However, care in treatment protocol design and experienced aggressive supportive care is essential to limit transplant-associated morbidity and minimize mortality.

At the University of Minnesota, all patients with active (not indolent) myeloma are considered potential candidates for transplantation therapy. Still, those with resistant, relapsed disease may have little chance of benefit--again suggesting the need to consider transplantation early in the management of myeloma. Eligible, consenting patients with myeloma are offered multistage treatment combining chemotherapy, radiation, and subsequent maintenance immunotherapy to enhance and extend the duration of their responses.

Treatment Protocol

First, two cycles of outpatient multidrug chemotherapy are used to reduce patients' myeloma tumor burden and to mobilize hematopoietic stem cells for collection from the peripheral blood. Recombinant hematopoietic growth factors are given both to minimize the morbidity of these cytoreductive/stem-cell priming cycles and to increase the yield of stem cells collected. The harvested peripheral blood stem cells are frozen following each cycle to be available for hematopoietic reconstitution following the transplant.

Next, patients receive pretransplant therapy using high-dose chemotherapy and fractionated total-body irradiation to maximally deplete any residual myeloma. Reinfusion of their previously collected stem cells, administration of growth factors, and aggressive supportive care are provided. This treatment plan has resulted in rapid hematologic recovery, minimal treatment-associated complications, and short hospital stays. Subsequently, patients receive interferon-alfa (Intron A, Roferon-A) as maintenance therapy to extend the duration of response and maximize their clinical benefit over time.

Multimodality Approach

This integrated multicomponent treatment capitalizes on multiple chemotherapy and radiation effects to produce a maximal clinical response and overcome drug resistance. Ongoing laboratory investigations are in progress to evaluate the quality and quantity of stem cells collected. Sensitive molecular measures of residual tumor burden also are in place to monitor patients over time. These studies will aid in the design of improvements in stem-cell collection, enhancements in eradication of residual malignant cells, and modifications of post-transplant immunotherapy protocols. This research is designed to improve the treatments; minimize patients' tumor burden; limit the duration of pancytopenia post-transplantation; and capitalize on the minimal disease state after transplantation with immunologic maintenance therapy.

This new treatment offers great hope for patients with myeloma. The therapeutic plan, when coordinated with laboratory research used to design the next generation of therapy, will allow transplantation to become simpler, safer, and less expensive. Most importantly, it can offer even better possibilities for extended survival for patients with myeloma.

 
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