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
Multiple myeloma is a malignant disease characterized by excessproliferation of monoclonal plasma cells. Its progression leadsto bone marrow failure, increased risk of infection, and painfulosteolytic bony lesions. Although patients are most often responsiveto multidrug chemotherapy, the median survival of myeloma patientsis only 3 years and conventional treatment is not curative. Advancedmyeloma, 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 orperipheral stem-cell transplantation offers the potential to intensify,and thus, improve the effectiveness of chemotherapy and radiationused for treatment of patients' myeloma. Drug intensification,as well as combined-modality radiation and chemotherapy, can resultin 50% to 70% of patients achieving a significant partial responseto therapy and, most encouragingly, nearly 50% of patients achievinga complete response--well above response rates expected with anyconventional-dose chemotherapy.
Experience from multiple centers, including the University ofMinnesota, and a large randomized trial suggest that this highcomplete response rate has great promise in extending survivalfor patients with myeloma. Transplantation within 1 year fromdiagnosis--and before extensive chemotherapy has compromised marrowreserve and induced multidrug resistance--may be critical in treatmentplanning. However, care in treatment protocol design and experiencedaggressive supportive care is essential to limit transplant-associatedmorbidity and minimize mortality.
At the University of Minnesota, all patients with active (notindolent) myeloma are considered potential candidates for transplantationtherapy. Still, those with resistant, relapsed disease may havelittle chance of benefit--again suggesting the need to considertransplantation early in the management of myeloma. Eligible,consenting patients with myeloma are offered multistage treatmentcombining chemotherapy, radiation, and subsequent maintenanceimmunotherapy to enhance and extend the duration of their responses.
First, two cycles of outpatient multidrug chemotherapy are usedto reduce patients' myeloma tumor burden and to mobilize hematopoieticstem cells for collection from the peripheral blood. Recombinanthematopoietic growth factors are given both to minimize the morbidityof these cytoreductive/stem-cell priming cycles and to increasethe yield of stem cells collected. The harvested peripheral bloodstem cells are frozen following each cycle to be available forhematopoietic reconstitution following the transplant.
Next, patients receive pretransplant therapy using high-dose chemotherapyand fractionated total-body irradiation to maximally deplete anyresidual myeloma. Reinfusion of their previously collected stemcells, administration of growth factors, and aggressive supportivecare are provided. This treatment plan has resulted in rapid hematologicrecovery, minimal treatment-associated complications, and shorthospital stays. Subsequently, patients receive interferon-alfa(Intron A, Roferon-A) as maintenance therapy to extend the durationof response and maximize their clinical benefit over time.
This integrated multicomponent treatment capitalizes on multiplechemotherapy and radiation effects to produce a maximal clinicalresponse and overcome drug resistance. Ongoing laboratory investigationsare in progress to evaluate the quality and quantity of stem cellscollected. Sensitive molecular measures of residual tumor burdenalso are in place to monitor patients over time. These studieswill aid in the design of improvements in stem-cell collection,enhancements in eradication of residual malignant cells, and modificationsof post-transplant immunotherapy protocols. This research is designedto improve the treatments; minimize patients' tumor burden; limitthe duration of pancytopenia post-transplantation; and capitalizeon the minimal disease state after transplantation with immunologicmaintenance therapy.
This new treatment offers great hope for patients with myeloma.The therapeutic plan, when coordinated with laboratory researchused to design the next generation of therapy, will allow transplantationto become simpler, safer, and less expensive. Most importantly,it can offer even better possibilities for extended survival forpatients with myeloma.