I am convinced that curing myeloma requires the full dedication of a bright and hard-charging team of creative investigators. Foremost, we have to embrace a well-founded optimism that the goal of cure or lifelong palliation is achievable.
During the first few decades of myeloma investigation, through the mid-1980s, a series of mildly cytotoxic regimens were employed so as to not further compromise patients’ immune status and hemato-poietic function, and thus potentially increase treatment-related mortality. Stem cell support and hematopoietic growth factors had not yet become available.
Inspiration was sparked by the remarkable activity of high does of dexamethasone, alone or administered as part of the VAD regimen, which was non-myelosuppressive and which effected bone marrow remissions regularly. Coincident with the findings of the late Tim McElwain that the increased dose intensity of melphalan did increase complete remission rates markedly, but was associated with toxic death due to prolonged neutropenia, we developed the autologous hema-topoietic stem cell support strategy using bone marrow even when infiltrated by up to 30% tumor cells. The hypothesis was that these were mainly terminally differentiated cells with little self-renewal capacity. In fact, the first patient ever to receive an autologous bone marrow transplant had 30% marrow plasmacytosis. Yet, the bone marrow was effectively used to support chemoradiotherapy with melphalan and total body irradiation, resulting in a 6-year subsequent survival.
A major breakthrough was the discovery by Gianni and colleagues that cyclophosphamide-mobilized peripheral blood stem cells, unlike those obtained from the steady-state bone marrow environment, could markedly accelerate both granulocyte and platelet recovery. This indeed reduced morbidity and mortality, especially among older patients, and has made it possible for most procedures to be done today in the outpatient setting with a high level of safety.
Emphasis should be placed on addressing the long-standing controversy among myeloma investigators about standard vs. single vs. double transplants. Our justification for the tandem transplants comes from the arithmetic: tumor burden at the time of clinically defined complete remission is reduced from a trillion to perhaps 1 to 5 billion remaining tumor cells. With the availability of peripheral blood stem cells affording rapid hematopoietic recovery, it became feasible to introduce treatment regimens that produce marked reduction of disease burden. Abandoning total body irradiation, we believed that a more radical intervention with tandem transplants was more likely to produce positive clinical outcome in the majority of patients. The French Myeloma Intergroup has been able to confirm in two carefully conducted randomized trials that single high dose therapy was superior to standard treatment, and, just recently, that two such cycles are superior to a single cycle.
In light of exciting new drug developments, a certain level of hype is infiltrating the myeloma medical and patient communities. Some are quick to abandon the impressive results obtained with tandem transplants. In pursuit of our strategy that the risk of treatment intervention should match the risk of the disease, we believe that exciting new agents whose long-term efficacy and toxicity is not yet known, should be tested in high-risk disease, e.g. myeloma with chromosome 13 deletion or high LDH. Given that 80% of such patients will likely progress or relapse within 2 years, the new approaches seem justified, as long as patients have the opportunity early on of autologous stem cell collection. Sufficient stem cell collection ensures that standard melphalan-based autologous transplant remains an option in the event of unanticipated marrow damage from new agents.
Other discussions have focused on the issue of early vs. late salvage transplantation. The mission of attaining durable disease control and cure, mandates that that best treatment options be applied up-front to battle the already enormously complex genomic instability that probably accounts for much of the standard dose drug resistance.
Finally, it is distressing to observe that the treatment discussion, even among hematologists and oncologists, is often about transplant vs. standard therapy. An autologous “transplant” is simply a transfusion of autologous cells. The critical component of the “transplant” is the drug administered at the proper dose and schedule. Toxicities and mortality from a melphalan transplant are strictly dependent on the total dose administered. Thus, if there is increased risk of morbidity, as in the case of associated amyloidosis involving the heart, a reduced melphalan dose in a safe range of 50-70 mg/m2 should be considered. In the case of “malignant myeloma,” we have begun to advocate other agent combinations, such as DT PACE, which do not target hematopoietic stem cells and are rather devoid of significant extramedullary toxicity, so that cycles can be administered as needed, within 2 to 3 weeks. This approach is critical for preventing rapid re-growth in a setting where single agent melphalan, even at high doses, fails to achieve a marked tumor reduction.
We anticipate that the comprehensive fundamental research into the molecular and biological disease features, as part of an organized clinical trial program, will make tremendous strides in the near future.
Note: For more information about the Myeloma Institute for Research and Therapy at UAMS, please call (501) 526-2873.