New Questions About Transplantation in Multiple Myeloma
New Questions About Transplantation in Multiple Myeloma
Multiple myeloma is now the most common indication for autologous stem cell transplantation (ASCT) in North America, with over 5,000 transplants performed yearly (Center for International Blood and Marrow Transplant Research [CIBMTR] data). While the role of ASCT as initial therapy in multiple myeloma has been established by randomized studies, newer therapies are challenging the traditional paradigm. The availability of novel induction agents and newer risk stratification tools, and the increasing recognition of durability of remissions are changing the treatment paradigm. However, even with arduous therapy designed to produce more complete remissions—for example, tandem autologous transplants—we have seen no plateau in survival curves. A tandem autologous procedure followed by maintenance therapy may be performed in an attempt to sustain remission. Sequential autologous transplants followed by nonmyeloablative allotransplants are pursued with the hope of "curing" multiple myeloma. We examine how the key challenges of increasing the response rates and maintaining responses are being addressed using more effective induction and/or consolidation treatments and the need for maintenance therapies after ASCT. We argue that given the biologic heterogeneity of multiple myeloma, risk-adapted transplant approaches are warranted. While the role of curative-intent, dose-intense toxic therapy is still controversial, conventional myeloablative allogeneic transplants need to be reexamined as an option in high-risk aggressive myeloma, given improvements in supportive care and transplant-related mortality.
Randomized studies[1,2] suggesting that autologous hematopoietic stem cell transplantation (ASCT) is superior to conventional chemotherapy prompted the adoption of this treatment into standard upfront management of multiple myeloma in eligible patients. Unfortunately, most patients eventually relapse and succumb to the disease despite transplantation. Over the course of the past decade, multiple strategies have been tried to improve the outcome of transplantation for multiple myeloma. These include intensification of therapy using tandem ASCT, immunotherapy approaches involving allogeneic transplantation and reduced-intensity conditioning, posttransplant maintenance therapies, adoptive immune approaches using donor lymphocytes, and the incorporation of novel antimyeloma therapy in induction and maintenance. Within the past 5 years, however, novel antimyeloma treatments have expanded nontransplant options and improved conventional therapy. At the same time, transplants have become increasingly safer and established as standard of care in multiple myeloma.
Single Autologous Transplantation
Prospective randomized clinical trials conducted by the Intergroupe Francophone du Myelome (IFM) group and the Medical Research Council (MRC) have clearly proven that upfront high-dose therapy with ASCT is superior to conventional chemotherapy by improving complete remission (CR) rates and both event-free survival and overall survival in multiple myeloma. Multiple systematic reviews and nonrandomized comparisons have also demonstrated that high-dose therapy is superior to conventional chemotherapy. There are, however, two studies that did not show a benefit.[3,4] In analyzing the ASCT vs chemotherapy studies it must be noted that patient eligibility requirements, the conventional chemotherapy regimen used, the conditioning chemotherapy for transplant, and response criteria have varied among the studies. These data are summarized in Table 1.
It is interesting to focus on the differences between these investigations. The US Intergroup study is the only randomized study that has failed to show a significant increase in CR rates for ASCT vs conventional chemotherapy. In this study, the transplant conditioning regimen used was melphalan (Alkeran), 140 mg/m2, with total-body irradiation (TBI), which would now be considered suboptimal. Conventional chemotherapy following VAD (vincristine, doxorubicin [Adriamycin], dexamethasone) induction for all patients was VBMCP (vincristine, carmustine [BCNU], melphalan, cyclophosphamide, prednisone) for 1 year. At the time of relapse, patients in the conventional arm were offered ASCT, thus contributing to the lack of a difference in the overall survival. This is also consistent with the French Group Myelome-Autogreffe (MAG) study, which showed no survival differences between early and delayed transplantation.
In contrast, the Programa para el Tratamiento de Hemopatas Malignas (PETHEMA) group randomized patients responding to induction chemotherapy for ASCT vs continuing conventional chemotherapy. Although CR rates were higher with transplantation, no significant differences in the event-free or overall survival between the two arms were observed. These data are consistent with the idea that an increase in CR may not necessarily translate into a survival advantage because patients who are initial responders constitute a good biologic risk group and may not derive significant additional benefit from high-dose therapy.
Similarly, the benefit of ASCT in older patients with multiple myeloma has not been formally established in randomized trials. This is particularly important as the median age at diagnosis of newly diagnosed multiple myeloma is 66 years, whereas the median patient age in the IFM and MRC series is 55 and 57 years, respectively. Pair-mate comparisons have in the past suggested a superiority of ASCT over conventional chemotherapy. However, a randomized study from the MAG group in patients aged 55 to 65 years with 10-year follow-up suggests that despite higher response rates and event-free survival rates, ASCT offers no overall survival benefit over chemotherapy. This study, however, did reveal improved quality-of-life score for patients undergoing ASCT, as measured by time without symptoms, treatment, and treatment toxicity (TwiSTT). Interestingly, 22% of patients in the chemotherapy group underwent ASCT at relapse, no doubt contributing to the similarity of overall survival and emphasizing the feasibility of ASCT in this population.
Complete Remissions and Clinical Benefit
Autologous stem cell transplant is the most powerful modality for achieving CR in multiple myeloma. Complete remission rates with single ASCT have been reported in the 25% to 35% range, whereas tandem autologous transplantation has an expected CR rate ranging from 35% to 50%. Before the advent of novel agents and novel combinations, none of the nontransplant combination regimens could achieve similar CR rates.
That said, the concept of complete response being a paramount determinant in survival in multiple myeloma does not hold up on close analysis. As noted above, the PETHEMA study suggested that in patients responding to initial chemotherapy, higher CR rates with transplantation did not result in a survival benefit. Similarly, the Mayo Clinic experience with single ASCT (where patients who underwent ASCT had a similar progression-free and overall survival whether they achieved CR or not following ASCT) and the Arkansas data showing that a CR at the 1-year landmark after tandem ASCT was not significantly related to overall survival (hazard ratio = 0.83; P = .39) suggest that the attainment of a strict CR does not necessarily predict overall survival. The natural history of multiple myeloma and the lack of concordance between response and survival caution us against using complete response rates as a surrogate for survival benefit.
Finally, the definitions of CR in various multiple myeloma studies have tended to vary widely, confounding cross-comparison. The prognostic significance of the exact method used to define CR is controversial. The IFM studies have expanded the definition of the best response following transplantation to include patients who attain more than a 90% reduction in paraprotein levels. Other groups have also defined "near CR" using the European Bone Marrow Transplant (EBMT)-International Bone Marrow Transplant Registry (IBMTR) criteria, with the exception of immunofixation positivity. Variable and nonstandard criteria for reporting responses following transplant thus continue to confound comparisons of studies