Role of Salvage Autologous Transplant in Multiple Myeloma

Dr. Gordon Cook and colleagues report the final results of the BSBMT/UKMF Myeloma X study — a multicenter, randomized, open-label, phase III trial comparing salvage autologous stem cell transplant (ASCT) with weekly oral cyclophosphamide in patients with relapsed multiple myeloma (MM). Eligible patients had to have relapsing MM after a prior ASCT. All patients were re-induced with bortezomib, doxorubicin, and dexamethasone for four cycles. Patients were randomized in a 1:1 ratio to either high-dose melphalan (200 mg/m²) and ASCT or weekly oral cyclophosphamide (400 mg/m² per week for 12 weeks). Two hundred ninety-seven patients were registered, and 174 were assigned.

The primary endpoint of this study was time to progression (TTP) but the study was also powered to look at overall survival (OS). TTP favored the salvage ASCT arm at 19 months versus 11 months (p<0.0001). OS was also superior in the salvage ASCT arm versus the weekly cyclophosphamide arm (67 months vs. versus 52 months, respectively; p=0.0169). Prior data suggest a benefit to salvage ASCT that is based on retrospective registry or single-center studies only.^1,2  This is the first prospective study to evaluate and demonstrate a significant benefit to salvage ASCT in the era of newer drugs.

One of the theoretical concerns of further melphalan exposure is an increased risk of a second primary malignancy. The cumulative incidence of second primary malignancies in this study was 5.2 percent. A total of 15 second primary malignancies were reported in 12 patients and were evenly distributed between the two arms (salvage ASCT [n=7] vs. cyclophosphamide [n=5]).

Other important points underscored by this study include the need for adequate stem cell collection at time of first collection and timing of ASCT as salvage therapy. Thirty-four percent of the registered patients were unable to proceed to randomization due to insufficient stem cells at the time of second collection. In light of the fact that most patients are now treated with continuous lenalidomide maintenance after first ASCT, which may impair future stem cell collection, stem cell collection adequate for two transplants should be advised at the time of first collection.

This study also suggests that earlier salvage ASCT is superior to salvage ASCT in the third-line setting where four-year OS was 61 percent versus 69 percent in the second-line setting. Notably, there were no differences in survival appreciated in terms of response achieved at the end of induction therapy; TTP following first ASCT; B₂-microglobulin concentration at trial registration; or presence of adverse cytogenetics, including del(17), t(4:14), or t(14;16). The median time to second transplant in this study was 2.8 years, possibly suggesting a remission duration of at least two years for salvage transplantation.

This study was conducted between 2008 and 2012. As such, the choice of single-agent cyclophosphamide would not necessarily be considered the current standard of care. Though this trial substantiates the role of early ASCT as salvage therapy, there is ongoing room for debate about the role for salvage ASCT in the context of newer drugs and the role of continuous therapy. For example, results from the ASPIRE trial comparing carfilzomib, lenalidomide, and dexamethasone (KRd) with lenalidomide and dexamethasone (Rd) alone for patients with relapsed disease treated with one to three prior lines of therapy demonstrated a progression-free survival of 26.3 months in the KRd arm versus 17.6 months in the Rd arm.³  Interim OS also favored the KRd group with a 24-month OS rate of 73 percent versus 65 percent in the Rd arm. These numbers are comparable to those in the salvage ASCT cohort where a 69 percent four-year OS was reported, despite the ASPIRE cohort being a more heavily pretreated patient population.