Autologous hematopoietic cell transplantation (AHCT) has been the standard treatment for patients with newly diagnosed multiple myeloma (NDMM) for the past 20 years. Several randomized trials done in the 1990s, mainly led by the Intergroupe Francophone du Myelome (IFM), confirmed the superiority of AHCT in terms of response rates, progression free-survival (PFS), and overall survival (OS) when compared to non-AHCT approaches. 1-5 With a median OS of two to three years for MM in the 1990s, the OS differences were easier to demonstrate, even with the shorter follow-up in the AHCT-based approach. 1, 6 The results of those studies, however, established the current standard of care for transplant-eligible patients, which is still a preferred strategy after an initial period of disease control. 2, 3, 7
In the two decades since these studies were published, several new drug classes have emerged, with some of these combinations providing excellent response rates as initial therapy. These include proteasome inhibitors, immunomodulators, and CD38 monoclonal antibodies that provided single-agent response rates of 20 to 30 percent in the relapsed setting, to approximately 100 percent response rates in patients with NDMM when used in combination. 8 Consequently, upfront AHCT has again become the subject of clinical trials 3, 4, 9 with comparisons being made against the modern induction. Two parallel randomized studies, the European IFM 2009 3 and U.S.-based DETERMINATION 9 trials, attempted to answer the question of early versus delayed AHCT in the context of modern induction with lenalidomide, bortezomib, and dexamethasone (RVD). DETERMINATION is an open-label phase III randomized trial in which patients with NDMM were randomly assigned to RVD induction with and without AHCT, followed by lenalidomide maintenance until progression based on the results of the Cancer and Leukemia Group B study 10 (vs. 1 year in IFM 2009). The primary end point of the study was PFS, while response rates, OS, quality of life, and adverse events were secondary end points.
The trial randomized 357 patients to RVD alone (median age, 57 years; 43% women) and 365 to AHCT (median age, 55 years; 41% women). African American patients comprised 19 percent of trial participants. At a median follow-up of 76 months, the trial met its primary end point and showed a significant improvement in PFS in the AHCT arm (median, 67.5 months) compared to the RVD alone arm (median, 46.2 months), translating into a 53 percent reduction in the risk of progression or death (HR, 1.53; 95% CI, 1.23-1.91; p<0.0001). The estimated five-year OS was similar between the RVD alone (79.2%) and AHCT (80.7%) arms (HR, 1.10; 95% CI, 0.73-1.65; p=0.99). Minimal residual disease–negative status at the start of maintenance was 54.4 percent in the AHCT group versus 39.8 percent in the RVD alone group. The mean average quality of life was similar between the two groups, and as expected, grade 3 or higher hematologic adverse events were higher in the AHCT group. There was no difference in the five-year cumulative incidence of second primary malignancies in both groups; 10 patients on the AHCT arm had acute myeloid leukemia and myelodysplastic syndromes versus none in the RVD alone group. Meanwhile, seven patients on RVD alone developed acute lymphocytic leukemia versus three in the AHCT group. In the RVD alone arm, 28 percent of patients received salvage AHCT, with the remaining patients receiving other therapies.
The results of the landmark DETERMINATION trial once again prove that upfront AHCT is still the best approach to reach deep and durable remissions in MM. In addition, the results underscore the value of lenalidomide maintenance until progression, as the median PFS was 20.2 months longer in the AHCT arm in this trial, compared to one year of lenalidomide maintenance in IFM 2009. The estimated five-year OS of approximately 80 percent in both arms highlights the ever-improving therapeutic armamentarium that we possess against this disease; however, lack of significance difference in OS between the arms should be interpreted with caution. First, the trial was underpowered to detect OS difference, and with a median OS of eight to 10 years in MM during the trial inception, a longer follow-up will be necessary to detect an OS difference after appropriate follow-up. The right conclusion is that median OS remains unreached for both arms.
There are no data to inform a tailored approach to MM based on NDMM, beyond the maintenance setting where proteasome inhibitor/immunomodulatory drug maintenance affords a PFS benefit for high-risk MM in phase II studies. 11, 12 MM remains an incurable disease for a vast majority of individuals, with frequent relapses, and attrition with each relapse. Furthermore, due to the attrition rate with each line of therapy, 13, 14 not every patient will receive every drug available. Therefore, achieving a deep and durable first remission is one of the most important goals. AHCT remains part of the treatment schema enabling this goal, and the body of evidence favors that AHCT be employed in the upfront setting. As we look to the future, there are very promising bispecific antibodies and chimeric antigen receptor T-cell therapies emerging in relapsed/refractory MM moving to the early lines of treatment. There are trials that aim to compare these new modalities to AHCT in the frontline setting. Until such trials show benefit, upfront AHCT remains a standard of care for eligible patients.
Dr. Dhakal and Dr. Usmani indicated no relevant conflicts of interest.