High-Dose Melphalan Is the Tom Brady of the Myeloma World

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.