Best of 2017 in Multiple Myeloma

For previous Year’s Best articles, we have highlighted exciting, new, recently approved therapies in multiple myeloma (MM) including daratumumab, elotuzumab, and ixazomib. This year, we are focusing on the RVD regimen (lenalidomide, bortezomib, and dexamethasone), now considered standard of care in newly diagnosed MM and familiar to readers of The Hematologist. This is motivated by the recent publication of SWOG S0777, a phase III trial that randomized patients with newly diagnosed MM to RVD versus the conventional doublet of lenalidomide and dexamethasone (Rd); following induction therapy, all patients received maintenance with Rd.¹  The RVD regimen was first described in a phase II trial by Dr. Paul Richardson and colleagues.²  Based on an unprecedented overall response rate of 100 percent, this regimen was rapidly embraced by the field and incorporated into the National Comprehensive Cancer Network guidelines,³  even though it was a single-arm study.

The SWOG S0777 trial is the first phase III trial demonstrating that integrating a proteasome inhibitor (PI), bortezomib, and an immunomodulatory drug (IMiD), lenalidomide, improves overall survival (OS) compared to the conventional Rd regimen (75 vs. 64 months; HR, 0.709; two-sided p=0.025). Moreover, RVD improved progression-free survival (PFS; 43 vs. 30 months; HR, 0.712; one-sided p=0.0018) and the overall response rate (ORR) (82% vs. 72%). Previous trials have shown benefit to combining a PI and an IMiD, but this was with bortezomib and thalidomide (VTD), which is not commonly used in the United States. Moreover, the benefit with VTD was mainly in response rate or PFS.^4,5  Additionally, the findings of the SWOG S0777 study extend on the meta-analysis showing improvement in PFS and OS with incorporating bortezomib in induction treatment.⁶  Finally, a recent study comparing VTD to another commonly used regimen, VCD (bortezomib, cyclophosphamide, dexamethasone), showed superior response rates with VTD, supporting a PI and IMiD combination as the preferred upfront regimen.⁷ 

What also sets SWOG S0777 apart is the inclusion of older patients who are not eligible for high-dose melphalan and autologous stem cell transplantation (ASCT). Trials in the past examining triplet combinations of RVD (or VTD) used these combinations for induction prior to intensive therapy with ASCT. In the SWOG S0777 study, 43 percent of patients were 65 years or older, and only a small proportion of patients (10%), actually underwent ASCT. Traditionally, a doublet regimen such as Rd has been considered the standard treatment for older patients, based on the results of the FIRST trial which showed that Rd had more favorable outcomes and tolerability than melphalan, prednisone, and thalidomide (MPT).⁸  The SWOG S0777 study establishes RVD as a standard regimen across all patient populations, irrespective of eligibility for high-dose melphalan. Of note, patients received bortezomib intravenously on days 1, 4, 8, and 11, reflecting standard practice during the time when patients enrolled — from 2008 to 2012. Consequently, and as expected, there were more grade 3 to 4 neuropathy and gastrointestinal adverse events with RVD than Rd, resulting in higher discontinuation rates of 23 percent and 10 percent, respectively. Since then, the standard has changed to administering bortezomib subcutaneously, with significant reduction in peripheral neuropathy.⁹  Furthermore, modifying the traditional RVD regimen to weekly dosing of bortezomib and decreasing the starting dose of lenalidomide from 25 to 15 mg (“RVD lite”) improves the tolerability of the regimen in the older patient population.¹⁰ 

Ongoing trials will likely challenge RVD’s position as the standard for newly diagnosed patients. A phase II trial of the next-generation PI carfilzomib with Rd (KRD) generated impressive, deep responses.¹¹  There is an ongoing trial, ECOG E1A11, comparing RVD to KRD in newly diagnosed patients (NCT01863550). The highly active anti-CD38 monoclonal antibody daratumumab is also being evaluated in newly diagnosed cases. For patients in whom ASCT is used, the Alliance GRIFFIN trial is randomizing participants to daratumumab with RVD versus RVD alone (NCT02874742), and another trial has combined daratumumab with KRD (MMY1001; NCT01998971).¹²  For older patients, the ALCYONE study evaluated traditional VMP (bortezomib, melphalan, and prednisone) versus daratumumab plus VMP, and this was presented as a late-breaking abstract at the 2017 ASH Annual Meeting.¹³  The addition of daratumumab led to an increase in ORR (90.9% vs. 73.9%) and a doubling of PFS. Finally, we await the results of the phase III MAIA study (NCT02252172), which randomized transplant-ineligible patients to daratumumab with Rd versus Rd alone, and has completed accrual.

With more effective induction therapies in development, an ongoing question is the role of ASCT. This year saw the publication of the pivotal IFM 2009 trial,¹⁴  which was previously covered in The Hematologist.¹⁵  This phase III trial was designed to answer the question of when to undergo ASCT — upfront as part of the initial treatment or at the time of relapse. In this trial, all patients (N = 700) received standard induction with RVD for three cycles followed by stem cell collection. The patients were then randomized to upfront high-dose melphalan and ASCT, followed by consolidation with two additional cycles of RVD. The other half went on to five additional cycles of RVD for a total of eight cycles. Following completion of initial treatment, all patients received maintenance lenalidomide for one year. On several measures, intensive therapy upfront proved better: median PFS, 50 versus 36 months (p<0.001); rate of complete response, 59 percent versus 48 percent (p=0.03); and absence of minimal residual disease, 79 percent versus 65 percent (p<0.001). These data have established upfront transplant as the standard of care even in the context of novel drugs. However, given the lack of an OS difference, there is an ongoing U.S. effort that parallels the IFM 2009 trial called the DETERMINATION trial. The combined data from these trials will inform the question of OS. Moreover, the DETERMINATION trial also addresses the issue of continuous maintenance therapy with lenalidomide and whether this will narrow the gap between upfront versus delayed transplantation.

Finally, cellular therapies using chimeric antigen receptor T (CAR T) cells continue to mature and impress in early findings, as reported at the 2017 ASH Annual Meeting. One of these, the Bluebird BB2121 anti-BCMA CAR T, showed in 21 patients a response rate of 89 percent, which rose to 100 percent for those treated at the higher dose levels.¹⁶  These patients were heavily treated with a median of seven prior lines of treatment. Given these promising data, the U.S. Food and Drug Administration has granted the Bluebird CAR T breakthrough status.

2017 saw continued progress in MM therapy. Rd, once considered “novel therapies”, are now a cornerstone of MM treatment. Newer approaches such as anti-BCMA monoclonal antibodies, bispecific T cell engager (BiTE) immunotherapy,¹⁴  and CAR-T have the potential to transform the care of myeloma patients. With this momentum, we and our patients look forward to seeing new developments in 2018.