Ps1371 Elotuzumab in Combination With Carfilzomib, Lenalidomide, and Dexamethasone (Krd) in Patients With Newly Diagnosed Multiple Myeloma (Ndmm): A Phase 2 mmrc Trial

Abstract

Background: Several recent studies have showed improved results with addition of antibodies to anti-myeloma regimens. The KRd combination is highly active in NDMM. We hypothesized that addition of elotuzumab (ELO) to KRd (E-KRd combination) would improve efficacy as compared to KRd. Aims: We report interim response data at key landmark timepoints of the study Methods: The study has enrolled newly diagnosed patients (pts) requiring treatment as per IMWG criteria, regardless of transplantation eligibility. Per protocol, pts receive 12-24 cycles of E-KRd, with adaptive design of the duration of E-KRd treatment based on sustained MRD-negativity by next gene sequencing (NGS) clonoSEQ (Adaptive Biotechnologies), followed by E-Rd maintenance. ELO is given at 10 mg/kg QW for Cycles 1-2, Q2W for Cycles 3+, and Q4W during E-Rd maintenance. Carfilzomib (K) is administered on Days 1, 8 and 15 of each 28-day cycle, 20 mg/m 2 on C1D1, then escalated up to 56 mg/m 2 or 70 mg/m 2 based on tolerability. Lenalidomide 25 mg is given on Days 1-21 and dexamethasone 20-40 mg per week. Per protocol, transplant candidates undergo stem cell collection after C4 using G-CSF plus plerixafor, and then resume E-KRd treatment. Pts who choose to discontinue treatment to receive autologous stem cell transplant (ASCT) are censored from the analysis at the time of their last cycle of treatment. Landmark evaluations are performed after 4, 8, 12, 18, and 24 cycles and include MRD evaluation using multi-color flow cytometry (MCF) with 10 -5 sensitivity and by NGS with 10 -5 -10 -6 sensitivity, and by Mass Spectrometry (MassSpec) for sCR confirmation. A total of 40, transplant ineligible and/or transplant eligible pts who agree to defer ASCT will be enrolled as well as an additional 15 pts who plan to proceed to ASCT. The primary end-point of the study is sCR/MRD(-) rate after 8 cycles of E-KRd therapy for the transplant ineligible/deferred pts and sCR/MRD(-) rate at the end of 4 cycles for all enrolled pts. Results: Twenty-four pts (median [range] age 61, ) were enrolled, of which 11 pts (46%) had IMWG high-risk cytogenetics, including 5 pts (21%) with del p53. At the cut-off date Feb 21, 2019, pts received a median of 4 (1-20) treatment cycles. Per protocol criteria, 10 pts escalated carfilzomib dose to 70 mg/m 2 . Median (range) duration of follow-up was 9.7 (1-19) months. Four (17%) pts discontinued treatment (1 adverse event [cardio-pulmonary toxicity]; 1 elective ASCT and 2 progressive disease). In intent-to-treat (ITT), ORR was 100% (50% CR/sCR, 95% at ≥VGPR (N = 22, 2 of 24 pts are too early to assess, <1 cycle); all pts achieved at least PR after C1 with CR/sCR rates 36% and 60% at the end of 4 and 8 cycles, respectively. For the ITT population, MRD(-) rates were 70% by MFC at the end of 4 cycles (N = 20) and 70% by MFC (N = 10) and 56% by NGS (N = 9) at the end of 8 cycles. The most common non-hematological AEs (all grades) were fatigue (63%), fever (33%), dyspnea (33%), upper respiratory infection (29%), constipation (25%), diarrhea (25%), ...

Carfilzomib, lenalidomide, and dexamethasone plus transplant in newly diagnosed multiple myeloma

“…There are also efforts to adopt risk-and MRD-adaptive treatment strategies for intensification and/or extending treatment duration as well as de-escalation or discontinuation. 16,38,39 MRD-negative response, or preferably sustained MRD-negative response, could be used to inform treatment of standard-risk patients in whom extended multidrug regimens or even ASCT may not be of benefit, or conversely, for high-risk patients who may require longer multidrug treatment to achieve sustained MRD response or the addition of novel agents. 31 Whether ASCT or an antibody, or both, should be added to a backbone of existing regimens along with duration of treatment will ultimately need to be sorted out in ongoing and future prospective randomized trials.…”

Immunotherapy in Multiple Myeloma—Time for a Second Major Paradigm Shift

“…8,9 While D-based quadruplet regimens consistently induce deeper responses and higher MRD negativity, overall survival (OS) at current follow-up remains similar and the benefit in high-risk MM subsets is not clear. [21][22][23][24][25] Achievement of MRD negativity, however, is recognized as a robust predictor of longer remissions and is an acceptable early practical surrogate end point. 26,27 The phase II MASTER study used the carfilzomib-based quadruplet (D-KRd) before ASCT followed by MRD guided D-KRd consolidation and reported remarkable MRD negative responses in NDMM.…”