Nausea/Vomiting and Diarrhea subscales, while consistently worse for ixazomib than placebo (LS mean [95% CI] change at interval 24, 5.
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%), ...
e19517 Background: The multikinase inhibitor sorafenib targets several serine/threonine and receptor tyrosine kinases by blocking RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway regulated by the Ras oncogene, which is mutated both in primary patient samples and in human MM lines (35–50%). As the frequency of these mutations increases with advancing disease and increasing drug resistance, inhibition of the RAF/MEK/ERK signaling pathway, as well the angiogenic VEGFR-2/PDGFR beta cascade by sorafenib may be a useful new approach for the treatment of MM. Methods: SWOG evaluated the effect of sorafenib as a single agent in relapsed/refractory MM patients. In this phase II study we assessed response rate, overall (OS) and progression-free survival (PFS) as well as toxicities associated with this treatment. Twenty-three heavily pretreated MM patients were enrolled in the study. Sorafenib was started at oral dose of 400 mg daily until progression or toxicity. This dose was based on the label for metastatic renal cell carcinoma. Results: The study was closed as planned due to lack of efficacy in first 18 patients who were assessable for toxicity and response. Three patients experienced Grade 4 toxicity consisting of thrombocytopenia, anemia and renal failure. 8 cases suffered Grade 3 toxicities including thrombocytopenia, neutropenia, anemia, hand-foot syndrome, diarrhea and dyspnea. No responses were observed. 3 patients had stable disease (2.4–15.9 months) and the remainder progressed. Median PFS is one month, and OS at 12 months is 50%. Conclusions: Thus, single agent sorafenib did not show activity in this group of heavily pretreated MM patients previously exposed to bortezomib. As the frequency of RAS oncogene mutations increases resulting in resistance to traditional chemotherapeutic agents as well as possibly supporting cytokine resistance to immune modulators, sorafenib might have a supportive role in combination therapy with bortezomib, lenalidomide or everolimus in relapsed/refractory MM which is currently being evaluated in ongoing studies. No significant financial relationships to disclose.
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