A Phase 2 Study of Carfilzomib, Lenalidomide, and Dexamethasone with Lenalidomide Maintenance (KRd-r) in Newly Diagnosed Multiple Myeloma (NDMM): Sustained Long Term Deep Remissions and Prolonged Progression-Free Duration Regardless of Age or Cytogenetic Risk after 5 Years of Follow up

Background: State of the art treatment for patients with NDMM involves induction with triplet-based regimens utilizing combinations of immunomodulatory drugs and proteasome inhibitors (PI) which improve time to progression (TTP), progression-free survival, and overall survival (OS) over doublet regimens. Carfilzomib is a selective PI with FDA approval in the KRd combination regimen for the treatment of patients with relapsed or refractory MM. Carfilzomib-based combinations are associated with increased clinical benefit over bortezomib-based combinations and carfilzomib does not cause neuropathy. This phase 2 study of 45 patients demonstrated that deep responses with KRd-r is achieved in the NDMM setting (Korde et al. JAMA Onc 2015). Here, we expand on our initial results in assessing response to present the long-term durability of minimal residual disease negativity (MRDneg) complete response (CR) and time to progression. We also characterize TTP by depth of response, age, and cytogenetic risk profile. Methods:Treatment-naïve patients with MM were treated for 8 cycles (28-day cycles) with carfilzomib 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg PO days 1-21, and dexamethasone 20/10 mg IV/PO days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after ≥4 cycles and then continued KRd treatment (i.e. without default autologous stem cell transplant (ASCT)). After 8 cycles of KRd, patients received 2 years of lenalidomide 10 mg PO maintenance on days 1-21. The primary objective of the study was to estimate the rate of ≥ Grade 3 peripheral neuropathy with secondary objectives of International Myeloma Working Group criteria for overall response rate (ORR), MRDneg CR, TTP, and response duration (DoR) assessed after every cycle during induction and subsequently after every 90 days of maintenance therapy. Assessment of MRDneg CR by multi-color flow cytometry (bone marrow aspirate; 10-5 sensitivity) was performed after 8 cycles of induction, 1 and 2 years of lenalidomide maintenance, and then annually. Results: Forty-five patients meeting eligibility criteria were enrolled (60% male; 42% ≥ age 65, range 40-89; race: 82% White, 13% Black, 4% Asian; isotypes: 51% IgG kappa, 16% IgG lambda, 13% IgA kappa, 9% IgA lambda, 9% free kappa, and 4% free lambda; 33% high risk cytogenetics, del(17p), t(4;14), t(14;16)or t(14;20)). The median potential follow up was 5.7 years (68.3 months). The ORR was 97.8% (95% Confidence Int