Phase II Clinical and Correlative Study of Carfilzomib, Lenalidomide, and Dexamethasone (CRd) in Newly Diagnosed Multiple Myeloma (MM) Patients

Carfilzomib (CFZ) is an irreversible proteasome inhibitor with potent anti-MM effects and significantly decreased peripheral neuropathy rates compared with bortezomib. In this single stage phase II trial, we plan to treat 45 newly diagnosed MM patients with 8 cycles of CRd followed by 1 year of Lenalidomide (LEN) maintenance. Unique to this study, transplant eligible patients default to “delayed” ASCT per protocol and depth of molecular responses are assessed using studies of minimal residual disease (MRD) (flow cytometry, PCR, and FDG PET-CT). Using this approach, we report the first n=18/45 patient results, showing that CRd induces rapid and deep remissions.

Untreated newly diagnosed non-transplant and transplant candidates are eligible for protocol. Patients are administered eight 28-day cycles of therapy including: CFZ IV 20/36 mg/m² on days 1, 2, 8, 9, 15, 16; LEN oral 25 mg days 1–21; and Dexamethasone IV/oral 20/10 mg on days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients default to “delayed” ASCT approach per protocol by harvesting and cryopreserving stem cells after 4 cycles of CRd and continuing with cycles 5–8 of CRd thereafter. After 8 cycles of CRd, all patients with SD or better receive cycles 9–20 of LEN maintenance 10 mg days 1–21. Primary endpoint is the incidence of ≥ grade 3 neuropathy. Secondary endpoints include response rate, profiling CFZ activity to biological endpoints, and impact of MRD studies on clinical outcomes. Bone marrow samples are collected at baseline, C1D2 (single agent CFZ exposed), CR /end of cycle 8 (cycles 1–8), and CR/end of cycle 20 (cycles 9–20). MRD studies are performed on achievement of CR/end of cycle 8 (during cycles 1–8) and CR/end of cycle 20 (during cycles 9–20).

18 patients meeting eligibility criteria have been enrolled (10 male, 8 female; median age 60; range 42–83). Among the patients enrolled, mean M- protein 2.9 g/dL (1.0–7.2 g/dL) and isotypes included 10 IgG, 4 IgA, and 4 light chain only. 15 patients were evaluated for toxicity and response. No patients have reported ≥ grade 3 neuropathy. After completing one cycle, the mean decline in M-protein (heavy chain, n= 10 IgG + 4 IgA) and involved – uninvolved light chains (light chain only, n=4) was 74% and 73%, respectively. Best responses after median of 4 cycles of CRd (range 1–8) completed, include 4 – sCR/2-nCR (40%), 5 – VGPR (33%), 3 – PR (20%), and 1 – SD (6%). For patients who achieved sCR, median time from initiation of CRd treatment to sCR was 5 cycles. Four patients with sCR had no evidence of immunophenotypic abnormal plasma cells on multiparametric flow cytometry during MRD assesment. In addition, PET-CT results for 3 out of 4 sCR patients showed substantial decrease in max standardized uptake value (SUV) avid lytic lesion seen at MRD assessment when compared with baseline (average SUV decline was 76%). 1 sCR patient did not have any FDG avid lesions at baseline. All patients maintained their best response and have no evidence of clinical disease progression. 4 patients completed 8 cycles of CRd, while 3 (2 sCR and 1 SD) continued to maintenance Len phase and 1 opted to exit study after achieving sCR. The patient with only SD (17p deletion on FISH at baseline) achieved a 65% decrease in plasma cell tumor burden in bone marrow and no evidence of disease progression after 10 cycles of therapy. Patients with non-hematologic toxicity events (≥ grade3) include: 3 (20%) - hypophosphatemia, 2 (13%) - ALT increase, 2 (13%) – CHF, 1 (6%) – fatigue, 1 (6%) - anxiety, 1 – (6%) syncope, and 1(6%) – rash. Patients with ≥ grade 3 hematologic toxicity events include 10 (66%) – lymphopenia and 1 (6%) - thrombocytopenia. Updated results on additional patients and molecular/MRD studies (flow cytometry, PCR, and FDG PET-CT) will be presented at meeting.

Using an approach that merges functional imaging with molecular responses beyond traditional clinical biomarkers, we show that CRd followed by LEN maintenance and delayed ASCT is a highly potent and tolerable combination regimen in newly diagnosed MM patients.

Off Label Use: In the clinical trial, we are using Carfilzomib in newly diagnosed multiple myeloma in combination with Lenalidomide and Dexamethasone. Currently, its label indication is single agent for use in relapsed/refractory multiple myeloma.