Phase II Trial of Elotuzumab in Combination with Carfilzomib, Lenalidomide and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma (RRMM) after One Prior Line of Therapy

Introduction: The treatment for RRMM in first relapse typically involves a triplet combination, with choice influenced by the type of treatment already received, and the initial response. Elotuzumab (Elo), an anti-SLAMF7 immunostimulatory monoclonal antibody, mediates plasma cell killing by activating signals in NK cells and via antibody-dependent cell-mediated cytotoxicity. Carfilzomib (K) and lenalidomide (R) can activate NK cells and enhance NK cell-mediated lysis, whereas dexamethasone (d) can potentiate these strong pro-inflammatory stimuli by altering NK cell activating receptor expression and by sensitizing T cells to anergy signaling. Here, we report the preliminary results of a phase II study of Elo in combination with KRd (Elo-KRd) for MM in first relapse [ClinicalTrials.gov Identifier: NCT03361306].

Methods: Patients with RRMM (biochemical and/or clinical) aged at least 18 years who had received one prior line of systemic therapy and had measurable disease were included. Patients refractory to bortezomib and/or R were eligible. Patients with plasma cell leukemia (PCL) were not excluded. Treatment consisted of 4 cycles of Elo-KRd Induction (Elo 10 mg/kg IV once weekly on days 1,8,15, 22; K 20/27 mg/m ² IV on days 1,2,8,9,15,16 ;R 25 mg oral daily on days 1-21; d 28 mg oral and 8 mg IV once weekly on days 1,8,15, 22) repeated every 28 days, followed by Elo-R maintenance (Elo 10 mg/kg IV every 2 weeks on days 1,15 for cycles 1-2 then 20 mg/kg IV on day 1 of each cycle; R 15 mg or last tolerated dose oral on days 1-21), cycle 5 and beyond until progression or unacceptable toxicity The primary endpoint of the study was very good partial response or better (≥VGPR) after 4 cycles of induction therapy. Secondary endpoints included overall response rate (ORR), overall survival (OS), progression free survival (PFS), minimal residual disease (MRD) and safety. Results are summarized with frequencies and proportions for categorical data, including response, and descriptive statistics for continuous data. Median survival outcomes were estimated with Kaplan Meier methods.

Results: A total of 15 patients were enrolled by the data cut-off of 04/23/2021. Median age was 64 (range, 46-74) years; 13% of patients were ≥70 years old. Patients were uniformly distributed within revised ISS stages I/II/III at time of diagnosis, 33.3% in each category. Six (40%) patients had high-risk features: 4 with chromosomal abnormalities [del17p, t(4;14) or t(14;16)], 1 primary PCL and 1 extramedullary MM (lymph nodes and muscles). Twelve (80.0%) were refractory to R, 5 (33.3%) were refractory to bortezomib, one (3.3%) had prior Daratumumab exposure, and 12 (80.0%) had undergone autologous stem cell transplantation. Twelve patients completed 4 cycles of Elo-KRd induction while 3 patients discontinued treatment (due to disease progression) prior to completing induction. At end of induction, the ORR was 66.7% including ≥VGPR in 33.3% (5/15), CR in 13.3%. Rate of ≥VGPR as best response during study was 53.3% (8/15), with an ORR of 80%. MRD-negative (10 ^-5) rate post-induction was 20% (3/15). After a median follow-up of 23.1 months (range, 3.8 to 38.6 months), the median PFS is 11.5 months (95% CI 1.9, 18), and median OS is not reached (95%CI 10.1, NA). Grade 3/4 treatment-emergent adverse events (TEAEs) occurring in ≥10% of patients were neutropenia (n=5), thrombocytopenia (n=3), hypophosphatemia (n=4), fatigue (n=3), thromboembolic event (n=2), and second neoplasms (n=1, renal cell carcinoma). Grade 3/4 infection rate was 13.3% (2/15). No patient discontinued treatment due to an adverse event. We intend to update the analysis of the study results at the meeting.

Conclusions: Elo-KRd was well tolerated and demonstrated activity in this high-risk patient population comparable to other contemporary approved triplet combinations in this population.