Carfilzomib, Elotuzumab and Dexamethasone for Relapsed or Refractory Myeloma Patients

Introduction: Due to its heterogenous nature including evolving mutations, multiple myeloma (MM) is still an incurable disease. Several novel agents have been introduced during the last decade resulting in prolonged median overall survival (OS) up to 7-8 years. Nevertheless, disease relapse is expected and eventually all patients will end up with relapsed and refractory multiple myeloma (RRMM). To benefit from all available drugs, novel combinations should be evaluated for feasibility and efficacy. Bortezomib (B), elotuzumab and dexamethasone (d) showed superiority to Bd with progression-free survival (PFS) of 9.7 vs. 6.9 months, respectively, without excessive toxicity. In this study we investigated the safety and efficacy of carfilzomib (K), elotuzumab (E) and dexamethasone (D) combination (KED) in RRMM patients.

Patients and methods: Altogether 15 RRMM patients after 1-3 prior lines including B or/and lenalidomide (Len) were included. Refractoriness for B or/and Len was allowed. The main exclusion criteria were age > 74 years, absolute neutrophil count < 1.0 x 10⁹/L and platelet count < 75 x 10⁹/L, hemoglobin < 80 g/L, active heart disease or left ventricular ejection fraction < 40%. Carfilzomib was given once weekly 20 mg/m² on C1D1 and thereafter 70 mg/m² in 28-day cycles on day 1, 8, 15 in cycles 1-8, thereafter on day 1, 15 combined with weekly elotuzumab 10 mg/kg on day 1, 8, 15 in cycles 1-2, thereafter on day 1, 15; dexamethasone 40 mg on day 1, 8, 15, 22 in cycles 1-8, thereafter on day 1, 15. Treatment continued until progression (PD) or toxicity. The primary endpoint was overall response rate (ORR). If patients achieved at least very good partial remission (VGPR) the quality of response was assessed with high-sensitivity multicolour flow cytometry according to the 8-color EuroFlow protocol. Patients also completed health-related quality of life (QoL) questionnaires at day 1 and 15 through cycle 1-8.

Results: The median age of patients was 69 (62-73) years, 80% (12/15) had received upfront autologous stem cell transplantation. The median number of prior lines was 2 (1-3). Proportion of Len or B refractory was 47% and 20% were double refractory. FISH, beside at diagnosis, was repeated and 73% (11/15) had at least one of following aberrations: del17p, t(4;14), t(14;16), t(14;20) or +1q. Del17 was found in 27% (4/15) of patients and +1q was frequent (67%). After the median follow-up of 18 months the ORR (at least partial response, PR) was 87% (13/15). Seven patients (47%) achieved VGPR, of these 6 patients continue in study, one was withdrawn due to thrombotic microangiopathy (TMA). The median measurable MRD level of VGPR patients was 0.005% (range 0.002-0.15%, one undetectable), and 0.003% (range 0.0007-0.26%) after one year, respectively. Regarding the rest of the patients 6 achieved PR, one minimal response and one was refractory. The median time to response was 7 (3-16) weeks. The estimated median PFS is 22 months (CI 95% 17.4-27.1). The OS has not been reached.

Two (13%) grade 2 infusion reactions during first infusion were noticed. One patient developed autoimmune hemolytic anemia (AIHA), but recovered and continued KD without reappearance of AIHA. Grade 1-2 respiratory infections appeared in 66% of patients. Altogether 22 severe adverse events (SAE) grade 3-4 were reported in 60% (9/15) patients, one third were infections. Grade 3-4 neutropenia was found in 40% which is slightly more compared to reports when elotuzumab is combined with Len or pomalidomide. The overall QoL trajectory was kept steady throughout the 8 cycles. Diarrhea and dyspnoe were reported during treatment, but with full recovery before starting the next cycle which had no consequence for further treatment.

Conclusion:

The primary endpoint, at least PR, was reached in 87% of study patients. After a median follow-up of 18 months KED resulted in durable responses in 7 of these 15 patients (47%), despite the high frequency of adverse cytogenetics by FISH, 67% with +1q and 27% with del17p. The number of non-hematological SAEs was 60%. We noticed 2 serious unexpected adverse reactions, AIHA and TMA with convulsions, and an additional case of pulmonary embolism, in responding patients. We recommend careful monitoring for the signs of microangiopathy and hemolysis. In summary, KED resulted in a high ORR, which was durable in approximately 50% of the patients. Side effects were manageable and randomized trials with KED are warranted.