P950: COMBINED PROTEASOME AND AUTOPHAGY INHIBITION IN RELAPSED/REFRACTORY MULTIPLE MYELOMA – A PHASE I TRIAL OF HYDROXYCHLOROQUINE, CARFILZOMIB AND DEXAMETHASONE

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Background: Multiple myeloma (MM) is characterized by malignant cells which produce large amounts of monoclonal immunoglobulin. MM cells are highly sensitive to drugs that target protein degradation. There are two important intracellular pathways for protein degradation (Lamark, 2010). The proteasome is responsible for the degradation of poly-ubiquitinated damaged, modified, misfolded and redundant proteins (Jung, 2009). This pathway of degradation is the target of proteasome inhibitors. The other main pathway is that of autophagy and lysosomal degradation, eliminating protein aggregates and damaged organelles. Hydroxychloroquine (HCQ) is an inhibitor of autophagy. In vitro studies have shown that HCQ potentiates carfilzomib (K) toxicity towards myeloma cells and could therefore be an attractive treatment option in myeloma (Baranowska, 2016). Here we present safety and efficacy data from a phase 1 study on the combination of HCQ, K and dexamethasone (d). Aims: This study aimed to answer the question whether combined inhibition of the proteasome and the autophagosome is safe and tolerable. The primary endpoint was to establish a maximum tolerated dose (MTD) of the combination HCQ-Kd. Methods: This phase I, single arm, open label dose escalation study (3 + 3 design), included patients with relapsed and/or refractory MM with at least two prior lines of therapy including bortezomib and an immunomodulatory agent. All patients started a 14-day run-in of HCQ at their intended HCQ dose level (DL) before the first cycle of HCQ-Kd. The HCQ DL were 200 mg (DL1), 400 mg (DL2), 600 mg (DL3), and 800 mg (DL4&5) daily. Intravenous carfilzomib was given in a dose of 20 mg/m2 in cycle 1 day 1, and thereafter 56 mg/m2 (DL1-4) and 70 mg/m2 (DL5) on day 8, 15, and in all subsequent cycles and doses. Oral dexamethasone 40 mg (20 mg pts >75y) was administered on day 1, 8, 15 and 22. Patients were treated with HCQ-Kd for a maximum of six 28-day cycles and continued Kd if still responding thereafter. The dose limiting toxicity (DLT) observation period was 28 days. Adverse events (AE) grade (G) 1-5 were registered from day 1 of run-in cycle and until 90 days post last dose of HCQ. Results: The clinical trial is completed, and we here report the data for MTD, safety and efficacy. 19 patients were included. One patient withdrew consent prior to first treatment cycle and was therefore not included in MTD and efficacy analyses. Median previous lines of therapy were 4 (2-9), 50% had high-risk cytogenetics. Only one DLT occurred at DL2 (G3 pneumonia), and MTD was not reached. 104 AEs were recorded, of which G1 45%, G2 32%, G3 22% and G4 1%. No deaths occurred. Most common AEs were anemia (74%), neutropenia (42%), thrombocytopenia (19%), skeletal pain (32%), respiratory tract infections (26%), insomnia (26%) and vomiting/nausea (21%). A total of 13 serious adverse events (SAEs) occurred during the study of which 2 led to treatment discontinuation. Responses were seen in 8 of 18 (ORR 44 %) including 3 PR (18%), 3 VGPR (18%), 1 CR (6%), 1 sCR (6%). Clinical benefit rate was 78 % when including 6 MR (33%) (figure 1). One patient reached MRD negativity. 7 patients did not complete all 6 cycles of HCQ-Kd, 5 due to PD and 2 due to SAEs. Image:Summary/Conclusion: HCQ given up to 800 mg daily in combination with weekly carfilzomib and dexamethasone is well tolerated in patients with relapsed/refractory multiple myeloma. Adverse events were mostly grade 1 and 2. The study results indicate a meaningful clinical efficacy of the combination.