P-215: A phase I/II study of Pomalidomide, Ixazomib, Clarithromycin and Dexamethasone (PICd) in patients with relapsed or refractory Multiple Myeloma (RRMM)

Background Clarithromycin (CL) is a macrolide antibiotic with anti-MM activity when combined with dexamethasone (dex), and imids. Immunomodulatory activity and altered dex metabolism are proposed mechanisms of CL activity, though concerns over toxicity remain. We designed a phase I/II study of pomalidomide (pom), ixazomib (ix), CL and dex (PICd) to assess the tolerability and efficacy of CL in RRMM. Methods The primary endpoints were the maximal tolerated and recommended phase 2 dose of PICd. Secondary endpoints were overall response rate (ORR)(≥ PR), disease control rate (DCR)(≥ SD), duration of response (DOR) and progression free (PFS) and overall survival (OS). Cycles were 28 days. CL 250 mg PO BID was given c1 d15-21 and d1-21 subsequently. Pom 4 mg PO daily for 21 days, ix 4 mg d1, 8, 15 and dex 40 mg (20 mg if age >75 years) d1, 8, 15 and 22 were given for 6 cycles. After C6, maintenance until unacceptable toxicity or PD consisted of reduced pom, ix, dex and CL doses at 2, 2.3, 20 and 250 mg respectively. CL was held during weeks 1-2 of cycle 1 to facilitate correlative studies. Results A total of 32 patients consented to study. Of these, 4 were unevaluable for response/survival due to rapid disease progression (n=2), late screen failure (n=1), and withdrawn consent (n=1). Of these, 3 were included in toxicity data. Median follow up was 20 months (mo). Median age was 68.5 (range 54 – 82), 74% were male. Median number of prior therapies was 2 (1 – 5). All patients had prior lenalidomide and proteasome inhibitor exposure. Of the 26 patients with FISH data, 15 (57%) had high risk cytogenetics. Of these, 9 (35%) had del(17p), 10 (38%) had + 1q and 2 (8%) had t(4;14). Four had del(17p) and +1q; 1 each had t(4;14) and del(17p) or +1q. At least 1 grade 3-4 adverse event (AE) was experienced by 17 (55%) patients. Grade 3-4 hematologic AEs were seen in 8 (26%), of which 5 (16%) had neutropenia. Ten (31%) experienced grade 3-4 non-hematologic AEs, of which infections were the most common [4 (13%) patients]. Grade 3-4 neuropathy was not seen. ORR was 75%, DCR was 100%; 13 patients (56%) achieved ≥VGPR while 4 (14%) achieved CR/sCR. High risk cytogenetics were not associated with ORR (Fisher exact test P=1) or ≥VGPR rates (Fisher exact test P=0.42). Median DOR was 23.2 mo (95% Confidence interval: 12.2 – not reached); median PFS was 24.7 mo (13.4 – NR). There was no difference in median PFS in patients with or without del(17p): 24.7 mo (7.5 – NR) vs 22.2 mo (11.0 – NR) respectively (log rank P=0.4). Patients with + 1q had a median PFS of 13.4 mo (11 – NR) vs to 39.6 mo (25 – NR) in those without +1q (log rank P=0.09). Median OS was 37.3 mo (21.5 – NR). Correlative studies examining immune effector subsets before and after the addition of CL will be presented at the meeting. Conclusions Overall, PICd is a promising all PO regimen which combines convenient administration, tolerable side effect profile, and long duration of disease control.