Clarithromycin, Ixazomib, Pomalidomide, Dexamethasone for Relapsed/Refractory Myeloma: Survival and Correlative Analysis

This all-oral quadruplet was well tolerated and had extended 22 months progression free survival in relapsed myeloma patients

Correlative studies identified predictive makers of response and identified alterations in immune subsets with this quadruplet

Clarithromycin is a macrolide antibiotic with anti-MM activity when combined with dexamethasone, and immunomodulatory agents. We designed a phase I/II study of clarithromycin, ixazomib, pomalidomide and dexamethasone (ClIPd) to assess the tolerability and efficacy of this oral quadruplet in RRMM.

The primary endpoints were the maximal tolerated and recommended phase 2 dose of ClIPd. Key secondary endpoints were overall response rate (ORR) (≥ PR), disease control rate (DCR) (≥ SD), progression free (PFS) and overall survival (OS). All four medications were given at full dose for 6 cycles. Pomalidomide, ixazomib and dexamethasone were given at reduced doses, with full dose clarithromycin, for subsequent cycles as maintenance. Treatment continued until unacceptable toxicity or PD. Clarithromycin was held during weeks 1-2 of cycle 1 to facilitate correlative studies.

28 patients were enrolled and evaluable for response/survival. ORR was 75%, DCR was 100%; 56% achieved ≥VGPR while 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 PFS was 22.2 months (13.3 – NR). There was no difference in median PFS in patients with or without del(17p): 26.8 months (10.2 – NR) vs 22.2 months (13.3 – NR) respectively (log rank P=0.4). Patients with +1q had a median PFS of 17.0 months (11 – NR) vs to 25.0 (13.3 – NR) in those without +1q (log rank P=0.3). Median OS was not reached.

Overall, ClIPd combines convenient PO administration, tolerable side effect profile, and long duration of disease control. NCT02542657