a Phase 1/2 Trial of Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin for Patients with Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: Berenson James , Stampleman Laura , Bessudo Alberto , Rosen Peter J , Klein Leonard M. , Woliver Thomas , Flam Marshall S. , Eshaghian Shahrooz , Nassir Youram , Regina Swift A , James Wang , Benjamin Eades , Spektor Tanya M. , Vescio Robert 
Published: October 2019

Abstract
Background
Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM.
Methods
The phase 1 portion enrolled MM pts w/progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who previously received POM treatment were ineligible. POM was administered orally on days 1-21 of a 28-day cycle, while DEX (40 mg) and PLD (5mg/m2) were both infused on days 1, 4, 8, and 11. During phase 1 enrollment, three cohorts were enrolled at 2, 3 and 4 mg doses of POM, and DEX and PLD were both administered at fixed doses. Phase 2 enrollment commenced once the MTD was established from the phase 1 portion of the study.
Results
As of August 1, 2015, 70 pts were screened, 68 were enrolled in the trial (with the pre-planned enrollment goal reached) and had received study drug, and a total of 50 pts were evaluable for safety and efficacy. Among all enrolled pts, 60pts discontinued treatment and 8 remain active. Pts had received a median of 4 prior treatments (range 1-18). Median number of cycles for all pts was 4 (range 1-8), with a median follow-up time of 5.5 months (range 0-22).
During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled.
Among the 57 pts enrolled in phase 2, 53% percent were refractory to LEN and steroids with or without other agents and 31% had previously received PLD. A median of 4 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Fifty-five pts were evaluable for response as 2 pts are active but have not yet had any post-baseline disease assessment. Among all evaluable pts (n=55) enrolled in phase 2, the overall response rate (ORR) was 33% (CR= 5%, VGPR= 5% and PR=23%) and clinical benefit rate (CBR) was 47% with 11 pts (26%) showing stable disease and 5 pts (12%) demonstrating progressive disease. For all evaluable pts enrolled in phase 2, the median follow-up time was 3.6 months (range 0-12 months) and the median PFS was 4.2 months (range 0.3- 29.0+). ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (36% and 51%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose.
Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (49 pts; 72.0%), lymphopenia (36 pts; 52.9%), leukopenia (33 pts; 48.5%), hyponatremia (27 pts; 39.7%), and hypokalemia (26pts; 38.2%). One pt died of grade 5 sepsis.
Conclusions
This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN.

Disclosures
No relevant conflicts of interest to declare.