Treatment Outcomes with Pomalidomide (POM) in Combination with Low-Dose Dexamethasone (LoDex) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM) and Del(17p13) and/or t(4;14)(p16;q32) Cytogenetic Abnormalities Who Have Received Prior Therapy with Lenalidomide (LEN) and Bortezomib (BORT)

Patients (pts) with MM who relapse and are refractory after therapy with bortezomib or immunomodulatory agents have overall survival (OS) and progression-free survival (PFS) of 9 mos and 5 mos, respectively (Kumar et al, Leukemia 2011). A number of cytogenetic abnormalities have also been associated with poor outcomes in MM, including t(4;14), and del(17p) (Avet-Loiseau et al, Blood 2007). In the multicenter, randomized, open-label MM-002 phase 1/2 study, the novel immunomodulatory agent POM, in combination with LoDEX, has demonstrated promising activity and favorable tolerability in pts with RRMM (Richardson PG, et al. Blood 2011;118:abs 634). Here we evaluated outcomes in pts participating in the study with high-risk cytogenetic profiles, with data as of 30 March 2012 presented.

Eligible pts with MM who had received ≥2 prior therapies (including LEN and BORT) and had disease progression within 60 days of their last treatment were randomized to treatment with either POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDEX, 40 mg/week) or POM alone. At progression, patients receiving POM alone could receive POM+LoDEX at investigator's discretion. Thromboprophylaxis with daily low-dose aspirin was mandatory. The endpoints in this study were PFS, response rates (using European Bone Marrow Transplantation [EBMT] criteria), duration of response, time to response, OS, and safety. Efficacy outcomes and safety in pts with high-risk cytogenetics were compared with those of pts with standard-risk cytogenetics as well as with the overall population who received POM+LoDEX as part of an exploratory analysis. High-risk cytogenetics were defined based on modified criteria and included the presence of the following abnormalities: del(17p13) and/or t(4;14)(p16;q32), based on interphase FISH analysis from marrow aspirates collected at study entry.

The intention-to-treat population included 113 pts who were treated with POM+LoDex. At baseline, high-risk and standard-risk cytogenetic profiles were identified in 30 pts (27%) and 57 (50%) pts, respectively; 26 pts (23%) were inevaluable. Cytogenetic abnormalities included del(17p13) in 19 pts and t(4;14)(p16;q32) in 25 pts. Median follow-up time was 13.2 mos for the high-risk group and 17.7 mos for the standard-risk group. The median ORR (≥PR) for all pts was 34%; median ORR for high-risk pts was 23%, compared with 40% for standard-risk pts. The overall median duration of response (≥PR) was 8.3 mos for all pts, 4.9 mos for high-risk pts, and 10.1 mos for the standard-risk pts. The median PFS was 4.6 mos for all pts. The median PFS was 3.1 mos for pts with high-risk cytogenetics and 5.5 mos for pts with standard-risk cytogenetic profiles, respectively. Median OS for all pts was 16.5 mos and was 13.2 mos in the high-risk pts vs 21.7 mos in the standard-risk pts.

The type and incidence of grade 3 or 4 adverse events (AEs) were similar in the high-risk pts (n=29) and those with standard-risk (n=57). The most common grade 3/4 AEs were neutropenia (48% vs 40%, respectively), thrombocytopenia (31% vs 16%), anemia (24% vs 25%), pneumonia (21% vs 28%), dyspnea (17% vs 11%), and fatigue (10% vs 18%). Febrile neutropenia developed in 2 pts (7%) with high-risk cytogenetics and in none with standard cytogenetics. There were no cases of grade 3/4 deep vein thrombosis in high-risk pts vs 2 pts (4%) in pts with standard-risk cytogenetics. There were no cases of grade 3/4 peripheral neuropathy in either group. Twenty-one (19%) of the POM+LoDex-treated subjects died during the study; 6 (21%) in the high-risk group (MM, n=3; disease progression, n=1; cardio-respiratory distress, n=1; not specified, n=1), and 10 (18%) in the standard-risk group (MM, n=4; disease progression, n=1; infection, n=3; cerebral/subarachnoid hemorrhage, n=2).

POM+LoDex treatment appears to be effective in MM pts with high-risk cytogenetic profiles and advanced disease. Although this subgroup of pts has a shorter duration of response compared with RRMM pts without high-risk cytogenetic abnormalities, pts with high-risk demonstrated an ORR of 23%, which is comparable to that expected for the overall population treated in this study, and is therefore encouraging. Longer follow-up for PFS and OS is needed to better assess clinical benefit, with combination approaches (such as with bortezomib) in this high-risk population warranting further study.

Richardson:Celgene, Millennium, Johnson & Johnson: Advisory Board Other. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Jakubowiak:Onyx: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Bahlis:Celgene: Honoraria; Johnson and Johnson: Honoraria, Research Funding. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Chen:Johnson & Johnson, Celgene, GlaxoSmithKline: Research Funding; Johnson & Johnson, Lundbeck, Celgene: Consultancy; Roche: Honoraria. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Larkins:Celgene Corporation: Employment, Equity Ownership. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.