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.
Asterisk with author names denotes non-ASH members.