Introduction: This independent phase 2 trial was designed to evaluate carfilzomib (C) combined with thalidomide and dexamethasone during induction and consolidation for feasibility, response and progression-free survival (PFS) in patients with newly diagnosed symptomatic MM, who were candidates for high-dose therapy. Patients with symptomatic MM and measurable disease, age 15 to 65 and no significant co-morbidity were eligible. At diagnosis Fluorescent in situ Hybridization (FISH) was performed of recurrent translocations, trisomy 9, del(17p), del (13q) and add(1q) Patients received 4 cycles of carfilzomib at 20 mg/m2 on days 1 & 2 followed by 27mg/m2 on days 8,9,15,16 of cycle 1 and on days 1,2, 8, 9, 15 & 16 of all subsequent 28-day cycles, thalidomide 200 mg days 1 - 28 of a 28 day cycle and dexamethasone 40 mg days 1, 8, 15 & 22 of a 28 day cycle. Stem cell harvest was performed with cyclophosphamide 2 g/m2 and G-CSF. Following HDM (200 mg/m2 ) and autologous stem cell transplantation (ASCT), consolidation therapy consisted of 4 cycles of carfilzomib 27 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle, thalidomide 50 mg days 1-28 of a 28 day cycle and dexamethasone 20 mg days 1, 8, 15, 22 of a 28 day cycle. The primary endpoint was response, other endpoints were complete response (CR) according to IMWG criteria, immunofixation-negative CR (sCR), VGPR all pre-and post HDM, PFS and overall survival (OS). An interim analysis was planned after 20 evaluable patients, primarily to guard against excessive toxicity and/or lack of response.
Results: While recruitment is still ongoing, 34 patients have been included, of which the first 20 patients were are evaluated for response and toxicity, with a median follow-up of 5 months. One patient was excluded because unavailability of data. Median age was 60 yr and ISS stages I/II/III were 8/6/5, respectively. Four patients went off treatment because of intolerance to thalidomide (n=1), tumor lysis syndrome with renal failure (n=1) or respiratory infections (n=2). Adverse events CTC grade 3+4 included tumor lysis syndrome (n=2), metabolic disorders (n=4), cardiovascular including DVT (n=5), gastrointestinal (n=2), skin rash (n=2) and reversible renal failure (n=3). Peripheral polyneuropathy grades 1+ 2 was observed in 7 (35%) of patients, but no grade 3 or higher. Responses after cycle 1 were CR + sCR 5%, VGPR 32%, PR 47%, SD 10%, NE 5% and after induction overall CR + sCR 21%, VGPR 47%, PR 16%, SD 10%, NE 5%. Median time to maximum response was 1 cycle. Secondary analysis revealed that responses occurred across cytogenetic subgroups as determined by FISH, i.e. add (1q) (n=2), t(4;14) (n=2), del(17p) (n=1) and del(13q) (n=5). Stem cell harvest was accomplished with standard CD34+ yield in all patients and HDM/ASCT was performed with complete hematologic recovery in 4/4 patients.
Conclusion: Carfilzomib combined with thalidomide and dexamethasone during induction and consolidation is feasible and effective. The complete data including response after consolidation will be reported at the ASH meeting.
This EMN trial was registered as NTR2422. Carfilzomib and an unrestricted grant was provided by ONYX Pharmaceuticals.