Carfilzomib Combined with Thalidomide and Dexamethasone (CTD) Is an Highly Effective Induction and Consolidation Treatment in Newly Diagnosed Patients with Multiple Myeloma (MM) Who Are Transplant Candidate

Combinations of a proteasome inhibitor (PI) with an Imid plus dexamethason such as VRD or VTD have shown significant activity in newly diagnosed Multiple Myeloma. The use of these regimens is hampered by toxicity such as polyneuropathy and costs. Carfilzomib is a second generation PI that has shown activity as single agent and in combinations.

This investigator sponsored, dose escalation phase 2 trial was designed to investigate carfilzomib (C) combined with thalidomide (T) and dexamethasone (D) (CTD) for induction and consolidation treatment in patients with newly diagnosed symptomatic MM, who were transplant candidates. Patients with measurable disease, aged 18 to 65 were eligible. Patients in cohort 1 received 4 cycles of carfilzomib at 20 mg/m2 on days 1 & 2 followed by 27 mg/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 through 28 of a 28 day cycle and dexamethasone 40 mg on days 1, 8, 15 & 22 of a 28 day cycle. In cohort 2 the dose of carfilzomib was 20 mg/m2 on days 1 & 2 followed by 36 mg/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. Stem cell harvest was performed with cyclophosphamide 2 g/m2 and G-CSF. Following single high-dose melphalan (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, (cohort 1) or 36 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle (cohort 2), 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 at least very good partial response (VGPR) after 4 CTD cycles, secondary endpoints were complete response (CR) according to IMWG criteria, stringent CR (sCR), VGPR and an objective response (at least PR) pre-and post HDM, progression-free (PFS) and overall survival (OS).

58 patients were included as of 1^stAugust 2012. We here report on the first 40 registered patients, who were included in the first cohort and who are evaluable for response and toxicity. Median age was 58 yrs and ISS stages I/II/III were 40%/35%/25%, respectively. Of 40 patients, 35 (87%) completed 4 CTD induction cycles, 31 (77) competed HDM/ASCT. So far, 17 patients completed 4 consolidation cycles.

68 % of patients achieved an objective response within 1 cycle. Cytogenetic FISH data were available in 88%. Responses were achieved across ISS (I/II/III) or FISH subgroups, i.e. gain (1q) (n=4), t(4;14) (n=4), del(17p) (n=3), del(13q) (n=10) or normal. Stem cell harvest was successfully accomplished with > 3×10*6 CD34⁺ yield in 34/34 patients and HDM/ASCT was performed with complete hematologic recovery in 31/31 patients. Progression-free survival was 97% at 12 months, overall survival was 100% at a median follow-up of 10.4 months. This regimen was well tolerated. Non-hematological toxicity CTC grade 3+4 included tumor lysis syndrome (5%), DVT (10%), gastro-intestinal symptoms (5%), skin rash (8%). Peripheral polyneuropathy grade 2 or 3 was observed in 6 and 1 (17%) patients. No hematological toxicity was observed.

Carfilzomib combined with thalidomide and dexamethasone is a rapidly effective induction regimen. With the same regimen used as consolidation, a significant upgrade of responses is observed.

Sonneveld:Onyx: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; celgene: Honoraria, Research Funding. Lokhorst:Genmab: Consultancy.