A Phase II Study With Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) For Newly Diagnosed Multiple Myeloma

The current treatment for newly diagnosed elderly multiple myeloma (MM) patients, not eligible for transplant, induces approximately 30% near-complete response/complete response (nCR/CR). Carfilzomib is a novel, irreversible proteasome-inhibitor with significant activity and favourable toxicity profile, including very low rates of peripheral neuropathy and neutropenia. We evaluated efficacy and safety of the combination carfilzomib-cyclophosphamide-dexamethasone (CCd) in elderly newly diagnosed MM patients.

The Bryant and Day two-stage design was used to evaluate both efficacy and safety. Patients received oral cyclophosphamide (300 mg/m² on days 1,8,15), oral dexamethasone (40 mg on days 1, 8, 15, 22) and iv carfilzomib administered over 30 minutes (20 mg/m² on days 1, 2, and 36 mg/m² on days 8, 9, 15, 16, cycle 1; 36 mg/m² on days 1, 2, 8, 9, 15, 16, cycles 2-9) every 28 days for 9 cycles, followed by maintenance with iv carfilzomib (36 mg/m² on days 1, 2, 15, 16) every 28 days until progression or intolerance.

Enrollment is complete (58 pts): median age was 71 years, 28% of patients were older than 75 years, 40% had ISS stage III, 35% had unfavorable FISH profile [t(4;14) or t (14;16) or del17p] and 31% are frail, defined according to Charlson co-morbidity index (≥2), geriatric assessment score ADL (<4) and IADL (<5) and age with cut-off setting at 80 years. Twenty-five patients completed induction. After 9 induction cycles, 96% of patients achieved at least PR, 76% VGPR, 64% CR/nCR, including 24% stringent-CR. The 1-year PFS was 86% and the 1-year OS was 87%. Grade (G) 4 hematologic AE included neutropenia (3 pts, 5%). G3-4 non-hematologic AEs were infections (4 pts, 7%), cardiac (3 pts, 5%), constitutional (2 pts, 4%), renal (2 pts, 4%) and gastrointestinal complications (1 pt, 2%). Peripheral neuropathy was experienced by 11% of patients and was limited in severity to grade 1 or 2. Overall, the CCd regimen was well tolerated, 20% of patients required dose reduction and only 11% of patients required drug discontinuation during induction due to AEs. Twenty-five patients were assessable for maintenance treatment. After a median duration of maintenance of 6 months, the PR rate was 100%, including 68% CR/nCR (Table). The most frequent toxicity (all grades) during maintenance was fever (G1-2 in 6 pts [24%], G3 in 2 pts [8%]), occurring during the evening following the Carfilzomib infusion and not associated with chills, rigors, dyspnea and/or creatinine increase. There was only 1 (4%) G3 neutropenia and 1 (4%) G2 pericardial effusion. Peripheral neuropathy remained limited (2 pts [8%], all G 1-2).

The CCd regimen is highly active, showing rapid and deep responses, reaching after 9 cycles, 64% (at least nCR) and 24% sCR, further improving approximately 10-15% during maintenance. These responses compare favorably with the best frontline regimens, showing a doubling in nCR rate. It is well tolerated with limited grade 3-4 AEs, only 11% of patients required drug discontinuation due to AEs. An update will be presented at the meeting.

Bringhen:Onyx: Consultancy. Sonneveld:Onyx: Honoraria, Research Funding. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.