A Phase II Study With Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) For Newly Diagnosed Multiple Myeloma
Authors: Bringhen Sara , Cerrato Chiara , Petrucci Maria Teresa , Genuardi Mariella , Gentilini Fabiana , Conticello Concetta , Oliva Stefania , Pantani Lucia , Offidani Massimo , Palladino Carmela , Benevolo Giulia , Montefusco Vittorio , Astolfi Monica , Villani Oreste , Siniscalchi Agostina , Rocci Alberto , De Paoli Lorenzo , Boccadoro Mario , Sonneveld Pieter , Palumbo Antonio 
Published: October 2019

Abstract

Background
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.

Methods
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.

Results
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).

Conclusions
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.

Disclosures:
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.