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Dr. Sara Bringhen - A phase II study with carfilzomib, cyclophosphamide, and dexamethasone (CCd) for newly diagnosed MM

Sara Bringhen, MD
Myeloma Unit, Division of Hematology
University of Torino
Torino, Italy

12.13.13

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation II

Monday, December 9, 2013: 4:30 PM, 393-394 (Ernest N. Morial Convention Center)

Sara Bringhen, MD1*, Chiara Cerrato, MD1*, Maria Teresa Petrucci, MD2*, Mariella Genuardi, MD1*, Fabiana Gentilini, MD3*, Concetta Conticello3*, Stefania Oliva1*, Lucia Pantani, MD3*, Massimo Offidani, MD3*, Carmela Palladino1*, Giulia Benevolo, MD3*, Vittorio Montefusco, MD3*, Monica Astolfi1*, Oreste Villani3*, Agostina Siniscalchi, MD3*, Alberto Rocci4*, Lorenzo De Paoli3*, Mario Boccadoro, MD1*, Pieter Sonneveld, MD, PhD5 and Antonio Palumbo, MD1

1Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy
2Division of Hematology, Department of Cellular Biotechnology and Hematology, Sapienza University of Rome, Rome, Italy
3Italian Multiple Myeloma Network, GIMEMA, Italy
4Division of Hematology, Department of Molecular Biotechnologies and Health Sciences, University of Torino, Torino, Italy
5Erasmus University Medical Center, Rotterdam, Netherlands

 

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.

Table. Response rates after 4th, 9th cycles and 6 months of maintenance.

 

 

 

4th cycle

 

9th cycle

 

Maintenance

 

Stringent Complete Response

 

14%

 

24%

 

24%

 

At least near Complete Response

 

41%

 

64%

 

68%

 

At least Very Good Partial Response

 

67%

 

76%

 

80%

 

At least Partial Response

 

92%

 

96%

 

100%

 

 


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