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Once-Weekly Carfilzomib with Dexamethasone Demonstrated Promising Safety and Efficacy in Patients with Relapsed or Refractory Multiple Myeloma Regardless of Age and Prior Bortezomib Exposure

Jesus G. Berdeja, Robert M. Rifkin, Roger Lyons, Hui Yang, Anita Zahlten-Kuemeli, Sanjay K. Aggarwal, Karim Iskander and James Berenson

Abstract

Background: The multicenter phase 1/2 CHAMPION-1 study (NCT01677858) showed that once-weekly carfilzomib and dexamethasone was well tolerated and active in patients with relapsed or refractory multiple myeloma (MM) (Berenson et al. Blood. 2016;127:3360−3368). We present a secondary analysis of the efficacy and safety of once-weekly carfilzomib with dexamethasone in the CHAMPION-1 study according to prior bortezomib (BTZ) exposure and age.

Methods: Patients with relapsed or refractory MM (1−3 prior therapies) were eligible. The primary objectives were to determine the maximum tolerated dose (MTD) of once-weekly carfilzomib with dexamethasone (phase 1) and to determine the overall response rate (ORR; phase 2). Secondary objectives included assessment of safety and tolerability, and evaluation of the clinical benefit rate and progression-free survival (PFS) in the phase 2 portion.

Patients received carfilzomib as a 30-minute, intravenous (IV) infusion on days 1, 8, and 15 of 28 day cycles. Patients received carfilzomib at 20 mg/m2 on cycle 1, day 1; subsequent doses were escalated to 45, 56, 70, or 88 mg/m2, using a standard 3+3 escalation schema to determine the MTD. In the phase 2 portion, patients received carfilzomib at the MTD. All patients received dexamethasone 40 mg (IV or orally) on days 1, 8, 15, and 22 of 28 day cycles for cycles 1−8; dexamethasone was omitted on day 22 for cycles ≥9.

The MTD of once-weekly carfilzomib (30-min IV infusion) with dexamethasone was established to be 70 mg/m2 (Berenson et al. Blood. 2016;127:3360−3368). In this secondary analysis, the efficacy and safety of once-weekly carfilzomib at this dose were evaluated by prior BTZ exposure (no prior exposure vs exposed but not refractory vs refractory) and age (<65 vs 65−74 vs ≥75 years).

Results: The data cutoff date for this analysis was Nov 5, 2015.A total of 104 patients (phase 1 and 2; <65 years, n=34; 65-74 years, n=41; ≥75 years, n=29) received carfilzomib at a dose of 70 mg/m2 (no prior BTZ exposure, n=17; prior BTZ exposure but not BTZ-refractory, n=33; BTZ-refractory, n=54). The ORR for all 104 patients receiving the 70 mg/m2 dose was 77%; the median PFS was 14.3 months. Efficacy by prior BTZ exposure is presented in Table 1. The ORRs were 94%, 91%, and 63% for patients with no prior BTZ exposure, those exposed but not refractory to BTZ, and BTZ-refractory patients, respectively. The proportions of patients who achieved a complete response (CR) or better were 35% (no prior BTZ exposure), 21% (exposed to but not refractory to BTZ), and 9% (BTZ-refractory). The median PFS durations were 21.0, 19.4, and 5.3 months in these subgroups, respectively.

The median treatment durations by age were 6.4 months (<65 years), 6.2 months (65-74 years), and 9.9 months (≥75 years); mean cumulative doses of carfilzomib received were 1876.8, 1846.5, and 2156.1 mg/m2, respectively. Efficacy and safety outcomes by age are shown in Table 2. The median PFS durations were 7.4 and 10.2 months for patients aged <65 and 65−74 years, respectively; the median PFS was not reached for those aged ≥75 years. The ORRs were 79%, 73%, and 79% for patients aged <65 years, 65−74 years, and ≥75 years, respectively. The ≥CR rates were 26% (<65 years), 15% (65-74 years), and 10% (≥75 years). Overall rates of treatment discontinuation were similar among age subgroups (Table 2). The rates of treatment discontinuation due to adverse events were 3% (<65 years), 17% (65−74 years), and 21% (≥75 years). The proportions of patients with at least one grade ≥3 adverse event were 56% (<65 years), 61% (65−74 years), and 76% (≥75 years). Rates of grade ≥3 adverse events of interest by age are shown in Table 2.

Conclusions: Once-weekly carfilzomib (70 mg/m2) with dexamethasone was safe and active for patients with relapsed or refractory MM, regardless of prior BTZ exposure or age. As expected, the median PFS durations in the BTZ-naïve or -sensitive patients were longer relative to that in the BTZ-refractory patients. Although there were higher incidences of grade ≥3 adverse events and treatment discontinuations due to adverse events in older patients (≥65 years) relative to younger patients (<65 years), median PFS was not negatively affected by increasing age. Overall, once-weekly carfilzomib with dexamethasone had a favorable benefit-risk profile in patients with relapsed or refractory MM, irrespective of prior BTZ exposure or age.

Disclosures Berdeja: Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding. Rifkin: Amgen/ONYX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Yang: Amgen Inc.: Employment, Equity Ownership. Aggarwal: Amgen: Employment, Equity Ownership. Iskander: Amgen Inc: Employment, Equity Ownership. Berenson: Amgen Inc: Consultancy, Honoraria, Research Funding, Speakers Bureau.

  • * Asterisk with author names denotes non-ASH members.