Mihaylov, Georgi

Abstract Introduction: Single-agent carfilzomib has shown encouraging activity in patients with relapsed and refractory multiple myeloma who harbor high-risk cytogenetic abnormalities (Jakubowiak et al, Leukemia 2013;27:2351-56). The phase 3 study ASPIRE (NCT01080391; N=792 patients) demonstrated that progression-free survival (PFS) was significantly improved with carfilzomib, lenalidomide, and dexamethasone (KRd), compared with lenalidomide and dexamethasone (Rd) in patients with relapsed multiple myeloma (RMM) (Stewart et al, N Engl J Med 2015;372:142-52). We present a pre-planned subgroup analysis of the efficacy and safety of KRd vs Rd in the ASPIRE study according to baseline cytogenetic risk status. Methods: Adults with RMM (1-3 prior lines of therapy) were eligible. Patients were randomized (1:1) to KRd or Rd. Treatment was administered in 28-day cycles. Patients in the KRd arm received carfilzomib as a 10-minute intravenous infusion on days 1, 2, 8, 9, 15, and 16 (starting dose, 20 mg/m2 on days 1 and 2 of cycle 1; target dose, 27 mg/m2 thereafter) during cycles 1-12; carfilzomib was omitted on days 8 and 9 during cycles 13-18 and was discontinued after 18 cycles. All patients received lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg on days 1, 8, 15, and 22. The primary end point was PFS. Secondary end points included overall survival, overall response rate (ORR), duration of response (DOR), health-related quality of life, and safety. Cytogenetic risk status was assessed using fluorescence in situ hybridization. The high-risk group consisted of patients with the genetic subtype t(4;14) or t(14;16) or with deletion 17p in ≥60% of plasma cells, according to central review of bone marrow samples obtained at study entry. The standard-risk group consisted of all other patients with known baseline cytogenetics. The cutoff value of 60% for the proportion of plasma cells with deletion 17p was used on the basis of recommendations from the International Myeloma Workshop Consensus Panel 2 (Munshi et al. Blood 2011;117:4696-700). Results: A total of 792 patients were randomized to KRd (n=396) or Rd (n=396). In patients with known baseline cytogenetics, baseline cytogenetic risk status was similar between the treatment arms (high-risk: KRd, 24.6%; Rd, 23.4%; standard-risk: KRd, 75.4%; Rd, 76.6%). Efficacy outcomes by cytogenetic risk status are presented in the Table. Median PFS in the high-risk group (n=100) was 23.1 months (95% confidence interval [CI]: 12.5-24.2) for KRd vs 13.9 months (95% CI: 9.5-16.7) for Rd (hazard ratio [HR]: 0.639; 95% CI: 0.369-1.106). Median PFS in the standard-risk group (n=317) was 29.6 months (95% CI: 24.1-not estimable) for KRd vs 19.5 months (95% CI: 14.8-26.0) for Rd (HR: 0.657; 95% CI: 0.480-0.901). ORRs were 79.2% (KRd) vs 59.6% (Rd) in the high-risk group, and 91.2% (KRd) vs 73.5% (Rd) in the standard-risk group. In the high-risk group, 29.2% (KRd) and 5.8% (Rd) of patients achieved a complete response (CR) or better, including 16.7% (KRd) and 3.8% (Rd) with a stringent complete response (sCR). In the standard-risk group, 38.1% (KRd) and 6.5% (Rd) of patients achieved ≥CR, including 15.0% (KRd) and 3.5% (Rd) with an sCR. Median DOR in the high-risk group was 22.2 months for KRd vs 14.9 months for Rd. Median DOR in the standard-risk group was 30.4 months for KRd vs 20.4 months for Rd. The rate of grade ≥3 adverse events was 89.1% (KRd) vs 78.4% (Rd) in the high-risk group, and 85.6% (KRd) vs 84.5% (Rd) in the standard-risk group. Rates of grade ≥3 adverse events of interest (dyspnea, hypertension, acute renal failure, cardiac failure, ischemic heart disease, and peripheral neuropathy) by cytogenetic risk status are presented in the Table. Conclusion: In patients with high-risk cytogenetics, treatment with KRd resulted in a median PFS of nearly 2 years, which was a 9-month improvement relative to that in patients treated with Rd. Treatment with KRd also led to a 10-month improvement in median PFS vs Rd in patients with standard-risk cytogenetics; similar reductions in the risk of progression or death with Kd vs Vd were observed in both cytogenetics risk groups. Treatment with KRd also led to higher response rates, greater response depth, and a longer DOR compared with Rd in patients with high- or standard-risk cytogenetics. KRd had a favorable benefit-risk profile in patients with RMM, irrespective of baseline cytogenetic risk status, and improved outcomes in patients with high-risk disease. Disclosures Fonseca: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Applied Biosciences: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Onyx/Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Dimopoulos:Celgene: Honoraria; Onyx: Honoraria; Genesis: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Spicka:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Masszi:Novartis: Consultancy; Janssen-Cilag: Consultancy; BMS: Consultancy; Takeda: Consultancy. Hájek:Janssen-Cilag: Honoraria; Celgene, Merck Sharp & Dohme: Consultancy, Honoraria. Rosiñol:Celgene: Honoraria; Janssen: Honoraria. Mateos:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy; Onyx: Consultancy. Wang:Celgene: Research Funding. Niesvizky:Celgene: Consultancy, Speakers Bureau. Oriol:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Jakubowiak:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: institutional funding for support of clinical trial conduct, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria. Bensinger:Onyx: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acetylon: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding. Kukreti:Lundbeck: Honoraria; Ortho: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Tonda:Onyx: Employment. Obreja:Amgen Inc: Employment. Moreau:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Lenalidomide with dexamethasone (Rd) is a standard of care used for pts with relapsed multiple myeloma (RMM). The randomized, open-label, multicenter, phase 3 study ASPIRE (NCT01080391) is comparing carfilzomib, lenalidomide, and dexamethasone (KRd) to Rd in pts with RMM. The primary end point is progression-free survival (PFS; assessed by an independent review committee). Secondary end points include overall survival (OS), overall response rate (ORR), duration of response (DOR), health-related quality of life (EORTC QLQ-C30 Global Health Status/QoL), and safety. Methods: Adults with RMM who received 1–3 prior regimens were eligible. Pts were randomized (1:1) to receive KRd or Rd and were stratified by β2-microglobulin levels (<2.5 vs ≥2.5 mg/L), prior bortezomib (no vs yes), and prior R (no vs yes). All pts received lenalidomide (25 mg) on days 1–21 and dexamethasone (40 mg) on days 1, 8, 15, and 22 of a 28-day cycle. In addition, KRd pts received K as a 10-min infusion on days 1, 2, 8, 9, 15, and 16 during cycles 1–12 (20 mg/m2 [days 1 and 2 of cycle 1]; 27 mg/m2 thereafter); K was omitted on days 8 and 9 during cycles 13–18 and was not administered beyond 18 cycles. Cycles were repeated until disease progression, unacceptable toxicity, or withdrawal of consent. The study had 90% power to detect a 25% reduction in risk for PFS events for KRd vs Rd (hazard ratio [HR]=0.75) at a 1-sided significance level of 0.025. A stratified log-rank test was used for the PFS comparison. Results: Data are presented for KRd followed by Rd throughout the abstract. Between July 2010 and March 2012, 792 pts from 20 countries were randomized. Baseline characteristics were balanced between the 2 groups. Median age was 64.0 years (range: 31.0‒91.0). Pts received a median of 2 prior regimens in each group. In both the KRd and Rd groups, 66% of pts received prior bortezomib; 20% of pts in each arm received prior R. Median treatment exposure was 22 cycles (KRd) and 14 cycles (Rd). At the time of the prespecified interim analysis, the study met the primary end point for PFS (HR=0.69; 95% confidence interval [CI]: 0.57–0.83; P<.0001), with a longer duration of median PFS in the KRd group (26.3 months [mo]; 95% CI: 23.3–30.5) compared with the Rd group (17.6 mo; 95% CI: 15.0–20.6). Median OS was not reached in either group; however, there was a trend toward longer OS with KRd compared with Rd (HR=0.79; 95% CI: 0.63–0.99; P=.018), which did not meet the prespecified statistical boundary at the interim analysis of survival (P=.005). The Kaplan-Meier OS event-free rates at 24 mo were 73.3% (95% CI: 68.6‒77.5) and 65.0% (95% CI: 59.9‒69.5). The ORR was 87.4% (95% CI: 83.7–90.5) with KRd and 66.9% (95% CI: 62.0–71.5) with Rd. Median DOR was 28.6 mo (95% CI: 24.9–31.3) and 21.2 mo (95% CI: 16.7–25.8). In the KRd and Rd groups, 31.8% vs 9.4% achieved a stringent complete response (sCR) or complete response (CR) (sCR: 14.1% vs 4.3%; CR: 17.7% vs 5.1%), and 70.4% and 40.7% achieved ≥very good partial response. KRd consistently improved Global Health Status/QoL compared with Rd over 18 cycles of treatment (P=.0001). Treatment discontinuation due to an adverse event (AE) occurred in 15.2% (KRd) and 17.4% (Rd) of pts. In each group, 7.7% and 8.5% of pts died while still on study treatment or within 30 days of receiving the last dose of study treatment. The most common hematologic treatment-emergent AEs (TEAEs) (≥grade 3) included neutropenia (29.6% vs 26.5%), anemia (17.9% vs 17.2%), and thrombocytopenia (16.6% vs 12.3%). The most common nonhematologic TEAEs (all grade) included diarrhea (42.3% vs 33.7%), fatigue (32.9% vs 30.6%), and cough (28.8% vs 17.2%). The most common nonhematologic TEAEs (≥grade 3) included pneumonia (12.5% vs 10.5%), hypokalemia (9.4% vs 4.9%), and hypophosphatemia (8.4% vs 4.6%). Other TEAEs of interest (grouped terms; all grade) included dyspnea (22.4% vs 18.0%), hypertension (preferred term; all grade: 14.3% vs 6.9%; grade 3: 4.3% vs 1.8%), acute renal failure (8.4% vs 7.2%), cardiac failure (6.4% vs 4.1%), and ischemic heart disease (5.9% vs 4.6%). Rates of peripheral neuropathy (PN) (grouped terms; all grade) were 17.1% and 17.0%; ≥grade 3 PN was infrequent (2.6% and 3.1%). Conclusion: The addition of carfilzomib to lenalidomide and dexamethasone in pts with RMM resulted in a statistically significant and clinically meaningful improvement in PFS. KRd had an acceptable safety and tolerability profile and represents a potential new standard of care. Disclosures Stewart: Novartis: Consultancy; Array BioPharma: Consultancy; BMS: Consultancy; Millenium: Research Funding; Celgene: Consultancy. Off Label Use: Carfilzomib is approved in the United States for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. ASPIRE is a randomized, multi-center, phase 3 study investigating the use of carfilzomib in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received 1–3 prior regimens.. Dimopoulos:Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Masszi:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Spicka:Janssen-Cilag: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Oriol:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Hájek:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosiñol:Celgene: Honoraria; Janssen: Honoraria. Siegel:Onyx: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Niesvizky:Onyx Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Jakubowiak:Onyx Pharmaceticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. San Miguel:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Millinnium: Membership on an entity's Board of Directors or advisory committees. Ludwig:Celgene: Research Funding, Speakers Bureau; Takeda Celgene: Research Funding, Speakers Bureau; Bristol-Myers: Research Funding, Speakers Bureau. Zojwalla:Onyx Pharmaceticals, an Amgen subsidiary: Employment, Equity Ownership. Tonda:Onyx Pharmaceticals, an Amgen subsidiary: Employment, Equity Ownership. Xing:Onyx Pharmaceticals, an Amgen subsidiary: Employment, Equity Ownership. Moreau:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo:Onyx Pharmaceuticals: Consultancy, Honoraria; Millennium Pharmaceuticals: Consultancy, Honoraria; Janseen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen, Inc,: Consultancy, Honoraria; Array BioPharma: Honoraria.

Key Points KRd has a favorable benefit-risk profile compared with Rd, regardless of baseline cytogenetic risk status, in patients with relapsed MM. KRd improves but does not abrogate the poor prognosis associated with high-risk cytogenetics in patients with relapsed MM.