Carfilzomib, Lenalidomide, and Dexamethasone vs Lenalidomide and Dexamethasone in Patients with Relapsed Multiple Myeloma: Interim Results from ASPIRE, a Randomized, Open-Label, Multicenter Phase 3 Study

Keith Stewart, MD
Mayo Clinic
Scottsdale, AZ, USA

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation II
A. Keith Stewart, MD1, S. Vincent Rajkumar, MD2, Meletios A. Dimopoulos3, Tamás Masszi, MD, PhD4, Ivan Spicka, Prof. MD, PhD5*, Albert Oriol, MD6*, Roman Hájek, MD, PhD, Prof. of Oncology7*, Laura Rosiñol, MD, PhD8*, David S. Siegel, MD, PhD9, Georgi G. Mihaylov, MD, PhD10*, Veselina Goranova-Marinova, MD, PhD11*, Péter Rajnics, MD, PhD12*, Aleksandr Suvorov, MD13*, Ruben Niesvizky, MD14, Andrzej Jakubowiak, MD, PhD15, Jesus F. San Miguel16, Heinz Ludwig, Univ. Prof. Dr.17, Naseem Zojwalla, MD18, Margaret E. Tonda, PharmD18*, Biao Xing, PhD18*, Philippe Moreau19* and Antonio Palumbo, MD20

1Division of Hematology/Oncology, Research, Mayo Clinic, Scottsdale, AZ
2Division of Hematology, Mayo Clinic, Rochester, MN
3Alexandra Hospital, Athens, Greece
4St. István and St. László Hospital, Budapest, Hungary
5Clinical Department of Haematology of the First Faculty of Medicine and General Teaching Hospital, Charles University, Prague, Czech Republic
6Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Barcelona, Spain
7Department of Haematooncology, University Hospital Ostrava, University of Ostrava, Ostrava, Czech Republic
8Hematology, Hospital Clínic, Barcelona, Spain
9John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ
10Clinic for Hematology, University Hospital Sofia, Sofia, Bulgaria
11Clinic of Hematology, University Hospital “Sv.Georgi”, Plovdiv, Bulgaria
12Mór Kaposi Teaching Hospital, Kaposvár, Hungary
13Hematology Department, First Republican Clinical Hospital of Udmurt Republic, Izhevsk, Russia
14Center for Myeloma, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, NY
15KCBD, University of Chicago, Chicago, IL
16Clinica Universidad de Navarra, University of Navarra, Pamplona, Spain
17Department of Medicine I, Wilhelminen Cancer Research Institute, Wilhelminenhospital, Vienna, Vienna, Austria
18Onyx Pharmaceuticals, an Amgen subsidiary, South San Francisco, CA
19Hematology Department, University Hospital Hotel-Dieu, Nantes, France
20Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy

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.

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Dr. A. Keith Stewart is Dean for Research, and Vasek and Anna Maria Polak Professor of Cancer Research in the Department of Internal Medicine at the Mayo Clinic in Arizona. Dr. Stewart graduated from Aberdeen University, School of Medicine in Aberdeen, Scotland. He specializes in hematology/oncology and transplant surgery. Visit Dr. A. Keith Stewart’s full biography.

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