Until a few years ago, the treatment of relapsed multiple myeloma was a major challenge. However, with the availability of new substances, the situation has improved significantly. Since the end of 2015, the proteasome inhibitor carfilzomib has also been approved for treatment from the second line of therapy in Switzerland [1].
Regulatory study ASPIRE
The open-label ASPIRE trial randomized 792 patients with relapsed disease to carfilzomib/lenalidomide/dexamethasone (carfilzomib group) or lenalidomide/dexamethasone (control group) after prior completion of one to three courses of therapy [2]. Carfilzomib showed an 8.7-month prolongation of median progression-free survival (PFS) at 26.3 months (vs. 17.6 months; HR 0.69; 95% CI 0.57-0.83; p=0.0001). PFS improvement was also observed in patients previously treated with bortezomib (HR 0.70; 95% CI 0.56-0.88) or lenalidomide (HR 0.80; 95% CI 0.52-1.22).
At interim analysis, overall survival (OS) showed a trend in favor of carfilzomib, but median OS was not yet achieved in either treatment arm. A two-year Kaplan-Meier OS rate of 73.3% was observed with carfilzomib (vs. 65.0%; HR 0.79; 95% CI 0.63-0.99; p=0.04).
The overall response rate (ORR) was 87.1% (vs. 66.7%). 31.8% (vs. 9.3%) of patients achieved a complete response (CR) (p<0.001). With carfilzomib, an ORR of 87.0% (vs. 70.1%; p<0.0001) even achieved a median PFS of more than two years, 29.6 months (vs. 17.6 months; HR 0.69; 95% CI 0.52-0.94).
From the second line of therapy, a median PFS of 25.8 months (vs. 16.7 months; HR 0.69; 95% CI 0.54-0.89) and an ORR of 87.3% (vs. 64.4%; p<0.0001) was observed. 33.7% (vs. 7%) of patients after only one line of therapy and 30.2% (10.9%) from the second line of therapy achieved a CR or even better outcome with carfilzomib [3].
The most common adverse effects (all grades) with carfilzomib included hypokalemia (27.6% vs. 13.4%), cough (28.8% vs. 17.2%), upper respiratory tract infections (28.6% vs. 19.3%), diarrhea (42.3% vs. 33.7%), pyrexia (28.6% vs. 20.8%), hypertension (14.3% vs. 6.9%), and muscle cramps (26.5% vs. 21.1%). Peripheral polyneuropathy was approximately equally frequent in both treatment arms (all grades: 17.1% vs. 17.0%, 3rd/4th grades: 2.6% vs. 3.1%) [2].
Health-related quality of life was better assessed with carfilzomib than in the control group after 12 and 18 cycles of treatment [2].
Carfilzomib in elderly and high-risk patients.
In the subgroup of those over 70 years of age, a median PFS prolonged by eight months was observed with carfilzomib compared with the control group (23.8 months vs. 16 months; HR 0.739). In patients <70 years, the difference in median PFS was 11 months (28.6 months vs. 17.6 months; HR 0.668). This was also reflected in significantly higher ORRs with carfilzomib in both age groups (<70 years: 86.0% vs. 66.9%; ≥70 years 90.3% vs. 66.1%, p<0.0001) [4].
Patients with high-risk cytogenetics (t(4;14), t(14;16), or del(17p)) also achieved a significantly prolonged median PFS with a median duration of response of 22.2 months (vs. 14.9 months) and an ORR of 79.2% (vs. 59.6%) with carfilzomib compared with lenalidomide/dexamethasone (23.1 months vs. 13.9 months) [5].
Conclusion
The combination of carfilzomib with lenalidomide and dexamethasone resulted in a significant PFS benefit compared with lenalidomide/dexamethasone in all patient groups studied with good health-related quality of life [2,4,5].
Literature:
- www.swissmedicinfo.ch.
- Stewart AK, et al: Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. New England Journal of Medicine 2015; 372(2): 142-152.
- Dimopoulos MA, et al: Effect of carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone in patients with relapsed multiple myeloma by line of therapy: interim results from the phase 3 ASPIRE study. EHA20 Congress 2015, Vienna, Abstract S427.
- Palumbo A, et al: Efficacy and Safety of Carfilzomib, Lenalidomide, and Dexamethasone (KRd) vs Lenalidomide and Dexamethasone (Rd) in Patients (Pts) With Relapsed Multiple Myeloma (RMM) Based on Age: Secondary Analysis From the Phase 3 Study ASPIRE (NCT01080391). Clinical Lymphoma Myeloma and Leukemia 2015; 15:e75-e76.
- Avet-Loiseau H, et al: Efficacy and Safety of Carfilzomib, Lenalidomide, and Dexamethasone Vs Lenalidomide and Dexamethasone in Patients with Relapsed Multiple Myeloma Based on Cytogenetic Risk Status: Subgroup Analysis from the Phase 3 Study Aspire (NCT01080391). ASH Annual Meeting 2015, Abstract 731.
InFo ONCOLOGY & HEMATOLOGY 2016; 4(2): 22-24.
