Carfilzomib represents a potent and effective addition to standard multiple myeloma therapy

Results of the phase III ASPIRE study, demonstrate that adding carfilzomib to the ‘gold standard’ in multiple myeloma therapy, consisting of lenalidomide and dexamethasone, results in an highly increased duration of remission without additional toxicity. In fact, adding carfilzomib to lenalidomide-dexamethasone leads to a 8.7 month improvement in the progression-free survival (PFS) of these patients (p< 0.0001). In addition to this, a trend for a better overall survival (OS) and a significantly higher overall response rate (ORR) was seen in the carfilzomib treated patients. Interestingly, adding carfilzomib did not lead to added toxicity. As a consequence, less adverse-event related treatment discontinuations were seen in the carfilzomib arm as compared to the lenalidomide-dexamethasone arm.

The current global standard of care for patients with relapsed or treatment-resistant multiple myeloma is a combination of lenalidomide, which specifically targets the immune system, and the steroid dexamethasone. In order to evaluate whether carfilzomib combined with this standard therapy might improve treatment responses in patients with relapsed or treatment-resistant multiple myeloma, researchers enrolled 792 patients from 20 countries in a Phase III clinical trial, randomizing them to receive the standard combination of lenalidomide and dexamethasone or the combination along with carfilzomib.

At the time of the analysis, the group treated with the three-drug combination demonstrated a longer duration of response without disease progression (26.3 months) compared with the lenalidomide-dexamethasone treated group (17.6 months) (HR[95%CI]: 0.69[0.57-0.83]; p< 0.0001). The difference in ORR between the two treatment groups was also significant, at 87.4% in the carfilzomib group compared to 66.9% in the lenalidomide-dexamethasone group (p< 0.0001). The mean time to response was 1.6 months in patients receiving the combination with carfilzomib and 2.3 months in the lenalidomide-dexamethasone arm. The median OS was not reached in either group with a trend towards a longer OS with the carfilzomib combination as compared to lenalidomide-dexamethasone (HR[95%CI]= 0.79[0.63–0.99]; p= 0.018). However, this did not meet the pre-specified statistical boundary at the interim analysis of survival (p = 0.005). The 2-year OS rate was 73.3% with the three-drug combination vs. 65% with lenalidomide-dexamethasone.

Interestingly, despite the addition of a drug to the regimen, no dramatic increase in toxicity was observed in the carfilzomib-lenalidomide-dexamethasone group. The rate of adverse event related treatment discontinuations was lower in patients treated with carfilzomib as compared to the standard lenalidomide-dexamethasone therapy (15.3% vs. 17.7%). The percentage of deaths due to an adverse event was similar in both arms at 6.9%. The most common hematologic treatment-emergent adverse events (≥ 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 non-hematologic treatment-emergent adverse events (all grades) included diarrhea (42.3% vs. 33.7%), fatigue (32.9% vs. 30.6%), and cough (28.8% vs. 17.2%). Grade 3 or higher pneumonia occurred in 12.5% vs. 10.5% of the patients while grade 3 or higher hypokalemia and hypophosphatemia was observed in 9.4% vs. 4.9% and 8.4% vs. 4.6% of patients, respectively. Importantly, patients in the carfilzomib arm consistently reported higher quality of life scores than those receiving lenalidomide-dexamethasone.

In summary, adding carfilzomib to the gold standard in multiple myeloma therapy results in remissions with an unprecedented duration, without additional toxicity. Moreover, a trend in OS favoring the carfilzomib combination was seen and the ORR was significantly higher. The investigators hope that the results of this trial will lead to the approval of this treatment combination in patients with relapsed multiple myeloma worldwide.

Reference

Keith Stewart A, Rajkumar V, Dimopoulos M, et al. Carfilzomib, Lenalidomide, and Dexamethasone vs Lenalidomide and Dexamethasone in Patients (Pts) with Relapsed Multiple Myeloma: Interim Results from ASPIRE, a Randomized, Open-Label, Multicenter Phase 3 Study. Presented at ASH 2014; Abstract #79.