Carfilzomib Plus Dexamethasone ‘Standard of Care’ For Relapsed/Refractory Multiple Myeloma

Patients with relapsed or refractory multiple myeloma derive a significant overall survival benefit from carfilzomib plus dexamethasone over bortezomib plus dexamethasone

medwireNews: ENDEAVOR results show that carfilzomib plus dexamethasone offers a significant and clinically meaningful improvement in overall survival (OS) for patients with relapsed or refractory multiple myeloma compared with bortezomib plus dexamethasone.

The second interim analysis of the head-to-head phase III trial for patients who had received 1–3 prior treatments follows the previously reported findings of significantly better progression-free survival (PFS) and a higher objective response rate (ORR) with the irreversible epoxyketone-based Proteasome inhibitor combination than the reversible, boronic acid-based proteasome inhibitor regimen.

“These results show that carfilzomib in combination with dexamethasone is a highly effective treatment option for patients with relapsed or refractory multiple myeloma, and it should be considered a standard of care”, write Meletios Dimopoulos, from National and Kapodistrian University of Athens in Greece, and co-authors in The Lancet Oncology.

Median OS was 47.6 months for the 464 patients randomly assigned to receive carfilzomib on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle, with a starting dose of 20 mg/m2 for the first cycle and 56 mg/m2 thereafter. Dexamethasone 20 mg was given on days 1, 2, 8, 9, 15, 16, 22 and 23.

This compared with a median OS of 40.0 months (hazard ratio [HR]=0.79) in the 465 patients treated with bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle, alongside dexamethasone 20 mg on days 1 2, 4, 5, 8, 9 , 11 and 12.

Similar proportions of patients used further antimyeloma therapies during follow-up and a post-hoc landmark analysis did not show a significant difference in OS from time of first progression, at a median of 21.5 months in both treatment arms.

“Given the relapsing nature of multiple myeloma, it would be of interest to know if the administration of one proteasome inhibitor in an early line of therapy affects the efficacy of another proteasome inhibitor given in a later line of therapy”, the researchers remark, noting that the ENDEAVOR trial is not powered to answer this question.

Grade 3 or more severe adverse events were reported by 81% of carfilzomib-treated patients and 71% of those given bortezomib, with the most common side effects including anaemia (16 vs 10%), hypertension (15 vs 3%), pneumonia (9 vs 9%), thrombocytopenia (9 vs 9%) and fatigue (7 vs 8%).

The authors report that carfilzomib was associated with a higher rate of grade 3 or more severe cardiac failure (6 vs 2%) and acute renal failure (6 vs 3%) than bortezomib, but a significantly lower rate of the secondary endpoint of grade 2 or worse peripheral neuropathy (7 vs 35%, odds ratio=0.139).

Serious adverse events were also more common with carfilzomib, affecting 59% versus 40% of bortezomib-treated patients; there were comparable rates of adverse event-related deaths (7 vs 5%) and treatment-related deaths (1 vs <1%).

The author of a linked comment summarises that carfilzomib plus dexamethasone is “an effective two-drug combination that should be considered in patients with multiple myeloma who have received more than one previous line of therapy.”

Niels van de Donk, from VU University Medical Center in Amsterdam, the Netherlands, notes, however, that other treatment combinations have also been approved in the relapsed and refractory settings, including regimens adding carfilzomib, ixazomib or daratumumab to lenalidomide plus dexamethasone.

“In the absence of head-to-head comparisons, choice of therapy depends on patient characteristics (age, comorbidities, and performance status), tumour-related features (cytogenetics, and aggressiveness of relapse), and type of and response to previous treatments”, he writes.

“Biomarkers that predict response, survival, and toxicity of these different regimens are urgently needed to guide treatment choices in individual patients,” says the commentator.

“Furthermore, the optimal sequence of available therapies is also an important question.”

References

Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol; Advance online publication 23 August 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30578-8

van de Donk NWCJ. Carfilzomib versus bortezomib: no longer an ENDEAVOR. Lancet Oncol; Advance online publication 23 August 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30613-7

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