Addition of isatuximab, a monoclonal antibody that binds a specific epitope on the human CD38 receptor, to pomalidomide–dexamethasone significantly improves progression-free survival (PFS) in patients with relapsed and refractory multiple myeloma. Isatuximab is an important new treatment option for the management of relapsed and refractory myeloma, particularly for patients who become refractory to lenalidomide and a proteasome inhibitor, wrote Prof. Michel Attal of the Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France and Prof. Paul G. Richardson of the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA on behalf of the ICARIA-MM study group in an article published on 14 November 2019 in The Lancet.
Although several new treatment options for multiple myeloma are now available, there is no cure for this disease. Despite therapeutic advances, relapse is an inevitable feature of multiple myeloma. Patients with relapsed and refractory disease who have had several lines of previous therapy or who are refractory to lenalidomide and proteasome inhibitors require new treatment options.
Monoclonal antibodies targeting CD38 have emerged as an important new class of drugs against multiple myeloma. Isatuximab has antitumour activity via multiple biological mechanisms, including antibody-dependent cellular-mediated cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and direct induction of apoptosis without crosslinking. Isatuximab directly inhibits CD38 ectoenzyme activity, which is implicated in many cellular functions.
An in-vitro study showed the combination of isatuximab with pomalidomide resulted in greater direct toxicity and lysis of CD38 multiple myeloma cells by effector cells compared with isatuximab alone. As monotherapy, and in combination with other therapies, isatuximab has been shown encouraging activity in anti-myeloma treatment in phase I and II studies.
The aim of the current study was to determine the PFS benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma.
The investigators performed a randomised, multicentre, open-label, phase III study at 102 hospitals in 24 countries in Europe, North America, and the Asia-Pacific regions. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. The patients were randomly assigned (1:1) to either isatuximab 10 mg/kg plus pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ≥75 years), or pomalidomide 4 mg plus dexamethasone 40 mg. Randomisation was done using interactive response technology and stratified according to the number of previous lines of treatment (2–3 vs >3) and age (<75 years vs ≥75 years). The isatuximab–pomalidomide–dexamethasone group received isatuximab intravenously on days 1, 8, 15, and 22 in the first 28-day cycle, then on days 1 and 15 in subsequent cycles. Both groups received oral pomalidomide on days 1 to 21 in each cycle, and oral or intravenous dexamethasone on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal. Dose reductions for adverse reactions were permitted for pomalidomide and dexamethasone, but not for isatuximab. The study primary endpoint was PFS determined by an independent response committee and assessed in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of study drug.
Between January 2017 and February 2018, the study team randomly assigned 307 patients to treatment: 154 to isatuximab–pomalidomide–dexamethasone, and 153 to pomalidomide–dexamethasone. At a median follow-up of 11.6 months, median PFS was 11.5 months in the isatuximab–pomalidomide–dexamethasone group versus 6.5 months in the pomalidomide–dexamethasone group; hazard ratio 0.596 (95% CI 0·44–0·81; p = 0.001 by stratified log-rank test).
The most frequent treatment-emergent adverse events (any grade; isatuximab–pomalidomide–dexamethasone vs pomalidomide–dexamethasone) were infusion reactions (56 [38%] vs 0), upper respiratory tract infections (43 [28%] vs 26 [17%]), and diarrhoea (39 [26%] vs 29 [20%]). Adverse events with a fatal outcome were reported in 12 patients (8%) in the isatuximab–pomalidomide–dexamethasone group and 14 (9%) in the pomalidomide–dexamethasone group. Deaths due to treatment-related adverse events were reported for one patient (<1%) in the isatuximab–pomalidomide–dexamethasone group (sepsis) and two (1%) in the pomalidomide–dexamethasone group (pneumonia and urinary tract infection).
ICARIA-MM is the first phase III study of an anti-CD38 antibody in combination with pomalidomide and dexamethasone. The results of this study indicate that the addition of isatuximab to pomalidomide and dexamethasone provides a significant PFS benefit over pomalidomide and dexamethasone. Patients assessed in the study were more treatment refractory than those included in several previous studies with other combination treatments.
This study provides evidence for the efficacy of isatuximab in combination with the current standard-of-care treatment (pomalidomide and dexamethasone) in patients with relapsed and refractory multiple myeloma. If approved, isatuximab will provide a new treatment option for this patient population.
The study was funded bySanofi.
Attal M, Richardson PG, Rajkumar SV, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. The Lancet; Published online 14 November 2019. DOI: https://doi.org/10.1016/S0140-6736(19)32556-5