The primary and prespecified updated analyses of ICARIA-MM (clinicaltrial gov. Identifier: NCT02990338) demonstrated improved progression-free survival (PFS) and a benefit in overall survival (OS) was reported with the addition of isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma. Here, we report the final OS analysis. This multicenter, randomized, open-label, phase III study included patients who had received and failed ≥2 previous therapies, including lenalidomide and a proteasome inhibitor. Between January 10, 2017, and February 2, 2018, 307 patients were randomized (1:1) to isatuximab-pomalidomide-dexamethasone (Isa-Pd; N=154) or Pd (N=153), stratified based on age (<75 vs. ≥75 years) and number of previous lines of therapy (2-3 vs. >3). At data cutoff for the final OS analysis after 220 OS events (January 27, 2022), median follow-up duration was 52.4 months. Median OS was 24.6 months (95% confidence interval [CI]: 20.3-31.3) with Isa-Pd and 17.7 months (95% CI: 14.4- 26.2) with Pd (hazard ratio=0.78; 95% CI: 0.59-1.02; 1-sided P=0.0319). Despite subsequent daratumumab use in the Pd group and its potential benefit on PFS in the first subsequent therapy line, median PFS2 was significantly longer with Isa-Pd versus Pd (17.5 vs. 12.9 months; log-rank 1-sided P=0.0091). In this analysis, Isa-Pd continued to be efficacious and well tolerated after follow-up of approximately 52 months, contributing to a clinically meaningful, 6.9-month improvement in median OS in patients with relapsed/refractory multiple myeloma.

• MeSH
• Survival Analysis MeSH
• Drug Resistance, Neoplasm MeSH
• Dexamethasone * administration & dosage   MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized * administration & dosage   therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Multiple Myeloma * drug therapy   mortality   pathology   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Recurrence MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Thalidomide * analogs & derivatives   administration & dosage   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: The primary analysis of the ICARIA-MM study showed significant improvement in progression-free survival with addition of isatuximab to pomalidomide-dexamethasone in relapsed and refractory multiple myeloma. Here, we report a prespecified updated overall survival analysis at 24 months after the primary analysis. METHODS: In this randomised, multicentre, open-label, phase 3 study adult patients (aged ≥18 years) with relapsed and refractory multiple myeloma who had received at least two previous lines of therapy, including lenalidomide and a proteasome inhibitor, and had an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 102 hospitals in 24 countries across Europe, North America, and the Asia-Pacific regions. Patients were excluded if they had anti-CD38 refractory disease or previously received pomalidomide. Patients were randomly assigned (1:1), using an interactive response technology with permuted blocked randomisation (block size of four) and stratified by number of previous treatment lines (2-3 vs >3) and aged (<75 vs ≥75 years), to isatuximab-pomalidomide-dexamethasone (isatuximab group) or pomalidomide-dexamethasone (control group). In the isatuximab group, intravenous isatuximab 10 mg/kg was administered on days 1, 8, 15, and 22 of the first 4-week cycle, and then on days 1 and 15 of subsequent cycles. Both groups received oral pomalidomide 4 mg on days 1-21 of each cycle, and weekly oral or intravenous dexamethasone 40 mg (20 mg if aged ≥75 years) on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Here' we report a prespecified second interim analysis of overall survival (time from randomisation to any-cause death), a key secondary endpoint, in the intention-to-treat population (ie, all patients who provided informed consent and allocated a randomisation number) at 24 months after the primary analysis. Safety was assessed in all patients who received at least one dose or part dose of study treatment. The prespecified stopping boundary for the overall survival analysis was when the derived p value was equal to or less than 0·0181. This study is registered with ClinicalTrials.gov, NCT02990338, and is active, but not recruiting. FINDINGS: Between Jan 10, 2017, and Feb 2, 2018, 387 patients were screened and 307 randomly assigned to either the isatuximab (n=154) or control group (n=153). Median follow-up at data cutoff (Oct 1, 2020) was 35·3 months (IQR 33·5-37·4). Median overall survival was 24·6 months (95% CI 20·3-31·3) in the isatuximab group and 17·7 months (14·4-26·2) in the control group (hazard ratio 0·76 [95% CI 0·57-1·01]; one-sided log-rank p=0·028, not crossing prespecified stopping boundary). The most common grade 3 or worse treatment-emergent adverse events in the isatuximab group versus the control group were neutropenia (76 [50%] of 152 patients vs 52 [35%] of 149 patients), pneumonia (35 [23%] vs 31 [21%]), and thrombocytopenia (20 [13%] vs 18 [12%]). Serious treatment-emergent adverse events were observed in 111 (73%) patients in the isatuximab group and 90 (60%) patients in the control group. Two (1%) treatment-related deaths occurred in the isatuximab group (one due to sepsis and one due to cerebellar infarction) and two (1%) occurred in the control group (one due to pneumonia and one due to urinary tract infection). INTERPRETATION: Addition of isatuximab plus pomalidomide-dexamethasone resulted in a 6·9-month difference in median overall survival compared with pomalidomide-dexamethasone and is a new standard of care for lenalidomide-refractory and proteasome inhibitor-refractory or relapsed multiple myeloma. Final overall survival analysis follow-up is ongoing. FUNDING: Sanofi.

• MeSH
• Dexamethasone MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized MeSH
• Humans MeSH
• Adolescent MeSH
• Multiple Myeloma * drug therapy   MeSH
• Follow-Up Studies MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Aged MeSH
• Thalidomide analogs & derivatives   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma. METHODS: We did a randomised, multicentre, open-label, phase 3 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. We randomly assigned patients (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). Treatments were assigned based on a permuted blocked randomisation scheme with a block size of four. 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 primary endpoint was progression-free survival, 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. This study is registered at ClinicalTrials.gov, number NCT02990338. FINDINGS: Between Jan 10, 2017, and Feb 2, 2018, we 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 (IQR 10·1-13·9), median progression-free survival was 11·5 months (95% CI 8·9-13·9) in the isatuximab-pomalidomide-dexamethasone group versus 6·5 months (4·5-8·3) 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). INTERPRETATION: The addition of isatuximab to pomalidomide-dexamethasone significantly improves progression-free survival 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. FUNDING: Sanofi. VIDEO ABSTRACT.

• MeSH
• Dexamethasone administration & dosage   MeSH
• Progression-Free Survival MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local drug therapy   MeSH
• Multiple Myeloma drug therapy   MeSH
• Antibodies, Monoclonal administration & dosage   MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Aged MeSH
• Thalidomide administration & dosage   analogs & derivatives   MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Video-Audio Media MeSH
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Comparative Study MeSH
• Geographicals
• Asia MeSH
• Europe MeSH
• North America MeSH