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Background: Isatuximab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide-dexamethasone and carfilzomib-dexamethasone for relapsed or refractory multiple myeloma. This phase 3, open-label study compared the efficacy of isatuximab plus carfilzomib-dexamethasone versus carfilzomib-dexamethasone in patients with relapsed multiple myeloma., Methods: This was a prospective, randomised, open-label, parallel-group, phase 3 study done at 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients with relapsed or refractory multiple myeloma aged at least 18 years who had received one to three previous lines of therapy and had measurable serum or urine M-protein were eligible. Patients were randomly assigned (3:2) to isatuximab plus carfilzomib-dexamethasone (isatuximab group) or carfilzomib-dexamethasone (control group). Patients in the isatuximab group received isatuximab 10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks. Both groups received the approved schedule of intravenous carfilzomib and oral or intravenous dexamethasone. Treatment continued until progression or unacceptable toxicity. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population according to assigned treatment. Safety was assessed in all patients who received at least one dose according to treatment received. The study is registered at ClinicalTrials.gov, NCT03275285., Findings: Between Nov 15, 2017, and March 21, 2019, 302 patients with a median of two previous lines of therapy were enrolled. 179 were randomly assigned to the isatuximab group and 123 to the control group. Median progression-free survival was not reached in the isatuximab group compared with 19·15 months (95% CI 15·77-not reached) in the control group, with a hazard ratio of 0·53 (99% CI 0·32-0·89; one-sided p=0·0007). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 136 (77%) of 177 patients in the isatuximab group versus 82 (67%) of 122 in the control group, serious TEAEs occurred in 105 (59%) versus 70 (57%) patients, and TEAEs led to discontinuation in 15 (8%) versus 17 (14%) patients. Fatal TEAEs during study treatment occurred in six (3%) versus four (3%) patients., Interpretation: The addition of isatuximab to carfilzomib-dexamethasone significantly improves progression-free survival and depth of response in patients with relapsed multiple myeloma, representing a new standard of care for this patient population., Funding: Sanofi. VIDEO ABSTRACT., Competing Interests: Declaration of interests PM reports honoraria from Amgen, Celgene, Janssen, Novartis, and Takeda; and a consulting or advisory role for Amgen, Celgene, Janssen, Novartis, and Takeda. M-AD reports consulting or advisory role for Amgen, Bristol Myers Squibb (BMS), Celgene, Janssen, and Takeda. JM reports honoraria from Celgene, Takeda, BMS, Janssen, and Amgen; and a consulting or advisory role for Amgen, BMS, Celgene, Janssen-Cilag, and Takeda. KY reports a consulting or advisory role for Amgen, Janssen, and Takeda; speaker's bureau for Amgen and Takeda; and research funding from Amgen and Sanofi. MC reports speaker's bureau for Amgen, Janssen, and Sanofi. TF reports an advisory role for Amgen, BMS, Celgene, Karyopharm, Oncopeptides, Roche, Sanofi, and Takeda; and speaker's bureau for Takeda. RH reports personal fees from AbbVie, Amgen, BMS, Celgene, Pharma Mar, Novartis, and Takeda; and grants from Novartis and Takeda. IS reports a consulting or advisory role for Amgen, BMS, Celgene, Janssen-Cilag, Novartis, and Takeda; and speakers' bureau for Amgen, BMS, Celgene, Janssen-Cilag, Novartis, and Takeda. TM reports research funding from Amgen and Sanofi. M-LR, GA, and SM are employed by Sanofi and may hold shares or stock options in the company. RB reports research funding from AbbVie, Acerta Pharma, Alexion, Amgen, Bayer, BMS, Boehringer Ingelheim, Celgene, CSL Behring, Daiichi Sankyo, Jansen-Cilag, MorphoSys, Pfizer, Portola, Rigel Pharmaceuticals, Roche, Sanofi, Takeda, and Technoclone; and consulting or advisory roles for Jansen-Cilag and Roche. KK reports research funding from BMS and Janssen; and honoraria from Amgen, BMS, Janssen, and Takeda. AO reports honoraria from Amgen, Celgene, and Janssen. KS reports honoraria from AbbVie, Amgen, BMS, Celgene, Jansen, Novartis, ONO, Sanofi, and Takeda; and consulting or advisory roles for AbbVie, BMS, and Celgene. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Carfilzomib, a proteasome inhibitor, is approved as monotherapy and in combination with dexamethasone or lenalidomide-dexamethasone (Rd) for relapsed or refractory multiple myeloma. The approval of carfilzomib-lenalidomide-dexamethasone (KRd) was based on results from the randomized, phase 3 study ASPIRE (NCT01080391), which showed KRd significantly improved progression-free survival (PFS) vs Rd (median 26.3 vs 17.6 months; hazard ratio (HR)=0.690; P=0.0001). This subgroup analysis of ASPIRE evaluated KRd vs Rd by number of previous lines of therapy and previous exposure to bortezomib, thalidomide or lenalidomide. Treatment with KRd led to a 12-month improvement in median PFS vs Rd after first relapse (HR 0.713) and a 9-month improvement after ⩾2 previous lines of therapy (HR 0.720). Treatment with KRd led to an approximate 8-month improvement vs Rd in median PFS in bortezomib-exposed patients (HR 0.699), a 15-month improvement in thalidomide-exposed patients (HR 0.587) and a 5-month improvement in lenalidomide-exposed patients (HR 0.796). Objective response and complete response or better rates were higher with KRd vs Rd, irrespective of previous treatment. KRd had a favorable benefit-risk profile and should be considered an appropriate treatment option for patients with 1 or ⩾2 previous lines of therapy and those previously exposed to bortezomib, thalidomide or lenalidomide.

Background: Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma., Methods: We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival., Results: Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in the carfilzomib group reported superior health-related quality of life., Conclusions: In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number, NCT01080391.).

Multiple myeloma is one of the most common hematological malignancies with increasing prevalence. Not until the introduction of 1 or 2 cycles of highdose therapy with the support of hematopoietic cells meant a certain progress in the prognosis of patients. The radical change in the therapy efficiency was not made possible until the so-called new or targeting drugs -  thalidomide, bortezomib and lenalidomide. The 2 latter preparations have particularly changed the approach to the disease itself from one of the least prognostically favourable hematological tumours to a longterm controllable malignancy with a potential to treat at least some of the patients. Currently, 3 ways of further progress towards more efficient treatment methods are under investigation: a) maintenance or consolidation treatment aimed at further intensification of therapeutic response, b) combination of targeting drugs and c) efficiency of the "second generation" targeting drugs.