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
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.
Paul Richardson introduces the paper on isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma as part of the ICARIA-MM study. Watch this abstract on YouTube
Introduction
Although several new treatment options for multiple myeloma are now available, there is no cure for this disease. Additionally, despite therapeutic advances, relapse is an inevitable feature of multiple myeloma, resulting in a continued need for new active treatments.1, 2 In particular, patients with relapsed and refractory disease who have had several lines of previous therapy or who are refractory to lenalidomide and proteasome inhibitors, the two more commonly used therapeutic classes for this disease, require new options.2, 3 Almost all patients with myeloma develop disease that is eventually refractory to lenalidomide and to proteasome inhibitors.
Monoclonal antibodies targeting CD38 have emerged as an important new class of drugs against multiple myeloma.4 Isatuximab is a monoclonal antibody that binds to a specific epitope on the human cell surface antigen CD38, which is widely and uniformly expressed on myeloma cells.5, 6, 7 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.8, 9, 10, 11, 12 Additionally, isatuximab directly inhibits CD38 ectoenzyme activity, which is implicated in many cellular functions.6, 9, 11
An in-vitro study10 showed the combination of isatuximab with pomalidomide (an immunomodulatory drug) 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 current standard-of-care therapies, isatuximab has been shown to be an active anti-myeloma treatment in phase 1 and 2 studies.13, 14, 15, 16, 17
Research in context
Evidence before this study
We searched PubMed for studies published from Jan 1, 2011, to Dec 31, 2016, with the terms “multiple myeloma”, “relapsed and refractory”, and “combination treatment”. At the time that this study was being designed, there were no studies published with an anti-CD38 monoclonal antibody in combination with pomalidomide–dexamethasone. Isatuximab is a monoclonal anti-CD38 antibody which has shown increased direct cytotoxic activity with pomalidomide compared with isatuximab alone in preclinical studies. Preliminary results from a phase 1 study showed that the combination of isatuximab with pomalidomide plus dexamethasone, was well tolerated and clinically active in patients refractory to both lenalidomide and a proteasome inhibitor. These encouraging results led to the design of our phase 3 study using the same combination in patients who have received at least two previous lines with lenalidomide and a proteasome inhibitor.
Added value of this study
To our knowledge, this was the first phase 3 study (ICARIA-MM) 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 benefit for progression-free survival over pomalidomide and dexamethasone. Patients assessed in the study were more treatment refractory than those included in several previous studies with other combination treatments.
Implications of all the available evidence
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, particularly those who become refractory to lenalidomide and a proteasome inhibitor. The use of an anti-CD38 antibody after a previous one in different lines of treatment still needs to be assessed.
The combination of pomalidomide and low-dose dexamethasone is an approved and established option for the treatment of relapsed and refractory myeloma in patients who have received at least two previous therapies including lenalidomide and a proteasome inhibitor.18, 19 Approval was based on the MM-003 randomised controlled trial,18 and this combination has subsequently become an established standard of care for patients with relapsed and refractory multiple myeloma. In a single-arm, non-randomised, phase 1 study20 of 103 patients with daratumumab, another anti-CD38 monoclonal antibody,20, 21, 22 combined with pomalidomide and dexamethasone, the median progression-free survival was 8·8 months and 60% of patients achieved an overall response. In a randomised phase 2 study23 of 60 patients assigned elotuzumab (a monoclonal antibody targeting signalling lymphocytic activation molecule F7) with pomalidomide and dexamethasone versus 57 assigned pomalidomide and dexamethasone, after a minimium follow-up of 9·1 months the median progression-free survival was 10·3 months in the elotuzumab group versus 4·7 months in the control group (hazard ratio [HR] 0·54, 95% CI 0·34–0·86; p=0·008). In a previous phase 1b dose escalation study, the combination of isatuximab with pomalidomide and low-dose dexamethasone was assessed in 45 patients with relapsed and refractory multiple myeloma, 82% of whom were refractory to lenalidomide and 84% of whom were refractory to a proteasome inhibitor.24 At a dose of 10 mg/kg (four weekly doses, then every 2 weeks in 31 patients), 64·5% achieved an overall response with isatuximab and median progression-free survival was 17·6 months (95% CI 6·80–20·5).24 Based on the results of the phase 1b study, we further assessed the combination of isatuximab with pomalidomide and dexamethasone in a similar population of patients with relapsed and refractory multiple myeloma in the phase 3 ICARIA-MM study.
We did a prospective, randomised, open-label, active-controlled, multicentre, phase 3 study,25 at 102 hospitals within 24 countries across Europe, North America, and the Asia-Pacific regions (appendix 3). The protocol was approved by institutional review boards and independent ethics committees of all participating institutions.
Eligible patients had relapsed and refractory multiple myeloma, received at least two previous lines of treatment, and had not responded to therapy with lenalidomide and
Results
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; figure 1). Data cutoff was Oct 11, 2018.
Patient characteristics were generally balanced across the groups (table 1). Median age was 67 years (IQR 60–73), and the median number of previous lines of treatment was 3 (IQR 2–4). More than half of the patients had received a previous transplantation, and all were previously treated
Discussion
In this study, the addition of isatuximab to pomalidomide and dexamethasone was associated with a significant and clinically meaningful benefit in progression-free survival in heavily treated patients with relapsed and refractory multiple myeloma with results from both the investigators and an independent response committee being consistent. Specifically, the Kaplan-Meier curves showed an early and sustained separation that translated into a 40% decrease in risk of death or progression for
Data sharing
Qualified researchers can request access to patient-level data and related study documents including the clinical study report, study protocol with any amendments, blank case report forms, statistical analysis plan, and dataset specifications. Patient-level data will be anonymised, and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data-sharing criteria, eligible studies, and process for requesting access are at: //www.clinicalstudydatarequest.com
Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study
Leukemia
(2012)
P Moreau et al.
Treatment of patients with multiple myeloma progressing on frontline-therapy with lenalidomide
Blood Cancer J
(2019)
C Varga et al.
Investigational agents in immunotherapy: a new horizon for the treatment of multiple myeloma
Br J Haematol
(2018)
P Lin et al.
Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma
Am J Clin Pathol
(2004)
D Atanackovic et al.
Immunotherapies targeting CD38 in multiple myeloma
Oncoimmunology
(2016)
NW van de Donk et al.
Monoclonal antibodies targeting CD38 in hematological malignancies and beyond
Immunol Rev
(2016)
L Moreno et al.
The mechanism of action of the anti-CD38 monoclonal antibody isatuximab in multiple myeloma
Clin Cancer Res
(2019)
J Deckert et al.
SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent antitumor activity in models of multiple myeloma and other CD38+ hematologic malignancies
Clin Cancer Res
(2014)
H Jiang et al.
SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide
Some therapeutic monoclonal antibodies, like daratumumab and elotuzumab, produce interfering monoclonal bands on serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE). Whether other common therapeutic antibodies also produce interference has not been systematically evaluated.
SPEP/IFE from patients receiving isatuximab (48 patients), belantamab mafodotin (BM; 41), and denosumab (41) were retrospectively reviewed for therapeutic antibody interference. Cases exhibiting isatuximab interference were quantified and the maximum duration of isatuximab effect was evaluated. To characterize band position, neat human serum was spiked with BM or denosumab at supratherapeutic concentrations. Band migration patterns were compared on SPEP and IFE, with band position expressed relative to other constant protein fractions.
Isatuximab-induced IFE interference was common (81.3 % of evaluated patients) with a maximum observed duration of 8 weeks. 10.4 % of isatuximab patients had IgG kappa monoclonal gammopathies that co-migrated with the drug; this subset could benefit from HYDRASHIFT 2/4 isatuximab testing. 8.3 % of IFE cases were negative for an isatuximab band but showed large, endogenous M-spikes migrating elsewhere. All patients in this group expired within 1 year of this finding. We hypothesize that an inability to detect isatuximab in this setting corresponds to a large residual myeloma burden that reduces isatuximab serum concentration. This observation may serve as a negative prognostic factor. Spiking studies demonstrated that BM and denosumab produce interference in vitro, but sustained interference was not observed in >40 treated patients.
Therapeutic antibody interference in patients receiving isatuximab is common, and can persist for at least 8 weeks after administration. >10 % of patients receiving isatuximab may benefit from HYDRASHIFT testing post-therapy. In contrast, BM and denosumab fail to produce sustained interference in treated patients.
A proportion of patients with multiple myeloma (MM) are older and/or have comorbidities, requiring dose adjustments. Data from OPTIMISMM (NCT01734928) supported the use of pomalidomide, bortezomib, and dexamethasone (PVd) for treating relapsed/refractory MM. This subanalysis of OPTIMISMM assessed outcome by frailty and/or bortezomib dose adjustment.
Patient frailty (nonfrail vs. frail) was classified using age, Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status. Data from patients requiring a bortezomib dose reduction, interruption, and/or withdrawal during PVd treatment were assessed.
Among 559 patients, 93 of 281 (33.1%) and 93 of 278 (33.5%) patients who received PVd and bortezomib and dexamethasone (Vd), respectively, were frail. Overall response rate (ORR) and median progression-free survival (PFS) were higher in nonfrail vs. frail with PVd treatment (ORR, 82.8% vs. 79.6%; PFS, 14.7 vs. 9.7 months); significantly higher than with Vd regardless of frailty. Grade ≥ 3 treatment-emergent adverse events (TEAEs) were higher with PVd vs. Vd, regardless of frailty. Discontinuations of PVd were lower in nonfrail vs. frail patients (19.2% vs. 30.1%); the median duration of treatment was similar (DoT; 8.8 vs. 8.9 months, respectively). Patients who received PVd with a bortezomib dose adjustment (n = 240) had a longer median DoT (9.3 vs. 4.5 months) and PFS (12.1 vs. 8.4 months) vs. those without.
Frail patients treated with PVd demonstrated a higher ORR and a longer PFS and DoT vs. Vd, despite a higher frequency of grade ≥ 3 TEAEs leading to pomalidomide, bortezomib, and/or dexamethasone discontinuation. Therefore, PVd treatment may improve patient outcomes, regardless of frailty.
Isatuximab-based combinations are among the accepted standard-of-care regimens for early-line treatment of patients with relapsed/refractory multiple myeloma (RRMM), based on the results of the Phase 3 ICARIA-MM and IKEMA trials. Further study findings have shown benefit with Isa-based combinations in patients with newly diagnosed MM, as reported from the randomized GMMG-HD7 and CONCEPT trials. Isa is currently approved in various countries for intravenous (IV) administration in patients with RRMM. A more convenient route of administration, such as subcutaneous (SC) injection, and faster IV infusion may substantially increase convenience of treatment. In this review, we outline evidence emerging from clinical trials that shows increasing clinical applicability of Isa across the MM therapeutic spectrum. We then review recent study results demonstrating that new treatment modalities, either SC Isa administration via an on-body delivery system (OBDS) or fast, 30-minute, fixed-volume IV infusion, are safe and effective, and enhance convenience of treatment with Isa for MM patients and healthcare providers. In the recently reported Phase 1b study, the safety profile and efficacy of Isa administered SC plus pomalidomide-dexamethasone were comparable to those observed with Isa administered IV plus pomalidomide-dexamethasone in the control arm and in the ICARIA-MM trial. Analysis of patient-reported outcomes indicated patient confidence in SC Isa administration and satisfaction with treatment delivery by OBDS. These findings point to SC administration as the preferred route for future treatment with Isa-based combinations, as well as to the use of fast, 30-minute IV infusions in settings where SC administration of Isa might not be available.
