Isatuximab plus pomalidomide and dexamethasone in frail patients with relapsed/refractory multiple myeloma: <scp>ICARIA‐MM</scp> subgroup analysis

Multiple myeloma (MM) typically affects elderly patients, with a median age at diagnosis of 69 years. Treatment is often challenging due to frailty, defined as a state of cumulative decline in physiological function, leading to high risk of adverse health-related outcomes, resulting in increased morbidity and mortality.1 The International Myeloma Working Group (IMWG) has developed a frailty score to guide therapy selection in patients with newly diagnosed MM.2 The IMWG frailty score combines age, comorbidities, and functional status based on the capacity to perform Activities of Daily Living (ADL). Facon et al. developed a simplified frailty score, measuring functional status using the Eastern Cooperative Oncology Group performance status (ECOG PS), a more commonly collected feature in clinical trials than ADL.3 On the basis of the pivotal phase 3 ICARIA-MM study (NCT02990338), isatuximab (Isa), a CD38 monoclonal antibody, is approved in a number of countries in combination with pomalidomide and dexamethasone (Pd) for the treatment of adult patients with relapsed/refractory MM (RRMM) who have received two or more prior therapies, including lenalidomide and a proteasome inhibitor. ICARIA-MM demonstrated the efficacy and safety of Isa-Pd in patients with RRMM across subgroups.4 Progression-free survival (PFS) was significantly improved with Isa-Pd versus Pd in patients ≥75 years old, and health-related quality of life parameters were better maintained in the triplet Isa-Pd arm, including in patients ≥75 years.4, 5 This post-hoc analysis used a simplified frailty score derived from patient baseline characteristics to investigate the impact of frailty on clinical outcomes and safety. A total of 307 RRMM patients were randomized to receive Isa-Pd (n = 154) or Pd (n = 153) and stratified by age (< 75 vs. ≥ 75 years) and number of previous lines of therapy (2–3 vs. > 3). Frailty scores at baseline were calculated based on age, modified Charlson Comorbidity Index (CCI), and ECOG PS (see Supplementary Materials). The modified CCI was calculated using detailed medical history recorded during a screening visit and coded with MedDRA v.21.0 for analysis. All patients provided written informed consent. The overall ICARIA-MM population comprised 28.0% frail (score sum ≥2) and 69.4% fit/intermediate patients; eight (2.6%) patients were excluded from the analysis because no medical history was available (Table S1). There were more frail patients in the Isa-Pd arm (31.2%) than in the Pd arm (24.8%), although this difference was non-significant (p = 0.2167). As expected, frail patients were older and had a higher ECOG PS than fit/intermediate patients in both arms. Additionally, a greater proportion of frail patients had International Staging System (ISS) stage III disease (p = 0.0015). This can be partially explained by the fact that frail patients were, on average, 10 years older than fit/intermediate patients. Also, the parameters used for ISS staging worsen with age, without necessarily reflecting an increase in tumor load. Other patient baseline characteristics were generally balanced (Table S1). The PFS benefit of Isa-Pd versus Pd in frail and fit/intermediate patients was consistent with that in the overall study population although not statistically significant (Figure 1A). For frail patients, median PFS was 9.0 months for those on Isa-Pd versus 4.5 months for those on Pd (HR = 0.81; 95% CI: 0.45–1.48, log-rank p = 0.4928). For fit/intermediate patients, median PFS was 12.7 months for those on Isa-Pd versus 7.4 months for those on Pd (HR = 0.49, 95% CI: 0.33–0.73, log-rank p = 0.0004; Figure 1A). At the time of analysis, overall survival (OS) data were not yet mature, and the log-rank p-values for the median OS in Isa-Pd versus Pd were 0.3053 for frail and 0.0689 for fit/intermediate patients, respectively (Figure 1B). One-year OS probabilities in frail patients were 66.9% (95% CI: 0.51–0.79) for those on Isa-Pd and 58.8% (95% CI: 0.41–0.73) for those on Pd, and the values for fit/intermediate patients were 75.0% (95% CI: 0.65–0.83) for those on Isa-Pd and 64.5% (95% CI: 0.54–0.73) for those on Pd. The overall response rate (ORR) and very good partial response or better (≥VGPR) rate were higher for those on Isa-Pd versus Pd regardless of frailty status (Figure 1C). In frail patients, ORR was 52.1% in those on Isa-Pd versus 34.2% in those on Pd (p = 0.0476). In fit/intermediate patients, ORR was 66.3% for those on Isa-Pd versus 35.7% for those on Pd (p < 0.0001). In frail patients, the ≥VGPR rate was 29.2% for those on Isa-Pd versus 2.6% for those on Pd (p = 0.0013), and in fit/intermediate patients, the rates were 34.7% for those on Isa-Pd versus 10.7% for those on Pd (p < 0.0001; Figure 1C). It is notable that the difference in the ORR rate between frail and fit/intermediate patients receiving Isa-Pd was not statistically significant (p = 0.3971). Whereas no patients in the Pd arm achieved minimal residual disease (MRD) negativity (evaluated with investigator-assessed complete response at 10−5 sensitivity by next-generation sequencing), 8/149 (5.4%) patients in the Isa-Pd arm had MRD negativity, with four patients each in the frail and fit/intermediate subgroups. Treatment duration was longer for those on Isa-Pd for both frail and fit/intermediate patients (Table S2). The median (range) durations of exposure for those on Isa-Pd versus Pd were 40.8 (1.3–75.1) versus 22.1 (1.6–69.0) weeks for frail patients and 41.6 (4.0–76.7) versus 24.0 (1.0–73.7) weeks for fit/intermediate patients. Additionally, the median (range) numbers of cycles started with Isa-Pd versus Pd were 9.5 (1–18) versus 5.5 (1–17) in frail patients and 10.0 (1–19) versus 6.0 (1–18) in fit/intermediate patients. The relative dose intensity for the three drugs was slightly lower in frail patients than in fit/intermediate patients, because they had higher reduction rates due to treatment-emergent adverse events (TEAEs; Table S2). All frail patients in both treatment arms experienced TEAEs (Table S3). All fit/intermediate patients in the Isa-Pd arm experienced TEAEs, as compared with 98.2% in the Pd arm. The most common any-grade non-hematologic TEAE in Isa-Pd versus Pd was diarrhea for frail patients (33.3% vs. 27.8%) and infusion reactions (40.0% vs. 0%) for fit/intermediate patients. Fewer infusion reactions were observed in frail patients (31.3%) compared with fit/intermediate patients (40.0%) treated with Isa-Pd (p = 0.3025). In the Isa-Pd arm, TEAEs with the greatest difference in incidence in frail and fit/intermediate patients were dyspnea (25.0% and 10.0%, respectively) and pyrexia (20.8% and 12.0%, respectively). There were more upper respiratory tract infections in patients receiving Isa-Pd versus Pd independent of their frail status (Table S3). Anemia and thrombocytopenia rates were similar in the Isa-Pd and Pd arms for both frail and fit/intermediate patients (Table S4). Grade 4 neutropenia was more common in patients in the Isa-Pd arm versus the Pd arm, independently of their frailty status: 68.8% versus 31.4% in frail patients, respectively, and 58.0% versus 31.8% in fit/intermediate patients (Table S4). The incidence rates of febrile neutropenia (all grade ≥ 3) were 12.5% in the Isa-Pd arm and zero in the Pd arm for frail patients and 12.0% in the Isa-Pd arm versus 2.7% in the Pd arm for fit/intermediate patients. Death during treatment with Isa-Pd versus Pd occurred in 10.4% versus 11.1% of frail patients and 6.0% versus 9.0% of fit/intermediate patients. Regardless of frailty status, fewer patients in the Isa-Pd arm discontinued treatment due to TEAEs, and they had greater time to treatment discontinuation compared with the Pd arm. Treatment discontinuation due to TEAEs in Isa-Pd versus Pd occurred in 8.3% versus 16.7% of frail patients and 7.0% versus 11.7% of fit/intermediate patients. Median times to premature or definitive treatment discontinuation for Isa-Pd versus Pd were 8.7 versus 4.9 months in frail patients (HR = 0.68, 95% CI: 0.40–1.16, p = 0.1546) and 9.4 versus 5.3 months in fit/intermediate patients (HR = 0.61, 95% CI: 0.43–0.86, p = 0.0041) (Figure S1). The reasons for definitive treatment discontinuation are shown on Table S5. There are limitations to this analysis, as this was not a prespecified subgroup analysis and the ICARIA-MM study did not enroll daratumumab-refractory patients. Modifications to the CCI score were applied to the simplified frailty score to use the available data to classify patients. Although the IMWG frailty score uses the patient-completed ADL questionnaires for functional status,2 recent frailty analyses have used ECOG PS as a proxy.3, 6, 7 The ADL questionnaires are time-consuming and prone to subjectivity,1 and usually not collected in clinical trials, including ICARIA-MM. Meanwhile, the ECOG PS is assessed by physicians and is commonly used in studies such as ICARIA-MM and in clinical practice. Additionally, the simplified frailty score was recently externally validated in a large, non-trial, real-world population cohort of transplant-ineligible newly diagnosed MM patients.8 Two recent analyses showed that the simplified frailty score predicted clinical outcomes in patients with RRMM treated with lenalidomide and dexamethasone (for whom bortezomib treatment had failed),7 and with carfilzomib-containing regimens (post-hoc analysis of the ASPIRE, ENDEAVOR, and ARROW phase 3 trials).6 To our knowledge, this is the first post-hoc analysis to show the benefit of a triplet regimen compared with a doublet therapy in frail patients with RRMM in the later-line setting. Frail patients in either arm had worse outcomes than fit/intermediate patients, suggesting that the simplified frailty score could properly identify the frail cohort. In ICARIA-MM, clinical outcomes (PFS, 1-year OS, ORR, and ≥VGPR) in frail patients tended to improve for those on Isa-Pd versus those on Pd. The prolongation of the median PFS with Isa-Pd in frail patients (4.5 months improvement; HR = 0.81, 95% CI: 0.45–1.48) was consistent with the increase in median PFS observed in patients ≥ 75 years (6.9 months improvement; HR = 0.48, 95% CI: 0.24–0.95) and in the overall population (5 months improvement; HR = 0.60, 95% CI: 0.44–0.81).4, 5 The toxicities observed in frail patients treated with Isa-Pd were manageable and similar to those observed in fit/intermediate patients, with comparable treatment discontinuation rates, treatment durations, and incidence rates of hematologic TEAEs. In conclusion, the response, long-term treatment benefit, and safety profile of frail patients treated with Isa-Pd are consistent with the elderly and the overall study populations, showing the feasibility of this triplet regimen in the frail population. Fewer frail patients discontinued Isa-Pd than Pd treatment due to TEAEs, further supporting the benefit of Isa-Pd in both frail and fit/intermediate patients with RRMM, and the translation of this triplet regimen to real-world practice. The ICARIA-MM study was sponsored by Sanofi. We thank the participating patients and their families, and the study centers and investigators, for their contributions to the study. We thank Professor Michel Attal from the Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France, who was a co-principal investigator of the ICARIA-MM study. Medical writing support was provided by Camile Semighini Grubor, PhD, of Elevate Medical Affairs, contracted by Sanofi Genzyme for publication support services. FS: honoraria – Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX and Takeda; participation on an entity's board of directors or advisory committees – Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi and Takeda; SB: honoraria – Amgen, Bristol-Myers Squibb, Celgene and Janssen; participation on an entity's board of directors or advisory committees – Amgen, Celgene, Janssen and Karyopharm; consultancy – Janssen and Takeda; PGR: research funding – Bristol-Myers Squibb, Celgene, Oncopeptides and Takeda; honoraria – Celgene, Janssen, Karyopharm, Oncopeptides, Sanofi and Takeda; AP: honoraria – Amgen, Bristol-Myers Squibb/Celgene, Janssen, Sanofi and Takeda; XL: honoraria – AbbVie, Amgen, Bristol-Myers Squibb, Carsgen Therapeutics Ltd, Celgene, Gilead Sciences, Janssen-Cilag, Karyopharm Therapeutics, Merck, Mundipharma, Novartis, Oncopeptides, Pierre Fabre, Roche, Sanofi and Takeda; non-financial support – Takeda; PM: honoraria – Amgen, Celgene, Janssen and Sanofi; MD: participation on an entity's board of directors or advisory committees – Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda; CH: honoraria – Amgen, Bristol-Myers Squibb/Celgene, and Sanofi; CT, MCF, EMP, and HvdV are employed by Sanofi and may hold shares and/or stock options in the company; TF: participation on an entity's board of directors or advisory committees – Amgen, Celgene, Janssen, Karyopharm, Oncopeptides, Roche and Takeda. Fredrik Schjesvold, Sara Bringhen, Aurore Perrot, Xavier Leleu, Philippe Moreau, Meletios Dimopoulos, Cyrille Hulin, Paul Richardson, and Thierry Facon were investigators in the study and contributed to data acquisition. Paul Richardson was a co-principal investigator of the ICARIA-MM study. Christina Tekle, Meredith C. Foster, Elizabeth M. Poole, and Helgi van de Velde contributed to the analysis and interpretation of data for the work. All authors revised the work for important intellectual content and assume responsibility for data integrity and the decision to submit this manuscript for publication; had full access to the study data; and edited, and reviewed manuscript drafts, and approved the final version for submission. Data availability statement: 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 anonymized, 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: https://www.clinicalstudydatarequest.com. Table S1. Frailty scores and baseline patient characteristics by frailty scores in the ICARIA-MM study – intent-to-treat population Table S2. Treatment duration in either the frail or the fit/intermediate subgroups – safety population Table S3. Treatment-emergent adverse events in ≥15% of patients treated with isatuximab in either the frail or the fit/intermediate subgroups (worst grade) – safety population Table S4. Hematologic abnormalities determined by laboratory analysis in the frail or the fit/intermediate subgroups (worst grade) – safety population Table S5. Reason for definitive treatment discontinuation in either the frail or the fit/intermediate subgroups – intent-to-treat population Figure S1. Time to premature or definitive treatment discontinuation in frail vs fit/intermediate patients in the ICARIA-MM study. Kaplan–Meier analyses in the safety population. HR and corresponding 95% CI are from a Cox proportional hazard model stratified by age and number of previous lines of therapy. The P values were derived from a log-rank test CI, confidence interval; d, dexamethasone; HR, hazard ratio; Isa, isatuximab; P, pomalidomide Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.