Isatuximab plus carfilzomib and dexamethasone in patients with relapsed multiple myeloma based on prior lines of treatment and refractory status: IKEMA subgroup analysis

To the Editor: Patients with multiple myeloma (MM) often relapse or become refractory to successive lines of therapy (LOT), warranting more effective treatments. Novel treatments have improved outcomes; however, MM is associated with a significant patient burden. Patients who are refractory to immunomodulatory drugs and proteasome inhibitors (PIs) have poor prognosis. Many patients with MM are exposed to lenalidomide or bortezomib in early LOT; those refractory to these agents are challenging to treat and represent a high unmet medical need. Based on the Phase 3 ICARIA-MM study (NCT02990338), isatuximab (Sarclisa), a CD38 monoclonal antibody, is approved in combination with pomalidomide and dexamethasone (Isa-Pd) for adult patients with relapsed and refractory MM (RRMM) who have received ≥2 prior therapies, including lenalidomide and a PI. Based on the IKEMA study (NCT03275285), to date, isatuximab in combination with carfilzomib and dexamethasone (Isa-Kd) is approved in the United States for adult patients with relapsed or refractory MM with 1–3 prior LOT, in the European Union for adult patients with MM with ≥1 prior therapy, and in Japan for adult patients with relapsed or refractory MM with one prior treatment. IKEMA demonstrated that, in patients with relapsed MM, Isa-Kd significantly improved progression-free survival (PFS) compared with Kd (hazard ratio [HR] 0.53; 99% confidence interval [CI] 0.32–0.89; p = .0007), with a clinically meaningful increase in minimal residual disease (MRD) negativity and complete response (CR) rates in the intentto-treat population, and a manageable safety profile. We conducted a prespecified subgroup analysis of IKEMA to evaluate the efficacy and safety of Isa-Kd versus Kd according to number of prior LOT (1 vs. >1), and an exploratory subgroup analysis based on refractoriness to two frequently used front-line agents, lenalidomide and bortezomib. Randomized patients (N = 302) received Isa-Kd (n = 179) or Kd (n = 123). Subgroup analyses were conducted by number of prior LOT (1 vs. >1) as entered by the investigator at randomization and by refractory status (defined as: (i) reason for discontinuation was progression, or (ii) progression ≤60 days posttreatment, or (iii) best response was stable disease or progressive disease). The study design and procedures are described in Supporting Information. In the overall population, patients received a median (range) of 2 (1–4) prior LOT in both treatment arms; 44.4% of patients received 1 prior line, 32.8% were lenalidomide-refractory, and 30.1% were bortezomib-refractory. Table S1 shows patient baseline characteristics in each subgroup. Compared with Kd, more patients with Isa-Kd were aged ≥75 years in the 1 prior line subgroup, fewer patients were International Staging System Stage I in the >1 prior line subgroup, and more were aged <65 years in the lenalidomide-refractory subgroup. Exposure to study treatment was longer with Isa-Kd than Kd. The median (range) number of treatment cycles with Isa-Kd versus Kd was: 20.0 (1–25) versus 16.5 (1–28), 1 prior line; 18.0 (1–27) versus 12.5 (1–26), >1 prior line; 14.0 (1–27) versus 11.5 (1–28), lenalidomide-refractory; 13.5 (1–26) versus 13.0 (1–28), bortezomibrefractory. More patients with Isa-Kd than Kd received ≥18 cycles in all subgroups: 65.8% versus 48.1%, 1 prior line; 51.0% versus 32.4%, >1 prior line; 43.9% versus 33.3%, lenalidomide-refractory; 38.5% versus 25.6%, bortezomib-refractory. These results are consistent with IKEMA overall population where a longer treatment duration was reported with Isa-Kd (median [range] number of cycles 19.0 [1–27] and 57.6% patients with ≥18 cycles) than Kd (14.5 [1–28] and 39.3% patients with ≥18 cycles). Consistent with IKEMA overall population, PFS improvement was observed with Isa-Kd versus Kd across all subgroups analyzed, regardless of number of prior LOT (HR 0.59 [95% CI, 0.31–1.12], 1 prior line; HR 0.48 [95% CI, 0.29–0.78], >1 prior line) or refractory status (HR 0.60 [95% CI, 0.34–1.1], lenalidomide-refractory; HR 0.69 [95% CI, 0.35–1.39], lenalidomide-refractory at last regimen; HR 0.62 [95% CI, 0.33–1.16], bortezomib-refractory; HR 0.38 [95% CI, 0.16–0.92], bortezomib-refractory at last regimen; Figure 1A). The p values for interaction suggest no interaction with any of the parameters evaluated. The PFS-event-free probability at 18months for Isa-Kd versus Kd was: 77% versus 64%, 1 prior line; 68% versus 45%, >1 prior line; 53% versus 31%, lenalidomide-refractory patients; and 63% versus 43%, bortezomib-refractory (Table S2). Overall response rate (ORR) in IKEMA overall population was high in both treatment groups with no statistically significant difference (87%, Isa-Kd vs. 83%, Kd; one-sided p = 0.19); thus, p values of subsequent key secondary endpoints (≥very good partial response [VGPR] Received: 3 March 2022 Revised: 5 May 2022 Accepted: 9 May 2022