Isatuximab in combination with carfilzomib and dexamethasone in 1q21+ patients with relapsed/refractory multiple myeloma: Long‐term outcomes in the Phase 3 IKEMA study

Gain/amplification of 1q21 (≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma, can negatively affect prognosis, due to its involvement in resistance to anti‐myeloma therapy and disease progression. In this updated subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285) in relapsed/refractory multiple myeloma (RRMM), we evaluated progression‐free survival (PFS) and depth of response with the anti‐CD38 antibody isatuximab plus carfilzomib‐dexamethasone (Isa‐Kd) versus Kd, in 1q21+ patients and related subgroups, at long‐term follow‐up (44.2 months). Our analysis included patients with 1q21+ (≥3 copies, with/without high‐risk chromosomal abnormality [HRCA]), isolated 1q21+ (≥3 copies, without HRCA), gain(1q21) (3 copies, with/without HRCA), and amp(1q21) (≥4 copies, with/without HRCA). PFS benefit was achieved with Isa‐Kd versus Kd in patients with 1q21+ (HR 0.58, 95% CI: 0.37–0.92), with isolated 1q21+ (HR 0.49, 95% CI: 0.27–0.92), with gain(1q21), or amp(1q21), consistent with the overall population and prior interim 1q21+ subgroup analyses. Median PFS with Isa‐Kd versus Kd was 25.8 versus 16.2 months in 1q21+ patients and 38.2 versus 16.2 months in patients with isolated 1q21+. Clinically meaningful, higher rates of very good partial response or better, complete response or better (≥CR), minimal residual disease (MRD) negativity, and MRD negativity and ≥CR were reached with Isa‐Kd versus Kd in patients with 1q21+, isolated 1q21+, gain(1q21), or amp(1q21). In Isa‐Kd and Kd, the MRD negativity and ≥CR rate was 29.3% versus 15.4% in 1q21+ patients, 36.2% versus 12.9% in patients with isolated 1q21+, 27.9% versus 13.5% in patients with gain(1q21), and 31.3% versus 20.0% in patients with amp(1q21), respectively. In conclusion, addition of Isa to Kd in triplet combination therapy has shown PFS benefit and deeper responses, compared with Kd, in 1q21+ patients at higher risk of progression, including patients with isolated 1q21+, gain(1q21), and amp(1q21), thus supporting Isa‐Kd an effective treatment option for patients with RRMM.


| Study design and patient inclusion/exclusion criteria
The randomized, open-label, active-controlled, Phase 3 IKEMA study (NCT03275285), conducted worldwide at 69 study centers in 16 countries, was described in detail previously. 16Briefly, patients with RRMM and measurable disease, who had received 1-3 prior treatment lines, were enrolled in the study and randomly assigned 3:2 to Isa-Kd (n = 179) or Kd (n = 123).Patients with primary refractory MM, serum free-light chain measurable disease only, or Eastern Cooperative Oncology Group performance status (ECOG PS) >2 were not included in the study.Patients were also not eligible if they had an estimated glomerular filtration rate (eGFR) <15 mL/min/ 1.73 m2 (by the modification of diet in renal disease equation), had a left ventricular ejection fraction <40%, had received prior carfilzomib therapy, or had a contraindication to treatment with dexamethasone.
Randomized patients were stratified by the number of previous treatment lines (1 vs. >1) and revised International Staging System (R-ISS; stage I or II vs. III vs. not classified) as entered in the Interactive Response Technology system. 16e study protocol was approved by the Institutional Ethics Committee or independent review board at each participating center.
The study was conducted following the Declaration of Helsinki and the International Council for Harmonisation (ICH) Guidelines for Good Clinical Practice.All patients provided written informed consent.

| Study endpoints and assessments
The primary endpoint was PFS, defined as the time from randomization to first documentation of progressive disease or death from any cause, whichever came first.PFS was centrally assessed and determined by an independent response committee (IRC) using central laboratory data for M-protein and central review of local imaging and local bone marrow aspirate results.The cut-off date for analysis of PFS was 14 January 2022.Secondary endpoints included rates of overall response, VGPR or better (≥VGPR), and CR, assessed according to the International Myeloma Working Group (IMWG) response criteria. 23Overall survival data (a secondary study endpoint) were not yet mature at the time of this analysis.Cytogenetics was assessed in bone marrow aspirates during patient screening, at a central laboratory, by fluorescence in-situ hybridization (FISH), with a cut-off of 50% for del(17p), and 30% for t(4; 14), t(14; 16) and 1q21þ. 16,17dogenous M-protein was measured in patient samples with potential Isa interference using the Hydrashift 2/4 Isa immunofixation electrophoresis (IFE) assay (Sebia, Lisses Evry Cedex, France). 24D was centrally assessed by next-generation sequencing (NGS) clonoSEQ assay (Adaptive Biotechnologies) 25

| Statistical analyses
Efficacy analyses were performed in the intent-to-treat (ITT) population.Safety analyses included patients who received at least one dose of treatment.Both efficacy and safety analyses were summarized by assigned treatment.Estimates of mPFS and corresponding 95% CIs were calculated using the Kaplan-Meier method.HRs were estimated from an unstratified Cox regression model that consisted of the factor (1q21þ status), treatment, and the two-way interaction between factor and treatment.
Continuous data were summarized for each treatment group using mean, median, standard deviations, and range.Categorical and ordinal data were summarized using the number and percentage of patients.Statistical analyses were performed using SAS, version 9.4 (SAS).

| Patients
In IKEMA, patients with RRMM were randomized 3:2 to Isa-Kd (n = 179) or Kd (n = 123): 75 (41.9%)patients in Isa-Kd and 52 (42.3%) in Kd had 1q21þ status.At the time of this updated analysis, more patients were still on treatment with Isa-Kd than Kd: 17.3% versus 3.8% in the 1q21þ group and 34.5% versus 16.4% in patients without 1q21þ.The most frequent reason for definitive treatment discontinuation was progressive disease (Supplementary Table S1).
Our results show the impact of 1q21þ, gain(1q21), and amp (1q21) with or without HRCA on PFS, thus underscoring the prognostic importance of this chromosomal abnormality particularly in patients with amp(1q21).Nonetheless, PFS benefit was achieved with Isa-Kd versus Kd in all the 1q21þ subgroups evaluated, although to a greater extent in patients with isolated 1q21þ and gain(1q21) than amp(1q21), as observed in the Isa-Kd versus Kd comparisons of PFS for the 1q21þ subgroups (Figure 2).

| Efficacy: Depth of response
Although overall response rates were comparable between treatment arms, as previously observed in the overall IKEMA study population, 16,17 clinically meaningful increases in the rates of ≥VGPR, ≥CR, MRD negativity, as well as MRD negativity and ≥CR were observed with addition of Isa to Kd, across all 1q21þ subgroups (Figure 3, Supplementary Table S2).The MRD negativity and MRD negativity ≥CR rates were at least double with Isa-Kd versus Kd in most 1q21þ subgroups, except for amp(1q21) in which benefit was less pronounced but remained clinically meaningful.In the Isa-Kd and Kd arms, the MRD negativity and ≥CR rate was 29.3% versus 15.4% in patients with 1q21þ status, 36.2% versus 12.9% in patients with isolated 1q21þ, 27.9% versus 13.5% in patients with gain(1q21), and 31.3%versus 20.0% in patients with amp(1q21), respectively (Figure 3C).

With 1q21þ
Without Patients with 1q21þ had a higher incidence of HRCAs compared with patients without 1q21þ, in line with prior observations that these chromosomal abnormalities may occur together and affect prognosis. 6,7The HR observed in IKEMA for the comparison of PFS reached with Isa-Kd versus Kd in patients with ultra-high-risk cytogenetics − 1q21þ patients with 1 or more HRCA [t(4; 14), del(17p), and/or t(14; 16)] − was 0.69 (95% CI: 0.34−1.39),as recently reported. 26The enrichment in HRCAs may confound the interpretation of outcomes when comparing 1q21þ patients with patients without 1q21þ, thus pointing to the importance of evaluating treatment effect in patients with isolated 1q21þ.In this updated IKEMA analysis, patients with isolated 1q21þ showed continued, substantial benefit from treatment with Isa-Kd (HR for PFS with Isa-Kd vs. Kd, 0.  27 In contrast to our study, the patients in this analysis were more heavily pretreated, as they had all received prior therapy with a PI and an IMiD, and they had a median of 4 prior treatment lines.Further results from a small, single-center, retrospective analysis conducted in RRMM patients with amp(1q21) (n = 8) treated with daratumumab in triplet combination therapy have shown a mPFS of 3.0 months (95% CI: 1.6-7.6)compared with not reached (95% CI: 2.3-39.4months) in patients without amp(1q21), underscoring the difficulty of treating patients with this chromosomal abnormality. 28r findings on the effects of treatment with Kd in 1q21þ patients on the control arm of IKEMA are in line with prior results at short-term follow-up. 18In that analysis, although with the limitations of cross-trial evaluations and different patient populations, treatment with Kd in IKEMA appeared to provide better disease control for 1q21þ patients than Pd in the ICARIA-MM study, compared to patients without 1q21þ. 18Further studies may help to better understand the activity of protease inhibitors, and carfilzomib in particular, in 1q21þ patients with or without HRCAs, as well as their effects on complement-dependent cytotoxicity in combination with Isa.
Overexpression of the complement inhibitory protein CD55 has been associated with resistance to daratumumab therapy, as Estimates of mPFS and corresponding 95% CIs were calculated using the Kaplan-Meier method.Hazard ratios were estimated from an unstratified Cox regression model, with terms for the factor, treatment, and their interaction.
complement-dependent cytotoxicity represents one of its main effector mechanisms, differently from Isa, which mediates antimyeloma activity to a greater extent by antibody-dependent cellmediated cytotoxicity. 19,29To date, it remains to be determined how expression of CD55, which is located on chromosome 1q32.2outside of the 1q21 band, could be affected in patients with gain or amplification of 1q21, as previously suggested. 27Definitive evidence to support the hypothesis that a differential sensitivity of anti-CD38 antibodies to complement inhibitory proteins upregulated in 1q21þ patients would lead to different outcomes should come from a randomized comparison between the agents combined with same backbone regimen.As anti-CD38 antibodies are increasingly becoming standard of care in NDMM, it would be most relevant to perform such randomized comparison in patients with NDMM.
Limitations of our analysis are the evaluation of fewer patients in some of the 1q21þ subgroups and the open-label design of the study.
However, this analysis was conducted per IRC assessment of centrally evaluated efficacy outcomes in the ITT population of a randomized, multinational Phase 3 study such as IKEMA, 16 thereby adding strength to the evidence presented in this report and consistency among all subgroups as observed in our analyses.
In conclusion, in this updated long-term analysis, addition of Isa are at higher risk of progression, including patients with isolated 1q21þ, gain(1q21), and amp(1q21), thus supporting Isa-Kd as an effective treatment option for patients with RRMM.
in patients with ≥VGPR, when they reached confirmed best response.The MRD negativity rate was the proportion of patients with MRD negativity at a sensitivity of 10 −5 , at any time point after initiation of study treatment.Adverse events (AEs) and laboratory abnormalities were monitored and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
F I G U R E 1 FACON ET AL.
to Kd in triplet combination therapy has shown PFS benefit and deeper responses, compared with Kd alone, in 1q21þ patients whoF I G U R E 3 FACON ET AL.