Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized Phase 3 study

Longer-term outcomes with the anti-CD38 antibody isatuximab in combination with carfilzomib-dexamethasone (Isa-Kd) were evaluated in the randomized Phase 3 trial IKEMA (NCT03275285), in a prespecified, follow-up analysis of progression-free survival (PFS, primary study endpoint), final complete response (CR) using Hydrashift Isa immunofixation assay, minimal residual disease (MRD) negativity, and safety. Enrolled patients had relapsed/refractory multiple myeloma (1–3 prior treatment lines). Isa 10 mg/kg was administered intravenously weekly in cycle 1 then biweekly. Efficacy analyses were performed in the intent-to-treat population (Isa-Kd: n = 179, Kd: n = 123) and safety evaluated in treated patients (Isa-Kd: n = 177, Kd: n = 122). Consistent with the primary interim analysis, the addition of Isa to Kd prolonged PFS (HR 0.58, 95.4% CI: 0.42–0.79; median PFS 35.7 [95% CI: 25.8–44.0] vs 19.2 [95% CI: 15.8–25.0] months). PFS benefit was observed with Isa-Kd across subgroups, including patients with poor prognosis. The stringent CR/CR rate was 44.1% vs 28.5% (odds-ratio: 2.09, 95% CI: 1.26–3.48), the MRD negativity rate 33.5% vs 15.4% (odds-ratio: 2.78, 95% CI: 1.55–4.99) and the MRD negativity CR rate 26.3% vs 12.2%, with Isa-Kd vs Kd. The safety profile of Isa-Kd was similar to that reported in the prior interim analysis. These findings further support Isa-Kd as a standard-of-care treatment for relapsed multiple myeloma patients. Clinical trial information: ClinicalTrials.gov, NCT03275285.


INTRODUCTION
Substantial advances have been made in the management of patients with relapsed and/or refractory multiple myeloma (RRMM) with the adoption of proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) within treatment regimens.This patient population is increasing worldwide due to improved life expectancy and other demographic changes [1][2][3][4][5][6][7].
The anti-CD38 monoclonal antibody isatuximab (Isa) exerts antimyeloma activity through several mechanisms of action including antibody-dependent cell-mediated cytotoxicity, complementdependent cytotoxicity, and direct induction of apoptotic cell death [9][10][11].Isa is approved in multiple countries in combination with pomalidomide and low-dose dexamethasone for patients with RRMM after ≥2 prior therapies, based on the results of the randomized Phase 3 ICARIA-MM study.
Isa was further approved in combination with carfilzomib and low-dose dexamethasone (Isa-Kd) in the United States for RRMM patients after 1-3 prior lines of therapy, in the European Union and other countries for patients with relapsed MM who have received ≥1 prior therapy, and in Japan for patients with RRMM [12][13][14][15][16][17][18].This approval was based on the results of the preplanned interim analysis of the randomized, multi-national, Phase 3 IKEMA study, in which the addition of Isa to Kd demonstrated a statistically significant improvement in progression-free survival (PFS) vs Kd (hazard ratio [HR], 0.53; 99% confidence interval [CI]: 0.32-0.89;one-sided p = 0.0007), with clinically meaningful improvement in the rates of very good partial response or better (≥VGPR, 72.6% vs 56.1%) as per independent response committee (IRC), minimal residual disease (MRD) negativity (29.6% vs 13.0%), and complete response (CR, 39.7% vs 27.6%) in the intent-to-treat (ITT) population, along with a manageable safety profile [15].
To evaluate longer term outcomes with Isa-Kd vs Kd in patients with relapsed MM, we conducted a follow-up, prespecified analysis of the IKEMA study population at 159 PFS events.Here, we report updated study results on PFS, CR rate, MRD negativity rate, MRD negativity and CR rate, in the intent-to-treat population, as well as updated safety findings.

METHODS Study design and patients
IKEMA was a prospective, randomized, open-label, active-controlled, Phase 3 study (NCT03275285) conducted worldwide, at 69 study centers in 16 countries.Study eligibility and exclusion criteria have been described in detail previously [15].Briefly, enrolled patients had relapsed and/or refractory MM with 1 to 3 prior treatment lines and measurable evidence of disease (serum M-protein ≥0.5 g/dL and/or urine M-protein ≥200 mg/24 h) [19].Patients with primary refractory MM, serum freelight chain measurable disease only, or Eastern Cooperative Oncology Group performance status (ECOG PS) > 2 were not eligible.Patients were also excluded if they had received prior carfilzomib therapy, had a contraindication to treatment with dexamethasone, had an estimated glomerular filtration rate (eGFR) <15 mL/min/1.73m² (by the modification of diet in renal disease formula) or had a left ventricular ejection fraction <40%.
The study protocol was approved by the Institutional Ethics Committee or independent review board at each 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.

Treatment
After confirmation of eligibility, patients were randomly assigned (by interactive response technology) in a 3:2 ratio to treatment with Isa-Kd or Kd (control arm).Patients were stratified by the number of prior treatment lines (1 vs >1) and Revised International Staging System stage (I or II vs III vs not classified).
Patients in the Isa-Kd arm received Isa 10 mg/kg intravenously (IV) on days 1, 8, 15, and 22 of the first 28-day cycle, and on days 1 and 15 of subsequent cycles.In both study arms, carfilzomib was administered IV at 20 mg/m 2 on days 1 and 2 and at 56 mg/m 2 on days 8, 9, 15, and 16 of cycle 1, followed by 56 mg/m 2 on days 1, 2, 8, 9, 15, and 16 of subsequent cycles.Dexamethasone 20 mg was administered IV or orally on days 1, 2, 8, 9, 15, 16, 22, and 23.Treatment continued until disease progression, unacceptable toxicity, or patient request to stop study treatment.

Assessments and endpoints
The blinded IRC continued to review, after the interim analysis, disease assessments for response and progression performed by central laboratory for M-protein quantification, central review of radiological assessments done locally, and local bone marrow aspiration for plasma cell infiltration when applicable.The Hydrashift 2/4 Isa immunofixation electrophoresis (IFE) assay (Sebia, Lisses Evry Cedex, France) [20], which was not available at the time of the interim analysis, was used on banked serum samples to measure endogenous M-protein in samples suspected of Isa interference (at time points before and after the cutoff date of the interim analysis).PFS, the primary study endpoint, was defined as the time from randomization to the first documentation of disease progression or death from any cause, whichever came first.The CR rate was the proportion of patients who achieved a stringent CR (sCR) or CR as best overall response according to the IMWG response criteria [21].Response and progression based on serum and/or urine M-protein were confirmed based on two consecutive assessments.PFS2 was defined as the time from randomization to disease progression on next-line treatment or death, whichever occurred first.Efficacy assessments were conducted on day 1 of every cycle and at the end of treatment; they were continued monthly for patients who discontinued study treatment without progression.
MRD was evaluated by next-generation sequencing clonoSEQ Assay (Adaptive Biotechnologies, Seattle, WA, USA) with a minimum sensitivity of 10 −4 [22] in patients with ≥VGPR, when the confirmed best response was reached.The MRD negativity rate was the proportion of patients for whom MRD was negative at a sensitivity of 10 −5 at any time point after the first dose 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.Safety was regularly reviewed by an independent Data Monitoring Committee until the PFS update.

Statistical analyses
Efficacy analyses were conducted in the ITT population and summarized by randomized treatment.Median PFS (mPFS) and 95% CIs were calculated using the Kaplan-Meier method.HRs were estimated using a Cox proportional-hazard model stratified by stratification factors as entered in the Interactive Response Technology system (ie, number of previous lines of therapy and R-ISS).The odds ratios were also stratified.Treatmentemergent AEs (TEAEs) were evaluated in the safety population (all treated patients).Categorical and ordinal data were summarized using the number and percentage of patients.Continuous data were summarized for each treatment group using the number of available observations, mean, median, standard deviation, minimum, and maximum.SAS 9.4 software (SAS, Cary, NC) was used for all the analyses.

Patients
At data cut-off (January 14, 2022), the median follow-up was 44 months; 49 (27.4%)patients in the Isa-Kd arm and 11 (8.9%) in the Kd arm were still on treatment (Fig. 1).The most frequent reason for discontinuation in both arms was progressive disease, although it was less frequent in Isa-Kd vs Kd (43.0%vs 52.0%).Twenty-two patients in each arm discontinued due to an AE (12.3% in Isa-Kd and 17.9% in Kd).
Patient demographic and baseline characteristics were balanced between treatment arms (Table 1).Median age was 65 years in Isa-Kd (range, 37-86) and 63 years in Kd (range, 33-90).ECOG performance status was 0 in 53.1% and 59.3% of patients in Isa-Kd and Kd, respectively.In either treatment arm, at baseline, 24-25% of patients had high-risk cytogenetic status (23.5% in Isa-Kd and 25.2% in Kd) and 42% had 1q21 + (by gain or amplification; 41.9% of patients in Isa-Kd and 42.3% in Kd).The number of prior treatment lines was comparable between study arms, with a median of 2 (range, 1-4) and with 44.1% vs 44.7% of patients with 1 prior treatment line in Isa-Kd vs Kd.A similar incidence of patients had received prior IMiD (76.0% in Isa-Kd and 81.3% in Kd) and/or prior PI therapy (92.7% and 85.4%, respectively).The incidence of lenalidomide-refractory patients was 31.8% in Isa-Kd and 34.1% in Kd.
To evaluate the robustness of the primary analysis, PFS sensitivity analyses using different censoring rules, as per IRC and per investigator assessment, were also updated (Supplementary Table S1).All PFS sensitivity analyses showed consistent benefit with Isa-Kd vs Kd, with HRs ranging from 0.57 to 0.64.A further analysis using censoring rules requested and considered by the United States Food and Drug Administration (FDA) as the primary PFS analysis (censoring PFS events occurring >8 weeks from the last valid disease assessment), showed results consistent with the main PFS analysis, with a HR of 0.59 (95.4% CI: 0.42-0.83)and a mPFS of 41.7 months (95% CI: 27.1-not calculable [NC]) with Isa-Kd vs 20.8 months (95% CI: 16.2-28.2) with Kd (Supplementary Table S1, Supplementary Fig. S1).
As presented in Fig. 3, PFS subgroup analyses, by patient main baseline characteristics and prognostic factors, showed consistent PFS benefit with Isa-Kd vs Kd across all subgroups, including patients with poor prognosis: e.g., elderly patients, patients with renal function impairment, high-risk cytogenetics [del17p, t(4;14) t(14;16)], or 1q21+ status, as well as lenalidomide-refractory patients (PFS subgroup analyses by FDA censoring rules are shown in Supplementary Fig. S2).
Although the overall response rates were comparable between treatment arms (86.6% vs 83.7%), deeper responses were seen with Isa-Kd vs Kd in the ITT population: the sCR/CR rate was 44.1% with Isa-Kd vs 28.5% with Kd (odds ratio Isa-Kd vs Kd: 2.09, 95% CI: 1.26-3.48)(Fig. 4A), with additional CRs compared with the interim analysis, 8 in Isa-Kd and 1 in Kd.Half of these 8 additional CRs in the Isa-Kd arm were linked to the availability and use of the Hydrashift 2/4 Isa immunofixation assay (which could detect endogenous IgG M-protein without Isa interference), at time points prior to the interim analysis cut-off (07Feb22).
As shown in Fig. 4B, the addition of Isa to Kd improved the MRD negativity rate to 33.5% vs 15.4% with Kd (odds ratio 2.78, 95% CI: 1.55-4.99for Isa-Kd vs Kd).The MRD negativity and CR rate with Isa-Kd was 26.3% vs 12.2% with Kd (odds ratio 2.57, 95% CI: 1.35-4.88for Isa-Kd vs Kd).The MRD negativity rates were consistently higher with Isa-Kd vs Kd across subgroups of patients with poor prognostic characteristics, including older age, renal function impairment, higher ISS stage at study entry, 1q21+ status, more lines of prior therapy, and refractoriness to lenalidomide (Supplementary Fig. S3).Further, exploratory analysis of PFS by MRD status showed that the Kaplan-Meier curves of the MRD-negative patients were largely above those of the  MRD-positive patients (Supplementary Fig. S4), with a HR for MRDnegative versus MRD-positive patients of 0.29 (95% 0.17-0.48) in the and 0.19 (95% CI: 0.08-0.47) in the Kd arm Table S2).The medians in MRD-negative patients were reached in either study arm.
Despite the high percentage of patients in Kd who received anti-CD38 in further anti-myeloma therapy, benefit with Isa-Kd over Kd was maintained late through PFS2 with a HR of 0.68 (95% CI: 0.50-0.94)(Fig. 5B).PFS2 was defined as the time from randomization to disease progression on next line of treatment or death, whichever occurred first.Median PFS2 with Isa-Kd was 47.2 (95% CI: 38.1-NC) months vs 35.6 (95% CI: 24.1-40.5)months with Kd.Analysis of overall survival (OS) is planned for 2023, 3 years after the interim PFS analysis that showed significant improvement in PFS.Nonetheless, in the current updated analysis, descriptive OS showed a trend in favor of Isa-Kd vs Kd with HR of 0.78 (95% CI: 0.54-1.12)(Supplementary Table S4).
The safety findings, summarized in Table 2, were consistent with previous findings of the interim analysis [15]; the addition of Isa to Kd did not increase the incidence of TEAEs with fatal outcome during study treatment (5.6% vs 4.9%) or of TEAEs leading to definitive discontinuation of all study treatment (12.4% vs 18.0%).

A B
Fig. 4 Best overall responses per IRC and MRD negativity rates with Isa-Kd vs Kd (ITT population).A Best overall responses, and B MRD negativity rates.CR complete response, d dexamethasone, IRC independent response committee, Isa isatuximab, ITT intent to treat, K carfilzomib, MRD minimal residual disease, neg negativity, NGS next-generation sequencing, ORR overall response rate, sCR stringent complete response, VGPR very good partial response.
At interim analysis [15], there was no difference in the of all-causality serious TEAEs, whereas a 10% difference was observed in this updated analysis between the Isa-Kd Kd arms (70.1% vs 59.8%, respectively).However, this difference was related to the longer treatment exposure in Isa-Kd, since of the event rate per patient year showed a similar incidence of serious TEAEs in the 2 treatment arms (0.58 in Isa-Kd vs 0.62 in Kd) (Supplementary Table S6).Keeping in consideration duration of treatment exposure, the results also showed that grade ≥3 TEAEs remained more frequent in Isa-Kd vs Kd at the final analysis with an event rate per patient year of 1.08 in vs in Kd, although the between the 2 arms decreased (1.26 in Isa-Kd vs 1.05 Kd at the interim analysis).With 2 additional years of follow-up, the of treatmentemergent events remained between study arms (5.6% vs 4.9%) and the event rate per patient year identical to the one reported at analysis (0.03 vs despite longer exposure in the Isa-Kd arm and the Covid-19 pandemic (Supplementary Table S6).

DISCUSSION
Results of this prespecified PFS updated analysis from IKEMA, at 44-month follow-up, are consistent with the prior interim analysis [15] and demonstrate improvement in PFS with addition of Isa to Kd (HR 0.58 vs Kd, 95.4% CI: 0.42-0.79),with an unprecedented mPFS of nearly 3 years (35.7 [95% CI: 25.8-44.0]months in Isa-Kd vs 19.2 [95% CI: 15.8-25.0]months in Kd), which is the longest PFS reported to date with a PI-based regimen in the relapsed MM setting [23][24][25][26].The extent of such a PFS benefit is in line with the current trend toward more intense therapy earlier in the course of the disease, as PFS generally shortens with each relapse due to the biological characteristics of MM and the development of more aggressive disease over time [27].The long-term benefit achieved in our study supports the use of the most effective, available drugs and combination therapies as early as possible in relapsed MM, in addition to the newly diagnosed MM setting [28], in order gain the best outcomes.
In other reports, updated analysis of PFS in the ITT population of the randomized phase 3 study CANDOR, which evaluated a combination of daratumumab with Kd (D-Kd) vs Kd in patients with RRMM, has shown a mPFS of 28.6 months (95% CI: 22.7-not estimable) with D-Kd vs 15.2 months (95% CI: 11.1-19.9) in the Kd arm (HR, 0.59 [95% CI: 0.45-0.78]),at a median follow-up of 27.8 months for D-Kd and 27.0 months for Kd [23].Although intertrial evaluations should be interpreted with caution, the HRs for PFS appeared comparable in the updated analyses of IKEMA and CANDOR, whereas mPFS as reported to date was longer in IKEMA.Also, shorter mPFS was observed in the ITT RRMM patient populations of the randomized phase 3 trials CASTOR (Dbortezomib [V]d vs Vd) and OPTIMISMM (pomalidomide-Vd vs

A B
Fig. 5 Time to next treatment and PFS2 a (ITT population).A Time to next treatment and B PFS2. CI confidence interval, d dexamethasone, HR hazard ratio, Isa isatuximab, ITT intent to treat, K carfilzomib, mPFS median progression-free survival, NC not calculable, TTNT time to next treatment.a PFS2 was defined as the time from randomization to disease progression on next-line treatment or death, whichever occurred first.
All PFS sensitivity analyses undertaken in IKEMA using different censoring rules, as per IRC or investigator assessment, favored Isa-Kd over Kd, HRs ranging from 0.57 to 0.64, adding to the robustness of the study findings.Further analysis showed consistent PFS benefit across all patients subgroups, patients with poor prognosis, such as older patients (≥65 years of age), patients with renal at baseline (eGFR <60 mL/min/1.73m 2 ), and patients with high-risk cytogenetic or 1q21+ status by gain or amplification.Median PFS in 1q21+ patients was 25.8 months with Isa-Kd vs 16.2 with Kd (HR, 0.58; 95% CI: 037-0.92) in favor of Isa-Kd.In addition, also patients who were refractory to lenalidomide derived greater PFS benefit from treatment with Isa-Kd than Kd (HR, 0.59; 95% CI: 0.35-0.97).
In this updated analysis of IKEMA, both the MRD negativity rate (10 −5 ) of 33.5% achieved with Isa-Kd vs 15.4% with Kd (odds ratio: 2.78, 95% CI: 1.55-4.99)as well as MRD and CR rate of 26.3% reached with Isa-Kd 12.2% with Kd (odds ratio: 2.57, 95% CI: 1.35-4.88)confirm, after 2 additional years of follow-up, clinically difference in favor of Isa-Kd observed at the interim analysis.Such substantial rates of CR and of negative CR are the rates achieved to with a PI-based regimen in an ITT population of patients with relapsed MM.The finding that the Kaplan-Meier PFS curves of the MRD-negative patients were substantially above those of the MRD positivepatients (HR for MRD-negative versus MRD-positive patients, 0.29 [0.17-0.48] in Isa-Kd and 0.19 [0.08-0.47] in Kd) supports the prognostic relevance of obtaining MRD negativity.It is recognized that MRD negativity could be a surrogate for potential cure in newly diagnosed MM [28] and a recent meta-analysis confirms that also patients with RRMM benefit from reaching MRD negativity [29].Thus, the MRD negativity rate that can be obtained with a treatment option in RRMM patients is an important criterion to consider, particularly for an optimal management of patients at first relapse.In view of the greater proportion of patients reaching MRD-negative status with Isa-Kd than Kd (33.5% vs 15.4%), Isa-Kd represents a very effective treatment option for patients with relapsed MM, offering the highest likelihood of reaching this status and a better long-term outcome.Numerically, the MRD negativity rate was also higher in the Kd arm of IKEMA than in the control arms of the CANDOR and CASTOR trials [24,25].The MRD negativity rate (10 −5 ) reported in the CANDOR study, regardless of overall response status, was 22.8% with D-Kd vs 5.8% with Kd (odds ratio: 5.15, p < 0.0001) and the best overall MRD-negative CR rate at any time was 13.8% with D-Kd vs 3.2% with Kd (odds ratio: 4.95, p < 0.0001) [24].The MRD negativity rate (10 −5 ) in the CASTOR study was 14% with D-Vd vs 2% with Vd in the overall population [25].Although, as previously mentioned, inter-trial considerations should be made with caution, it is noteworthy that the incidences of patients with prior lenalidomide exposure (40%, 39%, and 36% in the anti-CD38 arms vs 48%, 48%, and 49% in the control arms, respectively) and of patients refractory to lenalidomide (32%, 32%, and 24% in the anti-CD38 arms vs 34%, 36%, and 33% in the control arms, respectively) were similar in the IKEMA, CANDOR, and CASTOR trials [14,15,25].
The PFS2 observed in IKEMA favoring Isa-Kd vs Kd (HR: 0.68 [95% CI: 0.50-0.94])further supports a sustained treatment effect with this Isa triplet combination through subsequent therapies.Consistently, although OS analysis is planned for 3 years after the PFS interim at a median follow-up of 44 months, results showed a higher probability of survival at 36 and 42 months with Isa-Kd vs Kd: 68.7% vs 62.9% and 66.3% vs 54.5%, respectively.Median treatment duration with Isa-Kd was longer by ~32 weeks (94.0 vs 61.9 weeks with Kd), with a median relative dose intensity for Isa of 93.2%.The longer treatment in Isa-Kd did not affect the median relative dose intensity for carfilzomib, which was comparable between treatment arms (89.5% in Isa-Kd vs 90.8% in Kd), thus supporting Isa-Kd as a combination regimen that can be given continuously in a feasible manner, without discontinuation of key therapeutic agents.To facilitate treatment administration, a onceweekly schedule of carfilzomib is currently being evaluated in a multi-arm Phase 1b study (NCT02332850) in combination with Isa and dexamethasone in patients with RRMM and in a Phase 2 study (NCT04430894) in combination with Isa-Rd in transplant-eligible patients with newly diagnosed MM.Anti-CD38 therapy with Isa was administered in this trial by IV infusion than the subcutaneous (SC) route.However, in this particular regimen, the with carfilzomib, which also requires IV administration, would limit the convenience of an Isa SC Nonetheless, SC administration of Isa is being evaluated in combination with pomalidomide-dexamethasone in a Phase 1b study with promising, preliminary [30].
After 2 additional years of follow-up and notwithstanding the risks associated with the Covid-19 pandemic, the safety profile of treatment with Isa-Kd remains similar to the results previously reported in the interim analysis [15].The addition of Isa to Kd was not associated with an increase in fatal TEAEs or definitive treatment discontinuations.The higher incidence of any-grade serious TEAEs in Isa-Kd vs Kd was related to the longer treatment exposure in the Isa-Kd arm.Analysis of event rate per year showed that the higher incidence of grade ≥3 TEAEs in Isa-Kd vs Kd was lower in the final analysis (1.08 vs. 0.97) compared with the interim analysis and it did not lead to an increase in the rate of fatal TEAEs (0.03 vs 0.03) or serious TEAEs (0.58 in Isa-Kd vs. 0.62 in Kd).Consistent with the primary analysis [15], the most frequent TEAEs remained infusion reactions, diarrhea, hypertension, and upper respiratory tract infections, mostly of grade 1-2.Hypertension and cardiac failure (all-grade and grade ≥3) were reported with a similar incidence in the 2 arms.
A limitation of our study was the open-label design.However, central laboratory assessments for M-protein, MRD, and baseline cytogenetics (with cytogenetic information available for almost 90% of the patients) contributed to homogenous assessments across study sites and a reduction in the potential bias related to the open-label design.In addition, PFS, best overall response, MRD negativity rate, TTNT, and PFS2 analyses were all performed in the ITT population, and the efficacy analyses conducted per blinded IRC assessment.Utilizing the Hydrashift Isa immunofixation assay, response rates were adjusted after the assessment of residual serum M-protein without Isa interference.
In conclusion, the improvement in PFS observed in this updated analysis of IKEMA, with a mPFS of nearly 3 years, achievement of MRD negativity in a third of Isa-Kd treated patients, reaching MRD negativity and CR in >25% of them, and a manageable safety profile, further support Isa-Kd as a standard of care treatment for patients with relapsed MM.

Fig. 3
Fig. 3 Subgroup analyses of PFS with Isa-Kd vs Kd.CI confidence interval, d dexamethasone, eGFR estimated glomerular filtration rate, IMiD immunomodulatory drug, IRT Interactive Response Technology, Isa isatuximab, ISS international staging system, K carfilzomib, MDRD modification of diet in renal disease equation, PFS progression-free survival, PI proteasome inhibitor.*Prior treatment=last prior anti-myeloma regimen.
CrCl creatinine clearance, d dexamethasone, eGFR estimated glomerular filtration rate, IMiD immunomodulatory drug, Isa isatuximab, ISS International Staging System, ITT intent-to-treat, K carfilzomib, PI proteasome inhibitor.aBaseline eGFR by the modification of diet in renal disease (MDRD) formula.Incidence calculated on patients with race reported in case report forms: 165 patients in Isa-Kd arm, 111 patients in Kd arm.bHigh risk was defined as del(17p), t(4;14), or t(14;16) by fluorescence in situ hybridization.d

Table 3 .
Most common TEAEs (in ≥20% of patients, safety population) and selected TEAEs.Most common TEAEs (preferred terms), in ≥ 20% of patients in the Isa-Kd arm d dexamethasone, Isa isatuximab, K carfilzomib, TEAE treatment-emergent adverse event.a Groupings using standardized MedDRA query (narrow terms).b Groupings using customized MedDRA query.c Treatment-emergent and post-treatment.T. Martin et al.