Isatuximab–pomalidomide–dexamethasone vs. pomalidomide–dexamethasone in patients with relapsed and refractory multiple myeloma: final overall survival analysis

doi:10.21203/rs.3.rs-3117230/v1

Download PDF

Article

Isatuximab–pomalidomide–dexamethasone vs. pomalidomide–dexamethasone in patients with relapsed and refractory multiple myeloma: final overall survival analysis

https://doi.org/10.21203/rs.3.rs-3117230/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

The primary and pre-specified updated analyses of ICARIA-MM (NCT02990338) demonstrated improved progression-free survival and a benefit in overall survival (OS) was reported with the addition of isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide–dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma. Here, we report the final OS analysis. This multicenter, randomized, open-label, phase 3 study included patients who had received and failed ≥2 previous lines of therapy, including lenalidomide and a proteasome inhibitor. Between January 10, 2017, and February 2, 2018, 307 patients were randomized (1:1) to isatuximab–pomalidomide–dexamethasone (Isa-Pd; n= 154) or Pd (n = 153), stratified based on age (<75 vs. ≥75 years) and number of previous lines of therapy (2–3 vs. >3). At data cutoff for the final OS analysis after 220 OS events (January 27, 2022), median follow-up duration was 52.4 months. Median OS (95% confidence interval) was 24.6 months (20.3–31.3 months) with Isa-Pd and 17.7 months (14.4–26.2 months) with Pd (hazard ratio = 0.78; 95% CI, 0.59–1.02; 1-sided P = 0.0319). This analysis showed a clinically meaningful, continued OS benefit with Isa-Pd, which is well tolerated after follow-up of approximately 52 months in patients with relapsed/refractory multiple myeloma.

Trial registration: ClinicalTrials.gov, number NCT02990338

Health sciences/Diseases/Haematological diseases/Haematological cancer/Myeloma

Health sciences/Medical research/Drug development

anti-CD38 monoclonal antibody

ICARIA-MM

isatuximab

multiple myeloma

Multiple myeloma (MM) primarily remains an incurable disease, and although novel agents have improved response and survival rates, almost all patients relapse either on or after these treatments [1–4]. Treatment choice for relapsed and refractory MM (RRMM) is determined by refractoriness and exposure to prior drugs [5].

Due to the need for novel treatments for RRMM, monoclonal antibodies targeting CD38 have emerged, such as daratumumab and isatuximab [6–9]. Isatuximab is a monoclonal antibody targeting a specific epitope of the human cell-surface antigen CD38, which is widely and uniformly expressed on myeloma cells [10–12].

Isatuximab was investigated in combination with pomalidomide and dexamethasone in a phase 3, randomized, multicenter, open-label trial (ICARIA-MM [NCT02990338]) [13]. After a median follow-up of 11.6 months, median progression-free survival (PFS) was 11.5 (95% confidence interval [CI], 8.9–13.9) months with isatuximab–pomalidomide–dexamethasone (Isa-Pd) and 6.5 (95% CI, 4.5–8.3) months with pomalidomide–dexamethasone (Pd) alone [13]. Median overall survival (OS) was not reached in either treatment arm (hazard ratio [HR] = 0.687; 95% CI, 0.461–1.023; P = 0.0631) [13].

Results from a pre-specified updated analysis at 24 months after the primary analysis reported a median OS of 24.6 months (95% CI, 20.3–31.3) with Isa-Pd vs. 17.7 months (95% CI, 14.4–26.2) months with Pd (HR = 0.76; 95% CI, 0.57–1.01) [14].

Based on the primary results of ICARIA-MM, isatuximab has been approved in several countries in combination with Pd for adult patients with RRMM who have received ≥ 2 previous therapies, including lenalidomide and a proteasome inhibitor (PI) [11, 15].

This analysis of ICARIA-MM reports the final OS, conducted when 220 deaths occurred.

Study design and participants

ICARIA-MM is a prospective, multicenter, randomized, open-label, parallel-group phase 3 study conducted at 102 sites in 24 countries (Supplementary Materials p 2–3). Detailed inclusion and exclusion criteria, study design, randomization and masking, and procedures have been previously described and are detailed in Supplementary Materials (pp 4–7) [13, 14].

Briefly, eligible patients were ≥ 18 years old, had RRMM, received ≥ 2 previous therapies, and had failed therapy with lenalidomide and a PI (alone or in combination). Failure to therapy included progression on or within 60 days, intolerance to lenalidomide or the PI, or disease progression within 6 months after achieving at least a partial response (PR). Patients refractory to previous anti-CD38 therapy, with prior pomalidomide exposure, with an Eastern Cooperative Oncology Group Performance Status > 2, an ongoing toxic effect grade > 2 from previous therapy (grade according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03), with active primary amyloid light-chain amyloidosis, or concomitant plasma cell leukemia were excluded.

The trial complied with the International Conference on Harmonisation Good Clinical Practice Guideline and the Declaration of Helsinki. All participating institutional review boards and ethics committees approved the study protocol, and patients provided written informed consent.

Randomization and masking

Following eligibility confirmation, patients were randomized using an interactive response technology (IRT) system in a 1:1 ratio to the Isa-Pd (isatuximab) arm or to the Pd (control) arm. Randomization was stratified by age (< 75 vs. ≥75 years) and number of previous lines of therapy (2 or 3 vs. >3). A randomized patient was defined as having a signed informed consent and a randomization number by the IRT, regardless of whether the patient was treated. The centralized IRT prevented the investigator from knowing a patient’s treatment assignment in advance. Isatuximab administration was open label with respect to patients and investigators; however, disease response assessments were evaluated based on radiological and central laboratory assessments by the Independent Response Committee (IRC), which was blinded to treatment. IRC disease assessment was used until the primary endpoint (PFS) was determined.

Procedures

Intravenous isatuximab 10 mg/kg was administered on days 1, 8, 15, and 22 of cycle 1 and days 1 and 15 for subsequent cycles. Intravenous or oral dexamethasone 40 mg (20 mg if age ≥ 75 years) was administered on days 1, 8, 15, and 22, and oral pomalidomide 4 mg was administered on days 1–21. Pre-medication and isatuximab preparation were described previously [13, 14]. Treatment was discontinued based on patient request, disease progression, unacceptable adverse event (AE), poor compliance to study protocol, or loss to follow-up. Isatuximab dose reductions were not permitted. Dose reductions for pomalidomide and dexamethasone and/or cycle delay were permitted in case of toxicity. Investigators selected any subsequent therapy after progression. Efficacy assessments were completed on day 1 of each cycle. Safety evaluations were completed on days 1, 8, 15, and 22 of cycle 1; days 1 and 15 for subsequent cycles; and at 30 and 60 days following the last treatment administration. AEs were reported throughout the study. Tumor cytogenetics were assessed via central laboratory at screening, using fluorescence in situ hybridization, and results reported with a cutoff of 30% for t(4;14) and t(14;16) and 50% for del(17p).

Outcomes

The primary endpoint of ICARIA-MM was PFS as determined by the IRC. No PFS per IRC update is provided based on this additional follow-up. Key secondary endpoints include overall response rate (ORR) and OS. ORR was defined as the proportion of patients with complete response (CR), stringent CR, very good partial response (VGPR), and PR as best overall response, assessed by IRC using the International Myeloma Working Group criteria. No updated ORR per IRC is provided. OS was defined as the time from the date of randomization to date of death from any cause. If death was not observed before the analysis data cutoff date, OS was censored at the last date that the patient was known to be alive or at the cutoff date, whichever was first. Exploratory endpoints included PFS2, ORR on further therapy (best overall response reported by the investigator), PFS on the first line of further therapy, and time to next treatment (TTNT). PFS2 was defined as time from the date of randomization to the date of first documentation of progressive disease, as reported by the investigator, after initiation of further anti-myeloma treatment or death from any cause, whichever happened first. PFS on the first line of further therapy was defined as the time from the start date of the first line of further therapy to the date of the first documentation of progressive disease (as reported by the investigator) after initiation of the first line of further therapy or death from any cause, whichever happened first. TTNT was defined as the time from randomization to the start of further anti-myeloma treatment. Safety assessments for AEs/serious AEs (SAEs), laboratory parameters, vital signs, Eastern Cooperative Oncology Group Performance Status, and physical examinations were performed throughout the study or until the PFS analysis. Treatment-emergent AE (TEAE) data were collected from the time of signed informed consent to 30 days after the last study treatment administration. After the 30-day end-of-treatment visit, all ongoing related AEs; all ongoing SAEs, whatever the relationship with study treatment; and all new related AEs regardless of seriousness, were reported and followed until resolution or stabilization. All AEs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Infusion reactions (IRs) were analyzed using the investigator-reported term collected in the specific AE forms. AEs of special interest included grade ≥ 3 IRs and reports of pregnancy, symptomatic overdose with study treatment, and second primary malignancy (SPM). Clinical laboratory abnormalities were recorded as AEs only if they were serious or led to study treatment modification or discontinuation. A central laboratory was used for analyzing efficacy parameters (serum M-protein, serum immunoglobulins, free light chain, urine M-protein, high-risk cytogenetic assessment). High-risk cytogenetics was defined as presence of del(17p), t(4;14), or t(14;16). Definitive treatment discontinuation was defined as discontinuation of all study treatments, whereas premature discontinuation was defined as discontinuation of ≥ 1 study treatment while ≥ 1 study treatment was continued.

Statistical analysis

Based on the primary efficacy endpoint (PFS) using the assumptions that the control arm had a median PFS of 4.0 months; the Isa-Pd arm was assessed to have 40% risk reduction in hazard ratio vs. control, corresponding to an improvement in the true median PFS time from 4.0 to 6.67 months; and a log-rank test at a 1-sided 2.5% significance level, a total of 162 PFS events were calculated to be needed to achieve 90% power for the study. Based on these assumptions, 220 deaths were needed to achieve 80% power for the study.

For the final analysis, a data cutoff date of March 14, 2022, was selected, and data were included up to this date (last patient last visit). Per protocol, the cutoff date for the final OS analysis was to occur when 220 OS events had been observed. The 220th OS event occurred on January 27, 2022, and this date was considered to be the OS cutoff date for the primary OS analysis.

Efficacy analyses were conducted using the intention-to-treat (ITT) population, defined as patients who provided signed informed consent and were allocated a randomization number by the IRT. Safety was assessed in all patients from the ITT population who received at least a partial dose of study treatment. Patients were considered lost to follow-up if the last contact was ≥ 8 weeks prior to the data cutoff.

OS was analyzed using the Kaplan–Meier method and corresponding 95% CI, which was calculated with log-log transformation of survival function and the method devised by Brookmeyer and Crowley. HRs and corresponding 95% CIs are calculated from a Cox proportional hazards model, stratified by age and number of previous lines of therapy. The proportional hazard assumption was tested for PFS by investigator, OS, TTNT, and PFS on subsequent therapy or death using Schoenfeld residuals at the 5% threshold. One-sided log-rank tests stratified by age and number of previous lines of therapy were computed. The OS analysis significance level was set using the O'Brien-Fleming alpha spending function. Based on a pre-specified analysis, the consistency of OS results was evaluated across patient subgroups (age, baseline Eastern Cooperative Oncology Group Performance Status, cytogenetic abnormality, cytogenetic abnormality del[17p], cytogenetic abnormality gain [1q21], geographical region, International Staging System stage at study entry, MM type at diagnosis, number of previous lines of therapy, race, refractory to lenalidomide, refractory to lenalidomide at last regimen pre-study, refractory to PI, regulatory region, renal impairment [i.e., baseline creatinine clearance], revised International Staging System stage at study entry, and sex) with available results. Within each subgroup, treatment-effect HRs and 95% CIs were assessed via a Cox proportional hazards model. A treatment-by-factor interaction test at the 10% α level was conducted. A sensitivity analysis of OS using the rank-preserving structural failure time (RPSFT) method was completed, adjusting for patients who received daratumumab as subsequent therapy after progression (Supplementary Materials p 17).

Pre-specified analyses were completed for updated PFS by investigator assessment (sensitivity analysis), PFS on subsequent therapy or death, and PFS on the first line of subsequent therapy (separate summaries for subsequent therapy with/without daratumumab-based therapy), and TTNT using OS analysis methods. P values for exploratory endpoints are provided for descriptive purposes only. A post hoc, exploratory Kaplan–Meier analysis of OS was completed to compare all patients receiving isatuximab vs. control treatment who did/did not proceed to subsequent daratumumab therapy. Another post hoc analysis calculated time between last dose of investigational study treatment and subsequent daratumumab therapy.

Updated ORRs based on investigator assessments were described with patient numbers and percentages, by overall response (PR, VGPR, CR, or stringent CR), VGPR or better (≥ VGPR), and clinical benefit (i.e., minimal response or better). Additionally, 95% CIs were calculated for ORRs using the Clopper-Pearson method. A pre-specified exploratory analysis was conducted to summarize ORRs (VGPR and CR rates) on subsequent therapy by select therapeutic classes/agents (steroids, alkylating agents, immunomodulatory (IMiD) agents, PIs, and daratumumab), based on identical methods as for the ORR analysis. Minimal residual disease status is summarized descriptively.

All statistical analyses were performed with SAS (version 9.4; SAS Institute, Cary, NC) or R (version 3.4.3; R Foundation, Vienna, Austria). Since the updated analysis, no additional amendments to the protocol have been made. This study is registered with ClinicalTrials.gov: NCT02990338.

Role of the funding source

The funder of the study had a role in the study design, data collection, data interpretation, and writing of the report.

Between January 10, 2017, and February 1, 2018, 387 patients were screened and 307 were randomized (Isa-Pd, 154; control, 153) at 102 sites in 24 countries. Cutoff for the first OS interim analysis, at the time of the primary PFS analysis, was October 11, 2018 (reported previously) [13]. Cutoff for the pre-planned second interim analysis was October 1, 2020 (reported previously) [14]. Cutoff for the final OS analysis was January 27, 2022, per protocol (Fig. 1). Data cutoff for last patient last visit was March 14, 2022.

Baseline characteristics were similar in both arms, as previously published and briefly shown in Table 1. All patients previously received PIs and IMiD agents.

Median treatment duration was 11.0 (2.6–12.4) months among patients receiving Isa-Pd and 5.5 (4.4–21.8) months among patients receiving Pd. At data cutoff (March 14, 2022), 16 (10.4%) patients receiving Isa-Pd and 3 (2.0%) patients receiving Pd remained on treatment. The most frequent reason for definitive discontinuation was progressive disease (isatuximab, 65.6%; control, 76.5%).

After a median follow-up of 52.4 months, median PFS per investigator assessment (ignoring symptomatic deterioration) showed consistent improvement with longer follow-up (Isa-Pd: 11.1 [95% CI, 7.8–13.8] months; Pd: 5.9 [95% CI, 4.5–7.9] months; HR = 0.57 [95% CI, 0.44–0.73]; 1-sided P < 0.0001; Supplementary Materials p 11).

The pre-specified required number of 220 OS events occurred on January 27, 2022, which was the analysis cutoff date. Of the 220 deaths, 106 (68.8%) occurred in the Isa-Pd arm and 114 (74.5%) in the Pd arm. Median OS was 24.6 months (95% CI, 20.3–31.3) in the Isa-Pd group and 17.7 months (95% CI, 1 4.4–26.2) in the Pd group (HR = 0.78; 95% CI, 0.59–1.02; 1-sided P = 0.0319; Fig. 2). Early separation was observed in the OS curves between arms; however, because the 1-sided P value for statistical significance was set to 0.02 based on the previous interim analysis, the current analysis did not cross the level of significance. Censored patients (Isa-Pd: 48 [31%] of 154; Pd: 39 [26%] of 153) remained alive at data cutoff (Isa-Pd: 39 [81%] of 48; Pd: 31 [80%] of 39), were alive at the last contact before the cutoff date (1 [2%] of 48; 0 of 39), or were lost to follow-up (8 [17%] of 48; 8 [21%] of 39). Subgroup analyses of OS are shown in Supplementary Materials (p 12).

Among patients receiving subsequent anti-myeloma therapy, daratumumab was given to 23 (23%) of 102 patients in the Isa-Pd group and 71 (60%) of 119 patients in the Pd group (Supplementary Materials pp 15). To estimate the treatment effect in the absence of a switch to subsequent anti-cancer therapy with daratumumab, sensitivity analyses using the RPSFT model were performed, with overall similar results (HR = 0.706; 95% CI, 0.538–0.926) to the ITT estimate (HR = 0.776; 95% CI, 0.594–1.015; Supplementary Materials p 17). An OS sensitivity analysis was conducted to assess the impact of death due to coronavirus disease 2019 infection, with similar results to the ITT estimate (Supplementary Materials p 18).

Overall, 102 (66%) of 154 patients in the Isa-Pd group and 119 (78%) of 153 patients in the Pd group received subsequent anti-myeloma therapy. Median TTNT was longer with isatuximab (15.5 [95% CI, 12.1–19.8] months) vs. Pd (8.9 [95% CI, 6.3–11.5] months; 1-sided P < Isa-Pd0.0001; Fig. 3). Median PFS on subsequent therapy or death (PFS2) was longer in the Isa-Pd group (17.5 [14.9–19.2] months) vs. Pd (12.9 [10.1–16.6] months; 1-sided P = 0.0091; Fig. 2).

The proportional hazard assumption was met (Schoenfeld residuals test) for the following Cox models: PFS by investigator (P = 0.89), OS (P = 0.28), TTNT (P = 0.44), and PFS2 (P = 0.42).

The ORR was higher with Isa-Pd vs. Pd, consistent with the primary analysis and second interim analysis (Supplementary Materials pp 13–14). Deeper responses were also observed with Isa-Pd vs. Pd. Minimal residual disease negativity was observed in 10 (6%) patients in the Isa-Pd group at the 10^–5 sensitivity level (18 patients with data available) but in no patients in the Pd group (3 patients with data available; data not shown).

More patients in the Isa-Pd group vs. the Pd group received subsequent alkylating agents, PIs, corticosteroids, and other treatments (i.e., investigational anti-neoplastic drugs, cisplatin, etoposide, and stem cells), whereas IMiD agents were administered to a similar proportion of patients in both groups (Supplementary Materials p 15).

Exploratory analysis of ORR, CR, VGPR, or PR on selected subsequent therapies with/without daratumumab are shown in Fig. 4 and Supplementary Materials (p 16). Among non-daratumumab–based regimens, non-IMiD–based regimens vs. IMiD-based regimens led to better response rates with Isa-Pd (28/71 [39%] vs. 3/27 [11%]). Per the inclusion criteria, patients previously failed treatment with lenalidomide and a PI.

ORR with subsequent daratumumab in any subsequent line was lower for patients in the Isa-Pd group (5/21 [24%]) vs. the Pd group (23/57 [40%]); however, rates of ≥ VGPR were similar (3/21 [14%] vs. 10/57 [18%]). Daratumumab in combination led to improvements in both arms (Isa-Pd: 4/14 [29%]; Pd: 13/29 [45%]) vs. daratumumab monotherapy ± steroids (Supplementary Materials p 16). Some patients receiving daratumumab, alone or in combination, as a first subsequent line of therapy achieved ≥ VGPR, even after receiving prior isatuximab study therapy (2/8 patients [25%]) with a short washout period (median, 13 days) (Fig. 4).

Among patients receiving non-daratumumab–based therapy, median PFS on the first line of subsequent therapy was similar in the Isa-Pd group (4.6 months [95% CI, 3.1–6.6] in 69 [74%] of 93 patients receiving subsequent non-daratumumab therapy) vs. the Pd group (5.2 months [95% CI, 3.8–7.3] in 43 [64%] of 67 patients receiving subsequent non-daratumumab therapy) (Supplementary Materials p 19). However, among patients receiving daratumumab-based therapy as the first subsequent line (n = 9; Pd: n = 52), median PFS was lower with Isa-Pd (Isa-Pd: 2.2 months [95% CI, 0.03–7.4] in 7 [78%] of 9 patients receiving subsequent daratumumab) vs. Pd (5.7 months [95% CI, 3.8–10.8] in 39 [75%] of 52 patients receiving subsequent daratumumab) (Supplementary Materials p 19). The median time between the last dose of investigational medicinal product and the first subsequent therapy with daratumumab was shorter in the Isa-Pd group (n = 9; 13 days [range, 2–100 days]) vs. the Pd group (n = 52; 22 days [range, 1–822 days]; data not shown; post hoc).

With longer follow-up, no new safety concerns were identified with Isa-Pd. The overall safety summary is in Supplementary Materials (p 20), and the most frequently reported TEAEs are in Table 2. Compared with the Pd group, the Isa-Pd group, respectively, had longer cumulative exposure to treatment (216.1 vs. 137.3 patient-years) and a larger median number of cycles started per patient (11 [interquartile range, 4–22.5] vs. 6 [3–13]; Supplementary Materials p 10). In the safety population, 70 (46%) of 152 patients had pomalidomide dose reductions and 62 (41%) had dexamethasone dose reductions in the isatuximab group vs. 40 (27%) of 149 patients with pomalidomide dose reductions and 45 (30%) with dexamethasone reductions in the Pd group (Supplementary Materials p 10). The most frequently reported grade ≥ 3 TEAEs in the Isa-Pd and Pd groups were neutropenia (77 [51%] of 152 vs. 52 [35%] of 149), pneumonia (35 [23%] vs. 31 [21%]), and thrombocytopenia (20 [13%] vs. 18 [12%]; Supplementary Materials p 23). TEAEs reported in ≥ 10% of patients and ≥ 5% higher with isatuximab are shown in Supplementary Materials (p 22). TEAEs reported in ≥ 5% of patients are shown in Supplementary Materials (pp 24–25). IRs were reported with Isa-Pd (2 patients in the Pd group experienced IRs upon subsequent daratumumab therapy), and all were reversible; only 1 IR has been reported since the primary analysis (cycle 19; data not shown), whereas all others were reported in the first 3 infusions. Grade 3/4 IRs were reported in 4 (3%) of 152 patients. Hematologic laboratory abnormalities are shown in Supplementary Materials (p 26). SPM occurred in 10 (7%) of 152 patients in the Isa-Pd group and 3 (2%) of 149 in the Pd group (Supplementary Materials p 21). Of these, 3 (Isa-Pd) occurred during the post-treatment period.

Treatment-emergent SAEs occurred in 112 (74%) of 152 patients in the Isa-Pd group and 91 (61%) of 149 in the Pd group (Supplementary Materials p 27–28). Pneumonia was the most frequent SAE (all grades, both groups), reported in 35 (23%) of 152 patients in the Isa-Pd group and 31 (21%) of 149 in the Pd group. TEAEs with a fatal outcome were reported in 23 (15%) of 152 patients in the Isa-Pd group and 19 (13%) of 149 in the Pd group. There were 2 (1%) treatment-related deaths in the Isa-Pd group (sepsis, 1; cerebellar infarction, 1) and 2 (1%) in the Pd group (pneumonia, 1; urinary tract infection, 1; data not shown). Overall, 108 (71%) patients in the Isa-Pd group and 113 (76%) in the Pd group died during the on- or post-treatment period due to disease progression (Isa-Pd: 76 [50%]; Pd: 81 [54%]), AEs (7 [5%] vs. 8 [5%]), or other causes (25 [16%] vs. 24 [16%]; data not shown).

Dose reductions for pomalidomide and dexamethasone due to TEAEs were more frequent in the Isa-Pd arm vs. the Pd arm (pomalidomide reductions in 115 [76%] of 152 patients vs. 70 [47%] of 149 patients; dexamethasone reductions in 104 [68%] patients vs. 76 [51%] patients) and were primarily due to infections and neutropenia (data not shown). Definitive treatment discontinuation due to TEAEs was infrequent and occurred at similar rates in both treatment arms (19 [13%] of 152 patients in the Isa-Pd group vs. 22 [15%] of 149 patients in the Pd group; Supplementary Materials p 29).

This final OS analysis of ICARIA-MM showed a clinically meaningful benefit with a 6.9-month improvement in median OS with the addition of isatuximab to Pd (HR = 0.78; log-rank 1-sided P = 0.0319). This difference was not statistically significant because the 1-sided significance level was set to 0.02. The more frequent use of subsequent daratumumab in the control group (59.7% vs. 22.5% [isatuximab group]) may have affected the power to detect statistically significant OS, given the sample size, which was supported by the RPSFT analysis that demonstrated a slightly better estimate vs. the ITT estimate. The RPSFT method makes the strong assumption of a constant treatment effect over time.

Long-term outcome measures showed continuous overall benefit for patients randomized to isatuximab vs. control treatment, suggesting the prolonged benefit of isatuximab use in earlier lines without inducing more resistant disease refractory to subsequent treatments. There was a significant TTNT delay in the Isa-Pd group vs. the Pd group (15.5 vs. 8.9 months). Despite subsequent daratumumab use in the Pd group and its potential benefit on PFS in the first subsequent therapy line, median PFS2 was significantly longer with Isa-Pd vs. Pd (17.5 vs. 12.9 months; log-rank 1-sided P = 0.0091). Based on these data, anti-CD38 therapy should be used as early as possible during the treatment continuum.

Extended follow-up to approximately 52 months revealed continued efficacy and tolerability of the isatuximab regimen, representing an important option for patients who are refractory to other treatments, such as lenalidomide. At study entry, approximately 95% of patients were refractory to IMiD agents (93% to lenalidomide, specifically). Looking at all non-daratumumab–based therapies in any subsequent line, non-IMiD– vs. IMiD-based regimens appear to have better response rates after isatuximab. Similar rates of ≥ VGPR were seen between groups regardless of subsequent regimens.

More patients in the control group received subsequent therapy and subsequent daratumumab therapy, as more patients in the Isa-Pd arm were still receiving study treatment at data cutoff. As expected, ORRs were higher with subsequent daratumumab therapy after Pd vs. Isa-Pd; however, ≥VGPR rates were similar. Daratumumab-based combination therapy led to improved responses in both arms vs. monotherapy. Patients receiving daratumumab alone or in combination as first subsequent line of therapy achieved ≥ VGPR, even after Isa-Pd therapy with a short washout period. Patients who received daratumumab after Isa-Pd had shorter PFS than those who did not receive subsequent daratumumab; however, only 9 patients received daratumumab after the isatuximab combination. No cross-resistance to regimens without daratumumab was observed in the isatuximab group vs. the control group. Although limited by small sample size and open-label nature of the study, these results provide initial information on potential efficacy differences related to treatment sequencing.

After follow-up of approximately 52 months, more patients remained on treatment in the Isa-Pd vs. Pd group. The proportion of patients discontinuing due to AEs was similar in both arms, indicating no increased risk with the addition of isatuximab resulting from longer exposure in the isatuximab group. Importantly, the overall safety profile observed with Isa-Pd was not different from previous analyses of ICARIA-MM [13, 14]. At this final analysis, SPM were reported in 7% of patients in the isatuximab group, consistent with the second interim analysis [14], similar to the cumulative incidence of SPM in patients with MM at 10 years (7.4%) [16], and with ranges reported in RRMM registry studies [17]. Furthermore, SPM occurrence did not have a detrimental impact on OS in patients receiving Isa-Pd, supporting the overall favorable benefit of the regimen.

Although cross-trial comparisons must be conducted with caution, final OS analysis of the phase 2 ELOQUENT-3 trial demonstrated that elotuzumab, a monoclonal antibody targeting signaling lymphocytic activation molecule F7, in combination with Pd, significantly improved OS after a minimum follow-up of 45 months [18]. No information on depth of response or subsequent anti-myeloma therapy was reported. The proportion of patients with International Staging System Stage III at study entry (12% vs. 22%) in the triplet combination groups was substantially lower in ELOQUENT-3 than in ICARIA-MM. Results from the phase 3 APOLLO trial investigating daratumumab–pomalidomide–dexamethasone vs. Pd demonstrated clinically meaningful OS benefit with the daratumumab combination (34.4 vs. 23.7 months; HR = 0.82; 95% CI, 0.61–1.11; not statistically significant), similar to that observed in ICARIA-MM [19]. Patients in APOLLO received fewer prior lines of therapy and were less refractory vs. patients in the ICARIA-MM study (median prior lines, 2 vs. 3; 80% vs. 94% refractory to lenalidomide; 48% vs. 77% refractory to a PI; 42% vs. 72% refractory to both lenalidomide and a PI).

Limitations of the current study include its open-label nature, the absence of patients refractory to previous daratumumab therapy, and the imbalance of the subsequent use of daratumumab that may have affected the power to detect statistically significant OS.

In summary, the final OS analysis of this large, multicenter study confirmed that Isa-Pd continued to be efficacious and well tolerated after follow-up of approximately 52 months, contributing to a clinically meaningful benefit with a 6.9-month improvement in median OS, further supporting its position as a standard-of-care therapy for patients with RRMM and informing real-world practice [20].

ACKNOWLEDGEMENTS

This 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. Coordination of the development of this manuscript, facilitation of author discussion, and critical review were provided by Aidee Ayala Camargo, PhD, Sci Comms Director, at Sanofi. The authors thank Laure Malinge for statistical contributions to the manuscript. Medical writing support was provided by Erin Burns-Tidmore, PhD, of Elevate Scientific Solutions, funded by Sanofi.

AUTHOR CONTRIBUTIONS

PGR, AP, JS-M, MB, IS, XL, FS, PM, MAD, JS-YH, JM, MC, and HMP were investigators in the study and contributed to data acquisition. PGR and AP were coprimary investigators of the ICARIA-MM study. PGR, SM, RZ, FD, and MCM contributed to the analysis, verification, and interpretation of data for the work. KCA was the chairman of the study Steering Committee. 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, edited and reviewed manuscript drafts, and approved the final version for submission.

COMPETING INTERESTS

PGR reports research funding from Bristol Myers Squibb/Celgene, Karyopharm, Oncopeptides, and Takeda and participation on an entity’s board of directors or advisory committee for AstraZeneca, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Karyopharm, Oncopeptides, Protocol Intelligence, Regeneron, Secura Bio, Sanofi, and Takeda. AP reports honoraria from AbbVie, Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, Sanofi, and Takeda. JS-M reports honoraria from AbbVie, Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Haemalogix, Janssen, Karyopharm, Merck Sharp & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, and Takeda. MB reports honoraria from Amgen, Celgene, Janssen, Sanofi, and Takeda and participation on an entity’s board of directors or advisory committee for Amgen, Janssen, Oncopeptides, and Takeda. IS reports honoraria from Amgen, Bristol Myers Squibb, Celgene, Janssen-Cilag, Novartis, PharmaMar, Sanofi, and Takeda. FS reports research funding from Celgene, GlaxoSmithKline, Janssen, Oncopeptides, Sanofi, and Targovax; honoraria from AbbVie, Amgen, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Janssen, Novartis, Oncopeptides, Pfizer, Sanofi, SkyliteDX, and Takeda; and participation on an entity’s board of directors or advisory committee for AbbVie, Celgene, GlaxoSmithKline, Janssen, Oncopeptides, Sanofi, and Takeda. PM reports honoraria from AbbVie, Amgen, Celgene, GlaxoSmithKline, Janssen, and Sanofi. MAD reports honoraria from Amgen, BeiGene, Bristol Myers Squibb, Janssen, and Takeda. JM reports honoraria from Amgen, Bristol Myers Squibb/Celgene, Takeda, Janssen, and Sanofi and participation on an entity’s board of directors or advisory committees for Amgen, Bristol Myers Squibb/Celgene, Janssen, Oncopeptides, Sanofi, and Takeda. MC reports consulting fees from Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, and Sanofi and honoraria from Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, and Sanofi. SM, FD, RZ, and MCM are employees of Sanofi and may hold stock and/or stock options. KCA reports consulting fees from AstraZeneca, Janssen, Pfizer, and Precision Biosciences. XL, JS-YH, and HMP have nothing to disclose.

DATA AVAILABILITY

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.vivli.org.

ADDITIONAL INFORMATION

Supplementary information The online version contains supplementary material available at [insert DOI]

Correspondence and requests for materials should be addressed to Paul G. Richardson.

Reprints and permission information is available at https://www.nature.com/reprints

Abramson HN. The multiple myeloma drug pipeline-2018: a review of small molecules and their therapeutic targets. Clin Lymphoma Myeloma Leuk. 2018;18:611–27.
Legarda MA, Cejalvo MJ, de la Rubia J. Recent advances in the treatment of patients with multiple myeloma. Cancers (Basel). 2020;12:3576.
Ninkovic S, Quach H. Shaping the treatment paradigm based on the current understanding of the pathobiology of multiple myeloma: an overview. Cancers (Basel). 2020;12:3488.
Rajkumar SV, Kumar S. Multiple myeloma current treatment algorithms. Blood Cancer J. 2020;10:94.
Cornell RF, Kassim AA. Evolving paradigms in the treatment of relapsed/refractory multiple myeloma: increased options and increased complexity. Bone Marrow Transplant. 2016;51:479–91.
van de Donk N, Richardson PG, Malavasi F. CD38 antibodies in multiple myeloma: back to the future. Blood. 2018;131:13–29.
Munshi C, Aarhus R, Graeff R, Walseth TF, Levitt D, Lee HC. Identification of the enzymatic active site of CD38 by site-directed mutagenesis. J Biol Chem. 2000;275:21566–71.
Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, et al. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev. 2008;88:841–86.
Chillemi A, Quarona V, Antonioli L, Ferrari D, Horenstein AL, Malavasi F. Roles and modalities of ectonucleotidases in remodeling the multiple myeloma niche. Front Immunol. 2017;8:305.
Jiang H, Acharya C, An G, Zhong M, Feng X, Wang L, et al. SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide. Leukemia. 2016;30:399–408.
Sanofi. SARCLISA [package insert]. Bridgewater, NJ; 2021.
Tai YT, Anderson KC. Targeting CD38 alleviates tumor-induced immunosuppression. Oncotarget. 2017;8:112166–7.
Attal M, Richardson PG, Rajkumar SV, San-Miguel J, Beksac M, Spicka I, et al. 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. Lancet. 2019;394:2096–107.
Richardson PG, Perrot A, San-Miguel J, Beksac M, Spicka I, Leleu X, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study. Lancet Oncol. 2022;23:416–27.
European Medicines Agency. Sarclisa. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/sarclisa-0.
Wang J, Lv C, Zhou M, Xu JY, Chen B, Wan Y. Second primary malignancy risk in multiple myeloma from 1975 to 2018. Cancers (Basel). 2022;14:4919.
Musto P, Anderson KC, Attal M, Richardson PG, Badros A, Hou J, et al. Second primary malignancies in multiple myeloma: an overview and IMWG consensus. Ann Oncol. 2017;28:228–45.
Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, Hori M, et al. Elotuzumab plus pomalidomide and dexamethasone for relapsed/refractory multiple myeloma: final overall survival analysis from the randomized phase II ELOQUENT-3 trial. J Clin Oncol. 2022;41:568–78.
Dimopoulos MA, Terpos E, Boccadoro M, Delimpasi S, Beksac M, Katodritou E, et al., editors. Subcutaneous daratumumab plus pomalidomide and dexamethasone (D-Pd) versus pomalidomide and dexamethasone (Pd) alone in patients with relapsed or refractory multiple myeloma (RRMM): overall survival results from the phase 3 Apollo study. 64th ASH Annual Meeting and Exposition; 2022 December 10–13, 2022; New Orleans, LA.
Richardson PG, San Miguel JF, Moreau P, Hajek R, Dimopoulos MA, Laubach JP, et al. Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting. Blood Cancer J. 2018;8:109.

Tables 1 and 2 are available in the Supplementary Files section.

Yes there is potential conflict of interest. PGR reports research funding from Bristol Myers Squibb/Celgene, Karyopharm, Oncopeptides, and Takeda and participation on an entity’s board of directors or advisory committee for AstraZeneca, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Karyopharm, Oncopeptides, Protocol Intelligence, Regeneron, Secura Bio, Sanofi, and Takeda. AP reports honoraria from AbbVie, Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, Sanofi, and Takeda. JS-M reports honoraria from AbbVie, Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Haemalogix, Janssen, Karyopharm, Merck Sharp & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, and Takeda. MB reports honoraria from Amgen, Celgene, Janssen, Sanofi, and Takeda and participation on an entity’s board of directors or advisory committee for Amgen, Janssen, Oncopeptides, and Takeda. IS reports honoraria from Amgen, Bristol Myers Squibb, Celgene, Janssen-Cilag, Novartis, PharmaMar, Sanofi, and Takeda. FS reports research funding from Celgene, GlaxoSmithKline, Janssen, Oncopeptides, Sanofi, and Targovax; honoraria from AbbVie, Amgen, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Janssen, Novartis, Oncopeptides, Pfizer, Sanofi, SkyliteDX, and Takeda; and participation on an entity’s board of directors or advisory committee for AbbVie, Celgene, GlaxoSmithKline, Janssen, Oncopeptides, Sanofi, and Takeda. PM reports honoraria from AbbVie, Amgen, Celgene, GlaxoSmithKline, Janssen, and Sanofi. MAD reports honoraria from Amgen, BeiGene, Bristol Myers Squibb, Janssen, and Takeda. JM reports honoraria from Amgen, Bristol Myers Squibb/Celgene, Takeda, Janssen, and Sanofi and participation on an entity’s board of directors or advisory committees for Amgen, Bristol Myers Squibb/Celgene, Janssen, Oncopeptides, Sanofi, and Takeda. MC reports consulting fees from Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, and Sanofi and honoraria from Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, and Sanofi. SM, FD, RZ, and MCM are employees of Sanofi and may hold stock and/or stock options. KCA reports consulting fees from AstraZeneca, Janssen, Pfizer, and Precision Biosciences. XL, JS-YH, and HMP have nothing to disclose.

Download PDF

Editorial decision: revise
31 Jul, 2023
Review #2 received at journal
23 Jul, 2023
Review #1 received at journal
16 Jul, 2023
Reviewer #2 agreed at journal
08 Jul, 2023
Reviewer #1 agreed at journal
06 Jul, 2023
Reviewers invited by journal
06 Jul, 2023
Editor assigned by journal
29 Jun, 2023
Submission checks completed at journal
28 Jun, 2023
First submitted to journal
27 Jun, 2023

You are reading this latest preprint version

Isatuximab–pomalidomide–dexamethasone vs. pomalidomide–dexamethasone in patients with relapsed and refractory multiple myeloma: final overall survival analysis

Status:

Version 1

Abstract

Figures

INTRODUCTION

METHODS

Study design and participants

Randomization and masking

Procedures

Outcomes

Statistical analysis

Role of the funding source

RESULTS

DISCUSSION

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1