Isatuximab Combo Significantly Improves PFS in Relapsed Multiple Myeloma

The addition of isatuximab-irfc (Sarclisa) to carfilzomib (Kyprolis) and dexamethasone (Isa-Kd) resulted in a significant improvement in progression-free survival (PFS) vs carfilzomib plus dexamethasone (Kd) alone in patients with relapsed or refractory multiple myeloma, according to updated data from the phase 3 IKEMA trial (NCT03275285).¹

The findings, which were shared during the 2022 Controversies in Multiple Myeloma World Congress, showed that the median PFS with Isa-Kd (n = 179) was 35.7 months (95% CI, 25.8-44.0) per independent review committee assessment vs 19.2 months (95% CI, 15.8-25.1) with Kd alone (n = 123), translating to a 42% reduction in the risk of disease progression or death (HR, 0.58).

A PFS analysis following the FDA recommendations on censoring rules, as applied in the approved prescribing information for the United States, demonstrated a median PFS of 41.7 months in the investigative arm vs 20.8 months in the control arm (HR, 0.59; 95% CI, 27.1–not calculable [NC]). The addition of isatuximab to Kd also prolonged time to next treatment vs Kd alone, at 44.9 months (95% CI, 31.6-NC) vs 25.6 months (95% CI, 17.9-31.3), respectively (HR, 0.55).

Moreover, the safety and tolerability of isatuximab proved to be consistent with what has been reported with the agent in prior trials.

“The increase in PFS, observed consistently across all subgroups, when adding [isatuximab] to carfilzomib and dexamethasone is remarkable in patients with relapsed multiple myeloma in a proteasome inhibitor [PI] combination,” Philippe Moreau, MD, head of the Department of Hematology, University Hospital of Nantes, stated in a press release. “Relapse is common in multiple myeloma, creating the need for differentiated second-line treatments that provide patients a longer period of time without disease progression. This updated analysis reinforces the potential for [isatuximab] to become a new standard of care for patients with relapsed multiple myeloma.”

The prospective, randomized, open-label, parallel-group, phase 3 IKEMA trial enrolled patients with relapsed or refractory multiple myeloma who had measurable disease, received 1 to 3 prior lines of therapy, and were at least 18 years of age.²

If patients had primary refractory multiple myeloma, serum-free light chain measurable disease only, or an ECOG performance status greater than 2, they were excluded. Other exclusion criteria included having received antimyeloma therapy within 2 weeks of randomization, prior carfilzomib, having been refractory to an anti-CD38 antibody, or having had a contraindication to dexamethasone.

Study participants were randomized 3:2 to receive Isa-Kd vs Kd alone. Those in the investigative arm received intravenous (IV) isatuximab at 10 mg/kg on days 1, 8, 15, and 22 in the first 28-day cycle, and days 1 and 15 in subsequent cycles. In both arms, IV carfilzomib was administered at a dose of 20 mg/m2 on days 1 and 2 of cycle 1, and at 56 mg/m2 on days 8, 9, 15, and 16 of subsequent cycles. Moreover, dexamethasone was given at 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23.

Investigators administered dexamethasone, followed by isatuximab, and then carfilzomib. Patients received treatment until progressive disease, intolerable toxicity, or discontinuation criteria were met.

Key stratification factors included number of prior lines of therapy (1 vs more than 1) and revised International Staging System disease stage (stage I or II vs III vs not classified).

The primary end point of the trial was PFS, and key secondary end points included overall response rate, rate of very good partial response (VGPR) or better, minimal residual disease (MRD) negativity rate, complete response (CR) rate, and overall survival (OS).

Other end points comprised safety, duration of response (DOR), time to progression, time from randomization to first documentation of progressive disease (PFS2), time to first response, time to best response, renal response, pharmacokinetic analyses, immunogenicity analysis, and health-related quality of life (HRQOL).

The median age of study participants in the investigative arm was 65 years (interquartile range [IQR], 55-70) vs 63 years (IQR, 57-70) in the control arm; 49% and 54% of patients, respectively, were under the age of 65 years. Across the arms, slightly more than half of patients were male; most of these patients were White, had an ECOG performance status of 0, had stage I disease at study entry.

Moreover, in the Isa-Kd and Kd arms, respectively, most patients received 1 prior line of treatment (44% vs 45%), followed by 2 lines of treatment (36% vs 29%), 3 lines of treatment (18% vs 24%), and more than 3 prior lines (2% vs 2%). The most common antimyeloma therapies received included alkylating agents (94% vs 82%), PIs (93% vs 85%), immunomodulators (76% vs 81%), lenalidomide (Revlimid; 40% vs 48%), monoclonal antibodies (3% vs 1%), and daratumumab (1% vs 0%). All patients across the arms previously received corticosteroids.

Earlier data from the trial showed that at a median follow-up of 20.7 months (IQR, 19.4-22.1), the estimated 2-year PFS rate in the Isa-Kd arm was 68.9% (95% CI, 60.7%-75.8%) vs 45.7% (95% CI, 35.2%-55.6%) in the Kd-alone arm.

Moreover, in the intention-to-treat population, 87% of those in the investigative arm vs 83% of those on the control arm experienced an overall response to treatment (P = .19), but the difference observed between the arms was not statistically significant. Among those who received isatuximab, 73% experienced a VGPR or better vs 56% of those who did not (P = .0011); CRs were achieved by 40% and 28% of patients, respectively.

The addition of isatuximab to Kd resulted in a doubled MRD-negativity rate vs Kd alone, at 30% and 13%, respectively (P = .0004). Moreover, 20% of those in the investigative arm experienced a CR and MRD-negative response vs 11% of those in the control arm.

At the time of the interim analysis, PFS2 and OS data were not yet mature. The median time to first response in the isatuximab arm was 32 days (IQR, 30-40), which was comparable to the 33 days (IQR, 30-58) reported in the control arm. DOR was longer in the investigative arm vs the control arm (HR, 0.43; 95% CI, 0.27-0.67). Moreover, HRQOL was maintained with Isa-Kd.

Updated safety data showed that showed that treatment exposure with the isatuximab combination was 30 weeks longer than in the control arm. Grade 3 or higher treatment-emergent toxicities occurred in 83.6% of those in the investigative arm vs 73% of those in the control arm; serious adverse effects were reported in 70.1% and 59.8% of patients, respectively.

Moreover, the most common toxicities experienced in the investigative and control arms, respectively, included infusion-related reactions (45.8% vs 3.3%), diarrhea (39.5% vs 32%), hypertension (37.9% vs 35.2%), upper respiratory tract infection (37.3% vs 27%), fatigue (31.6% vs 20.5%), dyspnea (30.5% vs 22.1%), pneumonia (27.1% vs 21.3%), back pain (25.4% vs 21.3%), insomnia (25.4% vs 24.6%), and bronchitis (24.3% vs 12.3%).

“To observe PFS of more than 3 years in patients with relapsed multiple myeloma when [isatuximab] was added to a PI backbone of therapy is unprecedented and reinforces our confidence in [isatuximab] as a potential best-in-class anti-CD38 antibody,” Peter C. Anderson, MD, global head of oncology clinical development and pediatric innovation at Sanofi, added in the press release.

The updated findings will be shared with regulatory authorities at a future date, according to Sanofi.

References

1. Sarclisa (isatuximab) combination provides unprecedented median progression free survival in patients with relapsed multiple myeloma receiving a proteasome inhibitor therapy. News release. Sanofi; May 15, 2022. Accessed May 16, 2022. https://bit.ly/3ldXNkq
2. Moreau P, Dimpoulos M-A, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361-2371. doi:10.1016/S0140-6736(21)00592-4