Isatuximab Triplet Significantly Improves PFS in Relapsed/Refractory Myeloma

The triplet therapy of isatuximab-irfc (Sarclisa), carfilzomib (Kyprolis), and dexamethasone showed a statistically significant improvement in progression-free survival (PFS) versus carfilzomib and dexamethasone alone in patients with relapsed/refractory multiple myeloma, according to interim results of the phase 3 IKEMA study (NCT03275285) that were virtually presented during the 2020 European Hematology Association Annual Congress.¹

At a median follow-up of 20.7 months, findings showed that the median PFS, as assessed by an independent response committee (IRC), was not reached (95% CI, not evaluable [NE]–NE) in the isatuximab arm and was 19.15 months (95% CI, 15.770–NE) with carfilzomib/dexamethasone alone, leading to a 47% reduction in the risk of disease progression or death (HR, 0.531; 95% CI, 99% CI, 0.318-0.889; P = .0007). This crossed the pre-specified efficacy boundary (P = .005).

The isatuximab regimen also showed a clinically meaningful improvement in depth of response versus carfilzomib/dexamethasone alone and was also found to have a manageable safety profile.

“The addition of isatuximab to [carfilzomib/dexamethasone] resulted in a statistically significant improvement in PFS, with a hazard ratio of 0.531, corresponding to a 47% reduction in the risk of progression or death,” lead study author Philippe Moreau, MD, head of the Department of Hematology and professor of clinical hematology at the University Hospital of Nantes, France, said during the presentation. “Isatuximab with [carfilzomib/dexamethasone] may represent a new standard of care for patients with relapsed multiple myeloma.”

Isatuximab is an IgG1 CD38-directed monoclonal antibody that is currently approved by the FDA for use in combination with pomalidomide (Pomalyst) and low-dose dexamethasone for patients with relapsed/refractory multiple myeloma.

In the open-label, phase 3 IKEMA trial, 302 patients with relapsed/refractory myeloma who previously received 1 to 3 lines of therapy were randomized 3:2 to receive either intravenous isatuximab at 10 mg/kg plus carfilzomib and dexamethasone (n = 179) or carfilzomib/dexamethasone alone (n = 123). Isatuximab was administered on days 1, 8, 15, and 22 in cycle 1, and then every 2 weeks. Twice-weekly carfilzomib was administered at 20 mg/m² on days 1 to 2 and then 56 mg/m² thereafter for 3 to 4 weeks, and then twice-weekly dexamethasone at 20 mg. Treatment was given until disease progression, unacceptable toxicity, or patient decision.

Those who received prior carfilzomib, and/or were refractory to prior anti-CD38 therapy were not eligible to enroll on IKEMA. Stratification factors included line of therapy (1 vs more than 1) and Revised Multiple Myeloma International Staging System (R-ISS stage; I or II vs III vs not classified).

The primary end point of the trial was IRC-assessed PFS; the comparison between arms was conducted through log-rank testing. Secondary outcome measures included objective response rate (ORR), very good partial response (VGPR) rate or better, complete response (CR) rate, minimal residual disease (MRD) negativity rate, and overall survival (OS). Safety was assessed via treatment-emergent adverse effects (TEAEs). Additionally, the interim analysis was planned when 65% of the total expected PFS events were observed.

Baseline characteristics were similar in both arms, Moreau noted. The median age was 64 years (range, 33-90), and 8.8% of patients were 75 years or older. The percentages of those with R-ISS I, II, and III disease were 53.2%, 30.2%, and 15.4%, respectively. Moreover, 44.4% of patients had 1 prior line of therapy, 32.5% had 2, and 21.4% had 3 or more prior treatments. Nearly 90% of patients (89.1%) received a prior proteasome inhibitor while 78.7% of patients previously received an immunomodulatory drug (IMiD); 33% of patients were refractory to lenalidomide (Revlimid). Twenty-four percent of patients had high-risk cytogenetics.

Results also showed that the PFS benefit was consistent across patient subgroups, “including patients who are difficult to treat, such as [those with] high-risk cytogenetics or elderly patients,” Moreau said during the presentation.

The ORR was 86.6% with the isatuximab arm versus 82.9% with carfilzomib/dexamethasone (P = .19); the VGPR rates were 72.6% and 56.1%, respectively (P = .0011). Additionally, the CR rate was 39.7% with the isatuximab regimen versus 27.6% with carfilzomib/dexamethasone. The MRD-negativity rate (10⁵), as assessed via next-generation sequencing in the intent-to-treat population was 29.6% and 13.0% with the isatuximab and carfilzomib/dexamethasone–alone arms, respectively (P = .0004). When assessed in patients who achieved a VGPR or better, the MRD-negativity rate was 41.4% for isatuximab plus carfilzomib/dexamethasone and 22.9% for carfilzomib/dexamethasone alone.

While there was no difference in OS, Moreau stressed that the data remain immature with only 17.3% of events reported in the isatuximab arm and 20.3% of events in the carfilzomib/dexamethasone–alone arm having occurred.

The time to next treatment was significantly delayed with the addition of isatuximab, said Moreau, although the data in both arms were not reached (HR, 0.566; 95% CI, 0.380-0.841). Investigators are also evaluating the outcomes of patients on both arms who went on to receive subsequent therapy, he added. Subsequent therapies in the isatuximab and carfilzomib/dexamethasone alone arms, consisted of alkylating agents (55.3% vs 39.6%), proteasome inhibitors (34.0% vs 20.8%), IMiDs (83.0% vs 79.2%), monoclonal antibodies (23.4% vs 54.7%), and further transplant (12.8% vs 9.4%).

At the median follow-up duration, 52.0% and 30.9% of the isatuximab and doublet arms remained on treatment, respectively. A total 29.1% of patients on isatuximab discontinued treatment due to disease progression compared with 39.8% of those on carfilzomib/dexamethasone, while 8.4% and 13.8%, respectively, discontinued therapy due to

AEs. Moreover, high relative dose intensity of both isatuximab and carfilzomib/dexamethasone demonstrate the feasibility of the combination, Moreau said. In the triplet arm, the median treatment duration was 80.0 weeks versus 61.4 weeks in the doublet arm.

Grade 3 or higher treatment-emergent AEs (TEAEs) were reported in 76.8% and 67.2% of patients. Moreover, the rate of treatment-emergent serious AEs were similar in both arms (59.3% with the isatuximab regimen and 57.4% with carfilzomib/dexamethasone) as well as fatal TEAEs (3.4% vs 3.3%, respectively).

All-grade and grade 3/4 infusion-related reactions, which mainly occurred during the first infusion and were mostly grade 1/2, occurred in 44.6% and 0.6% of those on the isatuximab triplet and in 3.3% and 0% of patients on carfilzomib/dexamethasone.

Moreover, grade 3 or higher hypertension occurred in 20.3% of isatuximab-treated patients and in 19.7% of those treated with carfilzomib and dexamethasone alone. Grade 3 or higher cardiac failure were similar in both arms, at 4.0% of those on the isatuximab arm and 4.1% of those on the doublet regimen. Finally, grade 3/4 thrombocytopenia and neutropenia were in 29.9% and 19.2% of isatuximab-treated patients and in 23.8% and 7.4% of those who received carfilzomib/dexamethasone.

The IKEMA results are anticipated to form the basis of regulatory submissions planned for later in 2020, according to a press release.²

References:

1. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab plus carfilzomib and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (IKEMA): interim analysis of a phase 3, randomized, open-label study. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract LB3603.
2. Sarclisa (isatuximab) combination therapy demonstrated superior progression free survival and clinically meaningful depth of response in patients with relapsed multiple myeloma. News release. Sarclisa. June 2, 2020. Accessed June 13, 2020. bit.ly/3e3dw0B.