Significant Depth of Response Achieved in Relapsed Multiple Myeloma With Isa-Kd

The IKEMA study (NCT03275285) of isatuximab (Sarclisa), carfilzomib (Kyprolis), and dexamethasone (Isa-Kd) in patients with relapsed multiple myeloma demonstrated clinically meaningful improvement in depth of response, according to longer follow-up presented at the 19th Annual International Myeloma Society Meeting.¹

In the updated analysis of IKEMA, a randomized phase 3 trial, the highest rates of complete response (CR) were reported for a proteasome inhibitor-based regimen in this setting. Patients given Isa-Kd experienced a CR rate of 44.1% and those who reached minimal residual disease (MRD) negativity had a CR rate of 26.3%.

“MRD negativity rates with Isa-Kd were higher among patients with poor prognostic characteristics,” Roman Hajek, MD, PhD, said in his presentation. “Achieving MRD negativity led to better progression-free survival [PFS] in both treatment arms, with Isa-Kd patients having a more than 2-fold higher probability of achieving both MRD negativity or MRD negativity and CR.”

Isatuximab, an IgG1 monoclonal antibody targeting CD38, combined with carfilzomib and dexamethasone is approved for patients with relapsed and/or refractory multiple myeloma after 1 or more prior lines of therapy based on the initial results of the IKEMA study.2,3

On this trial, 302 patients were randomly assigned 3:2 to Isa-Kd (n = 179) versus carfilzomib and dexamethasone (Kd; n = 123) until progressive disease, unacceptable toxicity, or patient request. These patients had 1 to 3 prior lines of therapy, no prior treatment with carfilzomib, and were not refractory to prior anti-CD38 therapy. Stratification factors included 1 prior line of therapy versus more than 1, and Revised International Staging System (R-ISS) status of I or II versus III versus not classified. Patient demographics and baseline characteristic for the treatment arms were balanced.

The primary end point was PFS by Independent Response Committee, which was showed significant benefit in the final analysis of a median 35.7 months with Isa-Kd compared with 19.2 months with Kd (HR, 0.58; 95.4% CI, 0.42-0.79) after median follow-up of 44 months. Key secondary end points were CR rate, MRD negativity, overall response rate (ORR), very good partial response (VGPR) or better, and overall survival.

With the extended follow-up, Isa-Kd produced deeper responses than Kd in the intention-to-treat population. Although the ORR was similar at 86.6% versus 83.7% for Isa-Kd and Kd, respectively, the VGPR or better was 72.6% versus 56.1%. In the Isa-Kd arm, the CR rate or better was 44.1% compared with 28.5% in the Kd arm (odds ratio [OR], 2.09; 95% CI, 1.26-3.48).

MRD negativity, which was assessed by next-generation sequencing clonoSEQ assay and reported at 10-5 sensitivity level, was 33.5% in patients receiving Isa-Kd and 15.4% in those receiving Kd (OR, 2.78; 95% CI, 1.55-4.99). The MRD negative and CR rate was 26.3% and 12.2%, respectively (OR, 2.57; 95% CI, 1.35-4.88).

“Adding isatuximab to Kd, you can double the MRD negativity rate, which is really impressive,” said Hajek, professor of oncology and head of the Department of Haematooncology in the University of Ostrava, Czech Republic.

Over time, the depth and quality of response favored the experimental arm. The rates of partial response, VGPR, CR, and MRD negativity were higher and the time to first CR occurred earlier with Isa-Kd. However, Hajek doesn’t feel the time to first CR was as important because it was quickly reached in both arms.

For patients with poor prognostic characteristics, MRD negativity rates were higher with Isa-Kd. These characteristics included age of 65 years or older (31.9% vs 17.5%), renal impairment with estimated glomerular filtration rate less than 60 mL/min/1.73 m2 (39.5% vs 16.7%), ISS stage II or III upon study entry (29.2% vs 13.7%), 1q21+ present (34.7% vs 15.4%), more than 1 prior line of therapy (30.3% vs 10.3%), refractoriness to lenalidomide (29.8% vs 11.9%), and refractoriness to lenalidomide at last line (36.1% vs 12.9%).

In patients who achieved MRD negativity (n = 79), the PFS benefit was greater in both arms than those who were still MRD positive (n = 223). However, Isa-KD still improved PFS in those who were MRD positive compared with Kd (HR, 0.675; 95% CI, 0.483-0.943).

Additionally, more patients who reached MRD negativity stayed on treatment, with 29 patients (48.3%) still receiving Isa-Kd and 6 (31.6%) still receiving Kd compared with 20 (16.8%) and 5 (4.8%), respectively, who were MRD positive. Overall, 27.4% of patients given Isa-Kd continued on treatment by the 44-month median follow-up.

There were no new safety signals with longer follow-up of IKEMA. The safety findings for those with MRD negativity were consistent with the overall population, and the addition of isatuximab did not increase fatal treatment-emergent adverse events (TEAEs) or event leading to discontinuation.

“The observed clinically meaningful improvement in depth of response with Isa-Kd further supports its use as a standard-of-care therapy for relapsed multiple myeloma,” Hajek concluded.

_References:

_{1. Hajek R, Moreau P, Augustson B, et al. Depth of response of isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma: IKEMA updated analysis. Slides presented at: 19th Annual International Myeloma Society (IMS) Annual Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-046.}

_{2.FDA approves isatuximab-irfc for multiple myeloma. FDA. Updated April 1, 2021. Accessed August 27, 2022. https://bit.ly/3QXo5FU}

_{3. Moreau P, Dimopoulos MA, 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}