IKEMA Shows Advantage for Anti-CD38 in 1q21+ R/R Multiple Myeloma

Cristiana Costa Chase, DO

Assistant Professor of Medicine

Duke University School of Medicine

Durham, NC

Targeted Oncology: What was the significance of the IKEMA study (NCT03275285) in patients with relapsed/refractory multiple myeloma?

CRISTIANA COSTA CHASE, DO: The IKEMA study is a phase 3 study; patients were randomly assigned in a 3:2 fashion to undergo Isa-Kd [isatuximab (Sarclisa), carfilzomib (Kyprolis), and dexamethasone] or Kd [carfilzomib and dexamethasone] alone.¹ The primary end point was progression-free survival [PFS], and they were looking at response rates, minimal residual disease [MRD], complete response [CR] rate, and overall survival [as secondary end points]. The dose of carfilzomib that was used here was the twice weekly regimen with 56 mg/m²…I tend to use it once weekly. If I'm nervous about the patient, I may do 1 cycle per the trial. When we looked at the subgroups, it wasn't powered to detect statistical significance [for PFS], but the forest plot showed that within all of the subgroups there was a preference for Isa-Kd, particularly in older patients and patients who had 1q21 abnormalities and who had high risk features, and patients who were refractory to lenalidomide tended to benefit.

What were the results for the primary and secondary end points of IKEMA?

In terms of overall response, it was 86.6% ORR with Isa-Kd compared with 83%; it wasn't statistically significant [odds ratio, 2.09; 95% CI, 1.26-3.48], so rates of very good partial response and CR were not tested for statistical significance [though they were numerically superior with Isa-Kd]. But even in the MRD analysis, there was a difference in how many more patients were MRD negative on the intervention arm as compared with the control arm: 26% of patients who were in a CR [with Isa-Kd were MRD negative]. There was 33% MRD negativity [with Isa-Kd vs 15.4% with Kd].

In terms of PFS, it met the primary end point in the intent to treat population with a median PFS of 35.7 months with Isa-Kd compared with 19.2 months with Kd with an HR of 0.58 [95.4% CI, 0.42-0.79], so these were impressive data. The time to next treatment was also improved with the addition of isatuximab [HR, 0.55; 95% CI, 0.40-0.76]. PFS2, including the [time to progression on] next line of therapy, also tended to benefit those patients who had received isatuximab [HR, 0.68; 95% CI, 0.50-0.94].

The overall survival was a descriptive [analysis]; they're planning to look at it as an analysis soon, with a 22% improvement in risk of death with the addition of isatuximab [HR, 0.78; 95% CI, 0.54-1.12].

Which patients benefited most based on the long-term outcome analysis?

The one thing that [the investigators] have recognized is the importance of this drug particularly in those patients who have 1q21 abnormality, [including] 1q gain and 1q amplification.² What we saw was PFS and overall response rates that were higher in 1q [abnormalities including] amplification. The MRD negative CR rate was 31% with Isa-KD vs 20% with Kd in patients with 1q amplifications. The benefit of the addition of isatuximab gets carried throughout all of the 1q abnormalities, etc, of the patients who were enrolled on a trial, which were approximately 40% of patients they had on the study.

What was seen in terms of safety and tolerability of Isa-Kd on this trial?

What we noted was that patients on the triplet combination had lower rates of discontinuation than patients on carfilzomib alone, and the drug that tended to be the cause of discontinuation was carfilzomib.¹ In terms of safety, isatuximab is an infusional monoclonal antibody at the current time. There are ongoing efforts looking into the use of the drug administered subcutaneously, but right now it's an intravenous drug so infusion reactions are probably 1 of the more common adverse event that patients can experience. However, they're mostly grade 1 and 2; only 0.6% of patients experience grade 3 or higher [infusion reactions], so it's quite well tolerated. So much so that you don't have to give dexamethasone the day after like we do for daratumumab [Darzalex]. Patients do really well. In terms of the addition of monoclonal antibodies from carfilzomib treatment, we're not seeing an increased signal in cardiac failure or other cardiovascular events. What we do see, which we're very familiar with in the monoclonal antibodies, are upper respiratory tract infections, pneumonia, and those kinds of adverse events.

What are your takeaways on the use of isatuximab?

The location where I find this drug being extremely beneficial is in patients who have 1q abnormalities, which is 40% of those with newly diagnosed myeloma, as well as in patients with high-risk disease having an aggressive relapse post transplant—getting less than 2 or 3 years of response following transplant. That's where I'm particularly pushing for it.

_References:

_{1. Martin T, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized phase 3 study. Blood Cancer J. 2023;13(1):72. doi:10.1038/s41408-023-00797-8}

_{2. Facon T, Moreau P, Spicka I, et al. Long-term outcomes with isatuximab-carfilzomib-dexamethasone (Isa-Kd) in relapsed multiple myeloma patients with 1q21+ status: Updated results from the phase 3 IKEMA study. J Clin Oncol. 2023;41(16):8029. doi:10.1200/JCO.2023.41.16_suppl.8029}