Anti-CD38 antibody isatuximab improves treatment response, PFS in R/R multiple myeloma

Medical writer: Emily Kuhl, PhD

A novel anti-CD38 monoclonal antibody, isatuximab, may be a key player in improving progression-free survival (PFS) and treatment response among patients with relapsed/refractory multiple myeloma (RRMM).

“Isatuximab has become a breakthrough target in multiple myeloma therapy and is an important new treatment option for patients with RRMM,” co-investigator Paul G. Richardson, MD, of the Dana-Farber Cancer Institute and Harvard Medical School, said during his presentation on June 2 (Abstract 8004).

A previous phase Ib study showed that isatuximab combined with pomalidomide and dexamethasone was safe and effective for RRMM. Based on this, ICARIA-MM, a phase III, randomized, open-label, multicentre trial (NCT02990338), was initiated to examine the combination of isatuximab plus pomalidomide vs. pomalidomide alone. This was the first randomized phase III study to investigate the addition of an anti-CD38 antibody to pomalidomide. The primary endpoint was PFS, and key secondary endpoints were overall response rate and overall survival.

“These patients represented a true real-world analysis,” Dr. Richardson said. “We included a broad age range, a median time since initial diagnosis that was about 4 years, and, importantly, a number of older patients, patients with chronic obstructive pulmonary disease, and also patients with renal dysfunction and those at high cytogenic risk.”

Patients with RRMM who had received at least two prior lines of therapy with lenalidomide and a proteasome inhibitor (307 patients) were randomly assigned to isatuximab plus pomalidomide or pomalidomide alone.

At a median follow-up of 11.6 months, the median PFS was significantly longer in the isatuximab plus pomalidomide arm compared with the pomalidomide arm (11.5 vs. 6.5 months; HR 0.59, 95% CI [0.44, 0.81]; P = 0.001). ORR also was favorable in the combination group (60.4% vs. 35.3%; P < 0.0001). Very good partial response rate or better was 31.8% for isatuximab plus pomalidomide but only 8.5% for pomalidomide alone, and minimal residual disease negativity at 10^-5 was 5.2% in the isatuximab plus pomalidomide group compared with 0% in the pomalidomide group.

Median OS was not reached in either arm; however, a clinically meaningful trend toward improvement was observed with combination therapy (72% vs. 63%).

Even though the addition of isatuximab to pomalidomide increased rates of grade 3 or higher treatment-emergent adverse events (TEAEs; 86.8% in isatuximab plus pomalidomide vs. 70.5% in pomalidomide) and serious TEAEs (61.8% in isatuximab plus pomalidomide vs. 53.7% in pomalidomide), its safety profile was generally manageable. Fatal events and TEAEs leading to treatment discontinuation were statistically similar between the two groups. All-grade infusion reactions were reported in 38.2% of isatuximab plus pomalidomide treatment, including 2.6% with grade 3/4. Anaemia and thrombocytopenia also were similar, but grade 4 neutropenia was more common in the combination therapy arm. However, this did not appear to detrimentally impact the patients’ quality of life (QOL).

“When we looked at QOL, we were encouraged by the results,” Dr. Richardson said. “The QOL was maintained with the three drugs, vs. the two, with remarkable consistency.”

Discussant Faith Davies, MD, MRCP, MRCPATH, FRCPath, of NYU Langone Health, said that although “the data look fantastic,” they do raise important questions about how oncologists contend with having another clinical tool in their armamentarium.

“We now have three different drug combinations,” she said. “Which triplet combination do we use, and how do we choose that combination? Is it possible to have just one pathway for our patients with myeloma? I would argue that it’s not; we should treat them as individuals and look at the therapy they had before and their responses and side effects, and then choose the best treatment moving forward.”



Posted on 15 July 201918 March 2024