In patients with relapsed or refractory multiple myeloma, isatuximab in combination with pomalidomide and low-dose dexamethasone nearly doubled progression-free survival when compared with pomalidomide and dexamethasone alone, with a manageable safety profile, according to data from a phase III trial. Patients who received the triplet regimen also demonstrated significant improvements in overall response and depth of response, with significant delays in the time to next treatment.

Isatuximab is a novel CD38 monoclonal antibody that, when used in conjunction with pomalidomide and low-dose dexamethasone, can be considered a new treatment option for patients with relapsed or refractory multiple myeloma, the investigators reported. This is the first randomized phase III trial to add a CD38 antibody to the backbone of pomalidomide/dexamethasone.

Paul G. Richardson, MD

Suzanne Lentzsch, MD, PhD

These data were originally presented at the 2019 ASCO Annual Meeting by Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.¹ The study was later discussed at the Best of ASCO Austin by Suzanne Lentzsch, MD, PhD, Director of the Multiple Myeloma and Amyloidosis Program at Columbia University in New York, along with other top selected abstracts in plasma cell dyscrasia.²

Study Design

In this open-label, global study, patients with relapsed or refractory multiple myeloma who had received two or more prior lines of therapy, including lenalidomide and a proteasome inhibitor, were randomly assigned 1:1 to receive isatuximab in combination with pomalidomide and low-dose dexamethasone (n = 154) or pomalidomide and low-dose dexamethasone alone (n = 153). Patients who had received prior therapy with pomalidomide were excluded from the study.

The study arm received intravenous isatuximab at 10 mg/kg weekly for the first 4 weeks, then every 2 weeks thereafter. Both arms received approved schedules of pomalidomide (4 mg on days 1–21 of a 28-day cycle) and dexamethasone (40 mg [20 mg for patients older than age 75] weekly) every 28 days until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, with key secondary endpoints of overall response and overall survival. The median duration of follow-up was 11.6 months.

Patients in the experimental arm received ongoing treatment at almost double the rate of those in the control arm: 42.2% vs 22.9%, the investigators reported. Most patients in the pomalidomide/dexamethasone arm discontinued treatment due to progression of disease (57.5%).

Progression-Free Survival Benefit

The addition of isatuximab led to a statistically significant and clinically meaningful improvement in progression-free survival: 11.53 months vs 6.47 months (P = .001). This improvement was observed across all major subgroups, including patients who were refractory to lenalidomide.

“[This drug combination] led to a significant increase, near doubling of progression-free survival, which was very impactful,” noted Dr. Lentzsch.

Isatuximab added to pomalidomide/dexamethasone also resulted in significant improvements in overall response and depth of response. Overall response rates were 60.4% and 35.3% in the isatuximab and control arms, respectively (P < .0001).

“By adding isatuximab to pomalidomide and dexamethasone, the response rate almost doubled,” said Dr. Lentzsch. “And what is really impressive is the increase in very good partial responses, which went from 8% to almost 32%. It nearly tripled.”

The median time to first response was 35 days in the isatuximab arm, compared with 58 days in the control arm. However, according to Dr. Lentzsch, the true complete remission rate in the isatuximab arm is likely underestimated because of isatuximab interference with M-protein measurement.

At interim analysis, overall survival data were immature, but a trend toward overall survival benefit was observed with the addition of isatuximab.

“However, it’s becoming more and more difficult to determine the impact of a specific line of treatment on overall survival,” Dr. Lentzsch pointed out. “These patients might receive additional lines of treatment, including chimeric antigen receptor [CAR] T cells, so it’s difficult to pinpoint the effect of a specific line of treatment on overall survival.”

The time to next treatment was also significantly delayed with the addition of isatuximab. It has not yet been reached in the experimental arm, compared with 9.1 months in the pomalidomide/dexamethasone arm.

Side effects with isatuximab were manageable and similar to those seen with daratumumab.

Questions for Future Research

According to Dr. Lentzsch, these data raise several outstanding questions. “First, in which line of therapy should a CD38 antibody be used?” she asked. “Should we add this to all lines of therapy?” The findings also raise questions about the mechanisms of CD38 antibody resistance, and how they might be overcome. She maintains that the answers to both of these questions remain completely unclear.

Furthermore, does it matter which CD38 antibody—isatuximab or daratumumab—is given to these patients? Or, can isatuximab be given after daratumumab?

Finally, how can other targeted agents such as SLAMF7 (signaling lymphocytic activation molecule family 7) and BCMA (B-cell maturation antigen) cellular therapies be cycled with CD38 antibodies? According to Dr. Lentzsch, the sequence of these antibodies, or potentially the combinations of these antibodies, will be the focus of future research. ■

DISCLOSURE: Dr. Lentzsch is a shareholder in Caelum BioSciences; has served as a consultant or advisor to AbbVie, Bayer Schering Pharma, Bristol-Myers Squibb, Caelum BioSciences, Janssen, Novartis, Proclara Biosciences, and Takeda; has participated in a speakers bureau for Clinical Care Options/National Comprehensive Cancer Network; has received research funding from Karyopharm and Sanofi; holds “Patent 11-1F4 mAb for use in AL Amyloidosis”; has been reimbursed for travel, accommodations, or other expenses by Janssen; and has been a data safety monitoring board member of Sorrento. Dr. Richardson has served as a consultant or advisor to Celgene, Janssen, and Takeda and has received research funding from Celgene and Takeda.

REFERENCES

1. Richardson PG, Attal M, Rajkumar SV, et al: A phase III randomized, open label, multicenter study comparing isatuximab, pomalidomide, and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma. 2019 ASCO Annual Meeting. Abstract 8004. Presented June 2, 2019.

2. Lentzsch S: Hematologic malignancies: Plasma cell dyscrasia. 2019 Best of ASCO Austin. General Session. Presented July 26, 2019.