Summary
For patients with multiple myeloma, previous clinical studies have shown that deep responses have been associated with improvements in outcomes such as progression-free survival (PFS) and overall survival (OS). One particularly relevant trial for this patient population is the phase III ICARIA-MM study (NCT02990338), which is evaluating the anti-CD38 monoclonal antibody isatuximab in combination with the immunomodulatory agent pomalidomide plus dexamethasone (Isa-Pd arm) versus the active control of pomalidomide plus dexamethasone (Pd arm). A participating clinician in this study was Cyrille Hulin, MD, of the Department of Hematology, Hôpital Haut-Lévêque, Pessac, France.
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Original Article
Positive Results for Isatuximab-Pomalidomide-Dexamethasone Combo in Heavily Pre-Treated Multiple Myeloma
Oncology Times
Richard Simoneaux
For patients with multiple myeloma, previous clinical studies have shown that deep responses have been associated with improvements in outcomes such as progression-free survival (PFS) and overall survival (OS). One particularly relevant trial for this patient population is the phase III ICARIA-MM study (NCT02990338), which is evaluating the anti-CD38 monoclonal antibody isatuximab in combination with the immunomodulatory agent pomalidomide plus dexamethasone (Isa-Pd arm) versus the active control of pomalidomide plus dexamethasone (Pd arm). A participating clinician in this study was Cyrille Hulin, MD, of the Department of Hematology, Hôpital Haut-Lévêque, Pessac, France.
Regarding the analysis that was done in their study, Hulin noted, “We assessed the relationships between depth of response, including minimum residual disease (MRD) negativity, plus response kinetics and long-term outcomes, using data we obtained in the ICARIA-MM study.” In a presentation given at the 2019 ASH Annual Meeting, Hulin revealed their findings from the ICARIA-MM study (Abstract 3185).
Study Details
All participants received 4 mg pomalidomide orally (PO) on days 1–21 of each 28-day treatment cycle and 40 mg dexamethasone PO (patients aged 75 years or older received 20 mg) on days 1, 8, 15, and 22 of each treatment cycle. Isatuximab (10 mg/kg) was intravenously administered to those in the Isa-Pd arm on days 1, 8, 15, and 22 (cycle 1), and on days 1 and 15 of each treatment cycle subsequently.
“The depth and kinetics of response were analyzed for each different treatment group,” Hulin noted. MRD-negativity was assessed using next-generation sequencing in those patients displaying either a complete response (CR) or a stringent CR (sCR). Among the kinetic parameters for which data were recorded were time to tumor response, time to CRenal (renal response), and time to sustained CRenal (a CRenal lasting 60 days or more).
A total of 307 patients were randomized in this study: 154 to the Isa-Pd arm and 153 to the Pd arm. Patients had received 2-11 prior therapies with a median three prior lines of therapy. Notably, double-refractory disease was present in 73.4 percent and 71.9 percent of patients in the Isa-Pd and Pd groups, respectively. The median PFS values for the Isa-Pd and Pd arms were 11.53 months and 6.47 months, affording a hazard ratio (HR) of 0.596 (95% CI: 0.436–0.814).
“Generally, tumor responses for those in the Isa-Pd arm were more frequent and deeper than those in the Pd arm,” Dr. Hulin noted.
The overall response rates (ORRs) for the Isa-Pd and Pd arms were 60.4 percent and 35.3 percent, respectively, giving an odds ratio (OR) of 2.80 (95% CI: 1.72–4.56; p<0.0001). The rates for very good partial response or better (≥VGPR) were 31.8 percent versus 8.5 percent for the Isa-Pd and Pd arms, respectively, providing an OR of 5.03 (95% CI: 2.51–10.59; p<0.0001).
In the ITT population, the minimal residual disease-negativity rates were 5.2 percent versus 0 percent in the Isa-Pd and Pd arms, respectively.
“The depth of response clearly correlated with improved long-term outcomes in both arms,” Hulin observed.
For the MRD-negative (MRD−) patients in the Isa-Pd arm, all were progression-free and alive after a median follow-up of 11.6 months. There was a clear relationship between depth of response and PFS values in the Isa-Pd arm. The longest PFS values were noted in MRD- patients (median value not reached), while the shortest median PFS figure was noted in patients attaining less than a partial response (3.29 months). This same trend was also noted in the data for 1-year OS probabilities.
“The tumor responses in the Isa-Pd arm tended to occur more quickly than those in the Pd arm,” Hulin commented. For the 93 patients in the Isa-Pd arm and the 54 patients in the Pd arm achieving a partial relapse or better, the median times to first response were 1.1 months and 1.9 months, respectively.
Renal responses tended to occur faster in the Isa-Pd patients than those in the Pd arm. In the Isa-Pd arm, a CRenal was observed in 23 of 32 patients with a median time to response of 3.4 weeks. In the Pd arm, CRenal was noted in 8 of 21 patients with a median time to response of 7.3 weeks. Sustained CRenal was noted for 10 of 32 Isa-Pd patients with a median time to first response of 2.4 weeks and for 4 of 21 Pd patients with median time to first response of 4.8 weeks.
Discussion
“One thing in particular to note is that the patient population for ICARIA-MM was heavily pretreated,” Hulin stated. “In fact, patients were specifically selected who had disease resistance to the immunomodulatory agent lenalidomide.
“In this difficult-to-treat patient population, more frequent and faster tumor and renal responses were noted in the Isa-Pd arm than those obtained for the Pd arm,” Hulin said. “The depth of response, including MRD-negativity, was clearly improved in the Isa-Pd arm and this was associated with better long-term survival outcomes.”
Richard Simoneaux is a contributing writer.