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Isatuximab regimen extends PFS in relapsed, refractory multiple myeloma
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CHICAGO — The addition of isatuximab to pomalidomide and low-dose dexamethasone significantly improved PFS and overall response rate among patients with relapsed or refractory multiple myeloma, according to randomized phase 3 study results presented at ASCO Annual Meeting.
The regimen — which also exhibited a manageable safety profile — is an important new treatment option in this setting, Paul G. Richardson, MD, director of clinical research at Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute and a HemOnc Today Editorial Board Member, and colleagues concluded.
“Relapsed/refractory myeloma — particularly patients with double refractory disease or beyond — represents a clear unmet medical need,” Richardson told HemOnc Today. “The use of best agents upfront means that the refractory population is becoming much more challenging to treat. In that context, the success of this trial is encouraging, and we are pleased to now have a variety of three-drug combinations that are highly effective.”
Isatuximab (Sanofi) is a novel anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells, including direct tumor targeting and immune cell engagement.
A phase 1b study demonstrated the combination of isatuximab, pomalidomide (Pomalyst, Celgene) and dexamethasone was clinically active among and generally well-tolerated by patients with heavily pretreated relapsed or refractory myeloma. In addition, “a striking median PFS” in excess of 17 months was observed in that study, Richardson said.
Richardson and colleagues, therefore, conducted the ICARIA-MM trial to assess whether the addition of isatuximab to pomalidomide and dexamethasone would prolong PFS for this patient population. This was the first randomized phase 3 trial to evaluate the addition of a CD38 antibody to the pomalidomide-dexamethasone backbone.
The open-label, multicenter study included 307 patients (median age, 67 years; range, 36-86) with relapsed or refractory myeloma recruited from 92 centers in 26 countries. All patients had received at least two prior lines of therapy (median, 3; range, 2-11), including lenalidomide (Revlimid, Celgene) and a proteasome inhibitor.
All patients were refractory to their most recent therapy. The majority were refractory to lenalidomide (92.5%) and proteasome inhibitor (75.9%), and 19.5% of patients had high-risk cytogenetics. One-third (33.9%) of patients had estimated glomerular filtration rate less than 60 mL/min/1.73 m2.
Researchers assigned 154 patients to pomalidomide (4 mg orally on days 1 through 21) and dexamethasone (40 mg weekly orally or via IV, or 20 mg for those aged older than 75 years) in 28-day cycles. The other 153 patients received pomalidomide and dexamethasone plus isatuximab (10 mg/kg weekly via IV for the first 4 weeks, then every 2 weeks).
Treatment continued until disease progression or unacceptable toxicity.
The two groups were well-balanced with regard to median and type of prior therapies, prior autologous stem cell transplantation and refractory status.
PFS served as the primary endpoint. Key secondary endpoints included ORR and OS.
Median treatment duration was 41 weeks in the isatuximab group and 24 weeks in the control group.
After median follow-up of 11.6 months (95% CI, 11.4-12.2), 65 patients (42.2%) assigned isatuximab and 35 (22.9%) assigned pomalidomide-dexamethasone alone remained on treatment.
Researchers reported longer median PFS in the isatuximab group (11.5 months vs. 6.5 months; HR = 0.59; 95% CI, 0.44-0.81). The PFS benefit appeared consistent by investigator assessment and independent review, as well as across all major subgroups.
The addition of isatuximab to pomalidomide-dexamethasone also conferred a significant improvement in ORR (60.4% vs. 35.3%; P < .0001), very good partial response (27.3% vs. 6.5%), complete response/stringent complete response (4.5% vs. 2%), and near complete response (15.6% vs. 3.3%). Researchers noted the true complete response rate in the isatuximab group was underestimated because of the agent’s interference with M-protein measurement.
Median time to first response was 35 days in the experimental group and 58 days in the control group. A higher percentage of patients assigned isatuximab achieved minimal residual disease negativity at 10-5 (5.2% vs. 0%).
OS data were immature at the time of analysis, but researchers observed a trend in favor of isatuximab (HR = 0.68; 95% CI, 0.46-1.02). The regimen also significantly delayed time to next treatment (median, not reached vs. 9.1 months; HR = 0.53; 95% CI, 0.38-0.75).
At baseline, 32 patients assigned isatuximab and 21 assigned the control regimen had estimated glomerular filtration rates less than 50 mL/min/1.73 m2. During study follow-up, considerably more patients in the isatuximab group achieved complete renal response (71.9% vs. 38.1%) and sustained complete renal response (31.3% vs. 19%).
Slightly more than one-third (38.2%) of patients assigned isatuximab experienced infusion reactions (grade 3 to grade 4, 2.6%)
More patients assigned isatuximab experienced grade 3 or higher adverse events (86.8% vs. 70.5%), serious adverse events (61.8% vs. 53.7%), grade 3 or higher infections (42.8% vs. 30.2%), grade 3 or higher neutropenia (84.9% vs. 70.1%), and grade 3 or higher febrile neutropenia (11.8% vs. 2%).
However, fewer patients assigned the experimental regimen discontinued treatment due to adverse events (7.2% vs. 12.8%) or died due to adverse events (7.9% vs. 9.4%).
The most common adverse events in the isatuximab group included upper respiratory tract infections (all grades, 28.3% for isatuximab vs. 17.4% for control; grade 3, 3.3% vs. 0.7%), diarrhea (all grades, 25.7% vs. 19.5%; grade 3, 2% vs. 0.7%), bronchitis (all grade, 23.7% vs. 8.7%; grade 3, 3.3% vs. 0.7%) and pneumonia (all grade, 20.4% vs. 17.4%; grade 3, 15.1% vs. 13.4%; grade 4, 1.3% vs. 1.3%).
Rates of anemia and thrombocytopenia were comparable between treatment groups. Grade 4 neutropenia occurred more frequently in the isatuximab group (60.5% vs. 31.3%).
“There was higher infection risk with isatuximab and you certainly have to watch out for neutropenia, but it all was generally manageable in our experience,” Richardson said. “Importantly, we did a quality-of-life assessment and this showed no loss of quality of life with the addition of the third agent.”
The FDA granted special protocol assessment to the ICARIA-MM trial, meaning its design, clinical endpoints and statistical analyses were acceptable for FDA approval. Regulatory submissions in the United States and Europe for the isatuximab-pomalidomide-dexamethasone regimen are underway, Richardson said.
“All things considered, this is a very exciting result — and, we think, particularly promising because this was a real-world population, a substantial proportion of whom were older and had renal dysfunction,” Richardson told HemOnc Today. “Not only did isatuximab-pomalidomide-dexamethasone work well among those with renal dysfunction and in lenalidomide-refractory patients — especially in last line — but also in the group of patients with adverse cytogenetics, where the three-drug combination did much better than two. This was important to see because that is not always the case. So, in aggregate, we believe this is an important treatment option for patients with relapsed/refractory myeloma.” – by Mark Leiser
Reference:
Richardson PG, et al. Abstract 8004. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Richardson reports consultant/advisory roles with Celgene, Janssen and Takeda, as well as research funding from Celgene and Takeda. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Matthew Pianko, MD
Despite remarkable progress in drug development in myeloma, there continues to be a need for more therapeutic options for patients with relapsed/refractory disease. The long-awaited results of the ICARIA-MM study show that isatuximab — a monoclonal antibody that targets CD38 — when used in combination with pomalidomide and dexamethasone is an effective treatment option. This combination showed promising efficacy and safety in a difficult-to-treat patient population.
A second monoclonal antibody drug targeting CD38 is a welcome addition to the field. A key question is where isatuximab will fit in alongside daratumumab (Darzalex, Janssen) in the crowded treatment landscape of relapsed/refractory multiple myeloma. Daratumumab, another CD38-specific monoclonal antibody, is FDA-approved for treatment of relapsed/refractory disease with several other drug combinations and is being explored in multiple phases of treatment of myeloma.
Isatuximab does not activate the complement system to the same degree as daratumumab and could present a more favorable side effect profile for patients with asthma or chronic obstructive pulmonary disease. Isatuximab targets a distinct epitope of CD38 than that bound by daratumumab, which could theoretically position the drug for use by patients who progressed on daratumumab. Mechanisms of resistance to anti-CD38 monoclonal antibodies and the efficacy of isatuximab in daratumumab-exposed or -refractory patients both warrant formal study in clinical practice.
Long infusion times necessary to manage infusion-related reactions seen with CD38 monoclonal antibodies remain a significant burden on care delivery. Although reported isatuximab infusion times were shorter than those used to infuse daratumumab IV, impressive data from a phase 3 clinical trial were presented in the same session at ASCO describing a novel subcutaneously-administered formulation of daratumumab that can be administered in minutes compared with hours necessary for standard IV administration of daratumumab. If the subcutaneous formulation of daratumumab gains FDA approval and also can be effectively partnered with other myeloma agents, this may present a significant logistical challenge for isatuximab to compete with daratumumab from a convenience standpoint. Protocols that have reduced administration times of daratumumab to 90 minutes should be developed for isatuximab and explore feasibility of safely shortening infusion times. Despite administration issues, availability of a second CD38 monoclonal antibody drug likely will drive competition in the myeloma treatment space. Isatuximab is being explored with multiple drug combinations in both newly diagnosed and relapsed myeloma. From the perspective of physicians and patients with myeloma, more treatment choices such as isatuximab are always welcome.
References:
Barr H, et al. Leukemia. 2018;doi:10.1038/s41375-018-0120-2.
Mateos M-V, et al. Abstract 8005. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Richardson PG, et al. Abstract 8004. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
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