Fixed-Volume Isatuximab-Based Combination Efficacy Confirmed for Treating Newly Diagnosed Multiple Myeloma

Updated results confirmed the safety and efficacy of the quadruplet regimen of fixed-dose isatuximab-irfcc (Sarclisa) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (Isa-VRd) for newly diagnosed multiple myeloma with no immediate intent for transplant in a phase 1b study (NCT02513186) presented at the 18th International Myeloma Workshop.¹

Part B of the study assessed the efficacy of Isa-VRd in 46 patients who were ineligible or had not immediate intent for autologous stem cell transplant. At a median follow-up of 15.24 months the overall response rate was 97.8%, comprising a 53.3% complete response rate, a 37.8% very good partial response rate, and a 6.7% partial response rate.

Minimal residual disease (MRD) negativity was calculated using combined next-generation flow cytometry or sequencing methods at a threshold of 10-5. Of 45 patients who had a response, 23 (51.1%) had MRD negativity.

“[The] good efficacy of the approved short-duration, fixed-volume infusion method of isatuximab in combination with VRd [confirms the feasibility of this regimen for] patients with newly diagnosed multiple myeloma who are ineligible for transplant or who have no immediate intent for transplant,” said Enrique Ocio, MD, PhD, in a presentation of the data. Ocio is head of the Hematology Department of the University Hospital Marqués de Valdecilla in Santander, Cantabria, Spain.

The quadruplet therapy is the standard of care for patients ineligible for transplant; investigators aimed to evaluate isatuximab as a fixed-dose infusion in part B of the phase 1b study. In part A, patients received a weight-based infusion of isatuximab.

Isatuximab 10 mg/kg was administered from a 250 mL fixed-volume infusion—the standard dilution volume of the approved indications for the CD38 monoclonal antibody—for 4 six-week cycles with standard-dose VRd.² This was followed by maintenance therapy with isatuximab, lenalidomide, and dexamethasone for 28 days or until progression, unacceptable toxicity, or patient willingness to discontinue.

The median duration of treatment for treated patients in part B was 15.3 months (range, 1.4-21.4) with patients receiving a median of 14 treatment cycles (range, 1-21).

A marked improvement was observed in the time for median duration of infusion, making the fixed-dose infusion a more convenient treatment option for patients. Specifically, in part B, the median duration of fixed-volume isatuximab infusion decreased from 3 hours and 41 minutes for the first infusion to 1 hour and 55 minutes for the second infusion to 1 hour and 20 minutes for the third infusion and onward. The median duration of infusion in part A were 3 hours and 44 minutes, 2 hours and 49 minutes, and 2 hours and 17 minutes, respectively.

Patients enrolled to part B of the study had a median age of 70 years (range, 49-87), with a majority (65.2%) of patients aged at least 65 years to 74 years. Of the treated patients, 13 of 46 were eligible but had no intent for stem cell transplant. Of these patients, 7 proceeded to stem cell mobilization; data for 6 patients were reported: 2 received granulocyte colony-stimulating factor, 2 received plerixafor (Mozobil), and 2 received a combination of the 2 treatments.

At data cutoff of March 17, 2021, 30 patients (65.2%) remained on study treatment. Of the 16 who were off treatment, poor compliance to protocol and withdrawal by subject were reported for 1 patient each, 3 discontinued because of progressive disease, 3 proceeded to autologous stem cell transplant, and 8 discontinued because of treatment-emergent adverse effects (TEAEs). Specifically, diverticulitis, metastatic malignant melanoma, peripheral sensory neuropathy, cerebral venous sinus thrombosis, acute respiratory distress syndrome, and hepatocellular carcinoma were reported in 1 patient each. COVID-19 was reported as the reason for discontinuation in 2 patients.

No new safety signals were reported with Isa-VRd, Ocio said. Grade 3/4 TEAEs occurred in 69.6% of treated patients. Six TEAEs led to death; the 4 reported during the treatment period (within 30 days of the last dose of the study drug) included COVID-19 (n = 2), disease progression (n = 1), and metastatic breast cancer (n = 1). Two deaths occurred during the post treatment period and included metastatic malignant melanoma and diverticulitis.

The most common reported all-grade TEAEs were constipation (69.6%), asthenia (67.4%), diarrhea (56.5%), and peripheral sensory neuropathy (50.0%); the most common grade 3/4 TEAEs were diarrhea (8.8%), asthenia (6.5%), peripheral edema (4.3%), and insomnia (4.3%).

In terms of hematologic TEAEs, despite 100% of patients experiencing anemia, only 6.5% of patients had grade 3/4 anemia. Rates of grade 3/4 hematologic TEAEs were higher for lymphopenia (76.1%), neutropenia (41.3%), thrombocytopenia (34.7%), and leukopenia (30.5%).

Investigators noted that fixed-volume infusion reduced the incidence and severity of infusion-related reactions compared with part A. Specifically, infusion reactions (IRs) occurred in 63% of patients (N = 27) in part A vs 28% of patients in part B. Most IRs were grade 2. Of note, 1 grade 3 IR was reported in part A and led to discontinuation; no grade 3 IRs were reported for part B.

Most IRs occurred during the first infusion in both study groups (76.5% and 76.9%, respectively). All other IRs occurred at infusion 3 or later.

In part A, 7.4% of patients received montelukast as premedication and among these 2 patients, 1 had an IR compared with 67.4% of patients who received pretreatment in part B of whom 7 had an IR.

The quadruplet therapy is under investigation in 2 ongoing phase 3 trials. The first, IMROZ (NCT03319667) is assessing the combination in patients with newly diagnosed multiple myeloma who are ineligible for transplant. The second, GMMG HD7 (NCT03617731), is evaluating the efficacy the addition of isatuximab to VRd and lenalidomide maintenance vs VRd and lenalidomide maintenance alone.

References

1. Ocio EM, Perrot A, Bories P, et al. Update of safety and efficacy of isatuximab short-duration fixed-volume infusion plus, bortezomib, lenalidomide, and dexamethasone combined therapy for NDMM ineligible/with no immediate intent for ASCT. Presented at: 18th International Myeloma Workshop; September 8-11, 2021; Vienna, Austria.
2. Sarclisa. Prescribing information. Sanofi; 2021. Accessed September 9, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761113s003lbl.pdf