Isa-KRd Significantly Improves MRD Negativity Rates at Cutoffs Vs KRd in Newly Diagnosed Multiple Myeloma

Francesca Gay, MD, PhD

The combination of isatuximab-irfc (Sarclisa), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Isa-KRd) significantly increased the rates of minimal residual disease (MRD) negativity at the 10^-5 and 10^-6 cutoffs post-consolidation vs carfilzomib, lenalidomide, and dexamethasone (KRd) in patients with newly diagnosed multiple myeloma, according to findings from the phase 3 IsKia trial (NCT04483739) presented during the 2023 ASH Annual Meeting.

“The primary end point of the study was met,” Francesca Gay, MD, PhD, said in a presentation of the data. “The rate of MRD negativity by intention to treat analysis was significantly higher with Isa-KRd vs KRd.” Gay is an associate professor in the Department of Molecular Biotechnology and Health Sciences at the University of Torino and is a hematologist at the Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino in Italy.

At a median follow-up of 21 months, the MRD negativity rates at the 10^-5 cutoff post-consolidation were 77% in the Isa-KRd arm (n = 151) vs 67% in the KRd arm (n = 151; OR, 1.67; P = .049). At the 10^-6 cutoff post-consolidation, the rates of MRD negativity were 67% in the Isa-KRd arm vs 48% in the KRd arm (OR, 2.29; P < .001). Following consolidation, the very good partial response (VGPR) rate was 94% in both arms; 74% of patients in the Isa-KRd arm experienced a complete response compared with 72% in the KRd arm.

“In the context of this highly effective regimen that produced a high rate of response, the 10^-6 MRD negativity cutoff might be more informative than [another] response category. The follow up of this trial is short—we will probably be able to analyze the 1-year sustained MRD negativity [data] in the coming years, and with longer follow-up, survival end points,” Gay said. “The trial can potentially offer the opportunity to explore [the] correlation between depths of MRD negativity and survival end points.”

Enrollment Criteria and Dosing

Patients enrolled in the trial were less than 70 years of age and had transplant-eligible newly diagnosed multiple myeloma. The primary end point was MRD negativity by next generation sequencing (NGS) after post-autologous stem cell transplant (ASCT) consolidation. Secondary end point included MRD negativity after induction, progression-free survival, and sustained MRD negativity. MRD negativity was assessed by NGS following the induction, mobilization, post-ASCT consolidation, and light consolidation portions of the trial.

Patients in the KRd arm received four 28-day induction cycles of carfilzomib 20 mg/m² on day 1 of cycle 1 followed by 56 mg/m² on days 8, 15 of cycle 1 and on days 1, 8, 15 for cycles 2 to 4; lenalidomide 25 mg daily on days 1 to 21; and dexamethasone 40 mg on days 1, 8, 15, 22. Those in the Isa-KRd arm received isatuximab 10 mg/kg on day 1, 8, 15, and 22 during cycle 1 followed by 10 mg/kg on days 1 and 15 during cycles 2 to 4 in addition to the same schedule of KRd.

Following induction patients “proceeded with stem cell mobilization and collection, and high dose chemotherapy and ASCT,” Hillmen explained. “After that, the other 4 cycles of full dose consolidation with carfilzomib, lenalidomide, and dexamethasone [were at] exactly the same dose and schedule as during induction.”

Following post-ASCT consolidation, patients went to the light consolidation phase which included twelve 28-day cycles of reduced dose KRd. Patients in both arms received carfilzomib 56 mg/kg² on days 1 and 15; lenalidomide 10 mg daily on days 1 to 21; and dexamethasone 20 mg daily on days 1 and 15.

Baseline patient characteristics were well balanced between both arms. Patients were a median age of 61 years old (range, 55-66) in the Isa-KRd arm compared with 60 years old (range, 54-63) in the KRd arm and most patients were female (52% vs 56%), respectively. Patients had 0 (56% vs 54%), 1 (35% vs 35%), or at least 2 (9% vs 11%) high-risk cytogenetic abnormalities with missing data reported for 11 and 12 patients, respectively.

Per Second Revision of International Staging System criteria, patients in the Isa-KRd arm vs Krd arm had stage I (24% vs 25%), II (32% vs 34%), III (37% vs 37%), or IV (6% vs 4%) disease with 12 patients in both arms reported as missing data, respectively. Per Revised International Staging System criteria, patients had stage I (35% vs 34%), II (58% vs 59%), or III (7% vs 7%) disease, with 9 and 8 patients reported as missing data, respectively. Patients had standard risk disease (82% vs 81%) or high risk (18% vs 19%) per International Myeloma Working Group criteria with 11 and 12 patients missing data, respectively.

Additional Findings and Safety

MRD negativity rates improved over time—at the 10^-5 cutoff they were 45% vs 26% (OR, 2.34; P < .001) post-induction, 64% vs 49% (OR, 1.93; P = .006) post-ASCT, and 77% vs 67% (OR, 1.67; P = .049) post-consolidation in the Isa-KRd vs KRd arms, respectively. At the 10^-6 cutoff MRD negativity rates were 27% vs 14% (OR, 2.36; P = .004) post-induction, 52% vs 27% (OR, 3.01; P < .001) post-ASCT, and 67% vs 48% (OR, 2.29; P < .001) post-consolidation in the Isa-KRd vs KRd arms, respectively.

A subgroup analysis revealed that “the increase in [the] MRD negativity rate in the Isa-KRd arm was seen in all the subgroups of patients analyzed at the 10^-5 and 10^-6 cutoff. Interestingly, this was true for standard risk, high-risk, and very high-risk patients,” Gay said.

At the 10^-5 cutoff, the post-consolidation MRD negativity rates in patients with very high-risk disease were 77% in the Isa-KRd arm vs 53% in the KRd arm. At the 10^-6 cutoff these rates were 77% vs 27%, respectively.

Regarding treatment-related adverse effects (TRAEs), patients had at least 1 any grade hematologic toxicity in the Isa-KRd arm (55%) and the KRd arm (44%) with the most common including neutropenia (41% vs 26%), thrombocytopenia (34% vs 25%), and anemia (21% vs 19%), respectively. Grade 3 to 4 TRAEs were observed in 40% and 30% of patients, respectively.

Any grade non-hematologic toxicities occurred in 90% of patients in the Isa-KRd arm and 85% of patients in the KRd arm; grade 3 or 4 toxicities occurred in 41% vs 37% of patients, respectively. Gay noted that treatment was manageable in both arms, and she highlighted that SARS-CoV-2 infection (26% vs 19%), infections not including COVID-19 (36% vs 32%), cardiac disorders (7% vs 13%), and thromboembolisms (8% vs 11%) were among any grade non-hematologic toxicities occurring in the trial.

Reference

Gay F, Roeloffzen W, Dimopoulos MA, et al. Results of the phase III randomized IsKia trial: isatuximab-carfilzomib-lenalidomide-dexamethasone vs carfilzomib-lenalidomide-dexamethasone as pre-transplant induction and post-transplant consolidation in newly diagnosed multiple myeloma patients. Blood. 2023;142(suppl 1):4. doi:10.1182/blood-2023-177546