Isa-KRd Elicits MRD-Negative Remissions in Newly Diagnosed, High-Risk Myeloma

Lisa Leypoldt, MD

Treatment with the combination of isatuximab-irfc (Sarclisa), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Isa-KRd) generated high rates of minimal residual disease (MRD) negativity in patients with newly diagnosed, high-risk multiple myeloma, irrespective of transplant status, according to data from an interim analysis of the phase 2 GMMG-CONCEPT trial (NCT03104842).¹

Findings presented at the 2023 International Myeloma Society Annual Meeting showed that among evaluable transplant-eligible patients treated in arm A (n = 93), 67.7% (n = 63) were MRD negative at a 10^-5 sensitivity per next-generation flow at the end of consolidation (95% CI, 0.589-1; P = .0004). Additionally, 3.2% (n = 3) of patients were MRD positive, MRD assessment was not done or missing for 2.2% (n = 2) of patients, and 27.0% (n = 25) of patients had not reached the end of consolidation.

In evaluable transplant-ineligible patients in arm B (n = 24), the MRD-negativity rate at the end of consolidation was 54.2% (n = 13; 95% CI, 0.358-1; P = .012). No patients were MRD positive, and no patients had MRD data status missing or not completed. Notably, 45.8% (n = 11) of patients had not reached the end of consolidation.

Furthermore, 81.8% (n = 81) of transplant-eligible patients and 69.2% (n = 18) of transplant-ineligible patients achieved MRD negativity at any point. MRD negativity was sustained for at least 1 year in 62.6% (n = 62) and 46.2% (n = 12) of transplant-eligible and -ineligible patients, respectively. Sustained MRD negativity for at least 6 months was observed in 72.7% (n = 72) and 53.8% (n = 14) of transplant-eligible and -ineligible patients, respectively.

“Isa-KRd induces high rates of MRD-negative remissions in these [patients with] high-risk, newly diagnosed myeloma, [including those who are] transplant eligible and ineligible,” Lisa Leypoldt, MD, said in a presentation of the data. Leypoldt is a clinician scientist and research fellow at University Medical Center Hamburg-Eppendorf in Germany. She is also a member of the Department of Medical Oncology at Dana-Farber Cancer Institute and the Department of Medicine at Harvard Medical School, both in Boston, Massachusetts.

The nonrandomized, open-label, investigator-initiated GMMG-CONCEPT trial enrolled patients with newly diagnosed, high-risk multiple myeloma.² Patients were required to have International Staging Score (ISS) stage II or III disease with a 17p deletion, 4;14 translocation, 14;16 translocation, and/or 1q21 amplification with more than 3 copies.¹ Patients in arm A were required to be transplant eligible and no older than 70 years of age. Patients in arm B could be transplant ineligible or older than 70 years of age.

In arm A, patients underwent 6 28-day cycles of Isa-KRd induction therapy, consisting of 10 mg/kg of isatuximab on days 1, 8, 15, and 22 in cycle 1, then on days 1 and 15 in cycle 2 and beyond; 20 mg/m² of carfilzomib on days 1 and 2 of cycle 1, then 36 mg/m² on days 8, 9, 15, and 16 of cycle 1, then 36 mg/m² on days 1, 2, 8, 9, 15, and 16 in cycle 2 and beyond; 25 mg of lenalidomide on days 1 to 21 of all cycles; and 40 mg of dexamethasone on days 1, 8, 15, and 22 of all cycles. Stem cell mobilization occurred after the third cycle, and following the completion of induction, patients proceeded to high-dose therapy and autologous stem cell transplant (ASCT). Patients then received 4 cycles of Isa-KRd as consolidation, then 26 cycles of Isa-KR as maintenance.

In arm B, patients received 8 cycles of Isa-KRd induction, followed by 4 cycles of Isa-KRd consolidation and 26 cycles of Isa-KR maintenance.

The rate of MRD negativity following consolidation served as the primary end point. Progression-free survival (PFS) was a key secondary end point. Key tertiary end points included overall response rate, overall survival (OS), and safety.

The median age was 58 years (range, 35-73) in arm A (n = 99) and 74 years (range, 64-87) in arm B (n = 26). Among all patients in both arms, the majority were female (52.8%), had an ECOG performance status of 0 or 1 (82.4%), had ISS stage II disease (52.8%), and had Second Revision ISS stage III/IV disease (52.8%).

High-risk features included 17p deletions (arm A, 44.4%; arm B, 42.3%), 4;14 translocations (42.4%; 23.1%), 14;16 translocations (17.2%; 7.7%), and 1q21 amplification with at least 4 copies (31.3%; 53.8%).

Among all patients, 61.6% had 1 high-risk characteristic, and 30.4% had at least 2 high-risk characteristics. Additionally, 25.6% of patients had elevated lactate dehydrogenase (LDH) above the upper limit of normal, and 33.6% of patients received 1 prior cycle of therapy before enrollment. The median plasma cell infiltration was 60% (range, 1%-100%).

Additional data from arm A showed that at the end of induction, the complete response (CR) or better rate was 48% (95% CI, 38%-57%). The CR or better rates at the end of ASCT and end of consolidation were 65% (95% CI, 55%-73%) and 73% (95% CI, 63%-81%), respectively. A best response of CR or better was observed in 72.7% of patients.

In arm B, the CR or better rates at the end of induction, intensification, and consolidation were 38% (95% CI, 22%-57%), 38% (95% CI, 22%-57%), and 58% (95% CI, 39%-74%), respectively. A best response of CR or better was reported in 57.7% of patients.

The median PFS and OS were not met in either arm, and the study met its PFS end point in both arms. In arm A, the 1-, 2-, and 3-year PFS rates were 84.5% (95% CI, 77.5%-92.0%), 77.2% (95% CI, 69.2%-86.0%), and 68.8% (95% CI, 60.1%-78.7%), respectively. The 1-, 2-, and 3-year OS rates were 90.7% (95% CI, 85.1%-96.7%), 84.4% (95% CI, 77.5%-92.0%), and 72.8% (95% CI, 64.4%-82.3%), respectively.

In arm B, patients experienced a 1-year PFS rate of 75.1% (95% CI, 59.7%-94.5%), a 2-year PFS rate of 62.6% (95% CI, 46.0%-85.3%), and a 3-year PFS rate of 58.4% (95% CI, 41.7%-81.9%). The 1-, 2-, and 3-year OS rates were 83.5% (95% CI, 69.9%-99.7%), 71.0% (95% CI, 55.0%-91.6%), and 71.0% (95% CI, 55.0%-91.6%), respectively.

Findings also showed that elevated LDH, the presence of at least 2 high-risk characteristics, and 17p deletions were associated with impaired survival.

“Most strikingly, an elevated baseline LDH did show very significantly impaired survival,” Leypoldt said.

Investigators also conducted an analysis of PFS by MRD status for patients in arm A. An adjusted Simon-Makuch–Bernasconi plot showed that achievement of MRD negativity conferred a prognostic PFS benefit. A univariate time-varying Cox-regression model also demonstrated a prognostic PFS benefit for MRD negativity (HR, 0.118; 95% CI, 0.049-0.289; P = .0027).

“We could clearly see that the achievement of MRD negativity did confer a significant prognostic PFS benefit,” Leypoldt concluded.

Editor’s note: Dr Leypoldt reported serving in an advisory role or receiving honoraria from GSK, Sanofi, Janssen, Bristol Myers Squibb, and Celgene; receiving research support to her institution from AbbVie and GSK; receiving travel support from Sanofi; and receiving training/travel support from GSK, Sanofi, and AbbVie.

References

1. Leypoldt LB, Tichy D, Beserner B, et al. Analysis of sustained MRD-negativity and progression-free survival of Isa-KRd in high-Risk newly diagnosed multiple myeloma – additional data from planned interim analysis of the GMMG-CONCEPT trial. Presented at: 2023 International Myeloma Society Annual Meeting; September 27-30, 2023; Athens, Greece. Abstract OA-43.
2. Evaluation induction, consolidation and maintenance treatment with isatuximab, carfilzomib, lenalidomide and dexamethasone. ClinicalTrials.gov. Updated January 25, 2023. Accessed September 27, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03104842