Isatuximab Plus Kd Yields Consistent PFS Benefit Vs Kd Alone in Relapsed Multiple Myeloma

A progression-free survival (PFS) benefit consistent with interim results was observed in patients with relapsed multiple myeloma treated with isatuximab (Scarlisa) plus carfilzomib and dexamethasone (Kd) vs with Kd alone, according to updated results from the phase 3 IKEMA trial (NCT03275285), which were presented at the European Society of Medical Oncology Virtual Plenary Session.

In the isatuximab arm, the median PFS was 35.7 months (95% CI, 25.8-44.0) compared with 19.2 months (95% CI, 15.8-25.0) in the Kd alone arm (HR, 0.58; 95% CI, 25.8-44.0). After 2 years of follow-up, the reduction in risk of death was 42% in the experimental arm. The PFS subgroup analysis showed consistent benefit with isatuximab -Kd vs Kd across all subgroups. Moreover, the benefit of isatuximab and Kd was maintained through PFS2, defined as the time from randomization to disease progression on the next line of treatment or death. In the ITT population, the median PFS2 was 47.2 months (95% CI, 38.1-not calculable [NC]) in the isatuximab arm and 35.6 months (95% CI, 24.1-40.5) in the Kd arm. The updated results represent the longest median PFS for a second-line proteasome inhibitor in relapsed multiple myeloma.

“At the median follow-up of 44 months, the median PFS of nearly 3 years and MRD negativity in 1/3 or patients further supports isatuximab plus Ld as a standard of care for relapsed multiple myeloma,” Philippe Moreau, MD, vice president of the International Myeloma Society, head of the Hematology Department at the University Hospital of Nantes, France, and lead investigator of this study, said during the presentation.

A total of 302 patients with relapsed multiple myeloma were enrolled on the trial who were randomized 3:2 to receive either isatuximab plus Kd (n = 179) or Kd alone (n = 123). Patients were treated until progressive disease, unacceptable toxicity, or patient request. The primary end point was PFS, with key secondary end points including overall response rate (ORR), very good partial response (VGPR), minimal residual disease (MRD) negativity, complete response rate (CR), and overall survival (OS).

Patients were given 10 mg/kg of isatuximab on days 1, 8, 15, and 22 during cycle 1 then every 2 weeks thereafter; carfilzomib was given at 20 mg/m2 on days 1 and 2, 56 mg/m2 on days 8 to 9 and 15 to 16 during cycle 1, and 56 mg/m2 on days 1 to 2, 8 to 9, and 15 to 16 for all subsequent cycles; and dexamethasone was given at 20 mg on days 1 to 2, 8 to 9, 15 to 16, and 22 to 23 for each cycle.

To be eligible for treatment, patients needed to have 1 to 3 lines of prior therapy, no prior therapy with carfilzomib (Kyprolis), and not be refractory to prior anti-CD38 treatments.

Patient in the experimental and control arms, respectively, had a median age of 65 years vs 63 years, of whom 9.5% vs 8.1% were 75 years or older. At baseline, the cytogenetic risk was high in 23.5% vs 25.2%, standard in 63.7% vs 63.4%, and missing in 12.8% vs 11.4% in the isatuximab and Kd arms, respectively. The median prior lines of therapy in each arm was 2. A total of 92.7% of patients in the isatuximab arm had prior treatment with a proteasome inhibitor compared with 85.4% in the Kd arm, and 76.0% vs 81.3% received prior immunomodulatory drugs, respectively. Additionally, 31.8% and 34.1% of patients, respectively, were refractory to lenalidomide (Revlimid).

At a median follow-up of 44 months, 71.5% of patients in the Isa-Kd arm discontinued treatment vs 90.2% in the Kd arm, with reasons including progressive disease (43.0% vs 52.0%), adverse effects (12.3% vs 17.9%), patient request (10.6% vs 14.6%), and other reasons (5.6% vs 5.7%). At the last follow-up, 27.4% of patients in the Isa-Kd arm and 8.9% in the Kd arm were continuing treatment.

The ORR in the isatuximab arm was 88.6% vs 83.7% in the Kd arm, and VGPR or better was 72.6% vs 56.1%, respectively. The stringent CR/CR rate was 44.1% in the experimental arm vs 28.5% in the control arm (OR, 2.09; 95% CI, 1.26-1.48). In the isatuximab arm, the MRD negativity rate was 33.5% vs 15.4% in the Kd alone arm (OR, 2.78; 95% CI, 1.55-4.99). The MRD negativity rate in complete responders was 26.3% in the isatuximab arm and 12.2% in the Kd alone arm (OR, 2.57; 95% CI, 1.35-4.88).

The median time to next treatment in the intent-to-treat population was 44.9 months (95% CI, 31.6-NC) and 25.0 months (95% CI, 17.9-31.3) in the KD group (HR, 0.55; 95% CI, 0.40-0.76).

At 36 months, the OS rate in the isatuximab arm was 68.7% vs 62.9% in the Kd arm, and at 42 months it was 66.3% vs 54.5%, respectively. Sixty-four patients died in the isatuximab arm and 54 died in the Kd alone arm.

Any grade treatment-emergent adverse effects (TEAEs) occurred in 98.9% of patients in the isatuximab arm and 97.5% in the Kd alone arm, with grade 3 or higher TEAEs occurring in 83.6% vs 73.0% of patients, respectively. Drug-related TEAEs of grade 3 or higher were observed in 54.8% vs 51.6% of patients in each respective group. Serious TEAEs were seen in 70.1% of patients in the isatuximab arm and 59.8% in the Kd alone arm, and serious drug-related TEAEs were observed in 27.7% vs 27.9%. TEAEs that led to definitive discontinuation were reported in in 12.4% of patients in the isatuximab arm and 18.0% in the Kd alone arm. TEAEs that led to fatalities during treatment occurred in 5.6% of patients in the isatuximab arm, and 4.9% in the Kd alone arm.

References

Moreau P, Dimopoulos MA, Mikhael J, et al. Updated progression-free survival and depth of response in IKEMA, a randomized phase 3 trial of isatuximab, carfilzomib, and dexamethasone (Isa-Kd) vs Kd in relapsed multiple myeloma. Presented at the European Society of Medical Oncology Virtual Plenary Session. May 19, 2022.