Adding isatuximab to carfilzomib and dexamethasone significantly delays the disease progression of patients with relapsed/refractory multiple myeloma

The phase III IKEMA study assessed whether the addition of isatuximab (Isa) to a backbone of carfilzomib and dexamethasone (Kd) provides a clinical benefit to patients with relapsed/refractory multiple myeloma (RRMM). Results of this trial presented at EHA 2020 demonstrate that the addition of this anti-CD28 antibody to Kd indeed results in a statistically significant improvement in progression free survival (PFS). Patients who were treated with the Isa-Kd triplet experienced a 47% reduction in the risk of disease progression or death compared to patients who received Kd alone. This PFS benefit was consistently seen across multiple subgroups and the Isa-Kd combination also proved to be associated with a high rate of high quality responses, with 30% of patients showing no signs of minimal residual disease (MRD).

Background

Although the therapeutic options for patients with RRMM have greatly improved over the last decades, relapses are often inevitable and additional effective treatment options are still warranted. Isa is a monoclonal antibody targeting a specific epitope on CD38. This drug received EMA-approval in combination with pomalidomide and low-dose dexamethasone (d) for the treatment of adult patients with RRMM who received at least two prior therapies including lenalidomide and a proteasome inhibitor and who demonstrated disease progression on the last therapy.

In the phase III IKEMA study, patients (N=302) with RRMM who received 1-3 prior lines of therapy were randomised (3:2) to receive Isa-Kd or Kd alone. Patients in the Isa-Kd arm received isatuximab at a dose of 10 mg/kg weekly in cycle 1 then once every 2 weeks thereafter. Patients in both arms also received K (56 mg/m2 on days [d] 1, 2, 8, 9, 15, and 16, 20 mg/m2 on d 1 and 2 of cycle 1) and d (20 mg on d 1, 2, 8, 9, 15, 16, 22, and 23) in 28-day cycles until disease progression, patient choice, or unacceptable toxicity.

Results

Patient characteristics were balanced in both arms with a median age of 64 years and around 10% of the patients being older than 75 years. Roughly a quarter of study participants presented with a high cytogenetic risk at baseline. In total, 90% and 78% of the patients had received prior proteasome inhibitor therapy and immunomodulatory drugs respectively and around one third of the patients was refractory to lenalidomide.

After a median follow-up of 20.7 months, a higher percentage of patients was still on treatment in the Isa-Kd arm. In fact, a total of 37.4% patients in the Isa-Kd arm discontinued treatment due to disease progression or toxicity, as compared to 53.7% in the Kd arm. At the time of interim analysis, the median PFS was not yet reached for Isa-Kd while this was reported at. 19.15 months with Kd (HR [99%CI]: 0.531 [0.318-0.889], p=0.0007). This represents a statistically significant 47% reduction in the risk of progression or death with Isa-Kd compared to Kd alone. A consistent treatment effect was seen for Isa-Kd across subgroups.

The rate of patients with a partial response or better was comparable with both regimens at 86.6% for Isa-Kd and 82.9% with Kd (p=0.19). However, the quality of responses was better with Isa-Kd, which is reflected by the fact that 72.6% of patients treated with this regimen experienced a very good partial response or better as compared to 56.1% in the Kd arm (p= 0.0011). The complete response rate was 39.7% with Isa-Kd and 27.6% for Kd alone. The minimal residual disease (MRD) negativity rate (10^-5) in the intention to treat population was reported at 29.6% for patients in the Isa-Kd group, while this was only the case in 13.0% for patients randomised to Kd (descriptive p=0.0004). In addition, Isa-Kd resulted in a notable delay in time to next treatment (HR [95%CI]: 0.566 [0.380-0.841]). Overall survival data were not yet mature at the time of analysis and no difference could be observed yet (17.3% deaths events in the Isa-Kd arm versus 20.3% in the Kd arm). The median treatment duration was longer in the Isa-Kd arm (80.0 weeks) as compared to Kd (61.4 weeks) and the high relative dose intensity of both Isa (94.27%) and K (91.18%) in the Isa-Kd arm demonstrated the feasibility of the combination.

Despite more grade ≥3 treatment-emergent adverse events (TEAEs, 76.8% versus 67.2%), the addition of Isa to Kd did not increase the mortality (3.4% versus 3.3%), nor did it increase the incidence of serious TEAEs (59.3% versus 57.4%) or events leading to definitive treatment discontinuation (8.5% versus 13.9%). In general, Isa-Kd had a manageable safety profile with no new safety signals. Infusion reactions were reported in 44.6% of the patients but mainly occurred during the first infusion and were mostly grade 1 or 2 (only one patient experienced a grade ≥3 infusion-related reaction).

Conclusions

The addition of Isa to Kd resulted in a statistically significant improvement in PFS with a consistent benefit across multiple subgroups. This includes patients with difficult to treat RRMM, such as elderly patients, patients with high-risk cytogenetic profiles and patients with renal impairment. In addition, Isa-Kd was associated with a higher rate of deep responses compared to Kd alone. The triple regimen came with a manageable safety profile and favourable risk/benefit in patients with RRMM. Therefore, the authors concluded that Isa-Kd represents a new treatment option for patients with RRMM.

Reference

Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab plus carfilzomib and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (IKEMA): interim analysis of a phase 3, randomized, open-label study. Presented at EHA 2020; Abstract LBA2603.