IKEMA trial: Isa-Kd versus Kd for RRMM – final overall survival analysis

Isatuximab is an IgG1 monoclonal antibody which targets CD38 on myeloma cells. Therapeutic effects include induced apoptosis, immunomodulation, and ectoenzyme inhibition.¹ The combination of isatuximab, carfilzomib, and dexamethasone (isa-Kd) was approved by both the U.S. Food and Drug Administration and the European Commission in 2021 for the treatment of patients diagnosed with relapsed/refractory multiple myeloma who have received 1–3 lines of prior therapy.

Approval was based on results obtained from the phase III IKEMA trial (NCT03275285) investigating isa-Kd versus carfilzomib and dexamethasone (Kd).

During the 20th International Myeloma Society Annual Congress, Moreau presented the final overall survival (OS) analysis from the IKEMA trial. Here, we summarize the key points from the presentation. For more information on the IKEMA trial, see the dedicated page on the Multiple Myeloma Hub.

Study design¹

• The trial included a total of 302 patients who were randomized 3:2 to either isa-Kd or Kd alone.
• The full study design and eligibility criteria were previously reported on the Multiple Myeloma Hub.
• The primary endpoint of the trial was progression-free survival (PFS).
• The baseline patient characteristics for both treatment arms were well balanced (Table 1).

Table 1. Baseline patient characteristics*

IMiD, immunomodulatory agent; ISS, International Staging System; isa-Kd, isatuximab, carfilzomib, and dexamethasone; Kd, carfilzomib and dexamethasone; PI, proteasome inhibitor. *Adapted from Moreau.1
Characteristic, % (unless otherwise stated)	Isa-Kd (n = 179)	Kd (n = 123)
Median age, years	65.0	63.0
ISS stage
I	49.7	57.7
II	35.2	25.2
III	14.5	16.3
Cytogenetic risk
High	23.5	25.2
Standard	63.7	63.4
Missing	12.8	11.4
Number of prior lines of therapy
1	44.1	44.7
2	35.8	29.3
3	18.4	24.4
Prior PI	92.7	85.4
Prior IMiD	76.0	81.3
Patients refractory to
IMiD	43.6	47.2
Lenalidomide	31.8	34.1
PI	31.3	35.8
Last regimen	49.7	59.3

Results

• The final PFS and second progression-free survival analysis showed significant improvement with Isa-Kd versus Kd treatment (Figure 1).

Isa-Kd, isatuximab, carfilzomib, and dexamethasone; Kd, carfilzomib and dexamethasone; PFS, progression-free survival; PFS2, second progression-free survival.
†Progression-free survival is defined as the time from randomization to disease progression or subsequent therapy/death.
*Adapted from Moreau.¹

• A consistent treatment effect was observed across most subgroup comparisons.
• PFS benefit was maintained after the first subsequent therapy.
• Treatment duration was 1.5-times longer in the isa-Kd arm at 94 weeks versus 61.9 weeks in the Kd arm
  • Both treatment arms had a similar relative carfilzomib dose intensity
• OS analysis was planned at 3 years post primary PFS analysis at a median follow-up duration of 56.61 months.
  • Median OS was not reached in the isa-Kd arm versus 50.6 months in the Kd arm (p = 0.1836).
  • Extrapolated median OS for the isa-Kd arm was 63 months.
  • This corresponded to an estimated 1-year difference in median OS compared to the Kd arm.
• At the time of OS analysis, more patients remained on isa-Kd treatment (23.5%) versus Kd treatment (5.7%).
  • Fewer patients discontinued due to disease progression in the isa-Kd arm (45.3%) compared with the Kd arm (53.7%).
• Time to next treatment for patients in the isa-Kd arm was 43.99 months versus 25 months for patients in the Kd arm (p = 0.0002).

Safety

• The safety profile was similar to the OS analysis at the final PFS analysis.
  • The safety profile was also consistent with previous analyses.
• There was a similar incidence of cardiac failure in both arms, with 4.5% of patients on isa-Kd treatment experiencing a Grade ≥3 cardiac event versus 4.1% of patients treated with Kd.
• The proportion of treatment-emergent adverse events that were fatal or led to treatment discontinuation was similar between treatment arms.
  • This was despite the extra 30-week treatment period for the isa-Kd group.
• The percentage of carfilzomib-associated events was also comparable between arms, despite the longer treatment period of isa-Kd.

Conclusion

Patients treated with isa-Kd benefited from a more favorable OS compared with Kd treatment. This represents the longest OS achieved in a phase III lenalidomide-free trial in the relapsed setting. The isa-Kd treatment arm also experienced a more favorable time to next treatment and second progression-free survival compared with the Kd arm. Moreover, the benefit of isatuximab was sustained through subsequent lines of therapy. Overall, the final analysis of the trial supports the use of isa-Kd as the standard of care option for patients diagnosed with relapsed/refractory multiple myeloma.