IMW 2019 | ICARIA-MM: Cytogenetic subgroup analysis

At the XVII International Myeloma Workshop (IMW), Boston, US, Simon J. Harrison, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne, AU, presented a subgroup analysis from the ICARIA-MM trial (NCT02990338) of patients with high-risk cytogenetics.¹

The phase III ICARIA-MM trial compared isatuximab (Isa) + pomalidomide (P) + dexamethasone (d, Isa-Pd) to Pd alone in patients with relapsed/refractory multiple myeloma (RRMM). Patients (n= 307) were randomized (1:1) to Isa-Pd or Pd and received treatment until disease progression (PD) or unacceptable toxicity. The study had a primary endpoint of progression-free survival (PFS), with secondary endpoints of overall response rate (ORR) and overall survival (OS).²

The original report from the ICARIA-MM trial was presented by Prof. Paul Richardson at the American Society of Clinical Oncology (ASCO) meeting earlier this year. At ASCO Prof. Richardson and colleagues showed, at a median follow-up of 11.6 months, that Isa-Pd provided a statistically significant improvement in PFS (Isa-Pd vs Pd: 11.53 vs 6.47 months, hazard ratio [HR]: 0.596, 95% CI, 0.436–0.814). Median OS was not reached in either arm. ORR was higher in the Isa-Pd arm at 60.4% compared to 35.3% in the Pd arm. The main reason for discontinuation was PD or an adverse event (AE). Read the full results on the Multiple Myeloma Hub now.²

Subgroup analysis: patients with high-risk cytogenetics¹

At the IMW meeting, a subgroup analysis from ICARIA-MM was presented, comparing safety and efficacy of Isa-Pd to Pd in patients with high- and standard-risk cytogenetics.

• High-risk cytogenetics pre-specified as ≥ one of the following:
  • del(17p) – 50% cut-off
  • t(4;14) – 30% cut-off
  • t(14;16) – 30% cut-off
• Baseline cytogenetic profiles of the intention-to-treat (ITT) population are shown in Table 1

Table 1. Cytogenetics in the ITT population at baseline¹

• Safety analysis by cytogenetic risk is shown in Table 2
  • High-risk patients experienced more grade III or higher treatment-emergent AE (TEAEs) though the addition of Isa to the Pd regimen did not increase events leading to discontinuation
  • Treatment-related mortality did not increase in either subgroup
    • Two treatment-related grade V TEAEs occurred; both in the Pd arm, one in a patient with high-risk cytogenetics, and one in a patient with standard risk cytogenetics
  • Median duration of treatment exposure:
    • High-risk (Isa-Pd vs Pd): 32 vs 18 weeks
    • Standard-risk (Isa-Pd vs Pd): 42 vs 31.1 weeks
• Isa-Pd had a manageable safety profile in both standard- and high-risk patients

Table 2. Safety by cytogenetic subgroup

• Efficacy results by cytogenetics are displayed in Table 3
  • Odds ratio for Isa-Pd vs Pd (95% CI):
    • ORR, high-risk: 5 (1.33–19.79)
    • ORR, standard-risk: 2.54 (1.33–4.86)
    • ≥ Very good partial response (VGPR), high-risk: 14.41 (1.57–667.48)
    • ≥ VGPR, standard-risk: 4.78 (1.9–13.57)
  • The ORR and PFS (Table 4) benefit of Isa-Pd versus Pd was maintained in patients with high-risk cytogenetics
    • Benefit in ORR and PFS was also maintained regardless of the high-risk cytogenetic cut-off used

Table 3. Response rates by cytogenetics

Table 4. PFS by cytogenetics

Conclusion

Isa-Pd provided an ORR and PFS benefit over Pd, which was maintained in patients with high-risk cytogenetics, independent of the cytogenetic cut-off definition. Additionally, the safety profile was manageable in this patient population.

Isa-Pd could provide a new treatment option for patients with RRMM with high-risk cytogenetics who typically have few options available.