ASCO 2019 | ICARIA MM: Isatuximab + pomalidomide + dexamethasone for relapsed/refractory multiple myeloma: phase III results

During the Hematologic Malignancies — Plasma Cell Dyscrasia oral abstract session on Sunday, 02 June, 2019, at the annual American Society of Clinical Oncology (ASCO) meeting in Chicago, US, our Steering Committee member, Paul Richardson from Dana-Farber Cancer Institute, Boston, US, presented phase III data from the ICARIA MM study group trial, which investigated the safety and efficacy of isatuximab (Isa), pomalidomide (P) and low-dose dexamethasone (d) (Isa-Pd) in relapsed/refractory multiple myeloma (RRMM).¹ 

UPDATE | The results of the ICARIA study were subsequently published in The Lancet in November 2019. The Lancet article results are based on a data cut-off of 11^th October 2018, which is the same as the data in this article, as presented at the ASCO meeting.

Data given as Isa-Pd versus Pd unless otherwise stated

Background

Isa is an IgG1 monoclonal antibody that targets the CD38 transmembrane glycoprotein in multiple myeloma (MM), with many modes of action. Isa-Pd was investigated in a phase Ib dose-escalation study which identified a 10mg/kg once/twice weekly dose for future studies. These results demonstrated an overall response rate (ORR) of 62% and median progression-free survival (PFS) of 17.6 months.²

Study design and patient characteristics

• Open-label, multicenter, randomized phase III study
• Patients with RRMM (intention-to-treat [ITT] population, N= 307)
  • Two or more prior lines of therapy including lenalidomide and a proteasome inhibitor (PI)
  • No prior P exposure (Table 1)
  • Patients were representative of the wider RRMM population (Table 2)
• Randomized 1:1 to either;
  • Isa-Pd administered as:
    • Isa: 10 mg/kg on days 1, 8, 15 and 22 in cycle 1, and days 1 and 15 in subsequent cycles
    • P: 4 mg on days 1–21 of a 28-day cycle
    • d: 40 mg on days 1, 8, 15 and 22
      • Dose adjusted to 20 mg for patients ≥75 years
  • Pd administered as above, with the exclusion of isatuximab
• Treatment given until progressive disease (PD) or unacceptable adverse events (AEs)
• Primary endpoint: PFS
• Secondary endpoints: ORR and overall survival (OS)
• Median follow-up: 11.6 months (95% CI, 11.4–12.2)

Table 1: Prior anti-myeloma treatments by treatment group

Table 2: Patient characteristics of note in the ITT population

Efficacy

• PFS by independent review committee (IRC) assessment: 11.53 vs 6.47 months, P = 0.001, HR: 0.596 (95% CI, 0.436–0.814)
  • Isa-Pd provided a statistically significant improvement in PFS
  • Subgroup analysis showed the PFS benefit was maintained in subgroups based on baseline eGFR, cytogenetic risk and lenalidomide-refractory status
• Response data is shown in Table 3
  • Data cut-off: 11^th October 2018
  • It was noted that the true CR rate is underestimated due to isatuximab interfering with M-protein measurement; see Table 3 for the of near CR (nCR)
• OS: 72% vs 63% with HR: 0.687 (95% CI, 0.461–1.023)
  • Median OS not reached in either arm
• Time to next treatment (TNT): not reached vs 9.1 months (HR 0.538 [95% CI, 0.381–0.758])
  • Isa-Pd delayed TNT
  • Table 4 shows subsequent myeloma therapies
• Renal function was improved in the Isa-Pd arm
  • Patients with eGFR <50 ml/min/1.73 m² at baseline: 32 vs 21
    • Complete renal response: 71.9% vs 38.1%
    • Sustained renal response: 31.3% vs 19.0%
• Median treatment duration: 41.0 weeks (1.3–76.7) vs 24.0 weeks (1.0–73.7)
• Dose reductions:
  • P: 42.8% (n = 65) vs 24.2% (n = 36)
  • d: 32.9% (n = 50) vs 25.5% (n = 38)
• Infusion time of isatuximab:
  • First: 3.3 hours
  • Second: 2.8 hours

Table 3: Response data for Isa-Pd versus Pd

Table 4: Subsequent anti-myeloma therapies received by patients

Safety

• Discontinuations: 56.5% (n= 87) vs 74.5% (n= 114)
• Main reasons for discontinuation:
  • PD: 42.9% (n= 66) vs 57.5% (n= 88)
  • AE: 7.2% (n= 11) vs 12.8% (n= 19)
• AEs are shown in Table 5 and Table 6
  • There were more TEAEs in the Isa-Pd arm but these did not lead to a higher rate of fatal events or discontinuations
  • There was a higher rate of neutropenia in the Isa-Pd arm, but otherwise the safety profile was similar between groups
• Treatment is ongoing in: 42.4% (n= 65) vs 22.9% (n= 35)
• Infusion reactions in Isa-Pd group:
  • All grades: 38.2%
  • Grade ≥3: 2.6%
  • Most were during the first infusion

Table 5: Treatment-emergent adverse events (TEAEs)

Table 6: TEAEs grade 3– 4 by type in each subgroup

Conclusion

This is the first phase III study to demonstrate that adding an antibody to a standard doublet therapy can provide a significant and sustained PFS benefit in the RRMM setting. The Isa-Pd regimen had a manageable safety profile and should be considered a new option for treating patients with RRMM.