Isatuximab-Pd in the frail population: ICARIA-MM subgroup analysis

In light of the encouraging outcomes observed in the ICARIA-MM study (NCT02990338), evaluating isatuximab in combination with pomalidomide and dexamethasone (Isa-Pd) for the treatment of adult patients with relapsed/refractory multiple myeloma (RRMM), Isa-Pd has been approved in a number of countries. The triplet regimen is indicated for the treatment of adult patients with RRMM following treatment with ≥2 prior therapies, including lenalidomide and a proteasome inhibitor.

A recent subgroup analysis of the pivotal ICARIA-MM study sought to determine whether frailty influences the clinical outcomes and safety of Isa-Pd in patients with RRMM. The study utilized a simplified frailty score that considered patient age, modified Charlson Comorbidity Index (CCI), and Eastern Cooperative Oncology Group (ECOG) performance score. In a letter to the editor, Fredrik Schjesvold and colleagues¹ provided the results from this subgroup analysis, and the Multiple Myeloma Hub is pleased to provide a summary.

Results

Patient disposition

• Of the 307 patients enrolled in the ICARIA-MM study
  • 154 and 153 were assigned to the Isa-Pd and Pd arms, respectively;
  • 28.0% were considered frail;
  • 69.4% were considered fit/intermediate; and
  • 2.6% were not included in this subgroup analysis due to inadequate medical history records.
• There was not a significant difference in the number of frail patients in the Isa-Pd (31.2%) vs Pd arms (24.8%; p = 0.2167).

Efficacy

• Although not significantly different, progression-free survival was superior in patients who received Isa-Pd vs Pd, irrespective of frailty status (Table 1), and outcomes from this subgroup analysis are comparable to those observed in the overall study population.
• Overall response rates were not significantly different between patients receiving Isa-Pd classed as frail vs fit/intermediate and superior in patients who received Isa-Pd vs Pd, irrespective of frailty status (Figure 1).

Table 1. Patient outcomes to Isa-Pd vs Pd by frailty status*

Isa, isatuximab; Pd, pomalidomide + dexamethasone; PFS, progression-free survival. *Data from Schjesvold, et al.1
	Frail		Fit/intermediate
	Isa-Pd (n = 48)	Pd (n = 38)	Isa-Pd (n = 101)	Pd (n = 112)
PFS, months	9.0	4.5	12.7	7.4
1-year OS, %	66.9	58.8	75.0	64.5

CR, complete response; Isa, isatuximab; ORR, overall response rate; Pd, pomalidomide + dexamethasone; PR; partial response; sCR, stringent complete response; VGPR, very good partial response.
*Data from Schjesvold, et al.¹

Safety

• All patients classified as frail experienced treatment-emergent adverse events (TEAEs), irrespective of treatment arm.
• The most commonly observed non-hematologic TEAEs in frail and fit/intermediate patients were diarrhea and infusion reactions, respectively (Table 2).
• Rates of anemia and thrombocytopenia were comparable between patients in the Isa-Pd vs Pd arms irrespective of frailty, and Grade 4 neutropenia was elevated in patients who received Isa-Pd, again irrespective of frailty (Table 2).

 Table 2. Safety overview of Isa-Pd vs Pd by frailty status*

IRR, infusion related reaction; Isa, isatuximab; Pd, pomalidomide plus dexamethasone; TEAE, treatment-emergent adverse event. *Data from Schjesvold, et al.1 †Due to TEAEs.
	Frail		Fit/intermediate
	Isa-Pd (n = 48)	Pd (n = 36)	Isa-Pd (n = 100)	Pd (n = 110)
TEAEs, %
Any grade	100.0	100.0	100.0	98.2
Infections and infestations	83.3	75.0	80.0	62.2
Diarrhea	33.3	27.8	23.0	17.1
IRR	31.3	0	40.0	0
Bronchitis	27.1	11.1	22.0	8.1
Upper respiratory tract infection	25.0	8.3	29.0	20.7
Dyspnea	25.0	11.1	10.0	9.9
Pyrexia	20.8	19.4	12.0	12.6
Hematologic abnormalities, %
Neutropenia               Any grade	95.8	94.3	97.0	92.7
Grade 4	68.8	31.4	58.0	31.8
Febrile neutropenia               Grade ≥3	12.5	0	12.0	2.7
Other events
Death, %	10.4	11.1	6.0	9.0
Treatment discontinuation*, %	8.3	16.7	7.0	11.7
Time to treatment discontinuation, months	8.7	4.9	9.4	5.3

Conclusion

In summary, frail patients with RRMM treated with Isa-Pd demonstrate similar clinical responses to fit/intermediate counterparts. Furthermore, the safety profile of the triplet regimen in frail patients was comparable to the overall study populations, and Isa-Pd discontinuation rates were lower in patients classed as frail vs fit/intermediate. Of note, this was not a prespecified analysis of the ICARIA-MM trial, but it indicates that it is feasible to treat frail patients with RRMM with a triplet regimen, which is encouraging in this difficult-to-treat population.

For more information on the considerations when treating frail patients with MM, watch the video with Sonja Zweegman below.