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

Isa-Pd, isatuximab-pomalidomide and dexamethasone
Cytogenetic Risk	Isa-Pd (n= 154), %	Pd (n= 153), %
Standard	66.9	51
High	15.6	23.5
del(17p)	9.1	15
t(4;14)	7.8	9.2
t(14;16)	0.6	2.6
del(17p) and t(4;14)	1.9	2.6
del(17p) and (14;16)	0	0.7
Unknown or missing	17.5	25.5

• 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

* n= 33. Isa-Pd, isatuximab, pomalidomide dexamehasone; TEAEs, treatment-emergent adverse events
	High-risk		Standard-risk
%	Isa-Pd (n= 23), %	Pd (n= 34), %	Isa-Pd (n= 103), %	Pd (n= 76), %
Grade ≥ III TEAE	95.7	67.6	85.4	76.3
Serious TEAE	73.9	50	58.3	61.8
TEAE leading to definitive discontinuation	8.7	23.5	6.8	7.9
Grade V TEAE (fatal)	26.1	4 (11.8)	3.9	5.3
Grade ≥ III events occurring in > 10% of patients in either subgroup
Laboratory abnormalities
Neutropenia	82.6	25*	85.4	69.7
Thrombocytopenia	47.8	27.3*	26.2	25
TEAEs
Febrile neutropenia	13	0	11.7	2.6
Pneumonia	21.7	17.6	15.5	18.4

• 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

	High-risk		Standard-risk
%	Isa-Pd (n= 24), %	Pd (n= 36), %	Isa-Pd (n= 103), %	Pd (n= 78), %
ORR	50	16.7	65	42.3
CR/sCR	0	0	3.9	1.3
VGPR	29.2	2.8	28.2	7.7
PR	20.8	13.9	33	33.3
CR, complete response; Isa-Pd, isatuximab- pomalidomide and dexamethasone; ORR, overall response rate; PR, partial response; s, stringent; VGPR, very good partial response;

Table 4. PFS by cytogenetics

Isa-Pd, isatuximab-pomalidomide and dexamethasone; PFS, progression free survival
	Median PFS, months
Isa-Pd vs Pd (n)	Isa-Pd	Pd	HR	95% CI
All patients (154 vs 153)	11.5	6.5	0.6	0.44–0.81
Cytogenetic risk
High (24 vs 36)	7.5	3.7	0.66	0.33–1.28
Standard (103 vs 78)	11.6	7.4	0.62	0.42–0.93
del(17p)
Yes (14 vs 23)	9.1	7.4	0.76	0.3–1.92
No (118 vs 95)	11.5	5.6	0.57	0.4–0.82
t(4;14)
Yes (12 vs 14)	7.5	2.8	0.49	0.19–1.31
No (119 vs 101)	11.6	7	0.58	0.4–0.83

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.