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IMW 2019 | ICARIA-MM: Cytogenetic subgroup analysis

Oct 17, 2019

At the XVII International Myeloma Workshop (IMW),Boston, US, Simon J. Harrison, Peter MacCallum Cancer Centerand 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 Richardsonat 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 vsPd: 11.53 vs6.47 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 cytogenetics 1

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 baseline 1

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 vsPd): 32 vs18 weeks
      • Standard-risk (Isa-Pd vsPd): 42 vs31.1 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 vsPd (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 versusPd 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 vsPd (n)

Isa-Pd

Pd

HR

95% CI

All patients (154 vs153)

11.5

6.5

0.6

0.44–0.81

Cytogenetic risk

 

 

 

 

High (24 vs36)

7.5

3.7

0.66

0.33–1.28

Standard (103 vs78)

11.6

7.4

0.62

0.42–0.93

del(17p)

 

 

 

 

Yes (14 vs23)

9.1

7.4

0.76

0.3–1.92

No (118 vs95)

11.5

5.6

0.57

0.4–0.82

t(4;14)

 

 

 

 

Yes (12 vs14)

7.5

2.8

0.49

0.19–1.31

No (119 vs101)

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.

  1. Harrison S.J. et al., Efficacy of isatuximab/pomalidomide/dexamethasone in relapsed/refractory multiple myeloma: ICARIA-MM high-risk cytogenetics subgroup analysis. 2019 Sep 14. Abstract #AB530 XVII International Myeloma Workshop, Boston, US.
  2. Richardson P.G. et al. A phase III randomized, open label, multicenter study comparing isatuximab, pomalidomide, and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). 2019 Jun 02.  Abstract #8004. American Society of Clinical Oncologymeeting, Chicago, US.

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