Relapsed/refractory patients

IMW 2019 | A.R.R.O.W.: Subgroup analysis by frailty score

On Saturday 14th September, 2019, Professor (Prof.) Maria-Victoria Mateos, University Hospital Salamanca, Salamanca, ES, presented a subgroup analysis from the phase III A.R.R.O.W study at the XVII International Myeloma Workshop (IMW) in Boston, US. The results of this analysis are provided here by the Multiple Myeloma (MM) Hub.1

Background

The A.R.R.O.W. study evaluated the safety and efficacy of once-weekly versus twice-weekly carfilzomib (K), in combination with dexamethasone (d, Kd), in patients with relapsed/refractory MM (RRMM). Patients with RRMM who had received two to three prior lines of treatment, including exposure to a proteasome inhibitor (not K or oprozomib), and an immunomodulatory drug were enrolled.1 Patients (n= 478) were randomized (1:1) to receive K once-weekly (n= 240) as a 30-minute intravenous (IV) infusion (70mg/m2, Kd70) or twice weekly (n= 238) as a 10-minute IV infusion (27mg/m2, Kd27).1,2 The results from a pre-planned interim analysis of the A.R.R.O.W study were presented at the American Society of Clinical Oncology (ASCO) meeting in 2018 and can be viewed here.2

A subgroup analysis of patients < 65 years vs ≥ 65, showed hazard ratios (HRs) favored Kd70 (HR: 0.6, 95% CI, 0.42–0.86) over Kd27 (HR: 0.84, 95% CI, 0.61–1.15) for progression-free survival (PFS) in both patient groups.3 Aside from age, frailty is an important factor to consider when determining the appropriate treatment of patients with MM. Prof. Mateos and colleagues, therefore, conducted a subgroup analysis which aimed to evaluate efficacy and safety, post-hoc, by frailty status in the A.R.R.O.W. study.1

Frailty subgroup analysis1

Prof. Mateos and colleagues used a modified frailty index to explore patient outcomes in the A.R.R.O.W. study. The frailty algorithm considered age, medical history (derived Charlson comorbidity index [CCI]), and Eastern Cooperative Oncology Group (ECOG) score. Patients were evaluated and assigned frailty scores (Table 1), which were balanced between arms.

Table 1. Frailty scores in the Kd70 and Kd27 groups

 

Kd70 (n= 240)

Kd27 (n= 238)

Age group, years, n (%)

< 75

194 (81)

206 (87)

75–80

35 (15)

29 (12)

≥ 80

11 (5)

3 (1)

Modified CCI score, n (%)

≤ 1

124 (52)

138 (58)

> 1

105 (44)

92 (39)

Missing

11 (5)

8 (3)

ECOG performance status, n (%)

0

118 (49)

118 (50)

1

121 (50)

120 (50)

≥ 2

1 (0.4)

0

Frailty score, n (%)

0 (fit)

60 (25)

66 (28)

1 (intermediate)

89 (37)

103 (43)

≥ 2 (frail)

80 (33)

61 (26)

Missing

11 (5)

8         (3)

  • PFS analysis:
    • In the total cohort, PFS was improved with Kd70 compared to Kd272
      • Median PFS (Kd70 vs Kd27): 11.2 vs 7.6 months (HR: 0.69, 95% CI, 0.54–0.83)2
    • This benefit was maintained across the subgroups according to frailty status (Table 2)1
      • The HR for progression was 0.76 in the frail group, which is similar to the total cohort1
  • ORR was similar in the Kd70 group, irrespective of frailty status (fit vs intermediate vs frail: 67% vs 64% vs 56%), which was in line with the total cohort ORR in the Kd70 arm of 63%1

Table 2. PFS by frailty score and K-dosing regimen1

 

Fit

Intermediate

Frail

 

Kd70

Kd27

Kd70

Kd27

Kd70

Kd27

n

60

66

89

103

80

61

Median PFS (months)

15.7

5.7

11.7

7.7

10.3

6.6

HR (95% CI)

0.53 (0.33–0.86)

0.81 (0.55–1.19)

0.76 (0.49–1.16)

Table 3. Best overall response by frailty score1

 

Fit

Intermediate

Frail

N (%)

Kd70

Kd27

Kd70

Kd27

Kd70

Kd27

n

60

66

89

103

80

61

Stringent complete response (sCR)

1 (2)

0

2 (2)

0

0

0

Complete response (CR)

5 (8)

2 (3)

5 (6)

2 (2)

3 (4)

0

Very good partial response (VGPR)

18 (30)

4 (6)

23 (26)

14 (14)

20 (25)

9 (15)

Partial response (PR)

16 (27)

13 (20)

27 (30)

33 (32)

22 (28)

16 (26)

Overall response rate, % (95% CI)

67

53–78

29

18–41

64

53–74

48

38–58

56

45–67

41

29–54

  • Safety analysis:1
    • Kd70 was well-tolerated with similar incidences of hematological and non-hematological AEs as in Kd27 arm (Table 4)
    • AEs of interest were low in incidence across all subgroups and K-dosing regimens

Table 4. Safety by frailty status in the safety population1

 

Fit

Intermediate

Frail

N (%)

Kd70

Kd27

Kd70

Kd27

Kd70

Kd27

n

60

66

88

101

79

60

Grade ≥ III TEAE

33 (55)

41 (62)

60 (68)

58 (57)

61 (81)

42 (70)

Grade ≥ III TEAEs of interest

Peripheral neuropathy

0

1 (2)

0

0

0

0

Acute renal failure

0

3 (5)

6 (7)

6 (6)

3 (4)

4 (7)

Cardiac failure

1 (2)

1 (2)

3 (3)

3 (3)

3 (4)

5 (8)

Ischemic heart disease

1 (2)

0

0

1 (1)

0

1 (2)

Pulmonary hypertension

0

0

0

0

0

1 (2)

TEAE leading to discontinuation of K

2 (3)

5 (8)

11 (13)

11 (11)

16 (20)

11 (18)

Conclusion

Prof. Mateos concluded that both fit and frail patients experience a clinical benefit with Kd70 (once-weekly dosing of K) compared to Kd27 (twice-weekly). Additionally, no new safety signals were detected by subgroup analysis indicating a similar profile in fit and frail patients as per the general population. It was also noted that grade III or higher TEAEs of interest were uncommon across all subgroups.

This analysis supports the use of once-weekly carfilzomib for both fit and frail patients with RRMM.

References
  1. Mateos M-V. et al., Safety and efficacy of once-weekly carfilzomib (K) dosing in frail patients (pts): a subgroup analysis from the phase 3 A.R.R.O.W. study. Abstract #OAB-046. XVII International Myeloma Workshop (IMW), Boston, US. 2019 Sep 14.
  2. Mateos M-V. et al., Once-weekly vs twice-weekly carfilzomib (K) dosing plus dexamethasone (d) in patients with relapsed and refractory multiple myeloma (RRMM): Results of the randomized phase 3 study A.R.R.O.W. Abstract #8002. American Society of Clinical Oncology (ASCO) Annual Meeting, 2018 June 1–5; Chicago, IL, US.
  3. Moreau P. et al., Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Onc. 2018 Jun 01. DOI: 10.1016/S1470-2045(18)30354-1
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