General MM

EHA 2019 | Molecular subgroup analysis of the Myeloma XI phase III trial

On Saturday 15 June at the 24th Congress of the European Hematology Association (EHA), Charlotte Pawlyn from the Institute of Cancer Research, London, UK, presented an exploratory subgroup analysis of the phase III Myeloma XI study.1 This trial (NCT01554852) compared the efficacy of quadruplet induction therapy with carfilzomib (K), cyclophosphamide (C), lenalidomide (R), and dexamethasone (d; KCRd) versus triplet combinations (CRd or CTd [thalidomide, T instead of R]), in newly-diagnosed multiple myeloma (MM) patients.

The Myeloma XI trial was the first, multicenter, open-label, randomized, phase III trial to show in its primary analysis that carfilzomib addition to induction regimens leads to deep responses and a good toxicity profile in the naïve MM setting.2

In this Myeloma XI subgroup analysis, the efficacy of KCRd versus the triplet combinations was assessed in different molecular risk patient subpopulations that were involved in the study. The primary endpoints were progression-free survival (PFS) and overall survival (OS) per subgroup.

Study design & baseline characteristics
  • N=1056 patients with newly-diagnosed MM, who were eligible for autologous stem cell transplantation (ASCT)
  • Patients were randomized to minimum four cycles of KCRd or CRd/CTd before ASCT, as follows:
    • KCRd:
      • K: 36 mg/m2 intravenously on Days 1, 2, 8, 9, 15, 16
      • C: 500 mg orally on Days 1, 8
      • R: 25 mg orally on Days 1–21
      • d: 40 mg orally on Days 1–4, 8, 9, 15, 16
    • CRd:
      • C,R: same as KCRd dosing
      • d: 40 mg orally on Days 1–4, 12–15
    • CTd:
      • C: same as KCRd dosing
      • T: 100–200 mg as tolerated, orally on Days 1–21
      • d: same as CRd dosing
    • Patients randomized to CRd or CTd, who did not achieve a complete response (CR) or a very good partial response (VGPR) received further intensification therapy prior to ASCT, with Cd plus bortezomib (D; CVd) as follows:
      • C: Same as CRd dosing
      • V: 1.3 mg/m2 intravenously or subcutaneously on Days 1, 4, 8, 11
      • d: Same as CRd dosing
    • After ASCT, patients in all arms were randomized to R or observation, as maintenance therapy for three months
    • Median follow-up: 34.5 month
    • Table 1. Key baseline characteristics:

Baseline characteristic

CTd arm (n=265)

CRd arm (n=265)

KCRd arm (n=526)

Male patients

58.9%

64.2%

60.3%

Median age (range)

61 (38–74)

62 (36–74)

61 (33–75)

WHO performance:

0

1

2

≥3

Not applicable

 

46.4%

32.5%

12.5%

3.8%

4.9%

 

38.1%

37.0%

11.3%

6.8%

6.8%

 

42.8%

36.9%

11.0%

4.0%

5.3%

ISS:

I

II

III

Not applicable

 

31.7%

37.4%

22.3%

8.7%

 

30.2%

35.8%

23.8%

10.2%

 

31.7%

37.6%

22.2%

8.4%

High-risk lesions:

t(4;14)

t(14;16)

t(14;20)

del(17p)

gain(1q)

 

11.7%

0%

0%

7.4%

31.9%

 

12.9%

0%

0%

4.7%

35.3%

 

13.7%

3.4%

1.0%

8.35

34.8%

Risk category:

Standard risk 

High risk 

Ultra high risk 

 

59.6%

30.9%

9.6%

 

55.3%

36.5%

8.2%

 

49.5%

39.7%

10.8%

ISS; international staging system, standard risk; defined as no high-risk lesions, high-risk; defined as one hgih-risk lesion, ultra high-risk lesion; defined as ≥1 high-risk lesion

Key findings
  • Median number of treatment cycles completed (range):
    • CTd arm: 6 (1–13)
    • CRd arm: 5 (1–15)
    • KCRd arm: 4 (1–12)
  • Table 2. Response outcomes:

 

CTd arm (n=265)

CRd arm (n=265)

KCRd arm (n=526)

Prior ASCT

 

 

 

Overall response rate (ORR)

52.8%

64.9%

82.3%*

 

CTd arm (n=159)

CRd arm (n=179)

KCRd arm (n=394)

After ASCT

 

 

 

ORR

76.1%

82.1%

91.9%

* p<0.0001 between KCRd and CTd or CRd arms

  • No statistically significant differences were observed amongst different molecular risk patient subgroups (across all arms) in:
    • Depth of responses
    • ASCT patient rates
  • Three-year PFS rates (total patient cohort):
    • CRd or CTd arms (n=530): 50.3% (95% CI, 45.4–55.3)
    • KCRd arm (n=526): 64.5% (95% CI, 59.9–69.1)
    • Comparison: HR=0.63 (95% CI, 0.51–0.76); p<0.0001
  • Median PFS rates by patient risk subgroup:
    • Standard risk group (no high-risk lesions):
      • KCRd arm: Not reached
      • CRd/CTd arms: 37 months
      • Comparison: HR=0.62 (95% CI, 0.39–0.98)
    • High risk group (one high-risk lesion):
      • KCRd arm: Not reached
      • CRd/CTd arms: 37 months
      • Comparison: HR=0.68 (95% CI, 0.40–1.14)
    • Ultra high risk group (≥1 high-risk lesions):
      • KCRd arm: 35 months
      • CRd/CTd arms: 20 months
      • Comparison: HR=0.50 (95% CI, 0.20–1.25)
    • Patients with del(17p), t(4;14) and/or t(14;16):
      • KCRd arm: 38 months
      • CRd/CTd arms: 22 months
      • Comparison: HR=0.38 (95% CI, 0.19–0.77)
Conclusions

This subgroup analysis of the phase III Myeloma XI study, based on patient populations with standard, high or ultra-high molecular risk, showed that KCRd did not lead to different response rates in these subgroups. Moreover, the PFS benefit observed with KCRd treatment (3-year PFS 64.5% vs 50.3%) remained the same among patients with different molecular risk. Even with KCRd, patients with ultra-high-risk disease continue to have poor long-term outcomes, constituting a serious unmet medical need.

References
  1. Pawlyn C. Efficacy of quadruplet KCRD (carfilzomib, cyclophosphamide, lenalidomide and dexamethasone) induction for newly diagnosed myeloma patients: analysis of the myeloma XI study by molecular risk. Abstract S873. 24th Congress of EHA, Amsterdam, NL
  2. Jackson G.H. A Quadruplet Regimen Comprising Carfilzomib, Cyclophosphamide, Lenalidomide, Dexamethasone (KCRD) Vs an Immunomodulatory Agent Containing Triplet (CTD/CRD) Induction Therapy Prior to Autologous Stem Cell Transplant: Results of the Myeloma XI Study. Abstract 302. 60th Annual Meeting of the American Society of Hematology, 2018.

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