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

On Saturday 15 June at the 24^th 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:

C, cyclophosphamide; d, dexamethasone; ISS; international staging system, standard risk; defined as no high-risk lesions, high-risk; defined as one high-risk lesion, ultra high-risk lesion; defined as ≥1 high-risk lesion; K, carfilzomib; R, lenalidomide; T, thalidomide; WHO, world health organization
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%

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
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. ASCT, autologous stem cell transplantation; C, cyclophosphamide; d, dexamethasone; K, carfilzomib; ORR, overall response rate; R, lenalidomide; T, thalidomide

• 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.