Carfilzomib, cyclophosphamide, and dexamethasone for the treatment of transplant-ineligible patients with high-risk multiple myeloma

Patients with multiple myeloma (MM) and adverse cytogenetic abnormalities (CA), such as del(17p) and/or t(4;14) and/or t(14;16) have high risk of relapse and death.¹ This month, the MM Hub is exploring the theme of improvements in the frontline treatment of MM; here we present the results of a pooled data analysis of two phase I/II studies, IST-CAR-561 (NCT01857115) and IST-CAR-506 (NCT01346787), using carfilzomib (K), cyclophosphamide (C), and dexamethasone (d; KCd) for the treatment of transplant-ineligible patients with MM.²

Carfilzomib is a second-generation proteasome inhibitor, approved by the United States Food & Drug Administration and by the European Medicines Agency for use in combination with dexamethasone or with lenalidomide plus dexamethasone for patients with relapsed and/or refractory (RR) MM. This pooled analysis, published in Haematologica by Roberto Mina et al., aimed to compare the outcomes of transplant-ineligible patients with newly diagnosed MM (NDMM) with standard-risk (SR) vs high-risk (HiR) CAs after treatment with KCd followed by K maintenance.²

Study design and patient characteristics²

• The phase I/II IST-CAR-561 (N = 63) and phase II IST-CAR-506 (N = 58) studies enrolled patients with NDMM > 65 years or younger but ineligible for autologous stem cell transplant
• Treatment
  • Nine 28-day cycles of KCd followed by K maintenance
  • Dosing schedule
    • K = 70 mg/m² once weekly in the IST-CAR-561 study
    • K = 36 mg/m² twice weekly in the IST-CAR-506 study
    • C = 300 mg on Days 1,8, and 15 in both studies
    • d = 40 mg on Days 1,8,15, and 22 in both studies
  • Endpoints
    • Response to therapy
    • Progression-free survival (PFS)
    • PFS-2 (PFS from enrollment to second relapse/progression, or death, or date the patient was last known to be in remission)
    • Overall survival (OS)
  • Cytogenetic abnormalities, such as t(4;14), t(11;14), t(14;16), del13, and del17p, were detected by fluorescence in situ hybridization (FISH) analysis
  • Patients included in the high-risk group had at least one of these CAs: del17p, t(4;14), or t(14;16) as per revised International Stating System (ISS) criteria
  • Of the 121 patients enrolled in these studies, 94 had cytogenetic data available:
    • SR, 61% (n = 57)
    • HiR, 39% (n = 37)
      • del17p, 23% (n = 22)
      • t(4;14), 13% (n = 12)
      • t(14;16), 4% (n = 4)
    • Patient characteristics at baseline were similar between the two groups, with a median age of 72 years (range, 60–86) and no significant differences in age, sex, ISS stage, and frailty score
    • Ninety-two patients started the induction phase (SR, n = 56; HiR, n = 36) and 70 started the maintenance phase (SR, n = 42; HiR, n = 28)
    • Median duration of treatment
      • SR group, 16.9 months
      • HiR group, 14.6 months

Results²

Patient outcomes, after a median follow-up of 38 months, are reported in Table 1. No statistically significant differences were observed in response and survival rates between patients with SR and HiR MM.

Table 1. Patient outcomes²

CI, confidence interval; CR, complete response; HR, hazard ratio; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PFS-2, PFS from enrollment to second relapse/progression, or death, or date the patient was last known to be in remission
Parameter	Standard risk (n = 57)	High risk (n = 37)	p value
After induction ORR CR	86% 19%	92% 22%	0.52 0.80
After induction and maintenance ORR CR	88% 23%	95% 24%	0.47 1.00
Median PFS, months HR (95% CI)	NR	27.8 0.81 (0.44─1.48)	0.50
3-year PFS	52%	43%	0.50
Median PFS-2 HR (95% CI)	NR	44.1 0.67 (0.32─1.39)	0.28
Median OS HR (95% CI)	NR	NR 0.72 (0.34─1.52)	0.38
3-year OS	78%	73%	0.38

No statistically significant differences were observed between PFS, PFS-2, and OS in patients with del17p vs without del17p:

• PFS: 35 vs7 months (HR 0.92; 95% CI, 0.47–1.82; p = 0.82)
• PFS-2: 44.1 months vs NR (HR 1.20; 95% CI, 0.55–2.64; p = 0.65)
• OS: 47.5 months vs NR (HR 1.17; 95% CI, 0.52–2.62; p = 0.70)

Conclusion²

• No significant differences were observed in terms of response (PFS and OS) between the standard- and the high-risk group
• Similar PFS, PFS-2, and OS rates were observed between patients with or without del17p
• The small sample size represents a limitation of the study
• Altogether, these results showed that a K-based induction regimen followed by K maintenance improved the poor prognosis of HiR patients similar to that of SR patients; further investigation into K-based induction for HiR patients with NDMM is warranted