Phase II Carthadex study: carfilzomib, thalidomide and dexamethasone for newly diagnosed, transplant eligible multiple myeloma

The Carthadex study (#NTR2422), published in Haematologica by Ruth Wester, Erasmus MC Cancer Institute, Rotterdam, NL, and colleagues, investigated the use of carfilzomib, thalidomide and dexamethasone (KTD) in patients with newly diagnosed multiple myeloma (NDMM) who were eligible for transplant. This study used KTD as induction and consolidation in a dose escalation cohort of 111 patients, with results reported at a median follow-up of 58.7 months.¹

Background

Achieving a deep response to induction therapy and high-dose melphalan (HDM) with autologous stem cell transplant (ASCT) has been shown to increase progression-free survival (PFS) and overall survival (OS) rates in NDMM. The choice of induction and consolidation therapy is therefore important, with physicians needing to identify a highly effective and safe treatment plan that patients will adhere to.¹

Results from the initial cohorts of the Carthadex trial, reported in 2015, demonstrate a very good partial response (VGPR) or better of 89% and a complete response (CR) rate of 63%, after consolidation. The 3-year PFS was 72% and the authors concluded that the KTD combination was well-tolerated, as well as clinically active.²

Subsequently, this dose-escalation study, included the three original carfilzomib doses (27, 36 and 45 mg/m²) but also included a higher dose (56 mg/m²) based on the hypothesis that a higher dose could lead to a better response. No consensus exists on the optimum dose of carfilzomib, this trial sought to answer this question.¹

Patient characteristics and study design

• Adult patients with NDMM who are transplant eligible (N = 111)
• Median age: 58 (29–66)
• R-ISS stage III: 9%
• High-risk (defined based on cytogenetics and R-ISS stage): 39%
• Primary endpoints: response after induction, overall response, CR and VGPR
• Secondary endpoints: efficacy and safety, maximum tolerated dose (MTD), dose limiting toxicities (DLTs), PFS and OS

Treatment regimen

Treatment consisted of four cycles of induction therapy (28-day cycles) followed by HDM/ASCT and four cycles of consolidation therapy.

• Induction therapy:
  • Carfilzomib administered as a 30-minute infusion. For all cohorts, 20 mg/m² carfilzomib was given on days 1, 2 and then escalated to:
    • Cohort 1 (n = 50): 27 mg/m²
    • Cohort 2 (n = 20): 36 mg/m²
    • Cohort 3 (n = 21): 45 mg/m²
    • Cohort 4 (n = 20): 56 mg/m²
  • Oral thalidomide (days 1–28): 200 mg
  • Oral dexamethasone (days 1, 8, 15 and 22): 40 mg
• Stem cell mobilization:
  • Intravenous cyclophosphamide: 2–4 mg/m²
  • Daily granulocyte colony-stimulating factor: 10 μg
• Transplant: HDM (200 mg/m²) and ASCT
• Consolidation therapy (four cycles) as per the induction therapy but a lower dose of thalidomide: 50 mg
• Prophylactic antibiotics, antithrombotics and antiviral medications were given to all patients

Efficacy

Table 1 shows the response rates of the total cohort based on the stage of treatment. Table 2 displays the ≥ VGPR rates by carfilzomib dose.

Table 1: Response rates by stage of treatment

ASCT, autologous stem cell transplant; CR, complete response; HDM, high-dose-melphalan; PR, partial response; VGPR, very good partial response
Stage of treatment	≥CR	n	≥VGPR	n	Overall response (≥PR)	n
Post-induction	18%	20	65%	72	93%	103
Post-HDM/ASCT	31%	34	77%	86	94%	104
Post-consolidation	63%	70	86%	96	94%	104

Table 2: ≥ VGPR rates by stage of treatment and dose of carfilzomib

ASCT, autologous stem cell transplant; HDM, high-dose-melphalan
	27 mg/m2 (%)	36 mg/m2 (%)	45 mg/m2 (%)	56 mg/m2 (%)
N	50	20	21	20
Post-induction	27 (54)	16 (80)	13 (62)	16 (80)
Post-HDM/ASCT	32 (64)	17 (85)	19 (90)	18 (90)
Post-consolidation	40 (80)	18 (90)	20 (95)	18 (90)

• PFS:
  • Median PFS: 58 months (95% CI, 45–67)
  • Patients defined as high-risk had a poorer OS (P = 0.006)
  • Higher R-ISS was correlated with worse PFS (P = 0.04)
  • Carfilzomib dose was not associated with PFS
• OS:
  • Median OS: 83 months (95% CI, 83–not reached)
  • Five-year OS: 76% (95% CI, 66–83)
  • Carfilzomib dose and risk status were not associated with OS
• CR:
  • Post-induction: rates were comparable
  • Post-consolidation:
    • Dose level (27 vs 36 vs 45 vs 56 mg/m²): 56% vs 65% vs 67% vs 75% (P = 0.16)
    • High-risk vs standard risk: 67% vs 58%
    • R-SS stage I vs II vs III: 73% vs 57% vs 60%

Safety

• Hematological toxicity grade 3/4: 10%
• Non-hematological grade 3/4 AEs:
  • Infections: 11%
    • The rate of infections increased with higher doses of carfilzomib
  • Respiratory disorders: 8%
  • Skin disorders: 9%
  • Vascular disorders: 9%
  • Cardiac events: 5%
    • Three at 27 mg/m², one at 45 mg/m² and one at 56 mg/m²
• Serious AEs occurred in 42% of patients in total, and in each cohort as below:
  • Cohort 1 (27 mg/m²): 42% (n = 21)
  • Cohort 2 (36 mg/m²): 40% (n = 8)
  • Cohort 3 (45 mg/m²): 33% (n = 7)
  • Cohort 4 (56 mg/m²): 60% (n = 12)

Traditional triplets containing bortezomib are associated with higher rates of polyneuropathy (PN). This study explored the use of carfilzomib, a second generation proteasome inhibitor, as an alternative. In total, 52 patients (47%) experienced PN with 20% being grade 2 or higher. However, these were manageable and not associated with carfilzomib dose. There was one grade 3 event of PN at 27 mg/m².

Treatment discontinuations

In total, 83 patients completed the whole treatment pathway (75%). Nine patients discontinued treatment after induction therapy, six of which were due to AEs. Four did not receive HDM/ASCT. With regards to consolidation therapy, four patients discontinued prior to starting, and a further nine discontinued during consolidation.

Conclusion

• KTD is well-tolerated and effective for the frontline treatment in transplant eligible NDMM at all dose levels investigated. It does not appear to affect stem cell mobilization and is affordable. Furthermore, the use of consolidation therapy post-ASCT significantly improves response
• The authors recommend a dose of 36 mg/m² twice weekly in clinical practice, based on the results of this trial
• Further results of this study are expected from cohort five.
• Cohort five uses 8 cycles of induction therapy instead of 4
• Limitations of the study: small sample size and non-randomized design