General MM

Carfilzomib and dexamethasone (Kd) therapy in patients with newly diagnosed multiple myeloma: results from a phase II study  

The International Myeloma Working Group recommend patients with multiple myeloma (MM) who are elderly, frail or have existing comorbidities, are given a two- or three-drug combination as induction therapy, typically including lenalidomide and/or bortezomib. This recommendation was prior to the approval of novel agents such as carfilzomib (Kyprolis®) which has not been investigated in any doublet combination in the newly diagnosed MM (NDMM) setting.1

Studies using carfilzomib and dexamethasone (Kd) regimens have recently reported promising overall response rates (ORR) and very good partial response (VGPR) rates in patients with relapsed and refractory MM (RRMM); however Kd has not been studied in patients with NDMM.2 The CarBiRd study (NCT01559935) by Peter A. Forsberg, University of Colorado, CO, and colleagues reports the findings of a single institution, single-arm, open-label phase II study evaluating the efficacy and safety of Kd induction in patients with NDMM.3

Patient characteristics and trial design
  • Adult patients with histologically confirmed NDMM (N = 72)
  • Median age: 59 (42–85)
  • Kd induction therapy for as many cycles as required to reach maximum response (complete response [CR] or plateau without change in response markers over 8 weeks)
  • Induction was followed by consolidation with clarithromycin, lenalidomide and dexamethasone (BiRd) until maximum response and lenalidomide maintenance
  • The dose of carfilzomib administered was split into two cohorts:
    • Dose 1: 20/45 mg/m2 (N = 25)
    • Dose 2: 20/56 mg/m2 (N = 47)
    • Carfilzomib was given on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle over 30 minutes
  • Dexamethasone: 20 mg orally on days 1, 2, 8, 9, 15, 16, 22 and 23
  • Varicella and Pneumocystis jeroveci prophylaxis was given to all patients
  • Endpoints:
    • ORR with Kd induction
    • Toxicity and adverse events (AEs)
    • CD34+ stem cell collection yield
Key Findings

Efficacy

  • Median cycles of Kd: 5 (1–12)
  • Median time to partial response (PR): 2 cycles (1–5)
  • Median time to maximum response: 3 cycles (1–8)
  • ORR: 90% (N = 65)
  • Very good partial response (VGPR): 58% (N = 42)
  • Very good partial response (VGPR) or better: 65% (N = 47)
  • PR: 25% (N = 18)
  • Stable disease: 10% (N = 5)

Safety

  • AEs were experienced by 99% (N = 71) of patients
    • Grade 1/2: N = 547
    • Grade ≥3: N = 44
    • Patients experiencing ≥1 grade 3 AE: 32% (N = 23)
  • Most common AE grade ≥3:
    • Hypertension: 7% (N = 5)
    • Lymphopenia: 6% (N = 4)
    • Lung infection: 6% (N = 4)
  • Cardiovascular AEs (CVAEs):
    • Any: 25%
    • Grade ≥3: 11.1% with 8 observed events
    • The most frequent was hypertension in 21% of patients (N = 15)
    • Hypertension grade ≥3 was more common at higher Kd dosing (28% in the 56 mg/m2 cohort versus 8% in the 45 mg/m2 cohort)
    • One patient experienced grade 5 myocardial infarction at 56 mg/m2 Kd during the third cycle of Kd
  • Twelve patients discontinued treatment during Kd phase due to toxicity (N = 5), progressive disease (N = 2) and non-medical reasons (N = 5)
  • Dose reductions occurred in 10 patients in total, 1 in the 45 mg/m2 cohort (4%) and 9 in the 56 mg/m2 cohort (19%)

Other studies, such as IFM 2005-01 (NCT00200681) and SWOG S0777 (NCT00644228), evaluating doublet regimens as induction therapy in patients with NDMM have published promising ORR and VGPR rates. However, this study of Kd as induction therapy reports higher a ORR and VGPR rate, indicating it may be a favorable regimen.4,5 The EVOLUTION study (NCT00507442), investigating a triplet regimen of bortezomib/lenalidomide/dexamethasone (VRD) also looks encouraging in the NDMM setting, validating that studies comparing VRD to Kd may be worthwhile.6

The safety profile of Kd in patients with NDMM appears manageable with most AEs being grade I/II. There was a notably low rate of hematologic AEs; therefore it may prove particularly suitable in patients with cytopenias at diagnosis. CVAEs are the main concern with carfilzomib treatment and in this study, hypertension was the most common CVAE. Carfilzomib also appeared to have a stem cell mobilizing effect, indicating it is acceptable in the transplant-eligible population.

In conclusion, Kd may represent a new two-drug induction therapy for patients with NDMM. Further studies are warranted comparing this two-drug induction to other doublet and triplet regimens containing novel agents and in different patient populations.

References
  1. Palumbo A. et al. International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Onc. 2014 Jan 13. DOI: 10.1200/JCO.2013.48.7934
  2. Dimopoulos M.A., et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016 Dec 05. DOI: 10.1016/S1470-2045(15)00464-7
  3. Forsberg P.A. et al. Phase II study of carfilzomib and dexamethasone (Kd) therapy for newly diagnosed multiple myeloma. Am J Hemat. 2019 Feb 10. DOI: 10.1002/ajh.25435
  4. Harousseau J-L. et al. Bortezomib Plus Dexamethasone Is Superior to Vincristine Plus Doxorubicin Plus Dexamethasone As Induction Treatment Prior to Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: Results of the IFM 2005-01 Phase III Trial. J Clin Onc. 2010 Sep 07. DOI: 10.1200/JCO.2009.27.9158
  5. Durie B.G.M. et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2016 Dec 22. DOI: 10.1016/S0140-6736(16)31594-X
  6. Kumar S. et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10. DOI: 10.1182/blood-2011-11-395749
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