Carfilzomib, bendamustine, and dexamethasone (CBD) combination for patients with newly diagnosed multiple myeloma

Combinations of proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs®) are standard of care treatment for patients with newly diagnosed multiple myeloma (NDMM) in the United States. However, in order to save IMiDs for use at relapse, PIs can also be combined with alkylating agents.¹ Bendamustine (B) is a bifunctional alkylating agent that has been demonstrated to be safe and effective as frontline therapy, in combination with bortezomib and prednisone.²

In this single-arm, single-center phase I/II study (NCT02002598)¹, the authors tested the efficacy and safety of the combination of carfilzomib (C), a second-generation, irreversible PI with promising activity as frontline treatment³, with B and dexamethasone (D; CBD) in patients with NDMM.¹

Study design and patient characteristics¹

• The trial enrolled 20 patients ≥ 18 years old with measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0–2, and adequate renal, cardiac, and hepatic function
  • The trial aimed to enroll 34 patients, but due to slow accrual and loss of funding, the trial was closed once 20 patients had been enrolled
• The agents were given intravenously:
  • C: all patients received 20 mg/m² on Days 1 and 2 of Cycle 1, which was escalated to 27 mg/m² for the first patient, 36 mg/m² for the second and third patient, 45 mg/m² for the fourth patient and 56 mg/m² for the fifth patient and beyond, administered on Days 1, 2, 8, 9, 15, and 16
  • B: 70 mg/m², escalated to 90 mg/m² from the third patient onward, on Days 1 and 2
  • D: 20 mg, on Days 1, 2, 8, 9, 15, 16, 22, and 23
• Autologous stem cell transplant (SCT):
  • This study included both transplant eligible and ineligible patients
  • Transplant eligible patients received four cycles of CBD, underwent stem cell harvest, and four further cycles of CBD before undergoing ASCT
  • Transplant ineligible patients received eight cycles of CBD
• The recommended maintenance dose of carfilzomib was 36 mg/m², which was given on Days 1, 2, 15, and 16 for up to two years. The protocol was subsequently amended to allow for alternative maintenance therapies, such as lenalidomide
• Each cycle was 28 days and only patients who received ≥ 2 cycles of treatment were evaluated for response
• Primary endpoint: define the maximum tolerated dose (MTD; the highest dose at which ≤ 20% of patients experience dose-limiting toxicity [DLT])
• Secondary endpoints: overall response rate (ORR), time to response, progression-free survival (PFS), overall survival (OS), and toxicity
• Data cut-off: March 1, 2019
• The median age was 65 years (range, 48–74); one patient (5%) had high-risk cytogenetics and seven (35%) were Hispanic
• All patients were evaluable for safety; 19 were evaluable for response
• For maintenance, ten of 19 (53%) received carfilzomib, five lenalidomide, two were lost to follow-up, and two declined

Results¹

• Duration on study treatment was 9.7 months (range, 6.5–36)
• Sixteen patients completed eight cycles
  • Four discontinued early due to Grade 3 neutropenia, prolonged Grade 2–3 thrombocytopenia, Grade 2 fatigue, and Grade 3 acute transaminitis
• Of patients evaluable for response (n = 19), 15 were eligible for SCT. Thirteen proceeded to SCT, with two declining
• None of the patients discontinued study treatment due to disease progression
• No DLT was observed
• The MTD was C: 56 mg/m²; B: 90 mg/m²; D: 40 mg

Safety

The most common severe treatment-related adverse events (AEs) were hematologic:

• Grade 3/4
  • Lymphocytopenia: 90%
  • Neutropenia: 40%
  • Thrombocytopenia: 20%
• Grade 3
  • Anemia: 20%

Non-hematologic AEs were

• Grade 3/4 infection: 20%
• Grade 1/2 acute kidney injury: 45%
• Grade 1/2 diarrhea: 40%

Efficacy

The ORR was 100%. The best responses were

• Two (11%) partial responses (PR)
• Five (26%) very good partial responses (VGPR)
• Twelve (63%) confirmed complete responses (CR)
  • Of the CRs, five were measurable residual disease (MRD) negative

The median time to PR was 2.1 months and to VGPR was 6.5 months. With a median follow-up of 28 months (range, 11–71), two patients have progressed and two have died. The median PFS was 56 months, and median OS has not been reached.

Conclusion¹

• CBD represents a good option for patients with NDMM and allows IMiDs to be saved for use in relapse
• CBD is a tolerable and effective induction regimen with promising anti-myeloma activity
• Reducing the number of cycles of CBD may reduce the cumulative toxicity that led to four patients discontinuing treatment before the planned eight cycles of induction
• Once weekly carfilzomib dosing may also represent an option for adapting this regimen
• The small sample size and lack of high cytogenetic risk patients represent limitations of the study