Gomez-Arteaga A, et al. ASH 2017:4546

A phase II study of a novel conditioning regimen of bendamustine and melphalan followed by ASCT for patients with MM

Background

In a phase I trial by Gomez-Arteaga and colleagues, the addition of bendamustine to high-dose melphalan (200 mg/m2; MEL200) showed no additional toxicity above what is expected with MEL200 alone.1 At ASH 2017, results from a phase II study with bendamustine and MEL200 followed by autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM) were presented.2

Study design

  • This was a phase II, single arm, open-label study.
  • Patients were conditioned with bendamustine at 125 mg/m2 on Day –2 and 100 mg/m2 on Day –1 in combination with MEL200, prior to ASCT.
  • Maintenance therapy was allowed at the discretion of the treating physician.
  • Eligibility criteria included:
  • Patients 18–75 years old with MM considering transplant as initial consolidation or for recurrent/refractory disease;
  • Adequate mobilization (at least 2 x 106 of cluster of differentiation 34-positive hematopoietic stem cells); and
  • Karnofsky performance status >70%.
  • Major exclusion criteria included:
  • Uncontrolled comorbidities; and
  • Previous ASCT.
  • The primary objective was to determine the efficacy of the conditioning regimen.

Key findings

Baseline characteristics and disposition

  • A total of 35 patients were included in the study, with a median age of 61 years (range: 41–75).
  • Forty-six percent of the patients were male.
  • The majority of the patients had a 90%–100% Karnofsky performance status (77%) and standard cytogenetic risk (89%).
  • Most patients (54%) had one prior line of therapy, with 29% having two prior lines and 17% having three or four prior lines.
  • The majority of the patients had prior exposure to lenalidomide (91%) or bortezomib (80%).
  • The median follow-up of living patients after ASCT was 56 months (range: 4–78).

Efficacy

  • The overall response rates (ORRs) based on status of disease prior to ASCT and median progression-free survival (PFS) are presented in Table 1.
  • The ORR by Day +100 was 94%, of which 51% were complete responses (CRs; 10 patients) or stringent complete responses (sCRs; 8 patients).
    • Eleven of the 18 patients who achieved a CR or sCR were tested by multiparametric flow, which showed minimal residual disease negativity in three patients and positivity in the remaining eight.
  • The maximum combined sCR and CR rate by Day +100 was 54%, as one additional patient achieved a CR during maintenance therapy (seven months after ASCT).
  • After a median follow-up of 56 months (range: 4–78), 20 patients (57%) exhibited disease progression.
    • Of the patients who progressed, one patient demonstrated progression before Day +100, another before Day +180, and a total of five died.
  • The three-year overall survival and PFS were 91% (95% CI: 75.1–97.1) and 65% (95% CI: 45–79; median = 40 months), respectively. (Figure 1)
  • Maintenance therapy was administered in 20 patients (63%).
  • PFS was significantly impacted by the use of maintenance therapy (HR = 0.16; p = 0.004) and response to therapy prior to ASCT.
    • There was a significant improvement in median PFS with the use of maintenance (48 months vs. 14 months), of which the most common regimen was lenalidomide (85%).

Table 1. ORRs based on status of disease prior to ASCT and median PFS

Figure 1. Kaplan-Meier estimates by outcome

Safety

  • The grade 3 treatment-related adverse events (TRAEs) that occurred in at least two subjects and any grade 4 TRAEs are shown in Table 2.
  • The most common grade 3 TRAEs were febrile neutropenia (46%), hypocalcemia (34%), and hypokalemia (20%).
  • There was no transplant-related mortality.
  • A grade 4 TRAE (hyperbilirubinemia) occurred in one patient, and was associated with the use of antibiotics.

Table 2. Incidence of TRAEs in at least two subjects

Key conclusions

  • A combined conditioning regimen with bendamustine and standard dose MEL200 showed promising efficacy and can safely be used for ASCT in a diverse patient population with MM, including patients who had failed multiple lines of treatment and/or were chemorefractory.
  • Further evaluation of this conditioning regimen should include a phase III comparison trial with single agent MEL200, as well as newer induction approaches and standard maintenance therapies.
  • In the future, the role of this conditioning strategy should be examined in patients with MRD positivity after induction, poor cytogenics, and who have received ASCT as salvage therapy.

References 1. Mark TM, Reid W, Niesvizky R, et al. A phase 1 study of bendamustine and melphalan conditioning for autologous stem cell transplantation in multiple myeloma. Biol Blood Marrow Transplant 2013;19(5):831–7. 2. Gomez-Arteaga A, Mark TM, Guarneri D, et al. A phase II study of a novel conditioning regimen of bendamustine and melphalan followed by autologous stem cell transplant for patients with multiple myeloma. ASH Annual Meeting Abstracts 2017:4546.