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Safety and efficacy of bortezomib and melphalan combination in patients with relapsed or refractory multiple myeloma: updated results of a phase 1/2 study after longer follow-up

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Abstract

Bortezomib synergizes with melphalan in preclinical and early clinical studies. Updated data from our phase 1/2 study assessing the safety and efficacy of bortezomib plus melphalan in relapsed/refractory multiple myeloma (MM) are presented. Bortezomib (0.7, 1.0, or 1.3 mg/m2) on days 1, 4, 8, and 11 and oral melphalan (0.025–0.25 mg/kg) on days 1–4 of a 28-day cycle were administered. Hematologic toxicities defined the maximum tolerated dose as bortezomib 1.0 mg/m2 and melphalan 0.10 mg/kg. Because dose-limiting toxicities were attributed to the more myelosuppressive melphalan, cohorts 9 and 10 with higher bortezomib (1.3 mg/m2) and lower melphalan (0.025 and 0.10 mg/kg) doses were added. Responses occurred in 32/46 (70%) evaluable patients: two complete (4%), five near-complete (11%), 16 partial (35%), and nine minimal (20%). Complete and near-complete responses were observed only with higher bortezomib doses. Response rates were similar in patients with prior melphalan or bortezomib. Median progression-free survival was 9 months (range, 1–24), and overall survival was 32 months (range, 1–54). The most common grade 3/4 hematologic adverse events (AEs) were neutropenia (31%/0%), thrombocytopenia (25%/2%), and anemia (13%/0%). Grade 4 tumor lysis syndrome was reported in one patient. Fewer grade 3/4 hematologic AEs were reported in cohorts 9 and 10 than in cohorts receiving lower bortezomib and higher melphalan doses. In conclusion, bortezomib plus melphalan is a steroid- and immunomodulatory drug-free regimen that may provide a treatment alternative for elderly patients and patients with significant comorbidity.

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Acknowledgments

The authors thank Ingrid Koo, PhD, and Bless Castro, PhD, of Helix Medical Communications LLC for providing medical writing support on behalf of Millennium Pharmaceuticals.

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Authors and Affiliations

  1. Institute for Myeloma and Bone Cancer Research, 9201 Sunset Blvd, Suite 300, West Hollywood, CA, 90069, USA

    James R. Berenson

  2. Pacific Shores Medical Group, Glendale, CA, USA

    Hank H. Yang

  3. Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Robert A. Vescio & Youram Nassir

  4. Nassir Medical Corporation, Los Angeles, CA, USA

    Youram Nassir

  5. Venn5 BioConsulting, Laguna Hills, CA, USA

    Blake Morrison

  6. Millennium Pharmaceuticals, Inc., Cambridge, MA, USA

    Jacqueline Hilger

  7. Oncotherapeutics, West Hollywood, CA, USA

    James R. Berenson & Ori Yellin

  8. James R. Berenson, M.D., Inc., West Hollywood, CA, USA

    James R. Berenson, Russell Mapes, Shi-pyng Lee, Joanna Wilson & Regina Swift

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  1. James R. Berenson
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Correspondence to James R. Berenson.

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Berenson, J.R., Yang, H.H., Vescio, R.A. et al. Safety and efficacy of bortezomib and melphalan combination in patients with relapsed or refractory multiple myeloma: updated results of a phase 1/2 study after longer follow-up. Ann Hematol 87, 623–631 (2008). https://doi.org/10.1007/s00277-008-0501-0

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