Once- versus twice-weekly Bortezomib induction therapy with dexamethasone in newly diagnosed multiple myeloma

Abstract

In this study, we administered a modified schedule of weekly intravenous Bortezomib at 1.6 mg/m² with dexamethasone (BD) and compared it to the standard 1.3 mg/m² twice-weekly BD regimen in Chinese patients with newly diagnosed multiple myeloma (MM). We assessed the difference in efficacy, safety profile and survival between the once-weekly and twice-weekly cohorts (13 vs. 24 patients). The over response rate was similar with both arms of the study, being 77% in the once-weekly schedule and 74.9% in the twice-weekly schedule (P=0.690). The median overall survival was not reached in either schedule. Also, the median progression-free survival and duration of response of the once-weekly schedule did not significantly differ from those of the twice-weekly schedule (8 months vs.10 months, P=0.545 and 6 months vs.7 months, P=0.467 respectively). Peripheral sensory neuropathy and grade 3/4 hematologic toxic effects were more frequently reported in the twice-weekly schedule than the once-weekly schedule, but there was no statistically significant difference. This preliminary experience in Chinese patients with newly diagnosed MM indicated that once-weekly infusion of Bortezomib plus dexamethasone may improve safety without affecting outcome.

Keywords

Bortezomib / multiple myeloma / weekly schedule / response rate / adverse event

References

[1] RichardsonP.G., MitsiadesC., HideshimaT., et al.. Bortezomib: proteasome inhibition as an effective anticancer therapy. Annu Rev Med, 2006, 57: 33-47

[2] BirdJ.M., OwenR.G., D’saS., et al.. Guidelines for the diagnosis and management of multiple myeloma 2011. Br J Haematol, 2011, 154(1): 32-75

[3] KyleR.A., RajkumarS.V.. Treatment of multiple myeloma: a comprehensive review. Clin Lymphoma Myeloma, 2009, 9(4): 278-288

[4] HarousseauJ.L., AttalM., Avet-LoiseauH., 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. Clin Oncol, 2010, 28(30): 4621-4629

[5] AndersonK.C., AlsinaM., BensingerW., et al.. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: multiple myeloma. J Natl Compr Canc Netw, 2009, 7(9): 908-942

[6] OffidaniM., CorvattaL., PolloniC., et al.. Thalidomide, dexamethasone, Doxil and Velcade (ThaDD-V) followed by consolidation/maintenance therapy in patients with relapsed-refractory multiple myeloma. Ann Hematol, 2011, 90(12): 1449-1456

[7] San MiguelJ.F., SchlagR., KhuagevaN.K., et al.. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med, 2008, 359(9): 906-917

[8] MateosM.V., RichardsonP.G., SchlagR., et al.. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol, 2010, 28(13): 2259-2266

[9] PopatR., OakerveeH.E., HallamS., et al.. Bortezomib, doxorubicin and dexamethasone (PAD) front-line treatment of multiple myeloma: updated results after long-term followup. Br J Haematol, 2008, 141(4): 512-516

[10] ZhengW., WeiG., YeX., et al.. Bortezomib in combination with dexamethasone and subsequent thalidomide for newly-diagnosed multiple myeloma: A Chinese experience. Leuke Res, 2009, 33(12): 1615-1618

[11] PapandreouC.N., DalianiD.D., NixD., et al.. Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol, 2004, 22(11): 2108-2121

[12] deVosS.. Bortezomib plus rituximab in patients with indolent non-Hodgkin’s lymphoma (NHL): a phase 2 study. Blood ASH Annual Meeting, 2005, 106: 10a

[13] HainsworthJ.D., SpigelD.R., BartonJ., et al.. Weekly treatment with bortezomib for patients with recurrent or refractory multiple myeloma: a phase 2 trial of the Minnie Pearl Cancer Research Network. Cancer, 2008, 113(4): 765-771

[14] DurieB.G., HarousseauJ.L., MiguelJ.S., et al.. International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia, 2006, 20(9): 1467-1473

[15] Cancer Therapy Evaluation Program.. . Common terminology criteria for adverse events v3.0 (CTCAE), 2006, Bethesda, MD, National Cancer Institute

[16] RichardsonP.G., BriembergH., JagannathS., et al.. Frequency, characteristics, and reversibiliy of peripheral neuropathy during Treatment of advanced multiple myeloma with Bortezomib. J Clin Oncol, 2006, 24(19): 3113-3120

[17] AdamsJ., PalombellaV.J., SausvilleE.A., et al.. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res, 1999, 59(11): 2615-2622

[18] GoldbergA.L.. Protein degradation and protection against misfolded or damaged proteins. Nature, 2003, 426(6968): 895-899

[19] OrlowskiR.Z., StinchcombeT.E., MitchellB.S., et al.. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol, 2002, 20(22): 4420-4427

[20] MohtyB., El-CheikhJ., Yakoub-AghaI., et al.. Peripheral neuropathy and new treatments for multiple myeloma: background and practical recommendations. Haematologica, 2010, 95(2): 311-319

[21] RichardsonP.G., SonneveldP., SchusterM.W., et al.. Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline. Br J Haematol, 2009, 144(6): 895-903

[22] SuvannasankhaA., SmithG.G., JuliarB.E., et al.. Weekly bortezomib/methylprednisolone is effective and well tolerated in relapsed multiple myeloma. Clin Lymphoma Myeloma, 2006, 7(2): 131-134

[23] TokuhiraM., WatanabeR., NemotoT., et al.. Successful treatment with a modified bortezomib schedule of weekly and longer intervals for patients with refractory/resistance multiple myeloma. Leuk Res, 2011, 35(5): 591-597

[24] BringhenS., LaroccaA., RossiD., et al.. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood, 2010, 116(23): 4745-4753

[25] Munshi N C, Lee S, Kambhampati S, et al. Interim results of an ongoing clinical study suggests efficacy and improved toxicity profile with once a week bortezomib with dexamethasone in newly diagnosed multiple myeloma patients with older age and co-morbidities. Blood ASH Annual Meeting, 2010,116:Abstract 3061

[26] ArgyriouA.A., IconomouG., KalofonosH.P.. Bortezomib-induced peripheral neuropathy inmultiplemyeloma: a comprehensive review of the literature. Blood, 2008, 112(5): 1593-1599

[27] AgathocleousA., RohatinerA., RuleS., et al.. Weekly versus twice weekly bortezomib given in conjunction with rituximab, in patients with recurrent follicular lymphoma, mantle cell lymphoma and Waldenström macroglobulinaemia. Br J Haematol, 2010, 151(4): 346-353