Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma.

This phase 1/2 study is the first prospective evaluation of lenalidomide-bortezomib-dexamethasone in front-line myeloma. Patients (N = 66) received 3-week cycles (n = 8) of bortezomib 1.0 or 1.3 mg/m(2) (days 1, 4, 8, 11), lenalidomide 15 to 25 mg (days 1-14), and dexamethasone 40 or 20 mg (days 1, 2, 4, 5, 8, 9, 11, 12). Responding patients proceeded to maintenance or transplantation. Phase 2 dosing was determined to be bortezomib 1.3 mg/m(2), lenalidomide 25 mg, and dexamethasone 20 mg. Most common toxicities included sensory neuropathy (80%) and fatigue (64%), with only 27%/2% and 32%/3% grade 2/3, respectively. In addition, 32% reported neuropathic pain (11%/3%, grade 2/3). Grade 3/4 hematologic toxicities included lymphopenia (14%), neutropenia (9%), and thrombocytopenia (6%). Thrombosis was rare (6% overall), and no treatment-related mortality was observed. Rate of partial response was 100% in both the phase 2 population and overall, with 74% and 67% each achieving very good partial response or better. Twenty-eight patients (42%) proceeded to undergo transplantation. With median follow-up of 21 months, estimated 18-month progression-free and overall survival for the combination treatment with/without transplantation were 75% and 97%, respectively. Lenalidomide-bortezomib-dexamethasone demonstrates favorable tolerability and is highly effective in the treatment of newly diagnosed myeloma. This study is registered at http://clinicaltrials.gov as NCT00378105.

[1]  F. Zhan,et al.  Low venous thromboembolic risk with bortezomib in multiple myeloma and potential protective effect with thalidomide/lenalidomide-based therapy: review of data from phase 3 trials and studies of novel combination regimens. , 2011, Clinical lymphoma, myeloma & leukemia.

[2]  Michael L. Wang,et al.  Rapid control of previously untreated multiple myeloma with bortezomib–lenalidomide–dexamethasone (BLD) , 2010, Hematology.

[3]  D. Esseltine,et al.  Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  M. Boccadoro,et al.  Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) Followed by Maintenance with Bortezomib and Thalidomide for Initial Treatment of Elderly Multiple Myeloma Patients. , 2009 .

[5]  M. Dimopoulos,et al.  Combined Vorinostat, Lenalidomide and Dexamethasone Therapy in Patients with Relapsed or Refractory Multiple Myeloma: A Phase I Study. , 2009 .

[6]  S. Jagannath,et al.  Tanespimycin + Bortezomib in Relapsed/Refractory Myeloma Patients: Results From the Time-2 Study. , 2009 .

[7]  A. Krishnan,et al.  Tanespimycin + Bortezomib Demonstrates Safety, Activity, and Effective Target Inhibition in Relapsed/Refractory Myeloma Patients: Updated Results of a Phase 1/2 Study. , 2009 .

[8]  M. Terol,et al.  Thalidomide / Dexamethasone (TD) Vs. Bortezomib (Velcade)â/Thalidomide / Dexamethasone (VTD) Vs. VBMCP/VBAD/Velcadeâ as Induction Regimens Prior Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma (MM): Results of a Phase III PETHEMA/GEM Trial. , 2009 .

[9]  P. Wen,et al.  Bortezomib-Associated Peripheral Neuropathy: Relationship Between Clinical Neurophysiologic Evidence in Previously Untreated Multiple Myeloma Patients and Preclinical Characterization in a Mouse Model. , 2009 .

[10]  F. Zhan,et al.  Bortezomib Does Not Increase Thromboembolic Risk in Multiple Myeloma and May Offer a Protective Effect with Thalidomide/Lenalidomide-Based Therapy: Review of Data From Phase 3 Trials and Studies of Novel Combination Regimens. , 2009 .

[11]  I. Flinn,et al.  Novel Three– and Four–Drug Combinations of Bortezomib, Dexamethasone, Cyclophosphamide, and Lenalidomide, for Newly Diagnosed Multiple Myeloma: Encouraging Results From the Multi-Center, Randomized, Phase 2 EVOLUTION Study. , 2009 .

[12]  P. Moreau,et al.  High Complete and Very Good Partial Response Rates with Bortezomib—Dexamethasone as Induction Prior to ASCT in Newly Diagnosed Patients with High-Risk Myeloma: Results of the IFM2005-01 Phase 3 Trial. , 2009 .

[13]  M. Dimopoulos,et al.  Update On the Phase IIb, Open-Label Study of Vorinostat in Combination with Bortezomib in Patients with Relapsed and Refractory Multiple Myeloma. , 2009 .

[14]  M. Kaminski,et al.  Lenalidomide, Bortezomib, Pegylated Liposomal Doxorubicin, and Dexamethasone In Newly Diagnosed Multiple Myeloma (MM): Final Results of Phase I/II MMRC Trial , 2009 .

[15]  H. Avet-Loiseau,et al.  The role of complete response in multiple myeloma. , 2009, Blood.

[16]  D. Esseltine,et al.  Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  D. Esseltine,et al.  Lenalidomide, bortezomib, and dexamethasone in relapsed/refractory multiple myeloma (MM): Encouraging outcomes and tolerability in a phase II study. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  D. Esseltine,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 , 2009, British journal of haematology.

[19]  M. Dimopoulos,et al.  Improved survival of patients with multiple myeloma after the introduction of novel agents and the applicability of the International Staging System (ISS): an analysis of the Greek Myeloma Study Group (GMSG) , 2009, Leukemia.

[20]  I. Flinn,et al.  A247 Bortezomib, Dexamethasone, Cyclophosphamide, Lenalidomide (VDCR) Has High Efficacy in First-Line MM , 2009 .

[21]  M. Kersten,et al.  First Analysis of HOVON-65/GMMG-HD4 Randomized Phase III Trial Comparing Bortezomib, Adriamycine, Dexamethasone (PAD) Vs VAD as Induction Treatment Prior to High Dose Melphalan (HDM) in Patients with Newly Diagnosed Multiple Myeloma (MM) , 2008 .

[22]  Kenneth C. Anderson,et al.  A Phase IB, Multi-Center, Open-Label Dose-Escalation Study of Oral Panobinostat (LBH589) and I.V. Bortezomib in Patients with Relapsed Multiple Myeloma. , 2008 .

[23]  M. Terol,et al.  Thalidomide/Dexamethasone (TD) Vs. Bortezomib(Velcade®)/Thalidomide/Dexamethasone (VTD) Vs. VBMCP/VBAD/Velcade® As Induction Regimens Prior Autologous Stem Cell Transplantation (ASCT) in Younger Patients with Multiple Myeloma (MM): First Results of a Prospective Phase III PETHEMA/Gem Trial , 2008 .

[24]  D. Esseltine,et al.  Characterisation of haematological profiles and low risk of thromboembolic events with bortezomib in patients with relapsed multiple myeloma , 2008, British journal of haematology.

[25]  Bin Jiang,et al.  Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. , 2008, The New England journal of medicine.

[26]  J. Crowley,et al.  A randomized Southwest Oncology Group study comparing dexamethasone (D) to lenalidomide + dexamethasone (LD) as treatment of newly-diagnosed multiple myeloma (NDMM): Impact of cytogenetic abnormalities on efficacy of LD, and updated overall study results , 2008 .

[27]  P. Moreau,et al.  Bortezomib/dexamethasone versus VAD as induction prior to autologous stem cell transplantion (ASCT) in previously untreated multiple myeloma (MM): Updated data from IFM 2005/01 trial , 2008 .

[28]  M. Lacy,et al.  Thromboembolic events with lenalidomide‐based therapy for multiple myeloma , 2008, Cancer.

[29]  D. Dingli,et al.  Improved survival in multiple myeloma and the impact of novel therapies. , 2008, Blood.

[30]  N. Schmitz,et al.  Reduced-intensity conditioning compared with conventional allogeneic stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  Alessandro Corso,et al.  Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. , 2007, The New England journal of medicine.

[32]  Michael Wang,et al.  Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. , 2007, The New England journal of medicine.

[33]  H. van de Velde,et al.  Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma , 2007, Haematologica.

[34]  P. L. Bergsagel,et al.  Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. , 2007, Mayo Clinic proceedings.

[35]  R. Bataille,et al.  Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. , 2007, Blood.

[36]  J. Leonard,et al.  Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide or lenalidomide in myeloma , 2007, Leukemia & lymphoma.

[37]  B. Barlogie,et al.  International uniform response criteria for multiple myeloma , 2006, Leukemia.

[38]  John Crowley,et al.  Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone: benefit of aspirin prophylaxis. , 2006, Blood.

[39]  Robert A Kyle,et al.  Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. , 2005, Blood.

[40]  Hartmut Goldschmidt,et al.  Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. , 2005, The New England journal of medicine.

[41]  D. Collet.  Modelling Survival Data in Medical Research , 2004 .

[42]  Bart Barlogie,et al.  A phase 2 study of bortezomib in relapsed, refractory myeloma. , 2003, The New England journal of medicine.

[43]  T. Libermann,et al.  Molecular sequelae of proteasome inhibition in human multiple myeloma cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[44]  N. Munshi,et al.  Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. , 2002, Blood.

[45]  P. Elliott,et al.  The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. , 2001, Cancer research.

[46]  S. Jagannath,et al.  CRITERIA FOR EVALUATING DISEASE RESPONSE AND PROGRESSION IN PATIENTS WITH MULTIPLE MYELOMA TREATED BY HIGH‐DOSE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION , 1998, British journal of haematology.

[47]  R. Fonseca,et al.  Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. , 2010, The Lancet. Oncology.

[48]  A. Palumbo,et al.  Treatment of newly diagnosed myeloma , 2009, Leukemia.

[49]  B. Pégourié,et al.  Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study. , 2006, Haematologica.

[50]  D. Collett.  Modelling survival data , 1994 .