Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma

P G Richardson, C C Hofmeister, N S Raje, D S Siegel, S Lonial, J Laubach, Y A Efebera, D H Vesole, A K Nooka, J Rosenblatt, D Doss, M H Zaki, A Bensmaine, J Herring, Y Li, L Watkins, M S Chen, K C Anderson, P G Richardson, C C Hofmeister, N S Raje, D S Siegel, S Lonial, J Laubach, Y A Efebera, D H Vesole, A K Nooka, J Rosenblatt, D Doss, M H Zaki, A Bensmaine, J Herring, Y Li, L Watkins, M S Chen, K C Anderson

Abstract

This phase 1 dose-escalation study evaluated pomalidomide, bortezomib (subcutaneous (SC) or intravenous (IV)) and low-dose dexamethasone (LoDEX) in lenalidomide-refractory and proteasome inhibitor-exposed relapsed or relapsed and refractory multiple myeloma (RRMM). In 21-day cycles, patients received pomalidomide (1-4 mg days 1-14), bortezomib (1-1.3 mg/m2 days 1, 4, 8 and 11 for cycles 1-8; days 1 and 8 for cycle ⩾9) and LoDEX. Primary endpoint was to determine the maximum tolerated dose (MTD). Thirty-four patients enrolled: 12 during escalation, 10 in the MTD IV bortezomib cohort and 12 in the MTD SC bortezomib cohort. Patients received a median of 2 prior lines of therapy; 97% bortezomib exposed. With no dose-limiting toxicities, MTD was defined as the maximum planned dose: pomalidomide 4 mg, bortezomib 1.3 mg/m2 and LoDEX. All patients discontinued treatment by data cutoff (2 April 2015). The most common grade 3/4 treatment-emergent adverse events were neutropenia (44%) and thrombocytopenia (26%), which occurred more frequently with IV than SC bortezomib. No grade 3/4 peripheral neuropathy or deep vein thrombosis was reported. Overall response rate was 65%. Median duration of response was 7.4 months. Pomalidomide, bortezomib and LoDEX was well tolerated and effective in lenalidomide-refractory and bortezomib-exposed patients with RRMM.

Trial registration: ClinicalTrials.gov NCT01734928.

Conflict of interest statement

PGR has served on advisory committees for Celgene, Novartis, Millennium and Takeda. CCH, YAE and JR have nothing to disclose. NSR has served as a consultant for Celgene, Takeda, Bristol-Myers Squibb, Amgen, Onyx, Millennium and Novartis and has received research funding from AstraZeneca, Eli Lilly and Acetylon. DSS has served on speakers bureaus for Celgene, Amgen, Takeda, Novartis and Merck. SL has served as a consultant for and received research funding from Celgene, Millennium, Novartis, Bristol-Myers Squibb, Onyx and Janssen. JL has received research funding from Celgene, Onyx, Millennium and Novartis. DHV has served on speakers bureaus for Celgene and has received research funding from Idera Pharmaceuticals. AKN has served as a consultant for Onyx and Spectrum Pharmaceuticals. DD has served on speakers bureaus for Celgene and Takeda. MHZ, YL and MSC are employees of and hold equity ownership in Celgene. AB, JH and LW are employees of Celgene. KCA has served as a consultant for Celgene, Millennium, Bristol-Myers Squibb and Gilead and has equity ownership in Acetylon and Oncocorp.

Figures

Figure 1
Figure 1
MM-005 trial design. MM-005 included 5 dose-escalation cohorts. Three patients were treated at each dose level, and 7 additional patients were treated at the MTD in the expansion phase of the trial. An additional cohort of patients treated with SC bortezomib (BORT) was included (n=12). Patients were evaluated every 21 days until treatment discontinuation. Patients will undergo long-term follow-up for OS and secondary primary malignancies (SPM). *For cycles 1–8, then D1 and D8 for cycle ⩾9. †For cycles 1–8, then D1–2 and D8–9 for cycles ⩾9. ‡10 mg for patients aged >75 years. POM, pomalidomide.
Figure 2
Figure 2
Response outcomes. All treated patients were evaluated for response (better than or equal to PR). TTR and DOR were reported for patients who achieved response. BORT, bortezomib; CR, complete response; sCR, stringent complete response; VGPR, very good PR.

References

    1. Cornell RF, Kassim AA. Evolving paradigms in the treatment of relapsed/refractory multiple myeloma: increased options and increased complexity. Bone Marrow Transplant 2016; 51: 479–491.
    1. Ria R, Reale A, Vacca A. Novel agents and new therapeutic approaches for treatment of multiple myeloma. World J Methodol 2014; 4: 73–90.
    1. Kumar SK, Therneau TM, Gertz MA, Lacy MQ, Dispenzieri A, Rajkumar SV et al. Clinical course of patients with relapsed multiple myeloma. Mayo Clin Proc 2004; 79: 867–874.
    1. Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai Y et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000; 96: 2943–2950.
    1. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002; 99: 4525–4530.
    1. Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010; 116: 679–686.
    1. Richardson PG, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje NS et al. A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood 2014; 123: 1461–1469.
    1. Durie BGM, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP et al. Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone induction followed by lenalidomide and dexamethasone maintenance in patients with newly diagnosed myeloma without intent for immediate autologous stem cell transplant: results of the randomised phase III SWOG trial S0777. Lancet 2016; 389: 519–527.
    1. Quach H, Ritchie D, Stewart AK, Neeson P, Harrison S, Smyth MJ et al. Mechanism of action of immunomodulatory drugs (IMiDs) in multiple myeloma. Leukemia 2010; 24: 22–32.
    1. Pomalyst (pomalidomide) [package insert]. Celgene Corporation; Summit, NJ, USA, 2016.
    1. Leleu X, Attal M, Arnulf B, Moreau P, Traulle C, Marit G et al. Pomalidomide plus low dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myélome 2009-02. Blood 2013; 121: 1968–1975.
    1. Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood 2014; 123: 1826–1832.
    1. San Miguel J, Weisel K, Moreau P, Lacy M, Song K, Delforge M et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol 2013; 14: 1055–1066.
    1. Palumbo A, Dimopolous MA, Richardson PG, Siegel DS, Cavo M, Corradini P et al. A pooled analysis of the impact of age on outcomes in patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide plus low-dose dexamethasone. The 21st Congress of the European Hematology Association: Copenhagen, Denmark, 9–12, 2016; Poster of abstract E1295.
    1. Leleu X, Karlin L, Macro M, Hulin C, Garderet L, Roussel M et al. Pomalidomide plus low-dose dexamethasone in multiple myeloma with deletion 17p and/or translocation (4;14): IFM 2010-02 trial results. Blood 2015; 125: 1411–1417.
    1. Dimopoulos MA, Weisel KC, Song KW, Delforge M, Karlin L, Goldschmidt H et al. Cytogenetics and long-term survival of pomalidomide and low-dose dexamethasone in refractory or relapsed and refractory multiple myeloma. Haematologica 2015; 100: 1327–1333.
    1. Weisel KC, Dimopoulos MA, Moreau P, Lacy MQ, Song KW, Delforge M et al. Analysis of renal impairment in MM-003, a phase 3 study of pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in refractory or relapsed and refractory multiple myeloma. Haematologica 2016; 101: 872–878.
    1. Siegel DS, Weisel KC, Dimopoulos MA, Baz R, Richardson P, Delforge M et al. Pomalidomide plus low-dose dexamethasone in patients with relapsed/refractory multiple myeloma and moderate renal impairment: a pooled analysis of three clinical trials. Leuk Lymphoma 2016; 57: 2833–2838.
    1. Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 2011; 12: 431–440.
    1. Imnovid (pomalidomide) [summary of product characteristics]. Celgene Europe; Uxbridge, UK, 2016.
    1. Velcade (bortezomib) for injection [package insert]. Millennium Pharmaceuticals; Cambridge, MA, USA, 2015.
    1. Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20: 1467–1473.
    1. Revlimid (lenalidomide) [package insert]. Celgene Corporation; Summit, NJ, USA, 2015.
    1. Thalomid (thalidomide) [package insert]. Celgene Corporation; Summit, NJ, USA, 2015.
    1. Zou Y, Ma X, Yu H, Hu C, Fan L, Ran X. Carfilzomib/pomalidomide single-agent or in combination with other agents for the management of relapsed/refractory multiple myeloma : a meta-analysis of 37 trials. Oncotarget 2017; 8: 39805–39817.
    1. Voorhees PM, Mulkey F, Hassoun H, Paba-Prada CE, Efebera YA, Hoke E et al. Alliance A061202. A phase I/II study of pomalidomide, dexamethasone and ixazomib versus pomalidomide and dexamethasone for patients with multiple myeloma refractory to lenalidomide and proteasome inhibitor based therapy: phase I results. Blood 2015; 126: Abstract 375.
    1. Shah J, Niesvizky R, Stadtmauer E, Rifkin RM, Berenson J, Berdeja JG et al. Oprozomib, pomalidomide, and dexamethasone (OPomd) in patients (pts) with relapsed and/or refractory multiple myeloma (RRMM): initial results of a phase 1b study (NCT01999335). Blood 2015; 126: Abstract 378.
    1. Shah JJ, Stadtmauer EA, Abonour R, Cohen AD, Bensinger WI, Gasparetto C et al. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood 2015; 126: 2284–2290.
    1. Lacy MQ, LaPlant BR, Laumann KM, Kumar S, Gertz MA, Hayman SR et al. Pomalidomide, bortezomib and dexamethasone (PVD) for patients with relapsed lenalidomide refractory multiple myeloma (MM). Blood 2014; 124: Abstract 304.
    1. Krishnan A, Kapoor P, Palmer J, Tsai N, Kumar S, Lonial S et al. A phase I/II study of ixazomib (Ix) pomalidomide (POM) dexamethasone (DEX) in relapsed refractory (R/R) multiple myeloma: initial results. J Clin Oncol 2016; 34: Abstract 8008.
    1. Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ et al. Randomized multicenter phase II study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood 2016; 127: 2561–2568.
    1. Chari A, Cho HJ, Lau K, Morgan G, Florendo E, Catamero D et al. A phase II study of pomalidomide, daily low dose oral cyclophosphamide, and dexamethasone in relapsed/refractory multiple myeloma. American Society of Hematology 58th Annual Meeting and Exposition: San Diego, CA, USA, December 3–62016; Poster of abstract 4520.
    1. Chari A, Lonial S, Suvannasankha A, Fay JW, Arnulf B, Ifthikharuddin JJ et al. Open-label, multicenter, phase 1b study of daratumumab in combination with pomalidomide and dexamethasone in patients with at least 2 lines of prior therapy and relapsed or relapsed and refractory multiple myeloma. Blood 2015; 126: Abstract 508.
    1. Badros AZ, Kocoglu MH, Ma N, Rapoport AP, Lederer E, Philip S et al. A phase II study of anti PD-1 antibody pembrolizumab, pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Blood 2015; 126: Abstract 506.
    1. Niesvizky R, Richardson PG, Yee AJ, Nooka AK, Raab MS, Shain KH et al. Selective HDAC6 inhibitor ACY-241, and oral tablet, combined with pomalidomide and dexamethasone: safety and efficacy of escalation and expansion cohorts in patients with relapsed or relapsed-and-refractory multiple myeloma (ACE-MM-200 study). American Society of Hematology 58th Annual Meeting and Exposition: San Diego, CA, USA, December 3–62016; Poster of abstract 3307.
    1. Kaufman JL, Fabre C, Lonial S, Richardson PG. Histone deacetylase inhibitors in multiple myeloma: rationale and evidence for their use in combination therapy. Clin Lymphoma Myeloma Leuk 2013; 13: 370–376.
    1. Laubach JP, Voorhees PM, Hassoun H, Jakubowiak A, Lonial S, Richardson PG. Current strategies for treatment of relapsed/refractory multiple myeloma. Expert Rev Hematol 2014; 7: 97–111.
    1. Laubach JP, Paba Prada CE, Richardson PG, Longo DL. Daratumumab, elotuzumab, and the development of therapeutic monoclonal antibodies in multiple myeloma. Clin Pharmacol Ther 2017; 101: 81–88.

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