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.
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Introduction
The introduction of immunomodulatory agents and proteasome inhibitors (PIs) has transformed multiple myeloma (MM) therapy over the past decades, with significant improvement in response rates, progression-free survival (PFS) and overall survival (OS).1, 2 However, relapse is inevitable in almost all patients, and recurrence of MM is typically more aggressive with each subsequent relapse, justifying the development of new combinations mainly in MM-refractory disease.3
In preclinical studies, the immunomodulatory agents thalidomide and lenalidomide were each shown to potentiate the activity of bortezomib in combination with dexamethasone.4, 5 Results from clinical studies confirmed the antimyeloma activity of the combination of lenalidomide and bortezomib in patients with MM.6, Table 1).
Of the study patients, 59 were male and 56 and 44% had an Eastern Cooperative Oncology Group performance status of 0 and 1, respectively (Table 1). Median patient age was 58.5 years (range, 36–76 years). The median time from initial diagnosis was 3.4 years (range, 0.7–12.1 years); in the MTD groups with IV bortezomib and MTD groups with SC bortezomib, it was 4.2 years (range, 1.5–8.2 years) and 2.0 years (range, 0.7–9.1 years), respectively. All patients were refractory to lenalidomide, and all were exposed to a prior PI (97% bortezomib; 6% ixazomib). All patients had progressive disease after the last myeloma regimen, and the majority (91.2%) had progressed ⩽60 days after the last regimen. Twenty-three patients (68%) underwent prior stem cell transplant (SCT). The median number of prior lines of antimyeloma therapy received was 2 (range, 1–4). Compared with the IV bortezomib cohort, fewer patients in the SC bortezomib cohort received ⩾2 prior lines of antimyeloma treatment and prior transplant. At screening, 14 patients had peripheral sensory neuropathy, 11 of whom had a grade 1 event.
At the time of data cutoff (2 April 2015), all patients had discontinued study treatment (Table 2). The most common reason for treatment discontinuation was PD in 22 patients (65%): 9 (75%) in the dose-escalation cohort and 6 (60%) and 7 (58%) in the MTD cohorts with IV and SC bortezomib, respectively. One patient discontinued pomalidomide treatment due to metastatic pancreatic cancer diagnosed 1.1 months after study treatment initiation, and 3 patients discontinued because they went on to receive SCT. As of November 2016, 13 patients are in long-term follow-up.
Treatment exposure and safety
The median duration of treatment was 6.2 months (range, 1.2–27.6 months), and the median number of treatment cycles received was 9 (range, 2–36) for all treated patients (Table 3). Patients in the MTD IV bortezomib cohort received a median of 11 (range, 2–19) and patients in the MTD SC bortezomib cohort received a median of 8 (range, 3–15) cycles of treatment. The median relative dose intensity was 0.9 for pomalidomide throughout the study and 0.9 for bortezomib during the first 8 cycles of treatment. The incidences of dose interruptions and reductions due to TEAEs were 79 and 38% for pomalidomide and 74 and 44% for bortezomib, respectively. The number of dose interruptions was similar regardless of method of bortezomib administration. However, the number of reductions of pomalidomide and bortezomib dose due to TEAEs was slightly less frequent in the IV (40 and 30%, respectively) vs SC (50 and 58%, respectively) bortezomib cohort. Neutropenia was the most common TEAE leading to pomalidomide dose reductions (9%). Infections (47%), neutropenia (26%), pneumonia (9%), peripheral sensory neuropathy (9%), dizziness (9%) and fatigue (9%) were common TEAEs (⩾3 patients) leading to pomalidomide dose interruptions. Peripheral sensory neuropathy (12%) was the most common TEAE (⩾3 patients) leading to bortezomib dose reductions, whereas interruptions were primarily due to infections (44%), neutropenia (21%), pneumonia (12%) and fatigue (9%).
All of the 34 patients included in the safety population had ⩾1 TEAE; 29 (85%) had ⩾1 grade 3/4 TEAE (Table 4). Neutropenia and thrombocytopenia were the most common grade 3/4 TEAEs. The incidence of these events was higher in the IV bortezomib cohort (80 and 40%, respectively) compared with the SC bortezomib cohort (25 and 17%, respectively). Eighteen patients (53%) had treatment-emergent peripheral neuropathy, with 6 out of 12 (50%) in the escalation cohort, 3 out of 10 (30%) in the IV bortezomib cohort and 9 out of 12 (75%) in the SC bortezomib cohort; none of the events were grade 3/4. Treatment-emergent deep vein thrombosis was uncommon (6%); no patients experienced a grade 3/4 event. One death occurred during treatment cycle 3 as a result of cardiac arrest unrelated to study drugs.
Efficacy
All 34 patients were evaluable for tumor response (Figure 2). Disease control with at least stable disease was reported for all patients. The ORR (better than or equal to PR) for all treated patients was 65%. One patient in the MTD IV bortezomib cohort had a stringent complete response (sCR) and 2 patients in the MTD SC bortezomib cohort had a CR. Patients with sCR/CR received 1 or 2 prior lines of therapy (Table 5). ORR was 59% for all patients treated at the MTD: 70 and 50% in the IV and SC bortezomib cohorts, respectively. For all responding patients (n=22), the median TTR was 1.0 months (range, 0.7–5.1 months) and the median DOR was 7.4 months (95% CI, 4.4–9.6 months). This was similar for the patients treated at the MTD: median TTR of 0.9 months (range, 0.7–3.1 months) and median DOR of 7.4 months (95% CI, 4.1-not estimable).
Discussion
Preclinical and clinical studies have proven the clinical benefit of combination therapy with an immunomodulatory agent and a PI for the treatment of patients with RRMM.4, 5, 6, 7 In this phase 1 trial, we demonstrated that triple therapy with pomalidomide, bortezomib and LoDEX was highly active, resulting in an ORR of 65% and disease control in 100%, despite all patients being refractory to lenalidomide and nearly all having prior exposure to bortezomib. Responses were durable, lasting a median of 7.4 months. The MTD of the combination regimen was established at the MPD of pomalidomide 4 mg, IV or SC bortezomib 1.3 mg/m2 and LoDEX 20 mg (10 mg for patients aged >75 years). At this therapeutic dose level, 3 patients achieved sCR/CR.
The regimen of pomalidomide, bortezomib and LoDEX was well tolerated, and toxicities proved manageable, regardless of mode of bortezomib administration. Patients were able to receive a median of 9 cycles of therapy, and no patients discontinued treatment due to a treatment-related event. The incidences of dose interruptions and reductions for pomalidomide and bortezomib were consistent with those of prior studies.13, 19 There were also no reports of grade 3/4 peripheral neuropathy, deep vein thrombosis or other toxicities sometimes associated with immunomodulatory agents and/or PIs.10, 21, 23, 24 Consistent with the findings of the SC vs IV bortezomib phase 3 noninferiority trial, grade 3/4 TEAEs were less frequent with SC vs IV bortezomib administration.19 However, this finding may have been influenced by fewer patients receiving ⩾2 prior lines of antimyeloma treatment and prior transplant in the SC vs IV bortezomib cohorts. Patients in the SC cohort also received fewer cycles of treatment, which may have influenced the incidence of TEAEs. The finding that patients received fewer cycles of SC vs IV bortezomib may be due to the timing of when patients discontinued treatment for SCT; 1 patient in the IV group and 2 patients in the SC group went on to receive SCTs.
In studies of pomalidomide plus LoDEX, approximately one-third of patients with advanced RRMM achieved a tumor response (better than or equal to PR).25 As demonstrated in this trial and others, the addition of PIs to IMiD combinations has the potential to lead to deeper and more durable responses.26, 27, 28, 29, 30 Preliminary results of a phase 1/2 trial of once-weekly bortezomib with pomalidomide and LoDEX demonstrated a response rate of 85, with 19 and 45% of patients achieving sCR/CR and at least very good PR, respectively.29 Responses were durable, lasting a median of 13.7 months. This patient population differed somewhat because <30% of patients had refractory disease and just over one-half had prior exposure to bortezomib. In another phase 1 trial with the PI carfilzomib, given in combination with pomalidomide and LoDEX, the ORR was 50%, with a clinical benefit rate of 66%.28 Similar to data from the phase 1 trial presented here, all patients were refractory to lenalidomide, although the patients were more heavily pretreated (median 6 prior regimens (range, 2–12)) and nearly all were refractory to bortezomib. Results of the phase 1 portion of the Alliance A061202 study of an oral PI, ixazomib, given in combination with pomalidomide and LoDEX, demonstrated an ORR of 55% in patients with RRMM who had received a median of 3 prior lines of therapy (range, 2–10) and who were refractory to lenalidomide and a PI.26
Pomalidomide-based triple therapy combination regimens with other drug classes have also demonstrated high antimyeloma activity in patients with RRMM, including the triple therapy regimens of pomalidomide plus dexamethasone in combination with cyclophosphamide (ORR, 65–67%),31, 32 the monoclonal antibodies anti-CD38 (daratumumab; ORR, 71%)33 and anti–programmed cell death protein 1 (pembrolizumab; ORR, 60%)34 and a histone deacetylase inhibitor (ACY-241; ORR, 46%).35 Taken together, these studies demonstrate the utility of pomalidomide and dexamethasone as a platform for combining novel agents.
In conclusion, the MTD of pomalidomide 4 mg, bortezomib 1.3 mg/m2 and LoDEX 20 mg (10 mg for patients aged >75 years) was well tolerated and highly active in patients with RRMM who were refractory to lenalidomide and had been previously exposed to bortezomib. These findings support further evaluation in clinical trials and suggest that pomalidomide, bortezomib and LoDEX may be an important new treatment option for patients with RRMM. A large randomized, multicenter, international, phase 3 trial, MM-007 (OPTIMISMM), to confirm these findings is currently ongoing and is close to completing enrollment (ClinicalTrials.gov NCT01734928).
Future directions include the addition of other novel agents to this platform, such as the monoclonal antibodies discussed previously, as well as histone deacetylase inhibitors and other promising next-generation small molecules.36, 37, 38
Change history
14 September 2018
Following the publication of this article the authors noted that the pomalidomide dose for the additional SC cohort in Figure 1 was incorrectly listed. The correct dose for pomalidomide in the additional SC cohort should be the maximum tolerated dose of 4 mg/day, not 2 mg/day as listed in the original figure 1. The authors apologize for any inconvenience caused.
References
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.
Ria R, Reale A, Vacca A . Novel agents and new therapeutic approaches for treatment of multiple myeloma. World J Methodol 2014; 4: 73–90.
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.
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.
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.
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.
Richardson PG, **e 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.
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.
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.
Pomalyst (pomalidomide) [package insert]. Celgene Corporation; Summit, NJ, USA, 2016.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Imnovid (pomalidomide) [summary of product characteristics]. Celgene Europe; Uxbridge, UK, 2016.
Velcade (bortezomib) for injection [package insert]. Millennium Pharmaceuticals; Cambridge, MA, USA, 2015.
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.
Revlimid (lenalidomide) [package insert]. Celgene Corporation; Summit, NJ, USA, 2015.
Thalomid (thalidomide) [package insert]. Celgene Corporation; Summit, NJ, USA, 2015.
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.
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.
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.
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.
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.
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.
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.
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 3–6 2016; Poster of abstract 4520.
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.
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.
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 3–6 2016; Poster of abstract 3307.
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.
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.
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.
Acknowledgements
This study was funded by Celgene Corporation. We thank the patients and families who contributed to this study, as well as the MM-005 study investigators, nurses and clinical trial personnel. We received editorial assistance from Kerry Garza, PhD, and Peter J Simon, PhD, funded by Celgene Corporation, as well as Michelle Maglio, BS, funded by the RJ Corman Multiple Myeloma Research Fund.
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All authors contributed to the conception and design of the work, contributed to the acquisition, analysis or interpretation of data for the work, revised the manuscript critically for important intellectual content, approved the final version to be published and agree to be accountable for all aspects of the work in ensuring that all questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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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.
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Richardson, P., Hofmeister, C., Raje, N. et al. Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma. Leukemia 31, 2695–2701 (2017). https://doi.org/10.1038/leu.2017.173
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DOI: https://doi.org/10.1038/leu.2017.173
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