Phase I/II study of high dose pomalidomide with G‐CSF support and dexamethasone in patients with relapsed/refractory multiple myeloma
Authors: Elisabet E. Manasanch, Preetesh Jain, Wendy Chen, Onyeka Oriabure, Maria Badillo, Lei Feng, Zuzana Berkova, Robert Z. Orlowski, Michael Wang
Journal: American Journal of Hematology (2020)

Pomalidomide (POM)/dexamethasone (DEX) combination is an approved treatment for relapsed/refractory multiple myeloma (RRMM). So, POM 4 mg improved overall response rate (ORR; 30% vs 10%) and progression free survival (PFS; 4 vs 1.9 months) of RRMM patients, when compared to high dose DEX in a randomized Phase III trial.1 We hypothesized that increasing the dose of POM in POM/DEX in combination with G-CSF may increase the efficacy. In this phase I/II clinical trial, we aimed to find the maximum tolerated dose (MTD) of POM given with granulocyte-colony stimulating factor (G-CSF) to limit neutropenia (NCT01946152). The Phase I used a standard 3 + 3 design to determine the MTD (Table S1).2 The Phase II accrued additional patients at the MTD to determine preliminary efficacy with a target ORR of 45%. Both Phase I and II consisted of 6 x 28-day cycles of initial therapy [POM (dose escalation up to 10 mg in Phase I and MTD in Phase II) + G-CSF 5 mcg/kg on days 22-28 every 28 days and DEX 40 mg weekly]. This was followed by a maintenance schedule cycle seven onwards (POM 2 mg on days 1-21/28 days with DEX 40 mg weekly) given until progression or toxicity. Complete blood count with differential (CBC) was performed within 24 hours of day 1, and on days 8,15 and 22, of cycles one to six or as clinically indicated. Following cycle six, CBC was performed on day 1 of each subsequent cycle. Maximum tolerated dose was defined as the highest dose that caused a DLT in less than two out of six patients treated. The primary objective of the study was to determine the MTD of POM/DEX given with G-CSF support. The secondary objectives were overall response rate (ORR), progression-free survival (PFS) and further evaluation of safety at the MTD. Patients needed to have RRMM with measurable disease. Patients must have received ≥ two cycles of lenalidomide (LEN) and bortezomib (BTZ) (either in separate regimens or as part of the same regimen). Patients had to have received ≤ five lines of prior therapy (including stem cell transplant). Time-to-event endpoints including PFS and overall survival (OS) were estimated using the Kaplan-Meier method. Intent-to-treat analysis was applied for toxicity data. The Institutional Review Board of The University of Texas MD Anderson Cancer Center in accordance with the Declaration of Helsinki approved the protocol. Between June 2014 and November 12, 2016 patients were enrolled in the Phase I and eight in Phase II (Figure S1 ). The median age in both Phase I and II was 66 years, range 52-82 years and 61-78 years, respectively (Table 1). Patients completed a median of three (2–5) prior lines of therapy. Seven (7) of 12 (58%) patients in Phase I and 3/8 (38%) of patients in Phase II were refractory to LEN, and 1/12 (8%) and 2/8 (25%) were refractory to BTZ, respectively. All patients had undergone autologous stem cell transplant (ASCT) except 4/12 patients (33%) in phase I and 1/8 patients (12.5%) in Phase II. Three patients were treated in each with POM 4 mg and POM 5 mg dose levels without DLTs. Dose was escalated to POM 6 mg and six patients were treated (Table S1). Two patients had DLTs (one patient had febrile neutropenia and another patient grade 3 neutropenia and no fever). Patients completed a median of four (range 1-44) cycles of therapy (Figure S2). The ORR (best response ≥ partial response) for the Phase I was 50% (CR in 1/12, VGPR in 2/12 and PR in 3/12 patients). These responses were achieved after a median of one cycle (range 1-11) cycles of therapy (Table 1). The ORR (best response ≥ partial response) in phase I showed responses both in patients who were lenalidomide refractory (5/7; 71%) or sensitive (1/5; 20%) (Figure S2). The MTD and Phase II dosing was determined to be POM 5 mg + G-CSF 5 mcg/kg on days 22-28 every 28 days, and DEX 40 mg weekly. For the phase II, patients completed a median of 14.5 (range 2-26) cycles of therapy. The ORR (best response ≥ partial response) for the Phase II was 75% [VGPR in 1/8 (12.5%) and PR in 5/8 patients (62.5%)]. In LEN refractory and sensitive patients, ORR was 3/3 (100%) and 3/5 (60%), respectively. Responses were observed after a median of 2.5 (range 1-9) cycles of therapy (Figure S2). Patients came off Phase I/II study due to progressive disease (5/12 and 5/8), toxicity/intolerability (2/12 and 1/8), secondary malignancy (1/12 and 2/8), second autologous stem cell transplant (1/12 and 0/8), and patient preference (3/12 and 0/8, respectively). Overall, high dose POM was well tolerated. Grade 3 related hematologic adverse events were neutropenia (n = 6, 30%), febrile neutropenia (n = 1; 5%) and anemia (n = 1; 5%). There were 2 (10%) Grade 4 neutropenias reported on Phase II. The most frequent Grade 3 related non-hematological events were infections (n = 5; 25%) followed by arthralgia, dyspnea, fatigue, secondary cancers, pain of the extremities, peripheral sensory neuropathy and upper respiratory tract infections (each n = 2; 10%), and chest pain, dizziness, lung infection, myalgia, pain, sinusitis and skin disorders (each n = 1; 5%). There were no Grade 5 adverse events (Table S2). Median progression free survival (PFS) for all patients was 10.3 months (95% CI: 7.1–23.2 months) (Figure S2A). The median survival time was reached after a median follow-up time of 35.71 months (95% CI: 31.14–59.43 months) (Figure S3). For patients in Phase II, the median PFS was 17.3 months (95% CI: 4.8–NA months) and there were no deaths at median follow-up time of 33.33.months (95% CI: 31.14–35.71 months). Our study shows that POM can be safely administered at a dose of 5 mg if given concurrently with G-CSF support for 6 months, followed by a maintenance dose of POM 2 mg with weekly dexamethasone, until toxicity or disease progression. We can overcome treatment related neutropenia with the addition of G-CSF, and thus increase the dose of POM to 5 mg, which can be administered safely to patients for up to six cycles. At POM 5 mg, the ORR was 75%, median PFS 17.5 months and OS 100% at median follow up of 35 months. Richardson et al had established the MTD of POM/DEX in RRMM (n = 28) at 4 mg days 1-21/40 mg weekly every 28 days with an ORR of 21%, PFS 4.6 months and OS 18.5 months for all patients.3 This regimen was compared to high dose dexamethasone in a randomized phase III study for RRMM (n = 302) with an ORR 26%, PFS 4 months and OS 12.7 months.1 The promising efficacy in our study may be confounded by the fact that patients were significantly less pre-treated and refractory when compared to previous studies (median lines of prior therapy three vs six and five; 12.5% refractory to bortezomib/lenalidomide vs 63% and 75%, respectively).1, 3 These efficacy results are preliminary and should be interpreted with caution and validated in larger cohorts of patients. Differences in response in the phase II portion of the study between patients who were or were not LEN refractory is difficult to interpret due to low number of patients. The addition of G-CSF resulted in lesser grade 3/4 neutropenia (40%) when compared to previous studies (50%-80% at POM doses 4 and 5 mg)3 and (48%)1 but similar rates of febrile neutropenia 0% in3, 10% in1 and 5% in our study. Similar rates of febrile neutropenia may be due to careful neutrophil count monitoring on previous studies and addition of G-CSF and treatment hold as needed when neutropenia occurred. Improved activity and clinical outcomes have been reported over the past few years using POM/DEX in triplet combinations. For example, the ORR and PFS of POM/DEX with carfilzomib (50%, 7.2 months),4 daratumumab (60%, 8.8 months),5 elotuzumab (58%, 10.3 months)6 and recently, isatuximab (60.4%, 11.5 months)7 are impressive. These ORR are similar and PFS is even longer in our study. Despite this, no formal conclusions can be drawn in terms of efficacy due to the small cohort size (n = 8), almost absence of lenalidomide and bortezomib refractory patients in our study and less heavily pre-treated patients. Randomized studies are needed to determine the comparative efficacy and toxicity with the current approved dose of 4 mg or with any other triplet therapies. In settings where treatment options may be limited and POM is available, one could consider treatment with high dose POM and G-CSF support. This work was supported in part by The MD Anderson Cancer Center Support Grant (P30 CA016672), the Leukemia and Lymphoma Society Specialized Center of Research (LLS SCOR), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Multiple Myeloma Research Foundation, the Chapman Perelman Foundation and the University of Texas MD Anderson Moon Shot Program. RZO, the Florence Maude Thomas Cancer Research Professor, would like to acknowledge support from the National Cancer Institute (R01s CA184464 and 194264, and U10 CA032102), the Leukemia & Lymphoma Society (SCOR-12206-17), the Adelson Medical Research Foundation, the Brock Family Myeloma Research Fund, and the Jean Clarke High-Risk Myeloma Research Fund. We would like to thank participating patients and their families. E.E.M.: Consulting fees from Adaptive Biotechnologies, Celgene, Takeda, Sanofi, Janssen; Research Funding to University of Texas MD Anderson from: Merck, Quest Diagnostics, Sanofi, JW Pharma. M.I.W.: consulting for Acerta Pharma, Janssen; Research Funding to UT MD Anderson from: Acerta Pharma, Asana Biosciences, BeiGene, Celgene, Janssen, Juno Therapeutics, Kite Pharma, Onyx, Pharmacyclics, Proteolix; Honoraria from Celgene, Dava Oncology, Janssen, Proteolix,; Membership on an entity's Board of Directors or advisory committees: Janssen. R.Z.O.: Consulting for Amgen, Bristol-Myers-Squibb, Celgene, GSK Biologicals, Ionis Pharmaceuticals, Janssen, Juno Therapeutics, Kite Pharma, Legend Biotech, Molecular Partners, Sanofi, Servier, Takeda; Research funding to UT MD Anderson from: BioTheryX. Other authors declare no potential conflict of interest. E.M. treated patients, collected, analyzed, interpreted the data, and wrote the manuscript. L.F. analyzed the data. Z.B. analyzed, interpreted the data and wrote the manuscript. R.Z.O. designed the research, treated patients, and provided comments to the manuscript. P.J., W.C., O.O. and M.B. provided comments on the manuscript. M.W. designed the research, treated patients, and provided comments to the manuscript. Appendix S1: Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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