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154 Phase II Trial of Combination of Elotuzumab, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Novel Antibody Combinations in Myeloma
Hematology Disease Topics & Pathways:
antibodies, Biological, Diseases, Therapies, smoldering myeloma, immunotherapy, Plasma Cell Disorders, Clinically relevant, Lymphoid Malignancies
Saturday, December 1, 2018: 12:45 PM
Grand Ballroom 7 (Marriott Marquis San Diego Marina)

Chia-jen Liu, MD1,2,3*, Irene M. Ghobrial, MD1,2,3, Mark Bustoros, MD1,2,3, Kaitlen Reyes, NP1,2,3*, Kalvis Hornburg, BA1,2,3*, Ashraf Z. Badros, MD4, James J. Vredenburgh, MD5*, Adam Boruchov, MD6, Jeffrey V Matous, MD7, Aaron Caola, BS2*, Bradley Rivotto, BS2*, Alexandra Savell, BS2,8*, Patrick Henrick, BS2*, Claudia E. Paba-Prada, MD9*, Robert L. Schlossman, MD10, Jacob Laubach, MD2,3, Jacalyn Rosenblatt, MD11, Andrew J Yee, MD12, Omar Nadeem, MD13*, Rodrigo O. Maegawa, MD14*, Andrzej Jakubowiak, MD, PhD15,16, Saad Z. Usmani, MD17, Manisha Bhutani, MD18, Joseph Cappuccio, BS2*, Brianna Berrios, BS2*, Kimberly Noonan, NP2*, Oksana Zavidij, PhD10*, Tarek H Mouhieddine, MD10, Cody J Boehner2*, Carl-Jannes Neuse1,2*, Karma Ziad Salem, MD2*, Mairead Reidy, PhD2*, Jihye Park, BS, DVM10, Michael Agius, PhD2*, Mahshid Rahmat, PhD2*, Salomon Manier, MD, PhD2, Divaya Bhutani, MD 19, Jeffrey A. Zonder, MD 20, Nikhil Munshi, MD2,3, Daniel Auclair, PhD21*, Kenneth Anderson, M.D22 and Paul Richardson3,23

1The Center for Prevention of Progression of Blood Cancers, Dana-Farber Cancer Institute, Boston, MA
2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
3Harvard Medical School, Boston
4University of Maryland Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD
5Duke University, Durham, NC
6St. Francis Hospital, Avon, CT
7Colorado Blood Cancer Institute, Denver, CO
8Blood Cancer Research Partnership, Boston, MA
9Dana-Farber Cancer Institute, Boston, MA
10Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
11Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
12Hematology Oncology, Massachusetts General Hospital Cancer Center, Boston, MA
13Brown University, Newton, MA
14Cancer Care of Maine, Brewer, ME
15University of Chicago Medical Center, Chicago, IL
16University of Chicago, Chicago, IL
17Plasma Cell Disorders Section, Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC, Levine Cancer Institute, Charlotte, NC
18Plasma Cell Disorders Section, Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC, Levine L. Cancer Institute, Charlotte, NC
19Department of Malignant Hematology, Karmanos Cancer Institute/Wayne State University, Jersey City, NJ
20Karmanos Cancer Institute, Detroit, MI
21Multiple Myeloma Research Foundation (MMRF), Middletown, CT
22The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
23Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA

Background
This study aimed to determine the benefit of early therapeutic intervention with the combination of elotuzumab, Lenalidomide, and Dexamethasone in patients with high-risk smoldering multiple myeloma (SMM). ClinicalTrials.gov Identifier: NCT02279394.

Aims
The overarching objective of this trial is to determine progression free survival to symptomatic multiple myeloma (MM). Furthermore, the study examined whether genomic studies can help in determining patients who would benefit the most from this early therapeutic intervention.

Methods
Patients enrolled in this study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al, Blood 2014. Patients were administered weekly elotuzumab (10 mg/kg) on days 1, 8, 15, and 22 for the first two 28-day cycles while receiving lenalidomide on days 1-21. For cycles 3-8, patients were administered elotuzumab infusions on days 1, 8, and 15. dexamethasone (40mg) was given on days 1, 8 and 15 to 40 of the 50 enrolled patients. After 8 cycles or best response, patients were given the option to mobilize with either cyclophosphamide or plerixafor and collect stem cells for future transplant. Patients were then allowed to continue on maintenance therapy where they were administered elotuzumab (20 mg/kg) on day 1, in combination with lenalidomide days 1-21 of a 28-day cycle. Bone marrow (BM) samples of 32 patients were obtained before starting therapy for baseline assessment and whole exome sequencing (WES) of plasma cells.

Results
In total, 50 patients were enrolled on this study from January 2015 and completed accrual in December 2016, with the participation of eight sites. The median age of enrolled patients was 62 years (range, 29-79) with 18 males (36%) and 32 females (64%). Interphase fluorescence in situ hybridization (iFISH) detected high-risk cytogenetics (defined by the presence of 17p deletion, t(4;14), and 1q gain) in 20 patients. The median time to response was 2.8 months (range, 1.8–4.6). The most common toxicities were fatigue (92%), followed by diarrhea (72%), and hyperglycemia (62%). The most common grade 3 or more adverse events were hypophosphatemia (34%), neutropenia (26%), and lymphocyte count decreased (22%). Three patients (6%) had grade 4 hypophosphatemia during treatment. Additionally, grade 4 cholecystitis, cataract, lymphocyte count increase, hyperglycemia, neutropenia, and thrombocytopenia occurred in one patient (2%). Diabetic Ketoacidosis and sepsis led to death in a patient (2%). Stem cell collection was successful in all mobilized patients to date. As of this abstract date, the overall response rate is 84% (41/49). There were 3 complete responses (6%), 18 very good partial responses (37%), 20 partial responses (41%), 5 minimal responses (10%), 3 stable disease (6%), and 2 unevaluable patients. All the study participants except for three have finished treatment and are currently under follow up. None of the patients showed progression to overt MM to date. We continue to collect data for progression free survival.

WES was performed on 32 samples at the time of initiation of therapy. Recurrent mutations in the MAPK pathway (KRAS, NRAS) and tumor suppressor gene, TP53, were detected in 40% of the cases (16% and 24%, respectively), while mutations in the NF-KB and plasma cell differentiation pathways were present in 13% of patients. Somatic copy number alterations (SCNAs) were called based on WES: 1q duplication, 13q, 17p, and 1p deletions were identified in 25, 31, 12, and 7% of cases, respectively. Interestingly, in 6 patients, high-risk SCNAs (1q gain and 17p deletion) were not reported in iFISH but were detected by WES. The analysis of these 32 samples showed that patients who are harboring mutations in the DNA repair pathway genes, had modest response to treatment. Finally, we are analyzing the transcriptomic profile of CD138 negative cells, which represent the BM microenvironment cells (immune and stromal cells) to characterize the BM microenvironment at baseline and end of treatment, and thus, elucidate the role of these cells in the differential response to therapy.

Conclusion
The combination of elotuzumab, lenalidomide, and dexamethasone is well tolerated and demonstrates a high response rate with no progression to overt MM to date. Correlation with genomic studies can help define patients who benefit the most from this early therapeutic intervention.

Disclosures: Ghobrial: Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy. Bustoros: Dava Oncology: Honoraria. Badros: GSK: Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Research Funding. Matous: Celgene: Consultancy, Honoraria, Speakers Bureau. Rosenblatt: Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Jakubowiak: Karyopharm: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Usmani: Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy. Zonder: Alnylam: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Caelum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Munshi: OncoPep: Other: Board of director. Auclair: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA: Research Funding. Anderson: Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; OncoPep: Equity Ownership, Other: Scientific founder; Millennium Takeda: Consultancy; Celgene: Consultancy. Richardson: Takeda: Other: Advisory Committee Member, Research Funding; Jazz Pharmaceuticals: Other: Advisory Committee Member, Research Funding; Karyopharm: Other: Advisory Committee Member; Oncopeptides: Other: Advisory Committee Member; BMS: Other: Advisory Committee Member, Research Funding; Amgen: Other: Advisory Committee Member; Celgene: Other: Advisory Committee Member, Research Funding; Janssen: Other: Advisory Committee Member.

*signifies non-member of ASH