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PHASE II TRIAL OF COMBINATION OF ELOTUZUMAB, LENALIDOMIDE, AND DEXAMETHASONE IN HIGH-RISK SMOLDERING MULTIPLE MYELOMA
Author(s): ,
Irene Ghobrial
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
,
Aaron Caola
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
,
Patrick Henrick
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
,
Alexandra Savell
Affiliations:
Blood Cancer Research Partnership,Boston,United States
,
Joseph Cappuccio
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
,
Bradley Rivotto
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
,
Kaitlen Reyes
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
,
Claudia Paba-Prada
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
,
Robert Schlossman
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
,
Jacob Laubach
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
,
Paul Richardson
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
,
Kimberly Noonan
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
,
Nikhil Munshi
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
,
Chia-Jen Liu
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
,
Mark Bustoros
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
,
Ashraf Badros
Affiliations:
Multiple Myeloma,University of Maryland Greenebaum Cancer Center,Baltimore,United States
,
Jeffrey Matous
Affiliations:
Multiple Myeloma,Colorado Blood Cancer Institute,Denver,United States
,
Jacalyn Rosenblatt
Affiliations:
Multiple Myeloma,Beth Israel Deaconess Medical Center,Boston,United States
,
Andrew Yee
Affiliations:
Multiple Myeloma,Massachusetts General Hospital,Boston,United States
,
Rodrigo Maegawa
Affiliations:
Multiple Myeloma,Eastern Maine Medical Center,Bangor,United States
,
Saad Usmani
Affiliations:
Multiple Myeloma,Levine Cancer Institute,Charlotte,United States
,
James Vredenburgh
Affiliations:
Multiple Myeloma,St. Francis Hospital,Hartford,United States
,
Adam Boruchov
Affiliations:
Multiple Myeloma,St. Francis Hospital,Hartford,United States
,
Omar Nadeem
Affiliations:
Multiple Myeloma,Newton-Wellesley Hospital,Newton,United States
,
Divaya Bhutani
Affiliations:
Multiple Myeloma,Barbara Ann Karmanos Cancer Institute,Detroit,United States
,
Andrzej Jakubowiak
Affiliations:
Multiple Myeloma,University of Chicago Medical Center,Chicago,United States
,
Manisha Bhutani
Affiliations:
Multiple Myeloma,Levine Cancer Institute,Charlotte,United States
,
Karma Salem
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
,
Salomon Manier
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
Jihye Park
Affiliations:
Multiple Myeloma,Dana-Farber Cancer Institute,Boston,United States
(Abstract release date: 05/18/17) EHA Library. Ghobrial I. 06/25/17; 182066; S779
Irene Ghobrial
Irene Ghobrial
Contributions
Abstract

Abstract: S779

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:00 - 08:15

Location: Hall D

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).

Aims
The overarching objective of this trial is to determine progression free survival to symptomatic 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 on 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 for 40 of the 50 patients enrolled. 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 samples of 33 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 to date, with the participation of eight sites. The median age of patients enrolled was 62 years (range 29 to 79) with 18 males (36%) and 32 females (64%). Interphase fluorescence in situ hybridization (iFISH) detected high risk cytogenetics in 20 patients. The median number of cycles completed is 12 (range 1 to 24). Therapy related grade 3 toxicities included hypophosphatemia (30%), neutropenia (14%), infection (12%), anemia (2%), pulmonary embolism (2%), rash (4%), and diarrhea (2%). Therapy related grade 4 toxicities included thrombocytopenia (2%), neutropenia (2%) and one instance of cholecystitis (2%). Stem cell collection was successful in all patients collected to date. Of the 31 evaluable patients that completed the first 8 cycles of therapy, the overall response rate was 84%, including 2 complete responses (7%), 11 very good partial responses (36%) and 13 partial responses (42%), and a clinical benefit rate of 100%. None of the patients showed progression to overt MM to date. WES was performed on 25 samples at the time of initiation of therapy. Recurrent mutations in the MAPK pathway (KRAS, NRAS) and tumor suppressor gene, TP53, were detected in 32% of the cases (16% each), while mutations in NF-KB and plasma cell differentiation pathways were present in 10% of patients. CCND1 gene mutation was seen in 1 patient and was associated with t(11:14) as reported in the previous WES studies of MM. CNAs were called based on WES: 1q amplification, 13q, 17p, and 1p deletions were identified in 28, 20, 16, and 12% of cases, respectively. Interestingly, in 6 patients, high-risk CNAs were not reported in iFISH but were detected by WES. Finally, we assessed the correlation between neoantigen load and clinical response.

Conclusion
The combination of elotuzumab, lenalidomide, and dexamethasone is well tolerated and demonstrates a high response rates 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.

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): Smoldering, Multiple Myeloma, Monoclonal antibody, Immunomodulatory thalidomide analog

Abstract: S779

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:00 - 08:15

Location: Hall D

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).

Aims
The overarching objective of this trial is to determine progression free survival to symptomatic 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 on 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 for 40 of the 50 patients enrolled. 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 samples of 33 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 to date, with the participation of eight sites. The median age of patients enrolled was 62 years (range 29 to 79) with 18 males (36%) and 32 females (64%). Interphase fluorescence in situ hybridization (iFISH) detected high risk cytogenetics in 20 patients. The median number of cycles completed is 12 (range 1 to 24). Therapy related grade 3 toxicities included hypophosphatemia (30%), neutropenia (14%), infection (12%), anemia (2%), pulmonary embolism (2%), rash (4%), and diarrhea (2%). Therapy related grade 4 toxicities included thrombocytopenia (2%), neutropenia (2%) and one instance of cholecystitis (2%). Stem cell collection was successful in all patients collected to date. Of the 31 evaluable patients that completed the first 8 cycles of therapy, the overall response rate was 84%, including 2 complete responses (7%), 11 very good partial responses (36%) and 13 partial responses (42%), and a clinical benefit rate of 100%. None of the patients showed progression to overt MM to date. WES was performed on 25 samples at the time of initiation of therapy. Recurrent mutations in the MAPK pathway (KRAS, NRAS) and tumor suppressor gene, TP53, were detected in 32% of the cases (16% each), while mutations in NF-KB and plasma cell differentiation pathways were present in 10% of patients. CCND1 gene mutation was seen in 1 patient and was associated with t(11:14) as reported in the previous WES studies of MM. CNAs were called based on WES: 1q amplification, 13q, 17p, and 1p deletions were identified in 28, 20, 16, and 12% of cases, respectively. Interestingly, in 6 patients, high-risk CNAs were not reported in iFISH but were detected by WES. Finally, we assessed the correlation between neoantigen load and clinical response.

Conclusion
The combination of elotuzumab, lenalidomide, and dexamethasone is well tolerated and demonstrates a high response rates 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.

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): Smoldering, Multiple Myeloma, Monoclonal antibody, Immunomodulatory thalidomide analog

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