Contributions
Abstract: PB2214
Type: Publication Only
Background
The median progression free survival (PFS) and overall survival (OS) of multiple myeloma (MM) patients have prolonged due to novel agents combined with ASCT. However, the vast majority of patients will progress after a median of 2-3 years with median OS of 7-8 years. Thus, the possible benefit of new combinations and dosing of available agents has to be investigated. The first proteasome inhibitor (PI), bortezomib (B), combined with elotuzumab and dexamethasone (d) showed superiority to Bd resulting in PFS of 9.7 vs. 6.9 months, respectively, without excessive toxicity (Jakubowiak et al. Blood 2016;127:2833-401).
Aims
The aim of this study is to investigate the safety, feasibility and initial efficacy of a second generation PI carfilzomib plus a SLAMF7 antibody elotuzumab plus dexamethasone (KEd) in relapsed MM patients.
Methods
Forty patients with relapsed MM after 1-3 prior lines will be included in this phase 2 study after written informed consent. The primary endpoint is overall response rate. In patients achieving at least very good partial remission (VGPR) the quality of response and bone marrow lymphocyte subgroups will be assessed with high-sensitivity multicolour flow cytometry according to the 8-colour EuroFlow protocol. Carfilzomib (K) is given once weekly 20 mg/m2 on D1C1 and thereafter 70 mg/m2 in 28 day cycles on days 1, 8 and 15 in cycles 1-8 and on days 1 and 15 thereafter combined with weekly elotuzumab (E) 10 mg/kg on days 1, 8 and 15 in cycles 1-2, thereafter on days 1 and 15; dexamethasone (d) on days 1, 8, 15 and 22 on cycles 1-8, thereafter on days 1 and 15. Treatment will continue until progression or excessive toxicity. Carfilzomib dose was 20/56 mg/m2 for the first two cycles for the first five patients to evaluate the safety. Follow-up samples will be stored for later response analysis of elotuzumab interference on IgG-kappa paraprotein. Additionally, patient samples collected prior to treatment will be comprehensively profiled by whole exome and RNA sequencing and evaluated for ex vivo response to the agents. Furthermore, the previously described1 association of FcγRIIIa polymorphism with response will be measured. Together, the study addresses clinical response, ex vivo-in vivo translation, identifies molecular biomarkers for the KEd combination and facilitates precision guided clinical trials for relapsed refractory MM.
Results
By the end of Feb 2018 eight patients have been enrolled. After a median of four cycles one patient is in VGPR, four patients are in PR, one in MR, and two that are too early to assess. One patient had grade 2 infusion reaction after premedication. One patient developed autoimmune hemolytic anemia (AIHA) possibly related to elotuzumab and recovered with steroids. She continued on Kd without reappearance of AIHA, while elotuzumab was permanently discontinued. A grade 3 adverse event with asymptomatic elevation of liver transaminase was detected in another patient who recovered with dose reduction of dexamethasone to 12 mg and carfilzomib to 56 mg/m2 without any change in elotuzumab dose.
Conclusion
To the best of our knowledge this is the first study evaluating the carfilzomib plus elotuzumab plus dexamethasone combination in relapsed MM with comprehensive molecular annotations. Preliminary results of KEd treatment with weekly dosing of 70 mg/m2 resulted with at least PR response in 5/6 patients. We noticed an unexpected severe adverse event of AIHA in one study patient. AIHA should be excluded if unexpected anemia will appear during elotuzumab treatment.
Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical
Keyword(s): Monoclonal antibody, Multiple Myeloma, Proteasome inhibitor, Relapse
Abstract: PB2214
Type: Publication Only
Background
The median progression free survival (PFS) and overall survival (OS) of multiple myeloma (MM) patients have prolonged due to novel agents combined with ASCT. However, the vast majority of patients will progress after a median of 2-3 years with median OS of 7-8 years. Thus, the possible benefit of new combinations and dosing of available agents has to be investigated. The first proteasome inhibitor (PI), bortezomib (B), combined with elotuzumab and dexamethasone (d) showed superiority to Bd resulting in PFS of 9.7 vs. 6.9 months, respectively, without excessive toxicity (Jakubowiak et al. Blood 2016;127:2833-401).
Aims
The aim of this study is to investigate the safety, feasibility and initial efficacy of a second generation PI carfilzomib plus a SLAMF7 antibody elotuzumab plus dexamethasone (KEd) in relapsed MM patients.
Methods
Forty patients with relapsed MM after 1-3 prior lines will be included in this phase 2 study after written informed consent. The primary endpoint is overall response rate. In patients achieving at least very good partial remission (VGPR) the quality of response and bone marrow lymphocyte subgroups will be assessed with high-sensitivity multicolour flow cytometry according to the 8-colour EuroFlow protocol. Carfilzomib (K) is given once weekly 20 mg/m2 on D1C1 and thereafter 70 mg/m2 in 28 day cycles on days 1, 8 and 15 in cycles 1-8 and on days 1 and 15 thereafter combined with weekly elotuzumab (E) 10 mg/kg on days 1, 8 and 15 in cycles 1-2, thereafter on days 1 and 15; dexamethasone (d) on days 1, 8, 15 and 22 on cycles 1-8, thereafter on days 1 and 15. Treatment will continue until progression or excessive toxicity. Carfilzomib dose was 20/56 mg/m2 for the first two cycles for the first five patients to evaluate the safety. Follow-up samples will be stored for later response analysis of elotuzumab interference on IgG-kappa paraprotein. Additionally, patient samples collected prior to treatment will be comprehensively profiled by whole exome and RNA sequencing and evaluated for ex vivo response to the agents. Furthermore, the previously described1 association of FcγRIIIa polymorphism with response will be measured. Together, the study addresses clinical response, ex vivo-in vivo translation, identifies molecular biomarkers for the KEd combination and facilitates precision guided clinical trials for relapsed refractory MM.
Results
By the end of Feb 2018 eight patients have been enrolled. After a median of four cycles one patient is in VGPR, four patients are in PR, one in MR, and two that are too early to assess. One patient had grade 2 infusion reaction after premedication. One patient developed autoimmune hemolytic anemia (AIHA) possibly related to elotuzumab and recovered with steroids. She continued on Kd without reappearance of AIHA, while elotuzumab was permanently discontinued. A grade 3 adverse event with asymptomatic elevation of liver transaminase was detected in another patient who recovered with dose reduction of dexamethasone to 12 mg and carfilzomib to 56 mg/m2 without any change in elotuzumab dose.
Conclusion
To the best of our knowledge this is the first study evaluating the carfilzomib plus elotuzumab plus dexamethasone combination in relapsed MM with comprehensive molecular annotations. Preliminary results of KEd treatment with weekly dosing of 70 mg/m2 resulted with at least PR response in 5/6 patients. We noticed an unexpected severe adverse event of AIHA in one study patient. AIHA should be excluded if unexpected anemia will appear during elotuzumab treatment.
Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical
Keyword(s): Monoclonal antibody, Multiple Myeloma, Proteasome inhibitor, Relapse