TY - JOUR
T1 - Bortezomib, lenalidomide, and dexamethasone with or without elotuzumab in patients with untreated, high-risk multiple myeloma (SWOG-1211)
T2 - primary analysis of a randomised, phase 2 trial
AU - SWOG1211 Trial Investigators
AU - Usmani, Saad Z.
AU - Hoering, Antje
AU - Ailawadhi, Sikander
AU - Sexton, Rachael
AU - Lipe, Brea
AU - Hita, Sandi Fredette
AU - Valent, Jason
AU - Rosenzweig, Michael
AU - Zonder, Jeffrey A.
AU - Dhodapkar, Madhav
AU - Callander, Natalie
AU - Zimmerman, Todd
AU - Voorhees, Peter M.
AU - Durie, Brian
AU - Rajkumar, S. Vincent
AU - Richardson, Paul G.
AU - Orlowski, Robert Z.
N1 - Funding Information:
This study was supported by funding support from the National Institutes of Health and National Cancer Institute (grants U10CA180888-01 and U10CA180819-01), and in part by Bristol Myers Squibb and Celgene (a Bristol-Myers company). SZU is supported by the Leukemia and Lymphoma Society Scholar in Clinical Research Grant, Carolinas Myeloma Research Fund, and the William Britton Family Fund. RZO is a Florence Maude Thomas Cancer Research Professor and acknowledges support from the National Cancer Institute (R01 CA194264 and R01 CA184464), the Leukemia and Lymphoma Society, the Dr Miriam and Sheldon G Adelson Medical Research Foundation, and the MD Anderson Cancer Center High Risk Multiple Myeloma Moon Shot.
Funding Information:
SZU reports grants and personal fees from Amgen, AbbVie, and MundiPharma, grants from Bristol Myers Squibb and Pharmacyclics, and grants and personal fees from Celgene, Sanofi, Seattle Genetics, Janssen, Takeda, SkylineDX, and Merck, outside the submitted work. PGR reports grants from Bristol Myers Squibb, grants and honoraria (advisory committee member) from Oncopeptides, Celgene, Takeda, and Karyopharm and honoraria (advisory committee member) from Janssen, Sanofi, and SecuraBio, outside the submitted work. JAZ reports grants from Bristol Myers Squibb and personal fees from Amgen, Regeneron, and Caelum, outside the submitted work. BD reports personal fees from Amgen, Janssen, Celgene–Bristol Myers Squibb, and Takeda, outside the submitted work. PMV reports personal fees from Bristol Myers Squibb, Novartis, Oncopeptides TeneoBio, Janssen, GlaxoSmithKline, Adaptive Biotechnologies, and Takeda Pharmaceuticals, outside the submitted work. JV reports personal fees from Takeda Pharmaceuticals, Amgen, and Celgene, outside the submitted work. RZO reports grants from BioTheryX, CARsgen Therapeutics, and Exelixis, grants and personal fees from Celgene–Bristol Myers Squibb, Janssen Biotech, Sanofi–Aventis, and Takeda Pharmaceuticals North America, and personal fees from Amgen, EcoR1 Capital, Forma Therapeutics, Genzyme, GlaxoSmithKline, Ionis Pharmaceuticals, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, and STATinMED Research, outside of the submitted work. RZO is also Founder of Asylia Therapeutics with associated patents and an equity interest, outside of the submitted work. MD reports personal fees from Janssen, Amgen, Lava Therapeutics, and Roche–Genentech, outside the submitted work. MZ reports personal fees for Speaker Bureau from Celgene–Bristol Myers Squibb, Takeda, and Janssen, outside the submitted work. SA reports grants from Amgen, Cellectar, Pharmacyclics, Janssen, Bristol Myers Squibb, and AstraZeneca and personal fees from Takeda, Celgene, GlaxoSmithKline, Sanofi–Genzyme, and Oncopeptides, outside the submitted work. TZ reports stocks in AbbVie and BeiGene, outside the submitted work. All other authors declare no competing interests.
Funding Information:
This study was supported by funding support from the National Institutes of Health and National Cancer Institute (grants U10CA180888-01 and U10CA180819-01), and in part by Bristol Myers Squibb and Celgene (a Bristol-Myers company). SZU is supported by the Leukemia and Lymphoma Society Scholar in Clinical Research Grant, Carolinas Myeloma Research Fund, and the William Britton Family Fund. RZO is a Florence Maude Thomas Cancer Research Professor and acknowledges support from the National Cancer Institute (R01 CA194264 and R01 CA184464), the Leukemia and Lymphoma Society, the Dr Miriam and Sheldon G Adelson Medical Research Foundation, and the MD Anderson Cancer Center High Risk Multiple Myeloma Moon Shot.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/1
Y1 - 2021/1
N2 - Background: The introduction of immunomodulatory agents, proteasome inhibitors, and autologous haematopoietic stem-cell transplantation has improved outcomes for patients with multiple myeloma, but patients with high-risk multiple myeloma have a poor long-term prognosis. We aimed to address optimal treatment for these patients. Methods: SWOG-1211 is a randomised phase 2 trial comparing eight cycles of lenalidomide (25 mg orally on days 1–14 every 21 days), bortezomib (1·3 mg/m2 subcutaneously on days 1, 4, 8, and 11 every 21 days), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days; RVd) induction followed by dose-attenuated RVd maintenance (bortezomib 1 mg/m2 subcutaneously on days 1, 8, and 15; lenalidomide 15 mg orally on days 1–21; dexamethasone 12 mg orally on days 1, 18, and 15 every 28 days) until disease progression with or without elotuzumab (10 mg/kg intravenously on days 1, 8, and 15 for cycles 1–2, on days 1 and 11 for cycles 3–8, and on days 1 and 15 during maintenance). Patients were randomly assigned (1:1) to either RVd or RVd-elotuzumab. High-risk multiple myeloma was defined by one of the following: gene expression profiling high risk (GEPhi), t(14;16), t(14;20), del(17p) or amp1q21, primary plasma cell leukaemia and elevated serum lactate dehydrogenase (two times the upper limit of normal or more). The primary endpoint was progression-free survival, and all analyses were done on intention-to-treat basis among eligible patients who were evaluable for response. This study is registered with ClinicalTrials.gov, NCT01668719. Findings: 100 (RVd n=52, RVd-elotuzumab n=48) patients were enrolled between Oct 27, 2013, and May 15, 2016, across 26 cooperative group institutions in the USA. Median age was 64 years (IQR 57–70, range 36–85). 74 (75%) of 99 had International Staging System stage II or stage III disease, 47 (47%) of 99 had amp1q21, 37 (37%) of 100 had del17p, 11 (11%) of 100 had t(14;16), eight (9%) of 90 were GEPhi, seven (7%) of 100 had primary plasma cell leukaemia, five (5%) of 100 had t(14;20), four (4%) of 100 had elevated serum lactate dehydrogenase, and 17 (17%) had two or more features. With a median follow-up of 53 months (IQR 46–59), no difference in median progression-free survival was observed (RVd 33·64 months [95% CI 19·55–not reached], RVd-elotuzumab 31·47 months [18·56–53·98]; hazard ratio 0·968 [80% CI 0·697–1·344]; one-sided p=0·45]. 37 (71%) of 52 patients in the RVd group and 37 (77%) of 48 in the RVd-elotuzumab group had grade 3 or worse adverse events. No significant differences in the safety profile were observed, although some notable results included grade 3–5 infections (four [8%] of 52 in the RVd group, eight [17%] of 48 in the RVd-elotuzumab group), sensory neuropathy (four [8%] of 52 in the RVd group, six [13%] of 48 in the RVd-elotuzumab group), and motor neuropathy (one [2%] of 52 in the RVd group, four [8%] of 48 in the RVd-elotuzumab group). There were no treatment-related deaths in the RVd group and one death in the RVd-elotuzumab group for which study treatment was listed as possibly contributing by the investigator. Interpretation: In the first randomised study of high-risk multiple myeloma reported to date, the addition of elotuzumab to RVd induction and maintenance did not improve patient outcomes. However, progression-free survival in both study groups exceeded the original statistical assumptions and supports the role for continuous proteasome inhibitors and immunomodulatory drug combination maintenance therapy for this patient population. Funding: National Institutes of Health, National Cancer Institute, Bristol Myers Squibb, Celgene, Leukemia and Lymphoma Society.
AB - Background: The introduction of immunomodulatory agents, proteasome inhibitors, and autologous haematopoietic stem-cell transplantation has improved outcomes for patients with multiple myeloma, but patients with high-risk multiple myeloma have a poor long-term prognosis. We aimed to address optimal treatment for these patients. Methods: SWOG-1211 is a randomised phase 2 trial comparing eight cycles of lenalidomide (25 mg orally on days 1–14 every 21 days), bortezomib (1·3 mg/m2 subcutaneously on days 1, 4, 8, and 11 every 21 days), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days; RVd) induction followed by dose-attenuated RVd maintenance (bortezomib 1 mg/m2 subcutaneously on days 1, 8, and 15; lenalidomide 15 mg orally on days 1–21; dexamethasone 12 mg orally on days 1, 18, and 15 every 28 days) until disease progression with or without elotuzumab (10 mg/kg intravenously on days 1, 8, and 15 for cycles 1–2, on days 1 and 11 for cycles 3–8, and on days 1 and 15 during maintenance). Patients were randomly assigned (1:1) to either RVd or RVd-elotuzumab. High-risk multiple myeloma was defined by one of the following: gene expression profiling high risk (GEPhi), t(14;16), t(14;20), del(17p) or amp1q21, primary plasma cell leukaemia and elevated serum lactate dehydrogenase (two times the upper limit of normal or more). The primary endpoint was progression-free survival, and all analyses were done on intention-to-treat basis among eligible patients who were evaluable for response. This study is registered with ClinicalTrials.gov, NCT01668719. Findings: 100 (RVd n=52, RVd-elotuzumab n=48) patients were enrolled between Oct 27, 2013, and May 15, 2016, across 26 cooperative group institutions in the USA. Median age was 64 years (IQR 57–70, range 36–85). 74 (75%) of 99 had International Staging System stage II or stage III disease, 47 (47%) of 99 had amp1q21, 37 (37%) of 100 had del17p, 11 (11%) of 100 had t(14;16), eight (9%) of 90 were GEPhi, seven (7%) of 100 had primary plasma cell leukaemia, five (5%) of 100 had t(14;20), four (4%) of 100 had elevated serum lactate dehydrogenase, and 17 (17%) had two or more features. With a median follow-up of 53 months (IQR 46–59), no difference in median progression-free survival was observed (RVd 33·64 months [95% CI 19·55–not reached], RVd-elotuzumab 31·47 months [18·56–53·98]; hazard ratio 0·968 [80% CI 0·697–1·344]; one-sided p=0·45]. 37 (71%) of 52 patients in the RVd group and 37 (77%) of 48 in the RVd-elotuzumab group had grade 3 or worse adverse events. No significant differences in the safety profile were observed, although some notable results included grade 3–5 infections (four [8%] of 52 in the RVd group, eight [17%] of 48 in the RVd-elotuzumab group), sensory neuropathy (four [8%] of 52 in the RVd group, six [13%] of 48 in the RVd-elotuzumab group), and motor neuropathy (one [2%] of 52 in the RVd group, four [8%] of 48 in the RVd-elotuzumab group). There were no treatment-related deaths in the RVd group and one death in the RVd-elotuzumab group for which study treatment was listed as possibly contributing by the investigator. Interpretation: In the first randomised study of high-risk multiple myeloma reported to date, the addition of elotuzumab to RVd induction and maintenance did not improve patient outcomes. However, progression-free survival in both study groups exceeded the original statistical assumptions and supports the role for continuous proteasome inhibitors and immunomodulatory drug combination maintenance therapy for this patient population. Funding: National Institutes of Health, National Cancer Institute, Bristol Myers Squibb, Celgene, Leukemia and Lymphoma Society.
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U2 - 10.1016/S2352-3026(20)30354-9
DO - 10.1016/S2352-3026(20)30354-9
M3 - Article
C2 - 33357482
AN - SCOPUS:85098074289
VL - 8
SP - e45-e54
JO - The Lancet Haematology
JF - The Lancet Haematology
SN - 2352-3026
IS - 1
ER -