Cited by 305Multiple Myeloma Research and TreatmentsChronic Lymphocytic Leukemia ResearchBone health and treatments

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Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond

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Chim, C S, Kumar, S K, Orlowski, R Z, Cook, G, Richardson, P G, Gertz, M A, Giralt, S, Mateos, M V, Leleu, X, Anderson, K C·2018·Leukemia

DOI 10.1038/leu.2017.329PMC PMC5808071

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Abstract

Despite enormous advances, management of multiple myeloma (MM) remains challenging. Multiple factors impact the decision to treat or which regimen to use at MM relapse/progression. Recent major randomized controlled trials (RCTs) showed widely varying progression-free survivals (PFS), ranging from a median of 4 months (MM-003) to 23.6 months (ASPIRE). Based on these RCTs, next-generation proteasome inhibitors (carfilzomib and ixazomib), next-generation immunomodulatory agent (pomalidomide), and monoclonal antibodies (elotuzumab and daratumumab) were approved for relapsed and refractory MM. Daratumumab, targeting CD38, has multiple mechanisms of action including modulation of the immunosuppressive bone marrow micro-environment. In addition to the remarkable single agent activity in refractory MM, daratumumab produced deep responses and superior PFS in MM when combined with lenalidomide/dexamethasone, or bortezomib/dexamethasone. Other anti-CD38 antibodies, such as isatuximab and MOR202, are undergoing assessment. Elotuzumab, targeting SLAMF7, yielded superior response rates and PFS when combined with lenalidomide/dexamethasone. New combinations of these next generation novel agents and/or antibodies are undergoing clinical trials. Venetoclax, an oral BH3 mimetic inhibiting BCL2, showed single agent activity in MM with t(11;14), and is being studied in combination with bortezomib/dexamethasone. Selinexor, an Exportin-1 inhibitor, yielded promising results in quad- or penta-refractory MM including patients resistant to daratumumab. Pembrolizumab, an anti-PD1 check-point inhibitor, is being tested in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone. Chimeric antigen receptor-T cells targeting B-cell maturation antigen have yielded deep responses in RRMM. Finally, salvage autologous stem cell transplantation (ASCT) remains an important treatment in MM relapsing/progressing after a first ASCT. Herein, the clinical trial data of these agents are summarized, cautious interpretation of RCTs highlighted, and algorithm for salvage treatment of relapse/refractory MM proposed.

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San-Miguel J, Weisel K, Cook G, Leiba M, Suzuki K, Kumar S et alEfficacy by cytogenetic risk status for daratumumab in combination with lenalidomide and dexamethason or bortezomib and dexamethason in replapsed or refractory multiple myeloma EHA 2017. EHA Learning Center: Madrid, 2017 Haematologica 2017; 102 (S2): 1.
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Authors: Chim, C. S., Kumar, S. K., Orlowski, R. Z., Cook, G., Richardson, P. G., Gertz, M. A., Giralt, S., Mateos, M. V., Leleu, X., & Anderson, K. C.
Affiliations: Queen Mary Hospital (CN)
Mayo Clinic (US)
The University of Texas MD Anderson Cancer Center (US)
University of Leeds (GB)
Harvard University (US)
Memorial Sloan Kettering Cancer Center (US)
Universidad de Salamanca (ES)
Centre Hospitalier Universitaire de Poitiers (FR)
Corresponding author: Chim, C S
ORCID: Chim, C S
Kumar, S K
Orlowski, R Z
Cook, G
Richardson, P G
Gertz, M A
Giralt, S
Mateos, M V
Leleu, X
Anderson, K C
Venue: Leukemia
Publisher: Springer Science and Business Media LLC
Published: 2017-11-16
Volume: 32
Issue: 2
Pages: 252-262
ISSN: 0887-6924 (ISSN-L)
1476-5551
DOI: 10.1038/leu.2017.329
PMC: PMC5808071
OpenAlex: W2781388087
Cited by: 305
References: 76
Citations by year: 2026: 7 · 2025: 18 · 2024: 19 · 2023: 26 · 2022: 36 · 2021: 68 · 2020: 64 · 2019: 39 · 2018: 27
FWCI: 5.61
Type: journal article
Language: en
Update notices: correction (2019-03-06)
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
creativecommons.org/licenses/by-nc-nd/4.0 (tdm)
Locations: Leukemia (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders: Queen Mary University of London
Université de Nantes
National Cancer Institute (P30CA008748, P50CA186781)
Topics: Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
Health Sciences › Medicine › Oncology › Bone health and treatments
Keywords: relapsed/refractory multiple myeloma, novel agents, monoclonal antibodies, daratumumab, elotuzumab, anti-CD38 monoclonal antibody, isatuximab, SLAMF7, lenalidomide, pomalidomide, carfilzomib, ixazomib, venetoclax, selinexor, pembrolizumab, CAR T-cell therapy, BCMA, salvage autologous stem cell transplantation, progression-free survival, treatment algorithm
MeSH terms: Progression-Free Survival, Antibodies, Antineoplastic Combined Chemotherapy Protocols, Humans, Immunotherapy, Multiple Myeloma, Neoplasm Recurrence, Local, Randomized Controlled Trials as Topic

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Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond

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