Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib.
OBJECTIVE
Novel therapeutic agents have significantly improved the survival of patients with multiple myeloma. Nonetheless, the prognosis of patients with multiple myeloma who become refractory to the novel agents lenalidomide and bortezomib is very poor, indicating the urgent need for new therapeutic options for these patients. The human CD38 monoclonal antibody daratumumab is being evaluated as a novel therapy for multiple myeloma. Prompted with the encouraging results of ongoing clinical phase I/II trials, we now addressed the potential value of daratumumab alone or in combination with lenalidomide or bortezomib for the treatment of lenalidomide- and bortezomib-refractory patients.


METHODS
In ex vivo assays, mainly evaluating antibody-dependent cell-mediated cytotoxicity, and in an in vivo xenograft mouse model, we evaluated daratumumab alone or in combination with lenalidomide or bortezomib as a potential therapy for lenalidomide- and bortezomib-refractory multiple myeloma patients.


RESULTS
Daratumumab induced significant lysis of lenalidomide/bortezomib-resistant multiple myeloma cell lines and of primary multiple myeloma cells in the bone marrow mononuclear cells derived from lenalidomide- and/or bortezomib-refractory patients. In these assays, lenalidomide but not bortezomib, synergistically enhanced daratumumab-mediated multiple myeloma lysis through activation of natural killer cells. Finally, in an in vivo xenograft model, only the combination of daratumumab with lenalidomide effectively reduced the tumorigenic growth of primary multiple myeloma cells from a lenalidomide- and bortezomib-refractory patient.


CONCLUSIONS
Our results provide the first preclinical evidence for the benefit of daratumumab plus lenalidomide combination for lenalidomide- and bortezomib-refractory patients.
Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, the Netherlands. Department of Hematology, University Medical Center Utrecht, Utrecht, the Netherlands. Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands.
Inger S
IS
Nijhof
Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands. Department of Cell Biology, University Medical Center Utrecht, Utrecht, the Netherlands.
Richard W J
RW
Groen
Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands. Department of Cell Biology, University Medical Center Utrecht, Utrecht, the Netherlands.
Willy A
WA
Noort
Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, the Netherlands. Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands.
Berris
B
van Kessel
Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands. Department of Cell Biology, University Medical Center Utrecht, Utrecht, the Netherlands.
Regina
R
de Jong-Korlaar
Genmab, Utrecht, the Netherlands.
Joost
J
Bakker
Genmab, Utrecht, the Netherlands.
Jeroen J L
JJ
van Bueren
Genmab, Utrecht, the Netherlands. Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Paul W H I
PW
Parren
Department of Hematology, University Medical Center Utrecht, Utrecht, the Netherlands. Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands.
Henk M
HM
Lokhorst
Department of Hematology, University Medical Center Utrecht, Utrecht, the Netherlands. Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands.
Niels W C J
NW
van de Donk
Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands. Department of Cell Biology, University Medical Center Utrecht, Utrecht, the Netherlands.
Anton C M
AC
Martens
Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, the Netherlands. Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands. t.mutis@vumc.nl.
Tuna
T
Mutis
D051997:ADP-ribosyl Cyclase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000069286:Bortezomib / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000077269:Lenalidomide; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000175:diagnosis / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D013792:Thalidomide; D000069286:Bortezomib; D051997:ADP-ribosyl Cyclase 1; D000077269:Lenalidomide