CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma.
The anti-CD38 monoclonal antibody daratumumab is well tolerated and has high single agent activity in heavily pretreated relapsed and refractory multiple myeloma (MM). However, not all patients respond, and many patients eventually develop progressive disease to daratumumab monotherapy. We therefore examined whether pretreatment expression levels of CD38 and complement-inhibitory proteins (CIPs) are associated with response and whether changes in expression of these proteins contribute to development of resistance. In a cohort of 102 patients treated with daratumumab monotherapy (16 mg/kg), we found that pretreatment levels of CD38 expression on MM cells were significantly higher in patients who achieved at least partial response (PR) compared with patients who achieved less than PR. However, cell surface expression of the CIPs, CD46, CD55, and CD59, was not associated with clinical response. In addition, CD38 expression was reduced in both bone marrow-localized and circulating MM cells, following the first daratumumab infusion. CD38 expression levels on MM cells increased again following daratumumab discontinuation. In contrast, CD55 and CD59 levels were significantly increased on MM cells only at the time of progression. All-trans retinoic acid increased CD38 levels and decreased CD55 and CD59 expression on MM cells from patients who developed daratumumab resistance, to approximately pretreatment values. This resulted in significant enhancement of daratumumab-mediated complement-dependent cytotoxicity. Together, these data demonstrate an important role for CD38 and CIP expression levels in daratumumab sensitivity and suggest that therapeutic combinations that alter CD38 and CIP expression levels should be investigated in the treatment of MM. These trials were registered at www.clinicaltrials.gov as #NCT00574288 (GEN501) and #NCT01985126 (SIRIUS).
Department of Hematology, Cancer Center Amsterdam, Vrije Universiteit Medical Center, Amsterdam, The Netherlands; Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands;
Inger S
IS
Nijhof
Janssen Research & Development, Beerse, Belgium;
Tineke
T
Casneuf
Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands;
Jeroen
J
van Velzen
Department of Hematology, Cancer Center Amsterdam, Vrije Universiteit Medical Center, Amsterdam, The Netherlands;
Berris
B
van Kessel
Janssen Research & Development, Spring House, PA; and.
Amy E
AE
Axel
Janssen Research & Development, Spring House, PA; and.
Khaja
K
Syed
Department of Hematology, Cancer Center Amsterdam, Vrije Universiteit Medical Center, Amsterdam, The Netherlands;
Richard W J
RW
Groen
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Mark
M
van Duin
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Pieter
P
Sonneveld
Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands;
Monique C
MC
Minnema
Department of Hematology, Cancer Center Amsterdam, Vrije Universiteit Medical Center, Amsterdam, The Netherlands;
Sonja
S
Zweegman
Janssen Research & Development, Spring House, PA; and.
Christopher
C
Chiu
Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands;
Andries C
AC
Bloem
Department of Hematology, Cancer Center Amsterdam, Vrije Universiteit Medical Center, Amsterdam, The Netherlands;
Tuna
T
Mutis
Department of Hematology, Cancer Center Amsterdam, Vrije Universiteit Medical Center, Amsterdam, The Netherlands; Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands;
Henk M
HM
Lokhorst
Janssen Research & Development, Spring House, PA; and.
A Kate
AK
Sasser
Department of Hematology, Cancer Center Amsterdam, Vrije Universiteit Medical Center, Amsterdam, The Netherlands;
Niels W C J
NW
van de Donk
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D018958:CD55 Antigens; D018957:CD59 Antigens; D002999:Clone Cells; D051056:Complement Inactivating Agents / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D018958:CD55 Antigens; D018957:CD59 Antigens; D051056:Complement Inactivating Agents; C051590:CD59 protein, human; C556306:daratumumab; D014212:Tretinoin; D051997:ADP-ribosyl Cyclase 1