CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma

Abstract

Key Points• Response to the CD38-targeting antibody daratumumab is significantly associated with CD38 expression levels on the tumor cells.• Resistance to daratumumab is accompanied by increased expression of complementinhibitory proteins.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). (Blood. 2016;128(7):959-970)

Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab

“…We also demonstrated that response to daratumumab is partly dependent on baseline CD38 expression levels on the tumor cells(13). In addition, increased expression of CD38, either by transducing MM cells with the human CD38 gene or by treating cells with all- trans retinoic acid, significantly enhanced daratumumab-mediated killing(13,14).…”

“…We have previously shown that extent of CDC and ADCC in pretreatment samples was associated with clinical response to daratumumab as single agent(13). We also demonstrated that response to daratumumab is partly dependent on baseline CD38 expression levels on the tumor cells(13).…”

Advances and practical use of monoclonal antibodies in multiple myeloma therapy

“…Future directions include identifying biomarkers that may predict response to therapy and exploring mechanisms of innate and acquired resistance, some of which may involve varying levels of expression of target antigens on tumor cells 40 or the development of anti-drug antibodies over time with treatment. Moreover, new mAb targets beyond CD38 and SLAMF7 are being actively investigated in preclinical and clinical studies.…”

Daratumumab combinations: what can we learn?

“…2,3 Understanding of the mechanisms that control neutrophil turnover was revolutionized by the discovery that cell lifespan is regulated not only by intracellular signaling but also by global changes in gene expression that together comprise an apoptosis differentiation program. [4][5][6] These seminal studies overturned the notion that neutrophils have little or no capacity for transcription or translation and set the stage for subsequent studies of neutrophil lifespan in the context of specific infectious and inflammatory diseases. 3 The NR4A family of orphan nuclear receptors is composed of 3 members: NR4A1, NR4A2, and NR4A3.…”

“…Mechanisms involving downregulation of CD38 expression, exhaustion of the immune system, development of complement resistance, or target saturation failure have been postulated to lead to anti-CD38 failure. 5 The investigation of these escape mechanisms is crucial for the identification of optimal combinations and new targets that could be ) are associated with a PFS of about 4 months, whereas, given in combination, there is a PFS of about 9 months. Thus, for some patients, the sequential use of the 2 regimens could be associated with a similar outcome.…”