Among patients with multiple myeloma (MM) receiving daratumumab, balancing expression of CD38 on target and effector cells may help to improve therapy response, according to research published in Cancers.

On average, patients with MM have seen significant improvements in survival since the advent of stem cell transplantation and novel therapies, including proteasome inhibitors. The disease remains, however, incurable, with the majority of patients relapsing after first-line treatments.

Daratumumab, a monoclonal antibody targeting CD38, has shown promise for the treatment of MM in both the first-line and relapsed-disease settings. A hypothesized mechanism for monoclonal antibodies, including daratumumab, is the recruitment of the immune system’s natural killer cells using antibody-dependent cellular cytotoxicity (ADCC).

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There is, however, evidence that daratumumab depletes the number of natural killer cells by as much as 85%, suggesting that using CD38-expressing natural killer cells may help to improve responses to therapy. For this cell-line study, researchers evaluated whether CD38 expression modulation in target and effector cells has implications for the ADCC-dependent cytotoxic effects associated with daratumumab treatment.

Results of the cell line analysis suggested that adding all-trans retinoic acid (ATRA) or interferon-alpha to myeloma cells can modulate CD38 expression. ADCC was, furthermore, shown to depend on CD38 expression on both effector and target cells.

Adding ATRA or interferon-alpha, however, can mitigate these effects: ATRA increased surface-level CD38 expression by approximately 3-fold, while interferon-alpha increased this expression by approximately 2-fold.

“In conclusion, by using [natural killer]-92 cell line, which is off-the-shelf available, we showed that the balance between CD38 levels on effector and target cells is crucial for induction of ADCC,” the authors wrote. “This cytotoxicity could be further increased by either upregulating CD38 expression or neutralizing CD38 on effector cells with a blocking nanobody.”


Lejeune M, Duray E, Peipp M, et al. Balancing the CD38 expression on effector and target cells in daratumumab-mediated NK cell ADCC against multiple myeloma. Cancers (Basel). 2021;13(12):3072. doi:10.3390/cancers13123072