NK Cell Phenotype Is Associated With Response and Resistance to Daratumumab in Relapsed/Refractory Multiple Myeloma

The CD38-targeting antibody daratumumab has marked activity in multiple myeloma (MM). Natural killer (NK) cells play an important role during daratumumab therapy by mediating antibody-dependent cellular cytotoxicity via their Fc gamma RIII receptor (CD16), but they are also rapidly decreased following initiation of daratumumab treatment. We characterized the NK cell phenotype at baseline and during daratumumab monotherapy by flow cytometry and cytometry by time of flight to assess its impact on response and development of resistance (DARA-ATRA study; NCT02751255). At baseline, nonresponding patients had a significantly lower proportion of CD16(+) and granzyme B+ NK cells, and higher frequency of TIM-3(+) and HLA-DR+ NK cells, consistent with a more activated/exhausted phenotype. These NK cell characteristics were also predictive of inferior progression-free survival and overall survival. Upon initiation of daratumumab treatment, NK cells were rapidly depleted. Persisting NK cells exhibited an activated and exhausted phenotype with reduced expression of CD16 and granzyme B, and increased expression of TIM-3 and HLA-DR. We observed that addition of healthy donor-derived purified NK cells to BM samples from patients with either primary or acquired daratumumab-resistance improved daratumumab-mediated MM cell killing. In conclusion, NK cell dysfunction plays a role in primary and acquired daratumumab resistance. This study supports the clinical evaluation of daratumumab combined with adoptive transfer of NK cells

Monotone operators without enlargements

Enlargements have proven to be useful tools for studying maximally monotone mappings. It is therefore natural to ask in which cases the enlargement does not change the original mapping. Svaiter has recently characterized nonenlargeable operators in reflexive Banach spaces and has also given some partial results in the nonreflexive case. In the present paper, we provide another characterization of non-enlargeable operators in nonreflexive Banach spaces under a closedness assumption on the graph. Furthermore, and still for general Banach spaces, we present a new proof of the maximality of the sum of two maximally monotone linear relations. We also present a new proof of the maximality of the sum of a maximally monotone linear relation and a normal cone operator when the domain of the linear relation intersects the interior of the domain of the normal cone