Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma by Tineke Casneuf, Xu Steven.

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Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma by Tineke Casneuf, Xu Steven Xu, Homer C. Adams, Amy E. Axel, Christopher Chiu, Imran Khan, Tahamtan Ahmadi, Xiaoyu Yan, Sagar Lonial, Torben Plesner, Henk M. Lokhorst, Niels W. C. J. van de Donk, Pamela L. Clemens, and A. Kate Sasser BloodAdv Volume 1(23):2105-2114 October 24, 2017 © 2017 by The American Society of Hematology

Tineke Casneuf et al. Blood Adv 2017;1:2105-2114 © 2017 by The American Society of Hematology

CD38 antibody-mediated reduction of NK cells in in vitro ADCC/CDC assays. CD38 antibody-mediated reduction of NK cells in in vitro ADCC/CDC assays. Bars show percent change of NK cells in the lymphocyte (CD45+) population, averaged from 3 replicates from 3 PBMC donors. Error bars represent standard error. Samples were incubated for 3 days and then assessed by flow cytometry. Test sample values were normalized to no complement, no antibody controls. DARA, daratumumab; ISA, biosimilar SAR650984 antibody; Iso, isotype control; MOR, biosimilar MOR202 antibody. Tineke Casneuf et al. Blood Adv 2017;1:2105-2114 © 2017 by The American Society of Hematology

Reduction and recovery of NK cells after daratumumab treatment. Reduction and recovery of NK cells after daratumumab treatment. (A) Rapid, dose-dependent reduction of NK cells was observed upon daratumumab treatment at all dose levels except for 0.1 mg/kg. Recovery of NK cells was slower with increasing dose. The centered curves and shaded areas represent smoothing lines and the 95% confidence intervals around the smoothing curves, respectively. (B) Longitudinal data representation of absolute NK-cell counts over time in peripheral blood. Peripheral blood was obtained from 21 patients during treatment with daratumumab (16 mg/kg) in GEN501 at the time of progression, and at 3 and 6 months after development of progressive disease. Data are presented as mean ± standard error of the mean. (C) Reduction and recovery of NK-cell counts in the peripheral blood after daratumumab treatment. Patients received daratumumab 16 mg/kg on the recommended dosing schedule or 8 mg/kg (given once every 4 weeks); NK cells showed some recovery in patients treated with daratumumab 8 mg/kg. The lines and shaded areas represent the medians of those doses per time point and their interquartile range, respectively. P values between the indicated groups were calculated by using a paired Student t test. **P < .01; ****P < .0001. ns, not significant. Tineke Casneuf et al. Blood Adv 2017;1:2105-2114 © 2017 by The American Society of Hematology

Emax dose-response relationship between daratumumab exposure and maximum reduction in NK cells. Emaxdose-response relationship between daratumumab exposure and maximum reduction in NK cells. (A) Maximum percent reduction of NK cells from baseline by dose and (B) recovery rate of NK cells from nadir relative to baseline. The centered curves and shaded areas represent predicted average Emax curves and the 95% confidence interval around the Emax curves, respectively. Tineke Casneuf et al. Blood Adv 2017;1:2105-2114 © 2017 by The American Society of Hematology

NK cell dynamic metrics and clinical response with daratumumab treatment. NK cell dynamic metrics and clinical response with daratumumab treatment. ORR for patients divided into quartiles based on (top) baseline NK-cell count, (middle) maximum NK-cell reduction, and (bottom) NK-cell recovery rate. Numbers on the right show the mean and 95% confidence interval of ORR for that quartile, and the number of patients (n) and responders (R) in each group. Q, quartile. Tineke Casneuf et al. Blood Adv 2017;1:2105-2114 © 2017 by The American Society of Hematology

Correlation of ex vivo ADCC and clinical response. Correlation of ex vivo ADCC and clinical response. Percent of in vitro ADCC lysis against Daudi cells induced by patient PBMCs in both responders and nonresponders upon treatment. C, cycle; D, day; R, responder; NR, nonresponder. Tineke Casneuf et al. Blood Adv 2017;1:2105-2114 © 2017 by The American Society of Hematology

NK cell dynamic metrics and PFS with daratumumab treatment. NK cell dynamic metrics and PFS with daratumumab treatment. HRs according to PFS for patients divided into quartiles based on (top) baseline NK-cell count, (middle) maximum NK-cell reduction, and (bottom) NK-cell recovery rate. The numbers on the right show the mean and 95% confidence interval for the HR for that quartile and the number of patients (n) and PFS events in each group. Q1 was used as the reference group. Tineke Casneuf et al. Blood Adv 2017;1:2105-2114 © 2017 by The American Society of Hematology

Relationship between NK cell dynamic metrics and safety. Relationship between NK cell dynamic metrics and safety. Percent of patients with AEs divided into quartiles on the basis of (top) baseline NK-cell count, (middle) maximum NK-cell reduction, and (bottom) NK-cell recovery rate. Reduction in NK cells after treatment was not associated with the incidence of reported AEs. Tineke Casneuf et al. Blood Adv 2017;1:2105-2114 © 2017 by The American Society of Hematology