Efficacy and Safety of Durvalumab Combined with Daratumumab in Daratumumab-Refractory Multiple Myeloma Patients
by
, , ,
Kristine A. Frerichs
1,†, 
Christie P. M. Verkleij
1,†,
Meletios A. Dimopoulos
2
,
Jhon A. Marin Soto
1,
Sonja Zweegman
1,
Mary H. Young
3,
Kathryn J. Newhall
3,
Tuna Mutis
1 and 
Niels W. C. J. van de Donk
1,*
1
Cancer Center Amsterdam, Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
2
Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece
3
Bristol Myers Squibb, Seattle, WA 98102, USA
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2021, 13(10), 2452; https://doi.org/10.3390/cancers13102452
Submission received: 31 March 2021
/
Revised: 3 May 2021
/
Accepted: 14 May 2021
/
Published: 18 May 2021
(This article belongs to the Special Issue Combination Therapy Strategies for Cancer PD-1/PD-L1 Pathway Blockade Awareness)
Simple Summary
The CD38-targeting antibody daratumumab has marked activity in multiple myeloma through direct anti-tumor effects and immunomodulatory activity. However, eventually most patients will develop daratumumab-refractory disease. We hypothesized that daratumumab-resistance could be reversed by the addition of an inhibitor of the PD-1/PD-L1 signaling pathway, resulting in improved T- and NK-cell mediated anti-tumor immune responses. We therefore performed a phase 2 study to investigate the efficacy and safety of adding the PD-L1 checkpoint inhibitor durvalumab to daratumumab at the time of daratumumab failure. The toxicity profile of the daratumumab/durvalumab combination was acceptable, but none of the 18 enrolled patients achieved a clinical response. Immunomonitoring of bone marrow samples at baseline and during treatment showed a reduction of regulatory T-cell numbers and a decrease in the proportion of T-cells expressing LAG3 and CD8+ T-cells expressing TIM-3, whereas tumor cell characteristics were not affected. These results indicate that co-targeting PD-L1 at the time of daratumumab failure is insufficient to reverse daratumumab-resistance.
Abstract
Daratumumab is active both as a single agent and in combination with other agents in multiple myeloma (MM) patients. However, the majority of patients will develop daratumumab-refractory disease, which carries a poor prognosis. Since daratumumab also has immunomodulatory effects, addition of the PD-L1 blocking antibody durvalumab at the time of progression may reverse daratumumab-resistance. The efficacy and safety of daratumumab and durvalumab in daratumumab-refractory relapsed/refractory MM patients was evaluated in this prospective, single-arm phase 2 study (NCT03000452). None of the 18 enrolled patients achieved PR or better. The frequency of serious adverse events was 38.9%, with one patient experiencing an immune related adverse event (grade 2 hyperthyroidism). No infusion-related reactions were observed. Analysis of tumor- and immune cell characteristics was performed on bone marrow samples obtained at baseline and during treatment. Daratumumab combined with durvalumab reduced the frequency of regulatory T-cells and decreased the proportion of T-cells expressing LAG3 and CD8+ T-cells expressing TIM-3, without altering T- and NK-cell frequencies. Durvalumab did not affect tumor cell characteristics associated with daratumumab resistance. In conclusion, the addition of durvalumab to daratumumab following development of daratumumab-resistance was associated with an acceptable toxicity profile, but was not effective. This indicates that inhibition of the PD-1/PD-L1 signaling pathway at the time of daratumumab-resistance is insufficient to reverse daratumumab-resistance.
Keywords:
immunotherapy; multiple myeloma; PD-L1; CD38; daratumumab; checkpoint inhibitor; durvalumab
