Efficacy and safety of durvalumab combined with daratumumab in daratumumab-refractory multiple myeloma patients

Kristine A. Frerichs, Christie P.M. Verkleij, Meletios A. Dimopoulos, Jhon A. Marin Soto, Sonja Zweegman, Mary H. Young, Kathryn J. Newhall, Tuna Mutis, Niels W.C.J. van de Donk

Research output: Contribution to journalArticle*Academicpeer-review

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.

Original languageEnglish
Article number2452
JournalCancers
Volume13
Issue number10
DOIs
Publication statusPublished - 2 May 2021

Keywords

  • CD38
  • Checkpoint in-hibitor
  • Daratumumab
  • Durvalumab
  • Immunotherapy
  • Multiple myeloma
  • PD-L1

Cite this