Patients with multiple myeloma who are refractory to CD38-targeted monoclonal antibody therapy have poor outcomes, according to results of a retrospective study published online in Leukemia.1

CD38-targeting agents include daratumumab, a US Food and Drug Administration (FDA)-approved drug, and isatuximab, another agent under investigation. Daratumumab is approved by the FDA as a single agent and in combination with lenalidomide, bortezomib, or pomalidomide for patients with relapsed or refractory multiple myeloma, and in combination with bortezomib, melphalan, and prednisone for patients with newly diagnosed, transplant-ineligible multiple myeloma.2

This multicenter, retrospective study was performed to evaluate the natural history and outcomes of patients with multiple myeloma who are refractory to CD38-targeting agents.

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Patients with multiple myeloma were eligible for this study if they had received at least 4 weeks of treatment with daratumumab or isatuximab and showed evidence of progressive disease while on therapy or within 60 days of the last dose of CD38-targeting therapy following evidence of refractory disease. The time point where this definition of progressive disease was met was termed T0. Study data from 14 academic institutions was accessed between January 2017 and June 2018, and patients were classified into 3 groups:

  • “Penta-refractory” (ie, refractory to 1 CD38-targeted agent plus 2 proteosome inhibitors plus 2 immunomodulatory agents)
  • “Triple-refractory” (ie, refractory to 1 CD38-targeting agent plus 1 proteosome inhibitor plus 1 or 2 immunomodulatory agents) or “quad–refractory” (ie, refractory to 1 CD38-targeting agent plus 1 or 2 proteosome inhibitors plus 1 immunomodulatory agent)
  • “Not triple-refractory” (ie, refractory to 1 CD38-targeting agent, but not both a proteasome inhibitor and an immunomodulatory agent).

Of the 275 patients included in the study, the median interval between disease diagnosis to T0 was 50.1 months, the median lines of therapy before the CD38-targeting agent was administered was 4, and 25% and 54% of patients were classified as “penta-refractory” and “triple- or quad-refractory”, respectively.

The median follow-up of survivors (from T0) was 10.6 months. Median overall survival (OS) for the entire cohort, and the groups classified as “not triple-refractory,” “triple- and quad-refractory”, and “penta-refractory” were 8.6 months, 11.2 months, 9.2 months, and 5.6 months, respectively. 

Ninety percent of patients received at least 1 subsequent line of therapy beyond T0. The median progression-free survival (PFS) and OS in this group were 3.4 months and 9.3 months, respectively, although patients who did not receive subsequent therapy had a median OS of only 1.3 months.

Overall response rates to the first regimen following T0 were 31%, 38%, 29% and 30% for the overall cohort, and the groups classified as “not triple-refractory,” “triple- and quad-refractory”, and “penta-refractory,” respectively.

Results of analyses aimed at determining which first-line, post-T0 therapies were most effective in these patients suggested that PFS was longest in patients receiving carfilzomib plus an alkylator (5.7 months), and daratumumab plus an immunomodulatory agent (4.5 months). 

“Patients with multiple myeloma refractory to CD38-targeting agents have poor prognosis and this study provides a benchmark for new therapies to be tested in this population,” the authors wrote in conclusion.


  1. Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy [published online March 11, 2019]. Leukemia. doi: 10.1038/s41375-019-0435-7
  2. Daratumumab (Darzalex) [package insert]. Horsham, PA; Janssen Biotech, Inc.: 2018.