Identifying Surrogate End Points for PFS in Newly Diagnosed Multiple Myeloma

Minimal residual disease, overall response rate, complete response rate, and stringent complete response may be useful as surrogate end points to estimate progression-free survival (PFS) benefit for patients with newly diagnosed multiple myeloma.

In patients with newly diagnosed multiple myeloma (NDMM), progression-free survival (PFS) was significantly associated with overall response rate (ORR), complete response (CR), stringent CR (sCR), and minimal residual disease (MRD), indicating that they may be used as surrogate end points to estimate PFS benefit, according to a poster presented at the European Hematology Association 2021 Virtual Congress.

While overall survival is the gold standard of clinical end points, it requires a larger sample size and longer follow-up, and PFS is more commonly used as the primary survival end point in NDMM trials, the authors explained. “Validation of short-term surrogate endpoints for PFS that could be measured earlier is therefore of interest and appropriate in NDMM,” they wrote.

They conducted a systematic literature review using MEDLINE, EMBASE, and Cochrane databases, as well as a review of real-world evidence studies. Pearson’s correlation weighted by the sample size in each study arm was used to estimate correlations between PFS and ORR, CR, sCR, and MRD.

Seventy-five randomized controlled trials with 101 arms reported median PFS and were included in the review. They found:

  • There was a moderate correlation between ORR and median PFS, as well as CR and median PFS
  • Adjusted models predicted an extra 3.5 months and 2.9 months of median PFS per 10% increase in ORR and CR, respectively
  • There was a strong correlation between sCR and median PFS, as well as MRD and median PFS
  • Due to small sample size, they could not construct adjusted models, but unadjusted models predicted an extra 5.25 months of median PFS per 5% increase in sCR and an extra 8.75 months of median PFS per 25% increase in MRD

The review of real-world evidence included 49 studies with 10,082 patients. Thirty-seven studies were retrospective and 30 studies were done at a single center. Only 20 of the studies investigated correlations of OS/PFS with MRD/sCR. The studies showed:

  • A significant survival benefit (P < .05) for MRD-negative patients in 12 studies
  • Survival significantly increased among patients with sCR in 2 studies

The findings of both the literature review of randomized controlled trials and of real-world evidence studies support other evidence that MRD negativity is a “viable surrogate for PFS” in multiple myeloma, the authors wrote.

“Being able to predict survival outcomes through response end points available earlier in a trial may help to inform decisions on, and accelerate access to, novel therapeutics and drug combinations in NDMM,” they concluded.


Daniele P, Mamolo C, Cappelleri JC, et al. Overall, complete, and stringent complete response rates and minimal residual disease as potential surrogates for progression-free survival in newly diagnosed multiple myeloma. Presented at: EHA2021 Virtual Congress; June 9-17, 2021. Poster EP1025.