Research Fellow Mayo Clinic rochester, Minnesota, United States
Introduction: Defining refractoriness to specific drugs/ drug classes is important for determining eligibility for clinical trials and to compare results across studies in multiple myeloma (MM). As such, MM that is nonresponsive or progresses within 60 days of last therapy is currently considered to be refractory to that therapy. We hypothesized that subgroups of MM that typically exhibit faster response/ relapse kinetics (e.g., high risk MM) might require different intervals from last exposure for defining refractoriness, as compared to the current 60 days definition.
Methods: We retrospectively reviewed all newly diagnosed MM patients (pts) at our institute between January 2004 and December 2018 who experienced disease progression with first line lenalidomide (Len) containing regimens, and subsequently received another Len containing regimen at any time during the disease course. We collected the time duration from last Len dose to first disease progression, and assigned 30 days, 60 days, and 120 days as cut-offs for defining Len refractoriness. We then assessed progression free survival (PFS) for next line therapy and the next Len containing line of therapy using Kaplan Meier and Cox models and used Harrell’s Concordance Index (C) to measure the performance of different models.
Results: A total of 202 pts were included. Overall, 43%, 39%, and 18% pts were International Staging System Stage I, II, and III; 32% pts had high risk FISH as per mSMART. For Len refractory vs not refractory pts, the median PFS for next Len containing therapy was 10 months (95% CI: 6-13) vs 31 months (95% CI: 22-40) using a 30-days cutoff, and 10 months (95% CI: 6-13) vs 32 months (95% CI: 25-43) using 60-days and 120-days cutoffs (p < 0.001 for all). In the high-risk subgroup: for Len refractory vs not refractory pts, the median PFS for next Len containing therapy was 5 months (95% CI: 4-10) vs 41 months (95% CI: 19-NR) using a 30-days cutoff, and 5 months (95% CI: 4-7) vs 42 months (95% CI: 25- NR) using 60-days and 120-days cutoffs (p < 0.001 for all). Harrell’s C (95% CI) for 30-days, 60-days, and 120-days cutoffs were 0.605 (0.564-0.646), 0.637 (0.598-0.676), and 0.636 (0.597-0.675) respectively. In the high-risk subgroup, Harrell’s C for 30-days, 60-days, and 120-days cutoffs were 0.684 (0.613-0.755), 0.708 (0.641-0.775), and 0.708 (0.641-0.775) respectively. Similar trends were observed for all pts and high-risk MM pts for PFS with 2nd line therapy as well.
Conclusions: We did not find an improvement in separation of survival curves or Harrell’s C when using 30 days or 120 days as cutoffs for defining refractoriness, as compared to 60 days. The current 60 days cutoff from last drug exposure to disease progression functions well for defining refractoriness to MM drugs.
