Prognostic Impact of Response Kinetics and Influencing Factors in Multiple Myeloma Patients Treated with Carfilzomib- or Ixazomib-Based Treatment

Background A rapid response to treatment was commonly linked to improved survival outcomes in acute leukemia or lymphoma. However, contrasting results were shown in multiple myeloma. In the TOURMALINE trial with ixazomib-based therapy, a ‘late’ response was significantly associated with better survival. Similarly, in carfilzomib-based treatments, longer time to response was correlated with better survival outcomes. Here, we evaluated the prognostic significance of response kinetics in a uniformly controlled cohort of patients and investigated factors associated with these kinetics. Patients and methods Medical records of patients who received carfilzomib- or ixazomib-based second-line treatment from January 2015 to June 2021 were collected from 17 medical centers in South Korea. The best response was defined as the highest level of response achieved during the treatment. The time to best response was calculated from the initiation of therapy to the time point of achieving the best response. Survival outcomes were analyzed using the Kaplan-Meier method, and a landmark analysis was performed to eliminate time bias. To compare the characteristics of categorical variables, the chi-square test was utilized. Results A total of 393 patients were enrolled in the study: 314 patients (79.9%) received carfilzomib-based treatment and 79 patients (20.1%) received ixazomib-based treatment. Of these, 323 patients who achieved a partial response or better response were analyzed for response kinetics. The median time to best response was 3 months (range, 0.5-44.8 months). Patients treated with ixazomib-based regimens had a longer median time to best response of 3.7 months compared to 2.9 months for those treated with carfilzomib-based regimens. Patients were categorized based on the time to achieve the best response: rapid responders (achieving best response within 3 months) included 166 patients, while slow responders (achieving best response after more than 3 months) included 157 patients. Slow responders demonstrated significantly better survival outcomes compared to rapid responders in both progression-free survival (PFS) and overall survival (OS) (rapid vs. slow responders, median PFS: 23.5 vs. 37.8 months, p < 0.001; median OS: 23.4 months vs. not reached, p < 0.001). This trend was consistent in subgroups categorized by carfilzomib- or ixazomib-based treatment. There were no significant differences in classical prognostic factors at diagnosis, such as International Staging System (ISS), high-risk cytogenetics, and Revised-ISS, between slow and rapid responders. However, differences were observed in certain characteristics at the time of second-line treatment, including early relapse after first treatment <2 years (43.3% vs. 56.7%, p = 0.064), beta-2 microglobulin >3.5 mg/L (50.0% vs. 67.6%, p = 0.039), plasmacytoma (11.9% vs. 19.9%, p = 0.069), light-chain difference >300 mg/L (40.1% vs. 54.0%, p = 0.014), hemoglobin level <10 g/dL (23.2% vs. 33.7%, p = 0.038), and ALC/WBC ratio <20% (10.5% vs. 21.6%, p = 0.008). Conclusions Response kinetics were significantly associated with survival outcomes, with slow responders demonstrating better survival compared to rapid responders. Factors indicating high disease burden or poor prognosis at the time of second-line initiation were associated with response kinetics. Therefore, even if a response is not achieved at the first evaluation, it may be necessary to continue carfilzomib- or ixazomib-based treatment for several months if the tumor burden is not relatively high.