Outcomes of Relapsed and Refractory Multiple Myeloma with the Evolving Standard of Care

Introduction: Multiple myeloma (MM) remains an incurable disease despite the introduction of several agents in the last two decades. While the standard-of-care (SOC) drugs like proteasome inhibitors (PI), and immunomodulatory drugs (IMiD) are effective in controlling the disease and achieving remissions, disease progression and relapse invariably occur. During the disease course, most of the surviving patients will end up in a RRMM status with previous exposure or even resistance to all available treatments. This study aims to assess the impact of the evolving SOC on the outcomes in RRMM compared to those of an earlier cohort. Methods: This is a retrospective, observational study. Clinical and laboratory data parameters were collected from patients with MM treated at the Department of Hematology, Karolinska University Hospital in Stockholm, Sweden. Inclusion was based on the following criteria: ≥18 years at MM diagnosis, relapsed or refractory disease according to the International Myeloma Working Group criteria, most recent RRMM timepoint during 2013 through 2022, and having received at least one subsequent line of treatment (LOT) after first-line treatment. Patients were divided into two groups depending on the date of their last RRMM event: January 1, 2013 - June 30, 2018 (cohort A) and July 1, 2018 - December 31, 2022 (cohort B). The two cohorts were separated by the introduction of anti-CD38 monoclonal antibodies (mAb) to the treatment of MM at our center. The Kaplan-Meier method was used to calculate overall survival (OS) and progression free survival (PFS) for the entire cohort as well as for both groups using programming language R. Outcomes were analyzed from the start of the second LOT (2L) and for each subsequent LOT. A separate analysis was performed for patients with previous or ongoing exposure to at least 1 PI, 1 IMiD, and 1 anti-CD38 mAb during all LOTs. Results: 381 RRMM patients were identified according to the study criteria, 138 in cohort A and 243 in cohort B. Overall, 57% were male, the median age at MM diagnosis was 69 years, and the proportion of ISS I, II III were 15%, 46% and 23%, while 17% was not determinable due to missing data. In addition, 188 patients (49%) had an available cytogenetic risk profile at diagnosis, where 70 (37% of available) had high risk disease, defined as presence of del17p, t(4;14), t(14;16) or add1q. During follow-up, cohort A had a median of 3L (range 1-9) and cohort B 2L (range 1-7). The number of patients that started each LOT were 381 at 2L, 255 at 3L, 128 at 4L, 38 at 5L, 25 at 6L, 9 at 7L, 2 at 8L, and 2 at 9L. When stratified to cohorts A and B, the ratio of patients at each LOT was 138/243, 97/158, 52/76, 24/14, 16/9, 8/1, 2/0, and 2/0, at 2L to 9L, respectively. 162 patients received PI, IMiD, and anti-CD38 mAb during all LOT. Comparing mOS in cohorts A and B, the difference at 2L was 22.1 vs 69.2 months (p<0.0001), 3L 9.4 vs 42.9 months (p<0.0001), and 4L 6.65 vs 19.9 months (p=0.0028). The difference in mPFS in cohorts A and B was at 2L 7.8 vs 15.5 months (p=0.00094), 3L 4.4 vs 11.9 months (p<0.0001), 4L 2.3 vs 10.0 months (p=0.00014), 5L 2.8 vs 7.95 months (p=0.044), and 6L 1.6 vs 10.0 months (p=0.0093). The significantly longer mOS and mPFS in cohort B at 2L-4L show that the introduction of new drugs at our center, such as anti-CD38 mAb and carfilzomib, have improved outcomes in RRMM patients. Analyzing mOS in patients that received PI, IMiD and anti-CD38 mAb compared to patients not exposed to all 3 drug classes, mOS at start of 2L was 68.4 vs 29.4 months (p<0.0001), 3L 34.7 vs 13.8 months (p=0.00013), and 4L 19.9 vs 6.7 months (p=0.00083). Conclusions: In this real-world cohort, RRMM patients during recent years (2018 July - 2022) exhibit significantly superior OS and PFS compared to patients during the preceding 5.5 years. This significant difference in the third and fourth LOT, implies that the introduction of new drugs has had an impact in patient outcomes. Additionally, patients who received PI, IMiD, and anti-CD38 mAb had significantly longer survival. Our results highlight the need for continuing development of new treatment options for RRMM patients. In this setting, novel immunotherapeutic drugs have shown promising results in previous studies, however additional evidence is required from the real-world.