The clinical course and life expectancy of patients with multiple myeloma who discontinue their first daratumumab‐containing line of therapy
Authors: Agoston Gyula Szabo, Jonathan Thorsen, Katrine Fladeland Iversen, Mette Bøegh Levring, Birgitte Preiss, Carsten Helleberg, Marie Fredslund Breinholt, Emil Hermansen, Lise Mette Rahbek Gjerdrum, Søren Thorgaard Bønløkke, Katrine Nielsen, Eigil Kjeldsen, Elena Manuela Teodorescu, Marveh Dokhi, Eva Kurt, Casper Nørgaard Strandholdt, Mette Klarskov Andersen, Annette Juul Vangsted
Journal: American Journal of Hematology (2021)

Based on its efficacy in clinical trials, daratumumab has become an integral part of the treatment of multiple myeloma (MM) since its first approval in 2016. Until recently, only a few studies have reported on the real-world use of daratumumab, and these reports were based on small patient cohorts.1-4 Monoclonal Antibodies in Multiple Myeloma: Outcomes after Therapy Failure (MAMMOTH) was the first and to date only multicenter study that investigated the outcomes of daratumumab-refractory patients.5 This work included patients with active MM with evidence of progressive disease during treatment with CD38 antibody-containing regimen and described 275 MM patients from 14 academic centers in the United States. The median overall survival (OS) in the entire cohort after refractoriness to a CD38 antibody, occurring at a median of 50.1 months after diagnosis, was 8.6 months. We have previously described a complete, Danish, nationwide cohort of 635 patients with MM who initiated treatment with daratumumab prior to January 1, 2019.6 In the present work, we focus on the clinical course and life expectancy of patients who discontinue daratumumab. The methods of this study regarding patient identification and data collection have been previously described.6 In short, we conducted a retrospective review of the clinical course of all patients treated with a daratumumab-containing regimen prior to January 1, 2019. Treatment data were updated until January 1, 2019. The index regimen (IR) was defined as the first daratumumab-containing line of therapy. T0 was defined as the date of discontinuation of the IR. Based on the IR, patients were classified into four groups: daratumumab–bortezomib–dexamethasone (DVD), daratumumab–lenalidomide dexamethasone (DRD), daratumumab monotherapy (D-mono), and daratumumab in other combinations (D-other). Previous drug exposure at T0 was assessed based on four classes of drugs: alkylating agents, proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide), and daratumumab (no other CD38 antibody was used in the study population). Patients were classified into four groups at T0: double class exposed (exposed to daratumumab and another class of drugs), triple class exposed (exposed to daratumumab and two other classes of drugs), quadruple class exposed (exposed to daratumumab and three other classes of drugs) and alkylator–bortezomib–carfilzomib–daratumumab–lenalidomide–pomalidomide-exposed. Post-T0 lines of therapy 1–6 were termed P1–P6, respectively. The methods of statistical analysis are presented in Supplementary Methods in Appendix S1. We identified 474 patients who discontinued the IR. The characteristics of these patients are shown in Table S1. The median age at diagnosis was 66 years and 57% of patients were male. Patients received a median of three lines of therapy prior to the IR and 50% of patients had been treated with high-dose melphalan and autologous stem cell transplantation (HDM-ASCT). The IR was DRD in 44%, D-mono in 32%, DVD in 13%, and D-other in 11% of patients. The median duration of the IR was 5 months. The reasons for discontinuation of the IR are shown in Figure S1. The most frequent reasons for discontinuation were progressive disease (42%), toxicity (11%), and insufficient response (8%). The median time from diagnosis to T0 was 4 years. At T0, 12 (3%) patients were double class exposed, 53 (11%) were triple class exposed, 350 (74%) were quadruple class exposed, and 59 (12%) were alkylator–bortezomib–carfilzomib–daratumumab–lenalidomide–pomalidomide-exposed. The median follow-up after T0 was 9.2 (interquartile range [IQR]: 1.8–17.6) months. The median OS (mOS) in the entire cohort was 12.2 months (confidence interval [CI]: 9.9–14.7; Figure 1A). According to cytogenetic status, mOS was 8.6 months (CI: 5.8–13.3) in high-risk patients and 14.7 months (CI 11.6–22.3) in standard-risk patients (p = .006; Figure 1B). According to the previous IR, mOS was 11.4 months (CI 8.9–16.1) after DRD, 13.3 months (CI: 10.4–20.7) after D-mono, 17.8 months (CI: 12.7-not reached [NR]) after DVD and 5.8 months (CI 1.5–9.2) after D-other (p = .0003; Figure 1C). According to drug class exposure at T0, mOS was 15.3 months (CI: 8.9-NR) in double class exposed, 22.5 months (CI: 11.3-NR) in triple class exposed, 12.6 months (CI: 10.0–15.8) in quadruple class exposed, and 8.3 months (CI: 4.1–10.6) in alkylator–bortezomib–carfilzomib–daratumumab–lenalidomide–pomalidomide-exposed patients (p = .002; Figure 1D). According to the cause of discontinuation of the IR, mOS was 10 months (CI: 8.5–12.9) in patients who discontinued due to progressive disease and 15.8 months (CI: 11.4–25.7) in patients who discontinued due to other reasons (p = .009; Figure 1E). After T0, the number of patients receiving a subsequent line of therapy decreased from 375 (79%) in P1 to 28 (6%) in P6 (Table S2). The overall response rate (ORR) decreased from 44% in P1 to 11% in P6. Median time to next treatment (TNT) decreased from 4.7 months (IQR: 2.0; 8.3) in P1 to 1.8 months (IQR: 0.9; 3.2) in P6. The most frequently used regimens in P1 are shown in Table S3. Figures S2 and S3 show the ORR and TNT in P1 according to the previous IR. Figures S4 and S5 show the ORR and TNT in P1 according to drug class exposure at T0. Of the patients who received a subsequent line of therapy after T0, 192 (51%) were retreated with a daratumumab-containing regimen in P1 (Table S4). The number of patients who had progressed on the IR was 89 (46%) among patients retreated with daratumumab and 147 (80%) among patients treated without daratumumab. The most frequently used regimens in patients retreated with daratumumab were daratumumab–pomalidomide–dexamethasone (DPD; n = 57; 30%), DRD (n = 44; 23%), and DVD (n = 22; 12%). The IR prior to these combinations was D-mono in 41, 23, and 15 of cases, respectively. The most frequently used regimens in patients treated without daratumumab were carfilzomib–dexamethasone (n = 36; 20%), pomalidomide–dexamethasone (n = 22; 12%), and carfilzomib–pomalidomide–dexamethasone (n = 16; 7%). ORR was 48% in patients retreated with and 41% in patients treated without daratumumab (Figure S6). Median TNT was 4.6 months in both groups (Figure S7). Median OS was 23.6 months (CI: 17.5-NR) in patients retreated with and 11.3 months (CI: 9.5–15.1) in patients treated without daratumumab (p < .0001; Figure 1F). After multivariate analysis adjusting for age, previous HDM-ASCT, IR, drug class exposure at T0, treating site, time from diagnosis to T0, presence of cytogenetic high-risk markers, and discontinuation of the IR due to progressive disease, daratumumab retreatment was associated with longer OS (Cox regression; hazard ratio 0.59; CI: [0.41–0.87], p = .006). Based on an unselected nationwide cohort of every patient treated with daratumumab until January 1, 2019, this is the largest real-world study to report the outcomes of patients who discontinue their first daratumumab-containing line of therapy. The mOS of patients who discontinue their first daratumumab-containing line of therapy was 12.2 months, while it was 10 months in patients who discontinued due to progressive disease. Approximately half of the patients who received subsequent therapy were retreated with daratumumab. About 46% of daratumumab-retreated patients were daratumumab-refractory. The most frequently used regimens for daratumumab retreatment were DPD, DRD, and DVD used primarily after daratumumab monotherapy. In our cohort, daratumumab retreatment was associated with a superior OS on multivariate analysis. A strength of our work is that it investigates a complete, population-based cohort without referral bias. Among the limitations of our work are its retrospective nature and observational design, which resulted in a heterogeneous cohort of patients treated with various daratumumab-containing regimens. Instead of drug class refractoriness, our study reports previous drug class exposure. The life expectancy of patients discontinuing daratumumab was slightly more favorable based on our data than reported in the MAMMOTH study.5 This may be explained by differences in methodology. The mOS of 8.3 months in alkylator–bortezomib–carfilzomib–daratumumab–lenalidomide–pomalidomide-exposed patients indicates an unmet medical need. Drug-antibody conjugates, bispecific antibodies, and chimeric antigen receptor T cell therapy are among the promising treatment options for this group of patients. Whether daratumumab retreatment is associated with clinical benefit needs to be explored in prospective randomized clinical trials. This study was approved on behalf of the Danish Data Protection Agency by The Region of Southern Denmark (Journal 19/52220) and the Danish Patient Safety Authority (Journal 3-3013-2047/1 and 3-3013-2047/2). We thank the Department of Internal Medicine and the Hematological Clinical Research Unit at Vejle Hospital for providing the financial and logistical background for this study. Data management for this study was provided by Open Patient Exploratory Network, University of Southern Denmark. AGS: Consulting for Janssen, Sanofi, Takeda. AJV: Honoraria from Janssen and Celgene; consulting for Takeda, Sanofi, Oncopeptides. KFI, MBL, CH, NEH, STB, KN, EMT, MD, EK, CS, BP, MFB, LMRG, EK, MKA: No conflicts of interest. Agoston Gyula Szabo designed the study, established the study database, conducted patient chart review, entered clinical data in the study database, created figures, and wrote the manuscript. Jonathan Thorsen carried out data analysis, statistics, created figures, and participated in the writing of the manuscript. Katrine Fladeland Iversen, Mette Bøegh Levring, Carsten Helleberg, Emil Hermansen, Søren Thorgaard Bønløkke, Katrine Nielsen, Eigil Kjeldsen, Elena Manuela Teodorescu, Marveh Dokhi, Eva Kurt, Casper Nørgaard Strandholdt conducted patient chart review, entered clinical data in the study database, and participated in the writing of the manuscript. Birgitte Preiss, Marie Fredslund Breinholt, Lise Mette Rahbek Gjerdrum, Eva Kurt, Mette Klarskov Andersen collected cytogenetic data and participated in the writing of the manuscript. Annette Juul Vangsted conducted the patient chart review, entered clinical data in the study database, supervised the study, and participated in the writing of the manuscript. The datasets generated and analyzed during the current study are not publicly available due to the National and European Data Protection Regulation. Appendix S1. Supporting Information. Table S1. Characteristics of patients. Table S2. Efficacy of lines of therapy after discontinuation of the first daratumumab-containing line of therapy. Table S3. Most frequently used regimens in P1*. Table S4. The number of patients retreated with daratumumab in P1* across Danish sites. Figure S1. Reasons for discontinuation of the index regimen. Figure S2. Response to P1* by index regimen. Figure S3. TNT of P1* by index regimen. Figure S4. Response to P1* by prior exposure. Figure S5. TNT of P1* by prior exposure. Figure S6. Response to P1* by daratumumab retreatment. Figure S7. TNT of P1* by daratumumab retreatment. 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