Real-World Effectiveness and Safety of Intravenous Daratumumab in Patients with Multiple Myeloma: A Multicenter, Observational Study from Korea
Article information
Abstract
Purpose
Daratumumab is a novel, first-in-class monoclonal antibody approved for use as monotherapy and in combination with other treatments for patients with multiple myeloma (MM). The aim of this observational study was to evaluate the effectiveness and safety of daratumumab in real-world clinical practice.
Materials and Methods
This observational multicenter study collected data from patients with MM treated in Korea between June 1, 2018, and February 28, 2022.
Results
125 patients with a diagnosis of MM were included and followed until discontinuation or completion of 52 weeks’ follow-up. The median age was 67 years, and 97.6% of patients received more than three prior lines of therapy. The overall response rate was 52.5% (95% confidence interval [CI], 43.2 to 61.8), and a very good partial response was observed in 19.5% of patients (95% CI, 12.8 to 27.8). Of the patients who achieved a partial or higher response (52.5%), the median time to first response was 2.4 months (95% CI, 1.8 to 3.4), and the median time from start of daratumumab treatment until progressive disease was 4.1 months (95% CI, 2.9 to 5.1). Fever (24.0%) was the most frequently recorded adverse event (AE), while anemia (8.8%) and neutropenia (8.0%) were the most frequently observed grade 3-4 AEs. Overall, no unexpected safety signals were observed.
Conclusion
In a rapidly evolving treatment landscape, this analysis provides insight into the real-world outcomes for patients with MM receiving daratumumab in Korea and reveals that real-world outcomes were improved over results demonstrated in a clinical trial setting.
Introduction
Multiple myeloma (MM) is an incurable hematologic cancer originating in the bone marrow, characterized by the clonal proliferation of the malignant plasma (myeloma) cells [1]. MM accounts for approximately 1% of all new cancers globally [2] and is the third most common hematological malignancy in Korea, with an age-standardized incidence of 2.2 per 100,000 in males and 1.6 per 100,000 in females [3]. The incidence of MM is increasing worldwide, particularly in men aged over 50 years, with one of the highest increases in incidence observed in Korea [4]. MM presents with a range of clinical features, including bone disease, anemia, hypercalcemia, renal failure, and an increased risk of infections [5]. Survival for patients with MM improved significantly with the introduction of proteasome inhibitors (PIs) and immunomodulating agents (IMiDs); however, the prognosis for patients, particularly those who are resistant to PIs and IMiDs, remained poor [6]. The treatment landscape for patients with MM has since evolved with the introduction of targeted therapies, including monoclonal antibodies such as daratumumab [7].
Daratumumab is a novel, first-in-class monoclonal antibody binding specifically to tumor cells that overexpress CD38, a transmembrane glycoprotein, in a variety of hematological malignancies, including MM [8]. Daratumumab was approved as monotherapy by the Food and Drug Administration in 2015 for use in patients with MM who had received at least three previous lines of therapy (LOTs), including a PI and an IMiD (or who are refractory to both), based on results from the phase 2 SIRIUS trial [6,9]. Combination regimens were subsequently approved in 2016 for the treatment of patients with MM who have received at least one prior LOT, based on results from the POLLUX and CASTOR clinical trials [9-11]. In 2018, the Food and Drug Administration approved the use of daratumumab in a frontline setting for patients with newly diagnosed MM [12,13]. In South Korea, daratumumab was approved for multiple indications by the Ministry of Food and Drug Safety in 2017 [14] and has been reimbursable as monotherapy for patients with MM who have received at least three prior LOTs [15] since 2019.
The potential for discrepancies between efficacy results demonstrated through clinical trials, where an intervention is studied under ideal circumstances, and the effectiveness under real-world conditions is well established [16]. Likewise, despite promising results from clinical trials on the use of daratumumab in patients with MM, these trials inevitably exclude patients with significant comorbidities and poor performance status, meaning that these studies are not representative of the entire MM patient population. This is particularly the case for patients with relapsed or refractory MM, who become increasingly ineligible for clinical trial enrollment as their disease progresses [17]. Therefore, evidence on the use of daratumumab in routine clinical practice is necessary to evaluate real-world safety and effectiveness of daratumumab in addition to the data provided by clinical trials. For this reason, it is now mandated by the Korean Ministry of Food and Drug Safety, as a post-market commitment, to conduct real-world studies on treatment use and patient outcomes as part of the risk management plan [18].
Materials and Methods
1. Study design, setting, and participants
This was a multicenter, prospective, observational study to describe the treatment of patients with MM receiving daratumumab in routine clinical practice in Korea using data collected from patient medical records. The overall study period was between June 1, 2018, and February 28, 2022. To comply with mandatory regulations related to the risk management plan in Korea [18], this analysis included patients who received daratumumab for 3 years after the product launch. Patients were included if they had been administered daratumumab intravenously according to physician’s medical judgement; no patients were excluded from the study. Daratumumab was administered according to the product label, and patients were followed until discontinuation of daratumumab or completion of 52 weeks of follow-up.
2. Variables
Age, sex, and Eastern Cooperative Oncology Group (ECOG) performance status were recorded for all patients at baseline only. Medical history related to MM was recorded for all patients at baseline, including date of initial MM diagnosis, MM stage (based on the International Staging System), and myeloma-related results (cytogenetics, extramedullary plasmacytoma/lytic bone lesions, serum/urine proteins, and calcium elevation, renal insufficiency, anemia, and bone abnormalities [CRAB]). Daratumumab treatment data, concomitant therapies, clinical response, and any adverse events (AEs) were documented at baseline and/or during the observational period. The effectiveness of daratumumab treatment was evaluated based on International Myeloma Working Group criteria [19] using the following measures: overall response rate (ORR), categorized as stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response; time to first response, reported in days from start date of daratumumab treatment; and progression-free survival (PFS), reported in days from start date of daratumumab treatment. However, it should be noted that bone marrow biopsy for response assessment is not routinely performed in clinical practice in Korea. Safety was evaluated using AEs collected up to 30 days after the last dose and recorded in the case report form and patient medical records.
3. Statistical analysis
Demographic data and safety analyses were based on the safety analysis set, defined as all patients who received at least one dose of daratumumab and had at least one safety follow-up. Effectiveness evaluation was performed by analyzing the evaluable analysis set, which included all patients who met all eligibility criteria and had the required data for the effectiveness analysis. Demographic and safety data were summarized with descriptive statistics, based on the patients in the safety set; the analysis of effectiveness was summarized descriptively and used Kaplan-Meier methodology for time-to-event variables. Data imputation was not applied for missing effectiveness and safety evaluations; all available data for all patients were included.
Results
1. Patient population
A total of 125 patients were enrolled and received treatment (safety set) as of the data cutoff date of March 31, 2022; results for 118 patients were analyzed for clinical effectiveness (evaluable analysis set). The majority of patients (n=86, 68.8%) discontinued treatment at the discretion of the physician, 21 (16.8%) completed 52 weeks of daratumumab treatment, four (3.2%) were lost to follow-up, four (3.2%) withdrew consent, and three (2.4%) died; seven (5.6%) were due to other reasons (transferred to other hospitals [n=2], AE of general weakness, pneumonia, pneumonia and hypoxia, patient’s financial situation, and patient’s refusal of treatment without consent withdrawn [n=1 for each]). Among patients who discontinued treatment at the discretion of the physician, the most common reason was disease progression (n=69, 80.2%). The median age of patients was 67 years (range, 41 to 86 years), and more than half of the patient group were female (56.8%) (Table 1). The majority of patients (n=87, 69.6%) had an ECOG performance status of ≤ 1, and at diagnosis, 80 patients (64.0%) had stage II or III disease, whereas at baseline, 54 patients (43.2%) had stage II or III disease. More than half (n=71, 56.8%) of the patient group did not have a cytogenetic profile, and a chromosome 13 deletion was the most frequently recorded chromosome abnormality (n=14, 36.8%). Under the CRAB scoring system, a larger proportion of patients had an anemia score (n=61, 61.0%) than calcium elevation (n=1, 1.0%), renal impairment (n=14, 14.0%), or bone disease (n=24, 24.0%); in total, 25 patients (20.0%) did not have a CRAB score.
Patient baseline characteristics and prior treatment history – safety set
2. Prior lines of treatment
In total, 124 patients had received a prior LOT, of which 121 (97.6%) had received three or more prior LOTs; the median number of prior LOTs was four (range, 2 to 25), and the highest proportion of patients received three (n=48, 38.7%) or four (n=37, 29.8%) (Table 1). Among patients who had prior LOTs, prior administered PIs were bortezomib (n=123, 99.2%), carfilzomib (n=79, 63.7%), and ixazomib (n=4, 3.2%); prior IMiDs were lenalidomide (n=119, 96.0%), pomalidomide (n=89, 71.8%), and thalidomide (n=69, 55.7%). Cyclophosphamide was the most frequently administered prior chemotherapy (n=76, 61.3%), and dexamethasone was the most frequently administered prior steroid treatment (n=118, 95.2%). The most widely received prior combination therapies before daratumumab included a PI+IMiD+steroid (n=71, 57.3%). Eighty-one patients (64.8%) had received hematopoietic stem cell transplantation. The median time from initial diagnosis of MM to start of daratumumab treatment was 4.54 years (range, 0.1 to 21.7 years).
3. Clinical effectiveness
Among patients evaluated for clinical effectiveness (n=118), the ORR was 52.5% (95% confidence interval [CI], 43.2 to 61.8). There were no CRs, and a VGPR was observed in 23 (19.5%) patients (95% CI, 12.8 to 27.8). Partial response was observed in 39 patients (33.1%; 95% CI, 24.7 to 42.3), minimal response was observed in six patients (5.1%; 95% CI, 1.9 to 10.7), stable disease was observed in 32 patients (27.1%; 95% CI, 19.4 to 36.1), and 18 patients (15.3%; 95% CI, 9.3 to 23.0) had disease progression. Clinical benefit obtained by adding minimal response to the ORR was observed in 68 patients (57.6%; 95% CI, 48.2 to 66.7) (Table 2).
Best overall response – evaluable analysis set
For the 62 patients (52.5%) who achieved a partial response or higher to daratumumab treatment, the median time to first response was 2.4 months (95% CI, 1.8 to 3.4) (Fig. 1) and the median duration of response was 196 days (range, 9 to 413 days) with a median follow-up time of 234.5 days (range, 9 to 413 days). Among the 84 patients (71.2%) with disease progression, the median PFS was 4.1 months (95% CI, 2.9 to 5.1) (Fig. 2). Data on overall survival (OS) were not mature. A total of nine deaths were reported during the study.
Time to first response – evaluable analysis set.
Time to progression – evaluable analysis set.
Post hoc analyses for ORR were done based on number of prior LOTs and key eligibility criteria for the SIRIUS study. Among 115 patients who had data for prior LOTs and treatment response, the ORR was 55% (27/49) and 53% (35/66) for patients who had two to three lines and four or more lines of prior LOTs, respectively.
The number of patients who would have been excluded from the SIRIUS study was three patients for number of prior LOTs (fewer than three lines), eight for ECOG performance status (score of 3 or 4), 14 for absolute neutrophil count (≤ 1×109/L), four for hemoglobin (≤ 7.5 g/dL), 17 for platelet count (< 50×109/L), and five for creatinine clearance (≤ 20 mL/min/1.73 m2). The ORR for the subgroups of fewer than three prior LOTs, ECOG performance status score of 3 or 4, hemoglobin ≤ 7.5 g/dL, and creatinine clearance ≤ 20 mL/min/1.73 m2 was not calculated due to the small sample size. Response analyses were done in subgroups with at least 10 patients who did not meet the inclusion criteria of the SIRIUS study and had response data. Among 14 patients who had baseline absolute neutrophil count ≤ 1×109/L, the ORR was 42.9% (6/14). Among 15 patients who had baseline platelet count < 50×109/L, the ORR was 66.7% (10/15). Response rates among patients who did not meet the eligibility criteria of the SIRIUS study were considered comparable to the overall ORR, considering the small sample size in each subgroup.
4. Safety
Among all patients (the safety set), 702 AEs were reported in 121 patients (96.8%) and 164 treatment-related AEs were reported in 77 patients (61.6%). Fever was the most frequently observed AE with 38 events (n=30, 24.0%), followed by dyspnea with 27 events (n=25, 20%), chills with 24 events (n=21, 16.8%), anemia with 26 events (n=18, 14.4%), and nausea with 19 events (n=19, 14.4%). In total, 175 grade 3-4 AEs were reported (n=65, 52.0%), of which 20 (n=11, 8.8%) were treatment related. The most frequent grade 3-4 AEs were anemia with 13 events (n=11, 8.8%) and neutropenia with 18 events (n=10, 8.0%). Overall, 73 serious AEs were reported in 47 patients (37.6%), of which four were treatment-related (n=4, 3.2%). Infusion-related reactions occurred in 75 patients (60.0%) with 154 reported events; dyspnea was the most frequently recorded infusion-related reaction with 22 AEs reported in 20 patients (16.0%), followed by chills with 20 AEs in 19 patients (15.2%), pyrexia with 13 AEs in 13 patients (10.4%), and cough with eight AEs in eight patients (6.4%). Of the AEs that led to treatment discontinuation, pneumonia (six events in five patients [4.0%]), asthenia (three events in three patients [2.4%]), and pyrexia (two events in two patients [1.6%]) were the most frequently recorded. A total of nine AEs led to death (7.2%), including four reported as general disorders and administration site conditions (3.2%), four as infections and infestations (3.2%), and one as renal and urinary disorder (0.8%).
Discussion
The results presented here on the use of daratumumab in clinical practice in Korea provide a real-world update, in line with regionally mandated pharmacovigilance requirements, to results previously presented in the phase 2 SIRIUS study [6]. The approval of daratumumab by the Food and Drug Administration and Korean Ministry of Food and Drug Safety, and the subsequent approval for reimbursement of daratumumab in a fourth-line monotherapy treatment setting, has changed the treatment landscape for patients with MM, providing significantly improved outcomes for patients with this incurable disease in South Korea. However, these approvals were based on clinical trial data which may not accurately reflect the use and benefits of treatments in a real-world setting. The results presented here demonstrate the safety and effectiveness of daratumumab in a real-world setting and show that these results are comparable with those observed in clinical trials such as SIRIUS.
Baseline patient characteristics from this study and the SIRIUS study were compared. Among patients included in this study, the median age (67.0; range, 41.0 to 86.0 years) was older than those in the SIRIUS study (63.5; range, 31.0 to 84.0 years) and a higher proportion of patients were female (56.8% vs. 51% in SIRIUS); the proportion of patients included here with stage II or III disease was lower (64.0% vs. 76.0%), and an abnormal cytogenetic profile was observed in 30.4% of patients (n=38) compared with 82.1% (n=78) in the SIRIUS trial [6]. When compared with other real-world studies on the use of daratumumab monotherapy in patients with MM (after receiving three or more prior LOTs), the baseline patient characteristics reported were similar. The median age was consistent with patient populations in Poland and two previous studies performed in Korea [14,20,21]. A similar proportion of patients were male (~40%) in the Polish study; however, a higher proportion of patients were male (50%-55%) in the aforementioned Korean studies [14,20,21]. Staging results reported here were similar to Polish and Korean study results, with 60.0%-68.0% of patients having stage II or III disease [14,20,21]. Cytogenetic data were missing for more than half of the patient group analyzed here (56.8%). This pattern has also been observed in other real-world studies [14,21,22] and may reflect further differences and challenges associated with the collection and reporting of data in the real-world compared with a clinical trial setting.
In Korea, daratumumab is reimbursable only after three prior LOTs, reflected in the figures presented here, where almost all patients enrolled in this study (96.8%) received three or more prior LOTs. Patients receiving daratumumab after fewer than three prior LOTs are likely to reflect patients who have been treated in a self-paying setting. These results were comparable with those from the SIRIUS study, where patients were enrolled with a minimum of three prior LOTs; however, the median of four (range, 2.0 to 25.0) prior LOTs reported here was slightly lower than that reported in the SIRIUS study (median, 5; range, 2.0 to 14.0) [6]. This median prior LOT difference arises from differences in the reimbursed regimen for one and two LOTs for each country, and thus, prior drug exposure and the LOTs of the patients in this study reflect the reimbursement status of MM treatment in Korea. Prior administered PIs, IMiDs, and steroids reported here were also consistent with the results reported in the SIRIUS trial, with bortezomib, lenalidomide, and dexamethasone being the most frequently administered treatments, suggesting a similar prior treatment profile for patients in both studies [6]. The median number of daratumumab treatment cycles reported here was similar to the number reported in the SIRIUS study (five cycles [range, 1 to 14] vs. four cycles [range, 1 to 16] in SIRIUS); however, the number of treatment cycles in real-world clinical practice may be underestimated as a result of data censoring due to the limited period of the study.
The ORR observed in 62 patients in this study (52.5%) was higher than previously observed in the SIRIUS study (n=31; ORR 29.2%). Real-world studies tend to show a good degree of reproducibility for results such as ORR, PFS, and OS for patients with MM, showing consistent and sometimes improved rates of efficacy [23]; the overall response observed here was higher than observed in Denmark (where the ORR for daratumumab monotherapy was 44.9%), the UK (ORR, 49.0%), Poland (ORR, 42.8%), and in a previous real-world study performed in Korea (ORR, 42.1%) [6,14,20,24,25] (S1 Table). In total, 23 patients (19.5%) achieved at least a VGPR, which was higher than observed in the SIRIUS study, where 10 patients achieved a VGPR (9.4%). The VGPR results presented here were similar to results achieved in real-world studies in Denmark (19.3%), and in a previous Korean real-world study (19.0%), and in all cases, higher than observed in the SIRIUS trial (9.4%) [6,14,22,24,25]. The median time to first response observed in this study was 2.4 months (95% CI, 1.84 to 3.35), longer than seen in the SIRIUS study (1.0 months; 95% CI, 0.9 to 5.6). This is likely due to differences in patient monitoring in a real-world setting vs. a clinical trial where patients are monitored more frequently and at predetermined and precise time points. The median PFS in this real-world study was 4.1 months (95% CI, 2.92 to 5.06), comparable with the PFS of 3.7 months (95% CI, 2.8 to 4.6) observed in the SIRIUS trial, highlighting that the PFS was similar in this real-world setting, even though it was not within a controlled clinical environment. Real-world studies have also reported consistent improved progression results, with a UK study reporting a median PFS of 5.1 months and a Korean study reporting a median PFS of 6.0 months [14,24]. These improvements in PFS may be explained by differences in patient population, and therefore, it can be expected that daratumumab will consistently show comparable or better PFS results in the real world compared to a pivotal trial in the current reimbursement setting in Korea.
Safety results from this study demonstrate that daratumumab is well tolerated in patients with MM, with no new safety signals observed here. Toxicity appears to be lower overall in this real-world setting than observed in the SIRIUS trial; however, the higher number of grade 3-4 treatment-emergent AEs observed here (52.0%) than in the SIRIUS study (23.0%) is likely to reflect the inclusion of patients in a real-world setting that would not be included in a clinical trial. The most frequently occurring grade 3-4 treatment-emergent AEs were similar in both studies (neutropenia and anemia); however, thrombocytopenia was less frequently observed here (1.6% vs. 19.0%). These differences in reported safety outcomes may illustrate variations in how clinical trial and real-world safety data are captured or may be reflective of differences between non-selected vs. preselected patients, for example, patient comorbidities and the long-term burden of disease may have a more profound effect on patients assessed in a real-world vs. clinical trial setting [16]. In conclusion, though there were racial differences compared with SIRIUS trial, there were no unexpected safety signals from this study, and it can be confirmed that daratumumab is safe to use in the Korean population.
A key strength of this study is that clinical data were collected for all enrolled patients treated with daratumumab in South Korea for up to 3 years after market authorization. The availability of these data ensured a comprehensive overview of patient outcomes in a real-world setting, rather than among preselected patients in a clinical setting. Furthermore, the data analyzed here included patients with a range of prior treatment combinations that are available in South Korea but may not be recorded in other countries or in clinical studies, reinforcing the real-world nature of these data.
One of the limitations of this study, consistent with many real-world studies, is the potential for variations in how data are reported by investigators in routine clinical practice, and therefore, the possibility of missing or incomplete patient records [26]. With limited availability of test results (e.g., cytogenetic data, the number of lytic bone lesions, and the plasma cell percentage in bone marrow), some baseline characteristics of this study population may not be representative for the patient population with MM in Korea. For example, the percentage of patients having bone disease (24.0%) was relatively low considering a previous study showing that bone disease affects up to 80% of patients with newly diagnosed MM [27]. Furthermore, since bone marrow biopsies were not commonly included in routine clinical practice in Korea to assess response due to limited reimbursement, no confirmed CR or sCR was observed in this study; the lack of these data might limit deeper analysis of the impact of daratumumab at a more detailed patient level. Another limitation of this study was that the follow-up period was limited to 52 weeks, since the study was conducted as part of the risk management plan mandated by the Ministry of Food and Drug Safety. To observe the long-term effectiveness of daratumumab, especially OS, longer duration of follow-up is needed.
This prospective study demonstrated the safety and effectiveness of daratumumab in patients with heavily pretreated MM in clinical practice in Korea. Approximately half of the patients who received daratumumab achieved an overall response, with a fast onset. The clinical outcomes of this study were consistent with other real-world studies, where better ORR and numerically longer PFS were observed in real-world studies compared with a stricter clinical trial setting. Importantly, no unknown safety signals were detected in this study, and the AEs observed were comparable to the known safety profile of daratumumab. These insights provide valuable real-world evidence for the favorable risk-benefit profile of daratumumab in Korean patients with MM.
Electronic Supplementary Material
Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).
Notes
Ethical Statement
The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments. The study was approved by 29 institutional review boards (IRBs), which included the Seoul National University Hospital IRB, Samsung Medical Center IRB, InJe University Busan Paik Hospital IRB, Chonnam National University Hwasun Hospital IRB, Ulsan University Hospital IRB, The Catholic University of Korea, Seoul St. Mary’s Hospital IRB, Hallym University Sacred Heart Hospital IRB, WonKwang University Hospital IRB, Dong-A University Hospital IRB, Kosin University Gospel Hospital IRB, Kyungpook National University Hospital IRB, National Cancer Center IRB, KonYang University Hospital IRB, Ewha Womans University Mokdong Hospital IRB, Pusan National University Yangsan Hospital IRB, Korea University Anam Hospital IRB, National Health Insurance Service Ilsan Hospital IRB, Keimyung University Dongsan Hospital IRB, Soonchunhyang University Bucheon Hospital IRB, Yeungnam University Hospital IRB, Gachon University Gil Medical Center IRB, Kangbuk Samsung Hospital IRB, Dongguk University Ilsan Hospital IRB, KyungHee University Hospital IRB, The Catholic University of Korea, Incheon St. Mary’s Hospital IRB, Yonsei University Wonju Severance Christian Hospital IRB, Korea University Guro Hospital IRB, The Catholic University of Korea St. Vincent’s Hospital IRB, and ChungNam National University Hospital IRB. All patients provided informed consent.
Author Contributions
Conceived and designed the analysis: Koh Y, Yoon SS, Kim K, Lee JJ, Jung SH, Yoon SE, Park SS, Park Y, Yoon S, Min CK.
Collected the data: Koh Y, Yoon SS, Park Y, Min CK.
Contributed data or analysis tools: Koh Y, Yoon SS, Kim K, Lee JJ, Jung SH, Yoon SE, Park SS, Park Y, Yoon S, Min CK.
Performed the analysis: Koh Y, Yoon SS, Kim K, Lee JJ, Jung SH, Yoon SE, Park SS, Min CK.
Wrote the paper: Koh Y, Yoon SS, Kim K, Lee JJ, Jung SH, Yoon SE, Park SS, Park Y, Yoon S, Min CK.
Conflicts of Interest
YoungJu Park and Soomin Yoon are current employees of Janssen Korea Ltd. All other authors declared no competing interests for this work.
Funding
This work was supported by Janssen.
Acknowledgments
This work was supported by Janssen. Professional writing and editorial assistance were provided by Becky O’Connor, PhD, of Parexel, funded by Janssen.