Cortoos, Annelore

Abstract Introduction: DRd is the standard of care for frontline (FL) treatment (tx) of transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). This is supported by its superior efficacy and tolerable safety profile vs lenalidomide and dexamethasone (Rd) and vs bortezomib plus Rd (VRd) per the phase 3 MAIA clinical trial and real-world data. However, based on recent phase 3 CEPHEUS and IMROZ trial data, the tx paradigm is shifting toward the use of quadruplets for suitable TIE patients with NDMM. CEPHEUS demonstrated the superior efficacy of DVRd vs VRd in TIE and transplant-deferred patients with NDMM. DVRd-treated patients achieved significantly higher rates of minimal residual disease negativity and significantly improved progression-free survival vs VRd-treated patients. DVRd is listed as a National Comprehensive Cancer Network (NCCN) Category 1 preferred regimen in this setting and is therefore used in US real-world clinical practice. The objective of this study was to evaluate real-world usage patterns of FL DVRd and FL DRd in nontransplanted patients with NDMM and to assess the characteristics of patients treated with these regimens. Methods:Data from the Flatiron Health Research database were used for this retrospective observational study. Patients were included in this analysis if they received FL tx with DVRd or DRd for NDMM between Jan 1, 2019, and Dec 31, 2024. The index date was defined as the initiation date of FL DVRd or FL DRd. As the Flatiron database does not capture transplant eligibility status, the analysis excluded all patients who underwent hematopoietic stem cell transplantation at any time during the study period. Patients were also excluded if they were <18 years of age, enrolled in a clinical trial, had presence of other cancers, received chimeric antigen receptor T-cell therapy, or were diagnosed with amyloid light-chain amyloidosis before the index date. High cytogenetic risk was defined as the presence of abnormalities including del(17p), t(4;14), or t(14;16). Descriptive statistics were used to report demographic and clinical characteristics. Kaplan-Meier methods were used to estimate duration of therapy. Results: Among the nontransplanted NDMM cohort, 704 FL DVRd-treated patients and 396 FL DRd-treated patients were identified. At index, FL DVRd patients were generally younger than FL DRd patients (median age, 68 vs 78 years, respectively), more likely to be male (55.3% vs 49.5%), and less likely to have Medicare coverage (8.4% vs 17.2%). The 2 cohorts had similar proportions of Black/African American patients (18.9% and 18.7%). Among patients with available data, high cytogenetic risk was more frequently observed in FL DVRd (29.2%) vs FL DRd (17.5%) patients; a lower proportion of FL DVRd patients had International Staging System (ISS) stage III disease (27.1%) than ISS stage I disease (39.9%), whereas a higher proportion of FL DRd patients had ISS stage III disease (32.9%) than ISS stage I disease (25.5%). FL DVRd patients were more likely to be nonfrail (Intergroupe Francophone du Myélome simplified frailty score <2) vs FL DRd patients (64.6% vs 28.2%). Use of both DVRd and DRd increased during the study period; however, the increase was greater for DVRd, particularly in the later years. Notably, FL DVRd was started in 10 patients in 2019, increasing to 146 in 2022 and 222 in 2024. By comparison, FL DRd was initiated in 17 patients in 2019, increasing to 85 in 2022 and 97 in 2024. Median follow-up was 15.6 mo in the DVRd cohort and 20.3 mo in the DRd cohort. Median duration of DVRd therapy was 18.5 mo (95% CI, 14.8–22.7) and was 23.5 mo (95% CI, 19.0–31.7) for DRd therapy. Bortezomib as part of the DVRd regimen was given once weekly or less frequently in the majority (65.6%) of patients. Conclusions: These real-world data show the increasing FL use of the daratumumab-based quadruplet regimen DVRd among nontransplanted patients with NDMM. FL DVRd patients were generally younger and less frail but more likely to have high cytogenetic risk than those treated with DRd. These data also show that daratumumab-based regimens, either as a triplet (DRd) or a quadruplet (DVRd), are increasingly adopted over time in real-world clinical practice. These data further suggest that DRd and DVRd may be considered foundational for the tx of nontransplanted patients with NDMM regardless of patient characteristics, including age, frailty, cytogenetic risk, and ISS stage.

Background: Daratumumab (DARA) has demonstrated clinical benefit in multiple myeloma (MM) and is approved for the treatment of both newly diagnosed MM (NDMM) and relapsed refractory MM (RRMM). While single-center studies have shown the benefit of DARA retreatment in patients (pts) who are refractory to DARA (D-Ref), there is a lack of real-world data on the characteristics of pts who are retreated with DARA across multiple lines of treatment (LOTs). In this study, we examine DARA retreatment patterns and outcomes among pts who are D-Ref and those who are sensitive to DARA (D-Sens) after the first DARA exposure in the US real-world clinical practice. Methods: This study used the Flatiron MM Core Registry data to identify pts with MM treated with a DARA-containing regimen in ≥2 separate LOTs between November 1, 2015, and March 31, 2024. The first DARA-based LOT was defined as D1, and the second DARA-based LOT was defined as the retreatment LOT (D2). The following criteria, developed by Janssen Scientific Affairs, were used to classify pts as Dara-retreated: 1) pts treated with the same DARA-containing regimens in consecutive LOTs were classified as Dara-retreated if there was a gap of >90 days between D1 and D2, 2) pts treated with different DARA-containing regimens in consecutive LOTs were classified as Dara-retreated, 3) pts treated with DARA-containing regimens had ≥1 LOTs between D1 and D2 they were classified as Dara-retreated, regardless of whether the regimens were the same or different. Derived disease progression reported in the Flatiron data was used for this analysis. If disease progression was reported during D1, or within 60 days of discontinuing D1, the pt was considered as D-Ref, otherwise, the pt was considered as D-Sens. Kaplan-Meier (KM) analyses were conducted to evaluate duration of D2, proportion of pts not receiving subsequent treatment after D2, and progression-free survival (PFS) rates during D2. Results: Data for 201 pts retreated with DARA were identified in this analysis, 150 were D-Sens and 51 were D-Ref. In the D-Sens group, the median age at D2 initiation was 71 years, 44.0% of pts were female, 27.3% were ISS stage II and 16.0% were African American. In the D-Ref group, the median age at D2 initiation was 67 years, 45.1% of pts were female, 21.6% were ISS stage II, and 25.5% were African American. At D2 initiation, 64.7% (D-Sens) and 60.8% (D-Ref) of pts were frail, and 56.0% (D-Sens) and 52.9% (D-Ref) of pts had a Quan-Charlson Comorbidity Index of ≥3, indicating a high burden of comorbidities. About 31% of pts in both groups had high cytogenetic risk abnormalities, and about 20% had a 1q21 gain or amplification. The median time from MM diagnosis to start of D1 and to start of D2 was shorter in the D-Sens group (10.8 and 34.9 months) than in the D-Ref group (18.4 and 44.4 months). D-Sens pts were less likely to receive D1 in the third LOT or later compared to D-Ref pts (30.0% vs 45.1%). The median number of LOTs before D2 was three in both groups. The median gap between D1 and D2 was 9.3 months in D-Sens pts and 9.0 months in D-Ref pts, however, more D-Sens pts received D1 and D2 LOTs consecutively compared to D-Ref pts (62.0% vs 51.0%). The most common regimen used in D1 was DARA + lenalidomide + dexamethasone (dex; 18.7%) and DARA + bortezomib + dex (18.7%) among D-Sens pts, and DARA + pomalidomide + dex (23.5%) among D-Ref pts. The most common regimen used in D2 was DARA mono (31.3%) in D-Sens pts, and DARA mono (17.6%) and DARA + carfilzomib + dex (17.6%) in D-Ref pts. Overall, 32.0% of D-Sens and 35.3% of D-Ref pts received agents from the same drug class in D1 and D2. The KM median duration of D2 was 7.4 months (95% CI: 5.5-9.5) among D-Sens pts and 6.4 months (95% CI: 3.8-23.5) among D-Ref pts. The proportion of pts that had not received subsequent treatment after D2 was 38.7% and 29.5% at 12 months in the D-Sens and D-Ref groups, respectively. PFS rates at 12 months after D2 initiation were 77.1% in the D-Sens group and 49.4% in the D-Ref group. Conclusion: DARA retreatment is utilized frequently and is effective in the real-world, suggesting the ability to use this approach in subsequent LOTs among pts with RRMM. In the absence of other feasible alternatives, this may be a treatment strategy for patient benefit, regardless of whether they are D-Sens or D-Ref. Future studies are needed to definitively investigate the benefit of DARA retreatment in combination with drugs with novel mechanisms of action.

ABSTRACT Introduction Daratumumab, lenalidomide, and dexamethasone (DRd) and bortezomib, lenalidomide, and dexamethasone (VRd) are the only preferred treatment regimens for patients with transplant‐ineligible (TIE) newly diagnosed multiple myeloma (NDMM). As there are no randomized head‐to‐head studies of DRd versus VRd, this analysis aimed to compare real‐world time‐to‐next‐treatment (TTNT) or death in this population. Methods Patients with NDMM who received front‐line (FL) DRd or VRd were identified from the Acentrus database (January 1, 2018 to May 31, 2023). Those with a record of a stem cell transplant or aged < 65 years were excluded to limit analysis to the TIE population. Inverse probability of treatment weighting was used to balance baseline patient characteristics. A doubly robust Cox proportional hazards model was used to compare TTNT or death between cohorts. Results A total of 149 and 494 patients who initiated DRd and VRd, respectively, were identified. After weighting (weighted N DRd = 302, weighted N VRd = 341), cohorts had similar baseline characteristics. Of these, 98 (32.4%) DRd and 175 (51.2%) VRd patients either received a subsequent line of therapy or died, with a median TTNT or death of 37.8 months in the DRd cohort and 18.7 months in the VRd cohort (hazard ratio: 0.58, 95% confidence interval: 0.35, 0.81; p < 0.001). Conclusion Treatment of TIE NDMM patients with DRd led to a significantly longer TTNT or death compared to VRd, evidenced by a 42% risk reduction, supporting the effectiveness of DRd over VRd as FL treatment in this patient population.

Introduction: Daratumumab, lenalidomide, and dexamethasone (DRd) and bortezomib, lenalidomide, and dexamethasone (VRd) are the only two regimens that are considered as preferred per the National Comprehensive Care Network for transplant ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). While there are no head-to-head studies comparing clinical outcomes of DRd and VRd in this population, an indirect comparison (PEGASUS study [Durie et al., 2020]) has shown that DRd was associated with significantly lower risk of disease progression or death compared with VRd and Rd. This study aims at supplementing this information by comparing real-world time-to-next-treatment (TTNT) or death between NDMM TIE patients treated with front-line (FL) DRd or VRd. Methods: A retrospective cohort study was conducted for patients with NDMM who initiated FL DRd or VRd in Acentrus (1/1/2018 - 5/31/2023), an electronic medical record (EMR) database from academic and non-teaching hospitals in the United States. Patients were included if they had ≥2 records with an ICD-10-CM diagnosis code for MM, ≥6 months of data availability prior to first record with MM diagnosis (without use of antineoplastic agent), initiated FL treatment (initiation of DRd or VRd; index date) within 12 months of first record of MM diagnosis, and ≥90 days of data availability post-index. Patients with pre-index diagnosis of amyloidosis or other cancers and those who participated in a clinical trial before or during FL treatment were excluded. To limit the analysis to the TIE population, patients who had a record of a stem-cell transplant (SCT) before or during FL treatment and those who were &lt;65 years old (used as proxy to SCT eligibility) were excluded. Patient characteristics were evaluated up to 12-months pre-index (baseline period). Patients were followed from the index date until earliest of date of initiation of a next line of treatment, death, or end of data availability. Medications received within 60 days from the date of the first MM antineoplastic agent were considered as FL therapy regimen. Next line of treatment was identified as initiation of a new antineoplastic agent (excluding corticosteroids) outside of FL therapy or re-treatment of FL after &gt;90-day gap. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics between study cohorts, with variables with standardized differences &lt;10% considered balanced. Weighted Kaplan-Meier (KM) curves and a doubly-robust Cox proportional hazards model adjusting for baseline variables remaining imbalanced after IPTW were used compare TTNT or death between study cohorts. Results: Overall, 149 and 494 patients were identified in the DRd and VRd cohorts, respectively. After weighting (N DRd weighted = 302, N VRd weighted = 341), most baseline characteristics in both cohorts were similar, including mean age (DRd: 75.3, VRd: 74.5), female sex (DRd: 48.9%, VRd: 45.8%), white race (DRd: 55.8%, VRd: 58.7%), black race (DRd: 8.8%, VRd: 11.3%), Medicare insurance coverage (DRd: 62.7%, VRd: 65.9%), and mean Quan-Charlson comorbidity index (DRd: 3.8, VRd: 3.6; Table 1). Some imbalances remained for mean age, race, ethnicity, and index year, thus they were additionally adjusted for in doubly-robust Cox model. The median duration of follow-up was 20.2 months and 21.5 months among DRd and VRd patients, respectively. A total of 98 (32.4%) DRd patients and 175 (51.2%) VRd patients received a subsequent line of therapy or died, with the median TTNT or death being 37.8 and 18.7 months in the DRd and VRd cohorts, respectively (hazard ratio: 0.58, 95% CI: 0.35, 0.81; p&lt;0.001; Figure 1). KM estimates for patients remaining on FL therapy were significantly higher for DRd than VRd at 6 months (93.0% vs. 80.1%), 12 months (80.0% vs. 61.0%), 18 months (64.9% vs. 51.3%), and 24 months (60.2% vs. 42.9%). Conclusion: In this retrospective cohort study using EMR data, TIE NDMM patients who initiated DRd had a significantly longer time to next treatment or death than patients who initiated VRd. Results from this real-world study fills an unmet data gap by providing information on the comparative effectiveness evidence for DRd versus VRd among TIE NDMM patients. These findings support the use of DRd as an effective treatment option in the TIE NDMM patient population.

Abstract Background Patients with high-risk, newly diagnosed multiple myeloma (HR-NDMM) who are ineligible for autologous stem cell transplant (ASCT) have limited first-line treatment options. Recent meta-analyses evaluating the impact of incorporating daratumumab in the backbone regimen on progression-free survival (PFS) have found mixed results in these patients. Materials and Methods A pooled analysis of patient-level data for ASCT-ineligible patients with HR-NDMM [ie, del(17p), t(4;14), t(14;16)] from the MAIA and ALCYONE trials; stratified by study identifier and adjusting for cytogenetic abnormality subtype, baseline performance status, International Staging System stage, myeloma type, and renal impairment; was conducted. Impact of daratumumab on PFS and rates of complete response or better (≥CR), minimal residual disease (MRD)-negative CR, very good partial response or better (≥VGPR), and overall response (ORR) was compared to control. Results Among 101 patients in the daratumumab and 89 patients in the control cohort, median follow-up was 43.7 months. Daratumumab reduced the risk of progression or death by 41% (adjusted hazard ratio for PFS [95% confidence interval (CI)] = 0.59 [0.41-0.85]) versus control. At 36 months, the estimated proportion of patients who did not progress and were still alive was 41.3% in the daratumumab and 19.9% in the control cohort. Rates of ≥CR (41.6% vs. 22.5%), MRD-negative CR (24.8% vs. 5.6%), ≥VGPR (75.2% vs. 46.1%), and ORR (92.1% vs. 74.2%) were higher for daratumumab versus control. Conclusion These findings demonstrate that incorporation of daratumumab in frontline treatment regimens reduced the risk of progression or death and improved response rates among ASCT-ineligible HR-NDMM patients.