In the absence of head-to-head trial data, a matching-adjusted indirect comparison (MAIC) was conducted to compare the effectiveness, with respect to overall survival (OS) and progression-free survival (PFS), of PET-guided BrECADD versus PET-guided ABVD, BEACOPP, and eBEACOPP in advanced Hodgkin lymphoma. Individual patient data (IPD) from patients in HD21 and aggregate data from the SWOG S0816, RATHL, HD9, and Mondello 2020 studies were utilized. Potential effect modifiers and prognostic variables for advanced Hodgkin lymphoma were identified via literature review, clinician input, and statistical analysis. As there was no common arm between HD21 and the comparator trials, unanchored MAICs were conducted. Data from patients in HD21 were weighted to align with published aggregate characteristics of the comparator trials. BrECADD was associated with significantly improved PFS and OS compared with PET-guided ABVD among patients aged 18–60 (SWOG S0816; PFS HR: 0.24, 95

Brentuximab vedotin (BV) as post-autologous stem cell transplantation (ASCT) consolidation was shown to reduce the relapse risk among high-risk patients with relapsed/refractory Hodgkin lymphoma (RRHL) in the clinical trial setting. This systematic review and meta-analysis characterizes real-world evidence (RWE) on the effectiveness and safety of BV as post-ASCT consolidation in 1504 adult and pediatric patients with RRHL from 23 studies across 17 countries. A random-effects model yielded pooled progression-free survival (PFS) and overall survival rates (OS); PFS: 2-year, 74.2%; 5-year, 65.8%; OS: 2-year, 95.8%; 5-year, 91.9%. The most common any-grade adverse events were neuropathy (34.2%) and neutropenia (20.2%). Despite heterogeneity in populations and outcomes, this analysis utilizing real-world data corroborates the efficacy and safety of BV as post-ASCT consolidation in RRHL reported in the experimental arm of the Phase III AETHERA trial. The favorable PFS results in cases exposed to BV prior to ASCT indicate the value of BV in controlling Hodgkin lymphoma (HL) in the salvage setting. Continued research is essential to refine BV treatment strategies amid the evolving treatment landscape.

Introduction: According to National Comprehensive Care Network® guidelines, positron-emission tomography (PET)-guided adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), and brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (A+AVD) are currently the preferred front-line regimens for the management of advanced Hodgkin Lymphoma (aHL). The ECHELON-1 (E1) trial demonstrated improved outcomes with A+AVD over ABVD for both overall survival (OS) and progression-free survival (PFS). However, PET adaptation was not used to guide the choice of regimens in the E1 trial. The objective of this exercise was to review the existing evidence and subsequently investigate the comparative efficacy of A+AVD vs PET-guided ABVD in adult patients with aHL. Methods: A systematic literature review (SLR) of relevant published evidence through December 2023 on the clinical efficacy of front-line treatments for aHL was conducted, followed by an indirect treatment comparison (ITC) feasibility assessment of the relevant studies identified. Of 48 randomized controlled trials (RCTs) and 143 non-RCTs identified in the SLR, the Risk-Adapted Therapy for aHL (RATHL; randomized for PET-negative patients) and SWOG S0816 (non-RCT) were selected as relevant trials for comparison of PET-guided ABVD with A+AVD (E1). In both RATHL and SWOG S0816 trials, patients received 2 cycles of ABVD, followed by adapted therapy based on PET results. Long-term OS and PFS data were available for all 3 trials, with median follow-up of 89.3 (E1), 70.8 (SWOG S0816), and 87.6 (RATHL) months. Based on Cox regression analyses using individual patient-level data from E1 and expert opinion, age, international prognostic score (IPS), Eastern Cooperative Oncology Group performance status (ECOG), and extranodal site at baseline were considered to be both effect modifiers and prognostic variables. However, extranodal site data were not available in RATHL and SWOG S0816, and ECOG was not reported in SWOG S0816. Using an unanchored matching-adjusted indirect comparison (MAIC) approach, A+AVD (E1, restricted to patients aged ≤60 years to match the selection criteria in SWOG S0816) was compared with PET-guided ABVD (overall trial population) in SWOG S0816, adjusting for age and IPS. A+AVD (E1) was also compared with PET-guided ABVD (stage III and IV overall trial population) in RATHL, adjusting for age, IPS, and ECOG. Hazard ratios (HR) with 95% confidence intervals (CI) were generated using weighted Cox regression. For situations in which the proportional hazards assumption was violated, restricted mean survival time (RMST) at 8 years and piecewise Cox regression (split time into different intervals based on delayed separation of Kaplan-Meier curves) were performed. Results: MAIC reweighting resulted in an effective sample size of 521 and 526 of the A+AVD arm of E1 after matching to patient characteristics in SWOG S0816 and RATHL, respectively; 336 patients from SWOG S0816, and 702 patients from RATHL were included in the analyses.Using weighted Cox-regression, A+AVD (E1) demonstrated significantly improved PFS (HR=0.55 [95% CI: 0.40-0.75], p<0.001) and OS (HR=0.49 [95% CI: 0.26-0.92], p<0.05) compared to PET-guided ABVD in SWOG S0816. Similarly, A+AVD (E1) was associated with significant improvement in PFS (HR=0.56 [95% CI: 0.43-0.73), p<0.001) and OS (HR=0.37 [95% CI: 0.24-0.57], p<0.001) compared to PET-guided ABVD in RATHL. RMST and piecewise Cox regression were performed given the violation of the proportional hazard assumption in the PFS analyses. Compared with PET-guided ABVD in SWOG S0816 and RATHL, A+AVD (E1) was associated with significantly longer RMST of PFS (difference=8.46 months [95% CI: 3.77-13.15] and 6.67 months [95% CI: 2.98-10.37], respectively), and significantly improved PFS during the >6 months period (vs SWOG S0816, HR=0.47 [95% CI: 0.34-0.66]) and during the >16 months period (vs RATHL, HR=0.20 [95% CI: 0.12-0.34]). Conclusions: In patients with aHL, sustained PFS and OS benefit was shown for A+AVD (E1) vs PET-guided ABVD (SWOG S0816 and RATHL), providing insight into the durability of benefits associated with A+AVD. These results were consistent with the findings of E1 study based on long term survival data, supporting the use of A+AVD over PET-guided ABVD in treating patients with aHL.

7053 Background: In ECHELON-1 (NCT01712490), 6-year follow-up (FU) analyses demonstrated significant improvements in overall survival (OS) and progression-free survival (PFS) with A+AVD (brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), with a comparable safety profile. Here, we report data at 7-year median FU. Methods: Analyses of OS and PFS per investigator were conducted in the intent-to-treat (ITT) population (data cut-off March 11, 2023). Patients (pts) were randomized 1:1 to receive ≤6 cycles of A+AVD (n=664) or ABVD (n=670) on days 1 and 15, every 28 days. PET scan after cycle 2 (PET2) evaluation was mandatory. Long-term safety outcomes in the safety population included resolution or improvement of peripheral neuropathy (PN), second malignancies, and pregnancies. Results: At median FU of 89.3 months (95% CI 87.0–90.2), 7-year OS rates were 93.5% (95% CI 91.1–95.2) with A+AVD and 88.8% (95% CI 85.8–91.1) with ABVD; OS favored A+AVD over ABVD (HR 0.62; 95% CI 0.42–0.90; p=0.011). Subgroup analyses showed consistent OS benefit for A+AVD, including in the age <40 years and Stage IV disease subgroups (Table). 7-year PFS rates with A+AVD vs ABVD were 82.3% (95% CI 79.1–85.0) vs 74.5% (95% CI 70.8–77.7; HR 0.68 [95% CI 0.53–0.86]; p=0.001). PN improved/resolved in most pts at last FU (A+AVD: 86%; ABVD: 87%). Median (range) time to complete resolution of PN (A+AVD vs ABVD) was 16 (0–373) vs 10 (0–343) weeks; median (range) time to improvement was 42 (2–182) vs 19 (15–142) weeks. PN was ongoing in 28% (4% grade ≥3) of A+AVD and 20% (1% grade ≥3) of ABVD pts. Second malignancies were reported in 5% of A+AVD and 6% of ABVD pts. Pts and their partners reported 84/92 livebirths/pregnancies with A+AVD and 59/73 with ABVD; no stillbirths were recorded. Conclusions: At 7-year median FU, pts with stage III/IV cHL who received A+AVD showed a sustained PFS and OS benefit vs ABVD, with PFS rates indicating potential curability. The safety profile in pts treated with A+AVD showed no new safety signals at 7 years. Clinical trial information: NCT01712490 . [Table: see text]

Background Intensified systemic chemotherapy has the highest primary cure rate for advanced-stage, classical Hodgkin lymphoma but this comes with a cost of severe and potentially life long, persisting toxicities. With the new regimen of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), we aimed to improve the risk-to-benefit ratio of treatment of advanced-stage, classical Hodgkin lymphoma guided by PET after two cycles. Methods This randomised, multicentre, parallel, open-label, phase 3 trial was done in 233 trial sites across nine countries. Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage, classical Hodgkin lymphoma (ie, Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions). Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of escalated doses of etoposide (200 mg/m2 intravenously on days 1–3), doxorubicin (35 mg/m2 intravenously on day 1), and cyclophosphamide (1250 mg/m2 intravenously on day 1), and standard doses of bleomycin (10 mg/m2 intravenously on day 8), vincristine (1·4 mg/m2 intravenously on day 8), procarbazine (100 mg/m2 orally on days 1–7), and prednisone (40 mg/m2 orally on days 1–14; eBEACOPP) or BrECADD, guided by PET after two cycles. Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by progression-free survival with an absolute non-inferiority margin of 6 percentage points of BrECADD compared with eBEACOPP. An additional test of superiority of progression-free survival was to be done if non-inferiority had been established. Analyses were done by intention to treat; the treatment-related morbidity assessment required documentation of at least one chemotherapy cycle. This trial was registered at ClinicalTrials.gov (NCT02661503). Findings Between July 22, 2016, and Aug 27, 2020, 1500 patients were enrolled, of whom 749 were randomly assigned to BrECADD and 751 to eBEACOPP. 1482 patients were included in the intention-to-treat analysis. The median age of patients was 31 years (IQR 24–42). 838 (56%) of 1482 patients were male and 644 (44%) were female. Most patients were White (1352 [91%] of 1482). Treatment-related morbidity was significantly lower with BrECADD (312 [42%] of 738 patients) than with eBEACOPP (430 [59%] of 732 patients; relative risk 0·72 [95% CI 0·65–0·80]; p<0·0001). At a median follow-up of 48 months, BrECADD improved progression-free survival with a hazard ratio of 0·66 (0·45–0·97; p=0·035); 4-year progression-free survival estimates were 94·3% (95% CI 92·6–96·1) for BrECADD and 90·9% (88·7–93·1) for eBEACOPP. 4-year overall survival rates were 98·6% (97·7–99·5) and 98·2% (97·2–99·3), respectively. Interpretation BrECADD guided by PET after two cycles is better tolerated and more effective than eBEACOPP in first-line treatment of adult patients with advanced-stage, classical Hodgkin lymphoma. Funding Takeda Oncology.

Introduction: In advanced Hodgkin lymphoma (aHL), adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine (ABVD) is a recommended chemotherapy regimen despite a substantial proportion of patients experiencing relapse or incomplete disease control. Per the National Comprehensive Care Network (NCCN) guidelines, positron-emission tomography (PET)-guided ABVD and brentuximab vedotin + adriamycin (doxorubicin), vinblastine and dacarbazine (A+AVD) are preferred options for the front-line treatment of aHL (NCCN Guidelines. Hodgkin lymphoma. Version 2. 2023). In the ECHELON-1 (E1) trial, superiority of A+AVD vs ABVD x6 cycles (without PET adaptation at cycle 2) was demonstrated statistically in terms of overall survival (OS) and progression-free survival (PFS). Six-year follow-up of E1 patients showed improved OS with A+AVD vs ABVD. The aim of this study was to indirectly compare the effectiveness (OS and PFS) of A+AVD vs PET-guided ABVD as front-line treatments in the management of patients aged ≤60 years with aHL (Stage III or IV). Methods: A systematic literature review was conducted using electronic databases such as MEDLINE, Embase, and the Cochrane Library (database inception to July 2022), supplementary sources and data on file for relevant materials reporting on the clinical efficacy of front-line treatments for aHL. Following the identification of relevant randomized controlled trials (RCTs), unanchored matching-adjusted indirect comparison was performed to compare the efficacy of A+AVD (the E1 trial) with PET-guided ABVD (the Risk-Adapted Therapy for aHL [RATHL] trial). As the outcomes used in the analyses were reported among the overall population in RATHL, rather than stratified by specific treatment, there was no potential anchor for the analysis. PFS and OS data from RATHL were only available for adult patients ≤60 years old with stage III/IV aHL, therefore the treatment comparison was limited to patients within this age group. Matching variables were selected based on literature review and the results of Cox regression analyses of the E1 trial data. The International Prognostic Score and Eastern Cooperative Oncology Group scores were used as matching factors as available. The weights generated from the matching procedure were incorporated in weighted Cox regression models to generate hazard ratios (HR) and corresponding 95% confidence intervals (CI). To account for the potential of violating the proportional hazards assumption, additional metrics were calculated including piecewise HRs (95% CI) using Cox regression models for specific time intervals (i.e., 0 to 24, 24 months +) and restricted mean survival times (RMST). Results : In adult patients aged ≤60 years with Stage III/IV aHL, treatment with A+AVD generally led to increased PFS and OS vs PET-guided ABVD (Table1). As the proportional hazard assumption was violated, additional metrics were calculated (RMST and piecewise HRs). HRs and RMST for survival outcomes are reported in Table1. Conclusions: The findings of this indirect treatment comparison support the improved efficacy of A+AVD relative to PET-guided ABVD with respect to OS and PFS in patients with stage III and IV aHL consistent with the results of E1 study.

(1) Background: Most patients with mycosis fungoides (MF), a form of cutaneous T-cell lymphoma (CTCL), develop relapsed/refractory (R/R) disease following front-line systemic therapy. This report describes treatment patterns and outcomes from the subpopulation with R/R MF. (2) Methods: This observational, retrospective, cohort study analyzed patient records (1984–2016) from 27 clinical sites in Europe. Outcomes included treatments received, response to first-, second- and third-line treatment, overall survival (OS) and progression-free survival (PFS). (3) Results: Of 104 patients with MF, 100 received second-line and 61 received third-line therapy. The median (range) times from the start of first-line therapy to the first R/R MF and from the first to the second R/R MF were 11.2 (0.3–166.5) and 13.5 (0.0–174.6) months, respectively. Second-and third-line treatment options varied and comprised systemic therapies (85% and 79% of patients, respectively), radiotherapy (32% and 34%, respectively) and topical therapies (48% and 36%, respectively). The median (95% confidence interval [CI]) OS from the diagnosis of the first R/R MF was 11.5 (6.5–not reached [NR]) years and was higher with non-chemotherapy (NR) versus chemotherapy (6.5 years); the estimated median PFS (95% CI) from the time of the first R/R MF was 1.3 (1.0–2.1) years. (4) Conclusions: High rates of R/R disease were observed after second- and third-line treatments in this real-world cohort, with longer median OS in patients receiving non-chemotherapy treatment versus chemotherapy. Following the standard management of MF and using recently approved targeted therapies can help improve patient outcomes in advanced-stage MF.

The treatment pattern of cutaneous T-cell lymphoma (CTCL) remains diverse and patient-tailored. The objective of this study was to describe the treatment patterns and outcomes in CTCL patients who were refractory or had relapsed (R/R) after a systemic therapy. A retrospective chart review study was conducted at 27 sites in France, Germany, Italy, Spain and the United Kingdom (UK) of patients who received a first course of systemic therapy and relapsed or were refractory. Data were collected longitudinally from diagnosis to first-, second- and third-line therapy. The study included 157 patients, with a median follow-up of 3.2 years. In total, 151 proceeded to second-line and 90 to third-line therapy. In the first line (n = 147), patients were treated with diverse therapies, including single- and multi-agent chemotherapy in 67 (46%), retinoids in 39 (27%), interferon in 31 (21%), ECP in 4 (3%), corticosteroids in 3 (2%) and new biological agents in 3 (2%). In the second line, the use of chemotherapy and retinoids remained similar to the first line, while the use of new biologics increased slightly. In sharp contrast to the first line, combination chemotherapy was extremely diverse. In the third line, the use of chemotherapy remained high and diverse as in the second line. From the time of first R/R, the median PFS was 1.2 years and the median OS was 11.5 years. The presented real-world data on the current treatments used in the management of R/R CTCL in Europe demonstrate the significant heterogeneity of systemic therapies and combination therapies, as expected from the European guidelines.

AbstractClassical Hodgkin lymphoma (cHL) is curable in 90% of cases, but advanced stage patients who do not respond well to first‐line (1L) therapy have poorer outcomes. This retrospective study examines patient characteristics, treatment patterns, clinical outcomes, and safety management of 1L cHL therapies in common clinical practice in Italy (IT), Israel (IL), and Spain (SP). The overall sample (n = 256) included patients with stage IIb to IV cHL, of which 86.3% received ABVD as 1L therapy (n = 221). Clinical outcomes were similar for the overall population and ABVD subsample: complete response (CR) in 75% and 76.5%; 30‐month (30‐mo) survival (OS) of 92.5% and 93.6%; and 30‐mo progression‐free survival (PFS) of 70.7% and 72.6%. Thirty‐month PFS was significantly lower for patients ≥ 60 years and/or with high (4–7) IPS. Treatment‐induced pulmonary and cardiac toxicities, and febrile neutropenia occurred, respectively, in 10%, 2.3%, and 6.8% of ABVD‐treated patients. Interim PET or PET‐CT scans were performed after two cycles of 1L therapy (PET2) for 70.3% and 66.6% of the overall and ABVD cohorts, respectively. PET2 positive rates were nearly 30% (49/173), yet PET‐adapted strategy of dose modification only occurred in a small fraction of patients.

This systematic review and meta-analysis aimed to determine the effectiveness of brentuximab vedotin (BV) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL) in the clinical practice setting using most recent results. A total of 32 observational studies reporting on treatment patterns, overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and adverse events were found. After four cycles, a random-effect model yielded pooled ORR and CR rates of 62.6% (95% confidence interval (CI): 56.0-68.9; I-2 = 9.7%) and 32.9% (95% CI, 20.8-46.3, I-2 = 64.8%), respectively. Regarding survival, 1-year, 2-year, and 5-year PFS ranged from 52.1% to 63.2%, 45.2% to 56.2%, and 31.9% to 33.0%, respectively. OS rates were 68.2-82.7%, 58.0-81.9%, and 58.0-62.0%, respectively. Most common adverse events were hematological toxicities (neutropenia: 13.3-23%, anemia: 8.8-39.0%, and thrombocytopenia: 4-4.6%), and grade >= 3 peripheral neuropathy (3.3-7.3%). This study supports the effectiveness and safety of BV in R/R cHL patients in the real-world setting.

Objective To assess evidence on the safety and efficacy of ABVD (doxorubicin [Adriamycin (R)], bleomycin, vinblastine, and dacarbazine), BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), and A+AVD (brentuximab vedotin, with doxorubicin, vinblastine, and dacarbazine) for advanced-stage Hodgkin lymphoma (HL). Methods A systematic literature review (SLR) was conducted on 29 July 2016 (updated 26 July 2018) to identify randomized controlled trials (RCTs) and non-RCTs assessing the treatment of newly-diagnosed advanced-stage HL with ABVD and BEACOPP (and their variants), and A+AVD. Results The SLR identified 62 RCTs and 42 non-RCTs. Five-year overall survival rates for ABVD and BEACOPP were 60-97% and 84-99%, and 5-year progression-free survival rates were 58-81% and 83-96%, respectively. Both regimens were associated with tolerability issues and side effects. Discontinuation or dose reduction of bleomycin resulted in fewer adverse events, without significantly affecting efficacy. A head-to-head trial demonstrated improved efficacy for A+AVD vs ABVD, with an acceptable tolerability profile. No data from head-to-head trials comparing A+AVD with BEACOPP were available, and an indirect treatment comparison was not feasible. Conclusion New therapies, such as A+AVD, maintain the efficacy observed with current treatments, and may provide a more tolerable treatment option for patients with advanced-stage HL.

Real-world data on regimens for relapsed/refractory multiple myeloma (RRMM) represent an important component of therapeutic decision-making. This multi-centric, retrospective, observational study conducted by the treating physicians evaluated the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in 155 patients who received ixazomib via early access programs in Greece, the UK, and the Czech Republic. Median age was 68 years; 17% had an Eastern Cooperative Oncology Group performance status ≥ 2; median number of prior therapies was 1 (range 1–7); 91%, 47%, and 17% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Median duration of exposure to ixazomib was 9.6 months. Overall response rate was 74%, including 35% very good partial response or better (16% complete response). Median progression-free survival (PFS) was 27.6 months (27.6 and 19.9 months in patients with 1 or > 1 prior lines, respectively). IRd treatment for ≥ 6 months was associated with longer PFS (hazard ratio 0.06). Fourteen patients (9%) discontinued IRd due to adverse events/toxicity in the absence of disease progression. Peripheral neuropathy was reported in 35% of patients (3% grades 3–4). These findings support the results of the phase III TOURMALINE-MM1 trial in a broader real-world RRMM population.

EASEMENT is being conducted in real-world settings in Canada, Italy, and the UK with aims of understanding the burden of multiple myeloma (MM) and describing the perspectives of patients (pts), caregivers, and physicians on currently available treatment options. Here we report pt characteristics and treatment patterns in newly diagnosed (NDMM) and relapsed/refractory (RRMM) pts receiving injectable or oral therapies.

Brentuximab vedotin (BV) is the first approved novel agent for salvage treatment of relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after autologous stem cell transplantation (ASCT). In this study, a literature-based analysis was undertaken to assess, via an indirect treatment comparison, the comparative efficacy of BV to salvage chemotherapy as treatment for R/R cHL patients following ASCT. This comparative effectiveness research was undertaken to support a reimbursement submission for BV to the Australian Pharmaceutical Benefits Advisory Committee. Retrospective analysis of individual patient data from four data sources demonstrated that the use of BV as first salvage treatment in cHL patients relapsing or progressing post-ASCT achieved improvements in both clinical response and overall survival. More specifically, BV was associated with an incremental improvement of 22% in overall response rate compared to salvage chemotherapy. Five-year overall survival and progression-free survival rates were 92·2% [95% confidence interval (CI): 85·5-99·3%] and 32·2% (95% CI: 19·1-54·6%) respectively for BV, compared to 30·5% (95% CI: 22·2-42·0%) and 3·2% (95% CI: 1·1-8·9%) respectively for salvage chemotherapy. The encouraging results from this conservative analysis have the potential to support informed clinical management and funding decisions for the first salvage of cHL patients demonstrating recurrence after ASCT.

Background Recently, treatment options for RRMM have increased substantially with multiple approvals of novel agents/combination, making the treatment algorithm increasingly complex, with changes driven chiefly by access to novel agents/regimens. Furthermore, patient (pt) and disease characteristics have a profound impact on treatment decisions. To understand the impact of recently approved novel regimens on real-world (RW) treatment patterns, we conducted a multi-national survey to investigate the management of RRMM across Europe. Methods Retrospective, anonymized data from RRMM pts, treated in academic or community hospitals/clinics in 8 countries were extracted from Jan 2016 to Dec 2018. Data were analyzed overall and for Germany, Austria, and Switzerland (DACH) vs other countries (Belgium, France, Greece, Spain and UK) due to differences in treatment access. Results The cumulative number of pts included was 2782 in 2016, 3902 in 2017, and 4658 in 2018. Of the pts enrolled in 2016, 2017 and 2018, 40%, 49% and 51%, respectively, were in 3rd+ line (≥3L), potentially reflecting the increasing availability of treatment options for RRMM and extended survival in MM. Median age at diagnosis in pts enrolling in 2016, 2017, and 2018, was 68, 69, and 70 years, respectively, with 23%, 24%, 26% aged >75 years, underlining the fact that MM remains a disease of the elderly. The data revealed a difficult-to-treat RW population: 31%-36% of pts had an ECOG PS ≥2 at 2nd line (2L) in 2016-2018; increasing to 44%-49% at 4th+ lines (≥4L). At 2L, 42%-45% of pts presented ≥1 treatment-dependent comorbidity in 2016-2018, including hypertension (23-27%) and renal impairment (9-10%). Cytogenetic risk, evaluated in 38%-42% of pts at initial diagnosis, was reported as high in 8%-10% of the total population. Treatment initiation due to biochemical relapse was reported in 33%/36% of pts at 2L/3L in 2016, and in 30%/28% in 2018, indicating that ~1/3 of pts manifested an asymptomatic rather than clinical relapse. The proportion of pts treated with triplet regimens increased from 26%, 26%, and 30% at 2L, 3L and ≥4L in 2016 to 43%, 40%, and 38% in 2018, reflecting the adoption of newly approved triplets in RRMM, particularly in DACH countries. Use of proteasome inhibitor (PI)-based regimens increased from 35%, 30% and 34% at 2L, 3L and ≥4L in 2016, to 43%, 37% and 37% in 2018, driven by increased/earlier use of novel PIs (carfilzomib and ixazomib). These trends were more obvious in DACH, highlighting the impact of earlier access to modern treatment in these countries. Similarly, the proportion of pts on daratumumab-based regimens increased from 0, 5%, and 20% at 2L, 3L and ≥4L in 2016, to 10%, 24% and 31% in 2018. From 2016 to 2018, prior IMiD exposure at 2L increased from 11% to 20% in DACH, but remained stable at 42% in other countries; at 3L, there was an increase from 77% to 82% in all countries reflecting the uptake of novel triplet combinations. Most pts were IMiD-exposed or IMiD-refractory at ≥4L. Regarding the treatment algorithm, the rate of PI-based treatment at 1L was 74%-75%. PI- to IMiD-based therapy was the commonest treatment sequence from 1L to 2L, at 64%-66%, while PI- to PI-based therapy at 1L to 2L increased from 22% in 2016 to 30% in 2018. Key disease/pt characteristics associated with the selection of regimens at 2L and 3L are summarized in the Table. Prior IMiD treatment limited the use of IMiD-based therapy in subsequent lines. The use of KRd, IRd and DRd was mostly associated with ISS stage III, while the use of KRd was less frequently reported in pts with cardiac comorbidities. In pts with prior PI treatment, KRd and IRd (but not Kd) were more common at 2L, while DRd was preferred at 3L. A higher proportion of fit, young, or prior-SCT pts were treated with KRd or DRd, while IRd was the preferred treatment in pts with biochemical relapse. Conclusions Multiple drug approvals for RRMM in Europe have resulted in marked changes in the treatment algorithm, with a more immediate impact in countries with earlier access to new treatment options. Multiple decision drivers such as age, fitness, comorbidities and prior treatment are associated with uptake of different novel regimens at 2L and 3L. The increasing range of treatment options has resulted in pts receiving more lines of therapy for RRMM, highlighting the need for cautious planning of treatment sequencing to optimize the use of available combinations according to pt characteristics and disease factors. Disclosures Merz: Janssen: Other: Travel grants; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Abbvie: Other: Travel grants; Celgene: Other: Travel grants; Takeda Vertrieb GmbH: Other: Travel grants, Research Funding. Pérez:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees. Kolb:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: travel and registration for my participation to international medical congres (ASH). Symeonidis:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zomas:Takeda: Employment. Gonzalez:Takeda: Employment. Kellermann:Amgen: Research Funding; BMS: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Takeda: Research Funding. Goldschmidt:Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; John Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; ArtTempi: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; MSD: Research Funding; Molecular Partners: Research Funding; Mundipharma: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product.

ObjectivesTo evaluate the prognostic impact of hypercalcemia in newly diagnosed patients with symptomatic multiple myeloma (MM), especially after the incorporation of new agents. Methodswe analyzed the outcomes of newly diagnosed patients with symptomatic myeloma included in the database of the Greek Myeloma Study Group for the prognostic effect of the presence of hypercalcemia (defined as corrected serum calcium 11mg/dL) at diagnosis. ResultsAmong 2129 consecutive patients with symptomatic MM, 19.5% presented with hypercalcemia at the time of diagnosis. The presence of hypercalcemia was associated with anemia, thrombocytopenia, lower estimated glomerular filtration rate (eGFR), advanced ISS stage, and presence of lytic lesions. Hypercalcemia was more common in patients with high-risk cytogenetics and was associated with inferior survival across different time periods, age groups, and primary treatments. Hypercalcemia was also associated with a twofold increase in the risk of early death. In patients without available FISH, hypercalcemia could substitute for the presence of high-risk cytogenetics and identify patients with worse prognosis along with ISS stage and elevated serum LDH. ConclusionHypercalcemia remains a poor prognostic feature in the era of novel agents despite the improvement in the outcomes of patients who present with elevated calcium.