Frail Pts Research Articles

Second primary B-ALL after exposure to lenalidomide for multiple myeloma: A US multicenter study.

7533 Background: Maintenance treatment (rx) with lenalidomide (R) improves overall survival (OS) in multiple myeloma (MM). We report a retrospective cohort of patients (pts) with second primary B-cell acute lymphoblastic leukemia (ALL) diagnosed after R-rx for MM. Methods: We included pts who were exposed to at least 1 yr of R for MM rx prior to ALL dx. After approval by institutional review board, data were collected by chart review at participating centers using Redcap. OS was the primary endpoint. We used BlueSky statistics v10.3.1 for analysis. Results: Analysis included 33 ALL pts diagnosed from 2014-2022 at 7 sites. 52% pts were female. Median follow up was 9.6 yrs (95%CI,7.6-11.8) from MM dx and 3.2 yrs (CI, 2.1-4.7) from ALL dx. Pt characteristics at MM dx are given in Table. Induction rx included: proteasome inhibitor (PI) +immunomodulatory drug (IMiD) (43%), PI+alkylator (24%), IMiD (18%) & others (15%). 50% pts received autologous stem cell transplantation (ASCT). Median OS from MM dx was 11.2 yrs (CI, 8.9-NR). Time from MM dx and initial R rx to ALL dx were 5.0 yrs (range, 2.4-18.5) and 4.4 yrs (2.2-10.6) respectively. Median duration of R exposure before ALL dx was 3.8 yrs (1.6-10.4). Table shows characteristics of pts at B-ALL dx and genetic classification based on karyotyping (n=30), ALL FISH (n=28), chromosomal microarray (n=5) and next-generation sequencing (n=5). 31 pts received ALL-directed rx while 1 pt was initially managed with close observation as the pt attained CR on stopping R ( Lakshman et al; ASH 2019 ). Rx was unknown in 1 pt. Initial rx included: hyper-CVAD+/- rituximab- 49%, pediatric inspired protocols-18%, reduced intensity rx for frail pts- 21% and others- 12%. Response to first line rx were: CR- 56%, CRi- 28%, induction failure- 16%. 32% pts attained measurable residual disease (MRD) negativity. 48% pts underwent SCT for ALL. 14 pts died during follow up. 3-yr OS from ALL-dx was 50% (CI, 33%-76%). 3 pts required rx for MM after ALL diagnosis (2 had allo-SCT for ALL before MM relapse). Conclusions: Most pts had standard risk MM and were exposed to R for several years prior to dx of B-ALL, characterized by high incidence of hypodiploid karyotype; IKZF1 loss and TP53 deletions/mutations were detected in a subset of pts.MRD-adapted timely discontinuation of R in standard risk MM may decrease risk of second primary ALL. [Table: see text]

Frailty risk assessment and impact on acute myeloid leukemia outcomes (FRAIL-AML): A population-based study from Ontario, Canada.

6506 Background: In acute myeloid leukemia (AML), treatment decisions, specifically intensive versus non-intensive approaches, depend on the clinician’s assessment of patient fitness. Frailty as a measure of fitness is a broader concept than commodities and is associated with worse outcomes in many cancers. Frailty assessment is incorporated to provide the precision to oncology treatment selections in addition to disease-related factors. The impact of frailty on outcomes in AML is not well studied. Methods: This retrospective cohort study from population-based health administrative databases in Ontario, Canada (ICES) included all patients (pts) ≥18 years diagnosed with AML between 2006 and 2021, treated within 90 days after diagnosis. Frailty was measured using McIsaacs’s frailty index (MFI)- a validated tool. Progressively increasing tertiles of MFI were categorized as fit (FT), pre-frail (PFR), or frail (FR). Treatment intensity was classified as intensive (IT) or non-intensive (NIT) based on standard practices. The primary outcome was overall survival (OS). Association of frailty with OS was measured using Cox regression separately for IT and NIT AML. Results: Out of 5450 pts, with a median age of 65 (IQR 54-74), 55.8% were males and 44.2% were females. 65% (n=3543) received IT, out of which 29.4% and 35.5% pts were FR and PFR respectively. Remaining 35% (n=1907) received NIT, with 41.1% and 32.3% pts being FR and PFR. Median overall survival in months (OS, 95% CI) for the entire group, IT, and NIT were 12.5 (12.0-13.2), 16.7 (15.7-18.2), and 7.6 (7.0-8.2), respectively. OS (table) was notably lower in FR pts compared to fit pts (p<0.0001) in both IT and NIT. Univariate and multivariate analyses identified frailty, advanced age, and previous non-AML malignancy as risk factors associated with worse OS in both IT and NIT groups (table). Conclusions: Higher frailty is independently associated with worse OS in AML pts after adjusting for advanced age. A substantial proportion of AML pts in both IT and NIT groups exhibit a mismatch in treatment intensity assignments based on their frailty status, with about 30 % FR pts receiving IT and over 25 % FT pts receiving NIT. This study sheds light on the need for frailty evaluations using standardized tools to optimize treatment decisions in AML pts. [Table: see text]

Current trends of clinical trials for older patients with cancer: A systematic review.

1621 Background: While accounting for 40% of the cancer population, older adults are underrepresented in clinical trials. Older-age-selected studies are desirable, but their characteristics and overall performance are unknown. This systematic review assessed design and outcomes of trials focused on this patient population. Methods: We searched Embase and PubMed with the keywords “older adults”, “cancer” and “clinical trials”, from inception to March 1, 2023. We included phase (Ph) I, II and III trials testing systemic therapies in solid cancer patients (pts) aged ≥70 yrs. For each of the selected trials, we carried out an ad-hoc search for age-unselected trials testing the same interventions in the same setting. We followed the PRISMA guidelines for systematic reviews and registered the study on the PROSPERO database (CRD42023465089). Results: We screened 25,868 records and included 313 studies. 48 (15.4%) were Ph I-I/II, 232 (74.1%) Ph II, and 33 (10.5%) Ph III. The minimum-age threshold used to define ‘old’ was 70-74 yrs in 79.9%, 75-79 in 19.8%, and 80 in 0.3% of cases. Most trials (76.7%) were run in the palliative setting. Common tumors included lung (60.4%) and colorectal cancer (15%), while chemotherapy (88.5%) and targeted therapy (23.6%) were the most frequently tested treatments. Non-conventional primary endpoints (e.g., toxicity, feasibility, functional status, quality of life [QoL]) were used in 8.3% of Ph II-III trials. 24 studies were published in 1990-2000, 126 in 2001-2011, and 163 in 2012-2023. The median accrual time was 32 (IQR 21.5-44.5), 30 (IQR 20-43) and 43 months (IQR 36-65) for Ph I, I/II-II, and III, respectively. Of 234 trials reporting the pre-planned target accrual, 77.8% enrolled ≥90% of the required pts. Premature study discontinuation occurred in 50 studies (5.9% of Ph I, 14.2% of Ph II and 39.4% of Ph III), the major reason being slow accrual, while only 9 and 6 closed due to futility and overt efficacy, respectively. Among the 233 trials with a pre-defined statistical hypothesis, 60% met the primary endpoint, including 63.7% Ph I/II-II and 35.5% Ph III trials. Geriatric assessments (GA) and QoL analyses were carried out in 88 (28.1%) and 72 (23%) trials, respectively. Only 18 (5.8%) studies were dedicated to frail pts. Corresponding age-unselected trials were available for 154 older-patient studies. Compared with those, a higher proportion of age-unselected studies enrolled ≥90% of the required pts (95% vs 83.5%, p=0.03) and met the primary endpoint (80.3% vs 63.9%, p=0.03). Conclusions: The interest in clinical trials of solid tumors in older patients has increased over time. While Ph I and II trials are feasible, still a substantial proportion of Ph III trials suffer from slow accrual and premature discontinuation. Interventions to tackle barriers to recruitment should be implemented. Efforts should be made to systematically include GA and QoL analyses, which are key for this patient population.

Pulsed field ablation versus very high power short duration radiofrequency ablation in atrial fibrillation: what is better?

Abstract Background The newly introduced non-thermal pulsed field ablation (PFA) is a promising technology for catheter ablation (CA) of atrial fibrillation (AF) with high acute success rates and good safety features. However studies have shown that very high power short duration (VHPSD) ablation is also highly effective and fast with potentially less arrhythmia recurrence compared to conventional radiofrequency ablation. Data comparing this two methods are lacking Objective The aim of this study is to compare two source of energy used for CA of AF in terms of procedural, clinical and outcome data Methods We conduced a retrospective observational study enrolling all patients (pts) from september 2021 to may 2023 who underwent CA of AF with PFA system and VHPSD. In the PFA group pulmonary veins isolation (PVI) was obtained using 2KV with eight application each vein, posterior wall isolation (PWI) of left atrium (LA) was obtained with application in the flower configuration of the catheter and then additional lesion were deployed at the operator’s discretion. In the VHPSD group the encircling of PV was obtained with 90W for 4 seconds radiofrequency pulses in posterior portions of the LA including LA PW, whereas 50W with ablation index target of 500 was used in the anterior portions of the PV and additional lesions. General anesthesia or deep sedation was carried out in all pts Results A total of 205 pts were included, n = 86 (42%) in the PFA group and N = 119 (58%) in the VHPSD group: paroxysmal (n = 62[72%], N = 64[54%]), persistent (n = 19[22%], N = 43[36%]), long standing persistent (n = 5[5%], N = 10[8%]). PVI was successful in all pts and additional lesions were delivered in n = 26 (30%) in PFA group and N = 76 (64%) in HVPSD group, mostly at the PW (n = 24[92%]; N = 50[66%]). The PFA group revealed a shorter procedura duration (80 ± 29 min vs 108 ± 39 min; p = 0,00001) but longer fluoroscopic time (21 ± 8 min vs 14 ± 10 min; p = 0,00001). The VHPSD group revealed more complications (N = 7[6%] vs n = 3[3%]) but without statistically significant difference (p = 0,43), the most frequent in the PFA group was vascular access complications instead in the VHPSD group was post-procedural pericarditis. Only one patient in VHPSD group had major complication with a post-procedural stroke but without residual neurological deficits. At follow-up after median of 14 (26-6) months, n = 61 pts in the PFA group (71%) and N = 91 in the VHPSD group (76%) were free from atrial arrhythmia (p = 0,79). In both group 7 pts recurrenced as atypical atrial flutter (n = 7[28%] PFA; N = 7[25%] VHPSD; p = 0,061) Conclusion PFA and VHPSD are effective and safe to CA of AF with comparable arrhythmia recurrenses. However procedure duration with PFA is significantly shorter and therefore may be of potential benefit in particular for elderly and frail pts. Further research, including randomized controlled trials, is needed to validate and compare these techniques more comprehensively

Subcutaneous Daratumumab at Home Is a Safe and Effective Procedure for Frail Patients with Multiple Myeloma: A Myelhome Project Report

Background Treatment of Multiple Myeloma (MM) is often difficult due to patient (pts) frailty, bone lesions/fractures that can hinder transport and/or long distance from the hospital. The availability in the Viterbo province of a Domiciliary Hematologic Care Unit (DHCU) allowed to overcome these difficulties. Patients and methods Herein, the experience in 15 patients with MM treated as outpatients [10 at home (HC) and 5 in a Long Term Residential Accomodation (LTRA)] with subcutaneous (sc) daratumumab (dara) is reported, as part of the Myel-Home project. The initial 2 dara administrations, either intravenous or sc, were given in hospital to prevent side effects, while subsequent administrations were done as outpatients: the first dara administration as outpatient was done by nurse and physician, while subsequent ones by nurse only. Results: The main clinical features of pts at baseline of dara initiation are shown in the Table. Different reasons for outpatient management were: advanced age (> 80 years) in 3 pts, illness related symptoms in 8 pts, social conditions and/or long distance in 4 pts. Distance from DHCU to pts home was < 20 Km in 4 cases ( 27%), ≥ 20 < 40 Km in 10 (66%) and ≥ 40 Km in 1 (7%). Different lines of treatment and different schemes are reported in the Table: among 7 pts treated in 1 st line, 3 were transplant eligible and 4 transplant ineligible. On the whole, 110 administrations of sc-dara were performed by DHCU nurses as outpatient: during and/or immediately after home administration, only one pt had adverse events (grade 2 allergic reaction according WHO), leading to dara permanent discontinuation after the 2nd dose at home. Main adverse events during the course of domiciliary treatment were infections (pneumonia in 4 pts, sepsis in 2, cystitis in 1) and deep vein thrombosis in 1 pts. Moreover, 4/5 patients (80%) in LTRA had infections (which were fatal in 3 of them) compared to 3/10 pts (30%) in HC with only 1 related death. Two pts were not yet evaluable for response and one pt discontinued early: among the evaluable 12 pts, 1 achieved a stringent complete remission and 4 a very good partial remission, with an overall response rate of 42%, 5 pts had a stable disease and 2 pts a disease progression. At the last follow-up, 8 pts are alive (2 waiting for transplant procedure) and 7 pts died (3 from disease progression, 3 from infective complications and 1 from heart disease). Conclusions: Treatment at home with sc-dara in frail pts with MM is feasible and safe with improved quality of life, making possible a curative approach frontline as well as in advanced phases of disease also in subjects otherwise excluded by best available therapies or forced to long periods of hospitalization: it is worth of note that pts living in LTRA were at high risk of infective complications, thus limiting the advantages of a domiciliary management compared to pts living at our own house. In the next future, within the Myel-Home project, other monoclonal antibodies (belantamab-mafodotin and talquetamab) will be available for home administration.

Combination Chemotherapy in Patients with Newly Diagnosed Blastic Plasmacytoid Dendritic Cell Neoplasms (BPDCN): First Results of a Prospective French Trial (LpDessai)

Introduction Blastic plasmacytoid dendritic cell neoplasms (BPDCN) are now well-characterized diseases clearly referenced in the 5 th edition of the World Health Organization (WHO) Classification of Tumors (2022) 1 but treatment remains a real challenge. There is no consensus on the first line treatment even if CD123 targeted therapies are available in the USA and some European countries. Standard chemotherapy remains largely used as first line treatment with better results of leukemia-based regimens despite a high toxicity rate in this frail population 2,3. To establish a reference chemotherapy scheme, we prospectively evaluated the efficacy and toxicity of a combination chemotherapy (idarubicin, methotrexate, L-asparaginase, and dexamethasone) in newly diagnosed BPDCN patients (pts) in France. Patients and methods This single stage phase II study enrolled consecutive adult pts with suspected BPDCN in participating French centers. BPDCN diagnosis was centrally reviewed for cytology and immunophenotype (IF) (Pr Garnache Ottou F, UMR RIGHT BESANCON) and if needed for histology (Dr Petrella T, Montréal, Canada) according to published recommendations 1,4. After giving their informed consent, patients were evaluated for tumoral involvement by PET-scan, systematic lumbar puncture, and the mSWAT score was calculated for skin extension. Patients then received three 21 days-cycles of Ida/Metho/L-asp/Dex combination, before evaluation. Eligible patients with complete response (CR), complete response with incomplete bone marrow recovery (CRi) or partial response (PR) underwent allogeneic hematopoietic stem cell transplantation (HCT). Those not eligible received consolidation chemotherapy with 28 days cycles of Metho/L-asp/Dex (Figure 1). The primary objective was the proportion of patients with CR after 3 cycles of chemotherapy. Secondary objectives were the proportion of patients with an objective response (ORR) defined as CR, CRi or PR, the minimal residual disease (MRD) in responding patients evaluated by the presence of plasmacytoid dendritic cell blast measured by flow cytometry in the bone marrow, the incidence of severe adverse events and overall survival (OS). The competent ethics committee (Comité de Protection des Personnes Île de France 8) approved the study. The Besançon University hospital promoted the trial, financed by a grant of the French National Cancer Institute (INCa-DGOS_11093). Results Twenty-eight pts, originating from 16 centers, were screened between May 2019 and March 2023. Two patients with a misdiagnosis were screen failures. Two patients did not receive the planned chemotherapy due to clinical deterioration; 24 patients (21 male, 3 female) received at least one chemotherapy cycle and 23 are analyzed with a current end-point on June 30, 2023. Median age was 65y (21-79y). ECOG status was 0-1 in 20 cases, and 2 in 3 cases. A cutaneous involvement was identified in 16 pts (70%) and an extra medullary involvement was present in 13 (62%) pts: spleen, n= 6 (25%); lymph nodes, n= 7 (30%). Twenty-three pts (90%) had a bone marrow infiltration (identified only on IF in 4 cases), and 3 cases (14%) a documented central nervous system involvement. Nine pts had to stop planned treatment due to severe adverse events (3 deaths, 4 acute renal failure and 2 grade 4 febrile neutropenia) and in 4 pts, at least one cycle had to be delayed. Among the 15 pts receiving at least 3 cycles, 12 (80% and 50% of the whole cohort) were in ORR (CR = 8, CRi = 2, PR = 2) after the 3rd cycle of chemotherapy, 2 pts did not respond. Eight of ten (80%) CR/CRi pts had a MRD < 10 -4 without any further relapse. Nine of 12 responding patients (75%) received an allogeneic HCT 1-2 months after the end of the 3 rd cycle. Global OS at 6 months for responding or failing pts were 100% and 37% respectively (Figure 2). Conclusion In selected pts, an adapted chemotherapy could offer high CR rate in pts able to follow the planned treatment but remains toxic in frail pts, with only half of the them achieving a 3 rd cycle of chemotherapy. We confirm that pts achieving ORR and receiving HCT obtain prolonged CR. MRD level seems to correlate with OS and could be a useful tool to manage treatment toxicity in BPDCN frail pts.

SIE/Sies/GITMO Criteria in Elderly Patients with Acute Myeloid Leukemia (AML): Useful Also in the New Drug Era? a Multicentric Real-Life Study By the Hematological Network Rete Ematologica Lombarda (REL)

Introduction: In elderly acute myeloid leukemia (AML) patients (pts) the debate about the use of intensive chemotherapy (iC) as opposed to non-intensive therapy (niT) or best supportive care (BSC) is a hot topic, particularly after the introduction of venetoclax (VEN) use. Age, comorbidities, functional impairment, therapy benefits and risks, pts preferences, and AML features influence this choice. The SIE/SIES/GITMO (“fitness”) criteria (Ferrara, 2013) are a valuable and comprehensive tool, but a revalidation is needed in the light of the new treatment options. Methods: Within the Rete Ematologica Lombarda (REL), we evaluated 1) the concordance between “fitness” of pts, and the type of treatment they actually received, 2) the overall survival (OS) according to the “fitness”, to the prognostic European Leukemianet (ELN17) stratification and to the treatment received, and 3) the presence of other parameters, as Charlsons Comorbidity Index (CCI), potentially useful in therapy decision. Pts were classified as fit to iC (FIT), unfit to iC (UNFIT), or unfit even to niT (FRAIL), as defined by the SIE/SIES/GITMO criteria. Results: From Jan 20 to Dec 22, 503 AML pts (53% de-novo), with a median age of 76 years (y) (range, 65-93) were diagnosed consecutively at 11 Hematology Units. According to “fitness” criteria, 25% of pts were FIT, 61% UNFIT, and 14% FRAIL (Table1). Median age was significantly lower in FIT pts (70 y), as compared to UNFIT (78 y) and FRAIL (79 y) (p <0.0001). Overall, the concordance between “fitness criteria” and the treatment actually received by pts was 75.9% (71% in FIT, 76% in UNFIT and 84% in FRAIL). After a median follow-up of 12 months (m), median OS of the whole population was 7.4 m. Median OS of FIT, UNFIT and FRAIL pts was 13.7, 7.2 and 1.4m, respectively (p <0.0001, Fig 1a). According to physicians' decision, 18% of pts received iC, 55% niT, mainly hypomethylating agents (HMA: azacytidine or decitabine) + VEN, and 27% BSC. Median OS was 17m, 10.2m, 1.4m in iC, niT and BSC pts, respectively (p<0.0001, Fig 1b). According to ELN17, evaluable in 73% of pts, 19% were favorable (fav), 20% intermediate (int) and 61% adverse (adv), without differences into “fitness” groups. Median OS was significantly worse in ELN adv than in ELN fav and int (p: 0.001 and p: 0.002, respectively, Fig 1c). In FIT pts, median OS was 17m with iC and 11.4m with niT (VEN-HMA) (p: 0.3). The use of iC was associated with younger age (median age: 69 in iC vs 73 y in niT, p<0.0001), lower CCI (CCI< 2: 88.5% in iC vs 64% in niT, p: 0.0032) and not significantly with better ELN risk (ELN adv 49% in iC pts vs 70% in niT, p: 0.07). The use of iC or niT did not affect remission rate (64% vs 71%) nor OS in different ELN risk groups. In UNFIT pts, median OS was 14m with niT and 3.8m with BSC pts (p<0.0001). The use of niT compared to BSC was associated with younger age (median 77 vs 81 y; p<0.0001), not adv ELN risk (41% vs 7%, p: 0.0001), lower ECOG performance status (PS) and CCI (PS<2: 81% vs 65%, p: 0.0001; CCI<2: 66% vs 50%, p: 0.038). In UNFIT pts treated with VEN-HMA median OS was 11m vs 7.3m with HMA only (p: 0.019). The use of VEN-HMA rather than HMA only was associated with younger age (median: 76 vs 80 y; p: 0.0045), better PS and CCI (PS<2: 94% vs 84%, p: 0.026; CCI<2: 68% vs 50%, p: 0.008). ELN risk distribution was similar. In non-adv risk pts, OS was 17m with VEN-HMA, significantly better compared to HMA only (7m) (p: 0.03) as well as to adv risk pts treated with VEN-HMA (p: 0.0017). Age >82y, number of comorbidities, lack of caregiver were the most frequent reasons for the physician's preference for HMA therapy over VEN-HMA. InFRAIL pts, median OS was 2.9 m with niT and 1.1m with BSC pts (p: 0.04). The use of niT was associated with a relatively better PS and younger age (<73 y). At multivariable analysis, ELN fav and iC favorably affected survival, whereas a FRAIL fitness status, PS>2, and CCI>2 proved to be independent adverse prognostic factors. Conclusion: Fitness stratification of SIE/SIES/GITMO correlated to pts's survival and were useful in the decision-making approach of treatment also in the new drugs era. Within the “fitness” categories, age, CCI and particularly ELN risk, had an impact on the choice of the type of induction therapy, in FIT pts (iC vs niT) without changing the outcome, while in UNFIT pts an under-treatment worsened OS. These preliminary data should be implemented with a longer follow-up and a larger sample size.

Efficacy and safety of elranatamab by age and frailty in patients (pts) with relapsed/refractory multiple (RRMM): A subgroup analysis from MagnetisMM-3.

8040 Background: Multiple myeloma is predominantly a disease of elderly and frail pts, who are often ineligible for intensive therapies. Data from the ongoing Phase 2 MagnetisMM-3 (NCT04649359) study demonstrated the efficacy and safety of elranatamab in pts with RRMM and no prior BCMA-directed therapy (Cohort A). Here we report results for subgroups of pts by age and frailty. Methods: Eligibility criteria, dosing and administration were previously reported (Bahlis, ASH 2022). Subgroups of pts within Cohort A (n = 123) were analyzed by age: < 65 (n = 43) vs ≥65 years n = 80), and frailty: non-frail (n = 84) vs frail (n = 39). A simplified frailty scale was used (Facon et al, Leukemia 2020). Results include data up through ~12 months after last pt initial dose. Results: The median treatment duration was 8.2 vs 5.5 mo in the < 65 vs ≥65 years, and 6.4 vs 5.6 mo in the non-frail and frail subgroups, respectively. Discontinuation occurred in 62.8% vs 67.5% of pts aged < 65 vs ≥65 years and in 63.1% vs 71.8% of the non-frail vs frail groups, respectively. The most common reason for discontinuation in all subgroups was progressive disease, 51.2%, 32.5%, 42.9%, and 30.8% of < 65, ≥65 years, non-frail, and frail subgroups, respectively. The objective response rate (ORR) (95% CI) was 58.1% (42.1%, 73.0%) vs 62.5% (51.0%, 73.1%) for pts aged < 65 vs ≥65 years. Median duration of response was not reached in either age subgroup. The probability of maintaining response (95% CI) at 12 mo was 74.1% (51.0%, 87.5%) vs 73.8% (55.7%, 85.4%) for pts aged < 65 vs ≥65 years. The ORR (95% CI) for non-frail pts was 63.1% (51.9%, 73.4%) vs 56.4% (39.6%, 72.2%) for frail pts. Median duration of response was not reached in either frailty subgroup. The probability of maintaining response at 12 mo (95% CI) was 76.0% (60.2%, 86.2%) vs 70.5% (41.9%, 86.9%) for non-frail vs frail pts. Any Grade treatment-emergent adverse events (TEAEs) were reported in 100% of pts in the study. Grade 3/4 TEAEs were reported in 74.4%, 68.8%, 73.8% and 64.1% of pts in < 65, ≥65, non-frail and frail subgroups, respectively. Infections (Any Grade; Grade 3/4; Grade 5) were reported in 72.1%, 32.6% and 4.7% vs 68.8%, 40.0% and 6.3% in < 65 and ≥65 pts, respectively, and in 70.2%, 38.1% and 4.8% vs 69.2%, 35.9% and 7.7% in non-frail and frail pts, respectively. The rate of cytokine release syndrome was similar in patients with respect to age ( < 65, 58.1%; ≥65 years, 57.5%) and frailty groups (non-frail, 57.1%; frail, 59.0%). Immune effector cell-associated neurotoxicity syndrome was reported in 2.3%, 6.3%, 6.0% and 2.6% of pts in < 65, ≥65, non-frail and frail subgroups, respectively. Conclusions: Elranatamab is efficacious and has a manageable safety profile in elderly or frail pts with RRMM and may be a treatment option for those ineligible for more intensive myeloma therapies. Clinical trial information: NCT04649359 .

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: BTK-inhibitors have revolutionized treatment of CLL. However, although patients (pts) above 80 years of age represent roughly 20% of the general CLL-population they remain underrepresented in clinical trials. Comorbidities, frailty, and organ dysfunction have a high prevalence in older pts and significant impact on efficacy and tolerability of treatments as well as survival. The CLL-Frail trial aims to evaluate the efficacy and safety of acalabrutinib monotherapy in pts ≥80 years of age and/or a FRAIL scale score of ≥3. The FRAIL scale score is a 5-item questionnaire for pts correlating with Fried‘s frailty phenotype. Methods: Pts in need of treatment with previously treated and untreated CLL and ≥80 years of age and/or a FRAIL scale score ≥3 were eligible. A maximum of one previous therapy was allowed. At least 50% of pts needed to fulfil frailty criteria. Pts received acalabrutinib 100 mg BID until progression or intolerance. The primary endpoint was overall response rate at initial response assessment (cycle 7, day 1 = ∼6 months after initiation of therapy). A pre-planned interim safety analysis was conducted once 30 pts reached cycle 7, day 1. Results: 30 pts were enrolled in the first 12 months of recruitment. Median age was 82 years, 50% had a FRAIL scale score of ≥3. Median CIRS score was 10, with 73% of pts having a score >6. Median ECOG-Score was 1. Most pts had a Binet stage A (77%). Unmutated IGHV and TP53mut/del was present in 63% and 10%, respectively. 19 pts (63%) were treatment naïve. In the previously treated cohort, prior lines of treatment included chemoimmunotherapy in 73% and ibrutinib + obinutuzumab + venetoclax, bendamustine + ibrutinib + ofatumumab and obinutuzumab + venetoclax in 9% of pts each. At the data cut in November 2022 the median observation time was 8 months, 21 pts remained on therapy. Reasons for discontinuation were adverse events in five (56%) and death and withdrawn consent in two (22%) pts each, respectively. All pts experienced at least one AE, totalling in 200 AEs of which 35 (18%) were CTC grade >3 (patient level analysis is shown in Table 1). 15 severe adverse events were reported, of which eight (53%) were assessed as treatment-related by the investigator. There were no cases of severe (Grade ≥3) bleeding, two pts (6%) experienced atrial fibrillation with CTC grade two and three, respectively. Two cardiac SAEs termed cardiac failure were reported in pts who both had prior existing hypertension and atrial fibrillation. Four pts (13%) died, of which one death was deemed treatment related. Causes of death were infection in three cases (one bacterial and two COVID-19 pneumonia) and concomitant disease in one case. Conclusions: The first interim analysis of this international phase II study evaluating treatment with acalabrutinib in very old and/or frail pts with CLL did not show unexpected safety signals in comparison to prior published data. Encore Abstract - previously submitted to EHA 2023 The research was funded by: AstraZeneca Keywords: Cancer Health Disparities, Chronic Lymphocytic Leukemia (CLL), Ongoing Trials Conflicts of interests pertinent to the abstract. F. Simon Research funding: AstraZeneca T. Nösslinger Honoraria: Astra Zeneca, Abbvie, Beigene, Janssen, Roche, Gilead J. Bohn Other remuneration: Astra Zeneca, Abbvie, Janssen J. von Tresckow Consultant or advisory role: AbbVie, Amgen, AstraZeneca, Beigene, Janssen, Lilly, Roche Honoraria: AbbVie, AstraZeneca, Beigene, Janssen, Lilly. Roche Educational grants: AbbVie, AstraZeneca, Beigene, Janssen, Lilly, Roche C. Schneider Honoraria: AbbVie, AstraZeneca S. Stilgenbauer Consultant or advisory role: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis Honoraria: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis Research funding: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis K. Kreuzer Consultant or advisory role: Roche, Janssen, Abbvie, Mundipharma Honoraria: Roche, Janssen, Abbvie, Mundipharma Research funding: Roche, Janssen, Abbvie, Mundipharma A. Fink Honoraria: AstraZeneca Research funding: AstraZeneca, Celgene Educational grants: AbbVie K. Fischer Consultant or advisory role: AstraZeneca Honoraria: AbbVie, Roche, Lilly Educational grants: Roche V. Goede Consultant or advisory role: Astra Zeneca, AbbVie, Janssen, Gilead, Merck, Berlin Chemie Honoraria: Astra Zeneca, AbbVie, Janssen, Gilead, Heel M. Hallek Consultant or advisory role: Roche, Janssen, Gilead, Bristol Myers Squibb, Abbvie Honoraria: Roche, Janssen, Gilead, Bristol Myers Squibb Research funding: Roche, Janssen, Gilead, Bristol Myers Squibb, Abbvie B. Eichhorst Consultant or advisory role: Abbvie, Beigene, AstraZeneca, Novartis, Celgene, ArQule, Oxford Biomedica (UK), MSD, Fa. Hoffmann-La Roche Ltd., Gilead, Janssen Honoraria: Abbvie, Beigene, AstraZeneca, Novartis, Celgene, ArQule, Oxford Biomedica (UK), MSD, Fa. Hoffmann-La Roche Ltd., Gilead, Janssen, Adapative Biotechnologies, Hexal Research funding: Abbvie, Beigene, AstraZeneca, Fa. Hoffmann-La Roche Ltd., Gilead, Janssen Educational grants: Abbvie, Beigene, AstraZeneca, Novartis, Celgene, Fa. Hoffmann-La Roche Ltd., Gilead, Janssen

The effect of a reduced dose of enzalutamide on fatigue and cognition.

5051 Background: Enzalutamide (ENZA) is a highly effective treatment for patients (pts) with metastatic prostate cancer, but central nervous system (CNS)-associated side effects occur frequently and may hamper the quality of life. These side effects are addressed with dose reductions, while they potentially can be prevented by starting at a reduced dose, since androgen receptor saturation is already observed at dose levels above 60 mg once daily (OD) and ENZA plasma concentrations > 5 mg/L. We hypothesized that a lower starting dose of ENZA can reduce the risk of CNS side effects in frail pts while preserving efficacy. In this study (NCT03927391) the effect of a reduced dose of ENZA on fatigue and cognitive side effects is determined. Methods: This randomized multi-center trial compared the ENZA standard dose of 160 mg OD to the reduced dose of 120 mg OD in frail prostate cancer pts. At baseline, and 6, 12, and 24 weeks after start of ENZA, fatigue and cognitive side effects were measured by the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) and Functional Assessment of Cancer Therapy-Cognition (FACT-Cog) questionnaires. A change in scores of 3.0 for the FACIT-F and 7.0 for the FACT-Cog was considered clinically relevant. Linear mixed effects models were used to study within and between-group differences in fatigue and cognitive side effects over time. Furthermore, ENZA plasma concentrations were measured after 6, 12, and 24 weeks of treatment and PSA response (>50% PSA decline) was compared between the two dosing regimens. Results: A total of 51 pts were included (25 reduced dose, 26 standard dose). Completion rates for the questionnaires were high throughout the study (>90%). Pts treated at the reduced dose showed no significant changes in FACIT-F and FACT-Cog scores over time. Pts treated at the standard dose showed increasingly worse FACIT-F and FACT-Cog scores. This resulted in clinically relevant and statistically significant better FACIT-F and FACT-Cog scores for pts treated at the reduced dose compared to pts treated at the standard dose after 24 weeks (table). All pts had therapeutic ENZA concentrations (>5 mg/L) throughout the study. PSA response did not differ between both groups (87% for 120mg OD vs 80% for 160mg OD, p=0.796). Conclusions: By starting with a reduced dose of ENZA of 120mg OD CNS side effects can be prevented, which might beneficially affect the quality of life of frail prostate cancer pts, without any indication of interference with efficacy endpoints. Clinical trial information: NCT03927391 . [Table: see text]

P494 FRAILTY INFLUENCE ON PHYSICAL AND PSYCHOLOGICAL OUTCOMES IN POST–CARDIAC SURGERY PATIENTS CARDIAC REHABILITATION, A SINGLE CENTER STUDY

Abstract Cardiac rehabilitation (CR) is a clinically and cost–effective intervention in post–cardiac surgery patients (PCSp). However the influence of patients frailty on clinical and psychological outcomes in these patients are not well–known. The aim of our work was to evaluate the effectiveness of a personalized rehabilitative therapy in PCSp divided using the Cumulative Illness Rating Scale (CIRS) in group A (393 low–frail pts, CIRS <3, 230 M, 65±3 yrs) and in a Group B (540 frail pts, CIRS >4, 379 M, 67±10) ) evaluating pre and post–treatment the degree of autonomy recovery (Six–minute walking test SMWT, Barthel Index, BI) and the psychological behaviour (State–Trait Anxiety Inventory STAI–X1, Depression Questionaire QD–R). At admission the comparison between Group A vs B has show: a greater loss autonomy in frail patients (BI scale A 51.7±1 vs B 28.7±14, p 0.005; SMWT A 245±25 m vs B 155±18 m, p 0.005) a greater impairment in psychological characteristics in frail patients (STAI–X1 A 18±9 vs B 20±4 p 0.028, QD/R A 3.6±2 vs B4.4±3 p0.001) At discharge after a similar period of rehabilitation (A 24.7±11.8 days vs B 25.6±10 days, p ns) we observed: a more evident improvement of degree of autonomy recovery in low–frai group ((BI scale A 77.7±18 vs B 67.7±19, p 0.001; SMWT A 485±18 m vs B 341±25m, p 0.001) a similar improvement in anxiety and depression characteristic in both groups (STAI–X1 A 17.8±2 vs B 17.4±4 p ns, QD/R A 3.1±2 vs B 3.4±2 p ns) Conclusions In our experience the frailty status does not affect the cardiac rehabilitation in post–cardiac surgery patients in term of ensuring adequate functional recovery (although reduced compared to low–frail patients) but with similar improvement in psychological behaviours.

P218 WILD TYPE TRANSTHYRETIN CARDIAC AMYLOIDOSIS (WTATTR) AND HEART FAILURE WITH REDUCED EJECTION FRACTION (HFREF): CAN ANGIOTENSIN RECEPTOR/NEPRILYSIN INHIBITORS (ARNI) BE A THERAPEUTIC OPTION?

Abstract Background wtATTR is associated with high mortality rate, median survival from diagnosis is 43 months and mortality reaches 50% at 4 years. Most patients (pts) present with heart failure and preserved ejection fraction (HFpEF), fewer with HFrEF. Tafamidis is the only modifying–disease agent available in Italy and therapeutic strategy is based on diuretic titration. Beta blockers and therapies for neurohormonal antagonism have raised concerns about their efficacy and safety. The role of ARNI has not been explored. We report our experience of the use of ARNI in pts with wtATTR not eligible to Tafamidis due to advanced NYHA classes. Cases 4 male pts (median age 81 y.o.) received diagnosis of wtATTR between 2018 and 2019 when Tafamidis was not available. Median left ventricular ejection fraction (mLVEF) at the time was 51%. 2 years later they presented with acute HFrEF (Tab1–T0), NYHA classes III–IV with median systolic blood pressure 105 mmHg. Average N–terminal pro natriuretic peptide (NTproBNP) levels were 13888pg/ml and median estimated glomerular filtration rate (eGFR) was 36 mil/min/1,72m2. mLVEF was 23%. Once congestion was relieved pts started Sacubitril/Valsartan (S/V) with titration of dose. At 6 months follow–up (FU) (Tab1–T1) pts were downgraded to NYHA class II and no symptomatic hypotension was reported. Average NTproBNP levels were reduced to 7.800pg/l, only mild worsening of renal function was reported (median eGFR 31mil/minx1.73m2). Absolute increase of mLVEF (46%) was shown on echocardiography. At 12 months FU (Tab 1–T2) pts were clinically stable in NYHA class II, NTproBNP median values had mildly increased to 9700pg/ml and average eGRF was stable (30mil/minx1.73m2). Echocardiogram highlighted minimal reduction of mLVEF compared to previous result (41%). During FU only 1 of the pts required hospitalization for intravenous diuretic therapy and S/V was temporarily suspended. Conclusion The efficacy of S/V in HFrEF is well known. Our brief study proves that ARNI can be tolerated in frail pts affected by wtATTR with no other therapeutic options, guaranteeing a long hospitalization–free period with improvement in quality of life. The result may be purely due to the natriuretic effect of ARNI in patients so strictly reliant on volemic state. More complicated effects may be mediated by neprilisin on amyloid protein; further studies are warranted to establish the role of ARNI in wtATTR.

Integration between Geriatric Oncology and Palliative Care: A Single Center Experience for Hospitalized Older Patients with Cancer

Comprehensive Geriatric Assessment (CGA) is utilized to plan social and health care of the elderly and to complete the diagnostic-therapeutic choice of oncologist also considering early integration with palliative care. Cancer patients (pts) hospitalized aged ≥70 years were screened by the G8 questionnaire to define if necessary CGA. CGA identified: fit, unfit and frail pts. We screened 95 pts by G8 and 93 (98%) were at risk. Pts at risk, evaluated by CGA resulted: 3 fit, 45 unfit and 45 frail. 3 fit pts received standard medical or surgical therapy. 41 unfit pts (91%) received personalized care and 4 pts got worse quickly and died. The median age was 76 and median score IADL/ADL (Instrumental/Activities Daily Living) was 5. Malnutrition was present in 31% and MMSE (Mini-Mental State Examination) was normal in 62%. Among these 45 pts, 32 died with a median survival of 120 days: 14 at home, 13 in hospice and 5 during hospitalization. Among 45 frail pts, 3 received personalized care and 42 received the Best Supportive Care. The median age was 81 and the median score IADL/ADL was 2. Malnutrition was present in 55%, and MMSE was normal in 22%. Among these 45 pts 40 died with a median survival of 36 days: 12 at home, 24 in hospice, and 4 during hospitalization. Unfit pts have a better functional, cognitive and nutritional status than frail pts. Early integration between geriatric oncology and palliative care represents the possibility of create a personalized care pathway especially for frail pts.

Early efficacy results from atezolizumab (ATZ) with split doses of cisplatin plus gemcitabine in patients with locally advanced or metastatic urothelial carcinoma (SOGUG-AUREA).

502 Background: Urothelial carcinoma (UC) commonly affects patients (pts) who are ineligible for full doses of cisplatin-based chemotherapy (CT) due to bad performance status, advanced age, or renal impairment. The combination of split-dose cisplatin with ATZ might be a feasible treatment for pts with UC who are unfit for full doses of cisplatin. Methods: The phase II SOGUG-AUREA clinical trial recruited treatment-naive pts in advanced or metastatic settings considered unfit for full dose of platinum-based CT. Pts received a split dose of cisplatin (35 mg/m2) and gemcitabine (1000 mg/m2) days 1 and 8 (up to 6 cycles) in combination with 3-weekly ATZ 1200 mg in D1 intravenously until progression, unacceptable toxicity, or absence of clinical benefit. Here we present the early results from the confirmed objective response rate (ORR) according to RECIST 1.1, the primary endpoint for efficacy, progression-free survival (PFS), overall survival (OS) and safety. Results: Between Jan 2021 and Mar 2022, 82 pts were screened, 66 pts were enrolled and received at least one dose of study treatment. Baseline characteristics are outlined in the table. The median duration of ATZ treatment was 4.4 months (m) (95%CI: 4.1-4.6). The confirmed ORR was 40.9%, with 5 (7.6%) pts having CR and 22 (33.3%) PR. The median duration of the response was 7 m (95%CI: 4.9-10.4). The clinical benefit rate (CBR) was 53%, and SD (maintained > 6m) was reported in 8 (12.1%) pts. Eight (12.1%) pts were not evaluable for response due to exitus previous to disease evaluation (9.1%), non measurable target lesions (1.5%) or withdrawal (1.5%). With a median follow-up of 9.3 m (range: 0.6-18.1), the median PFS was 6.9 m (95%CI: 6.4-9.2), with a 6-m PFS rate of 67.1% (95% CI: 56.5-79.7). The reasons for platinum ineligibility did not correlate with PFS. The 6-m OS rate was 78.2% (95%CI: 68.6-89). Most frequent grade 3-4 toxicities were neutrophil count decreased (24.2%), anemia (21.5%) and platelet count decreased (13.6%). Conclusions: ATZ with split doses of CT was safely administered in a population of frail pts with mUC who were unfit for CT showing promising preliminary survival outcomes in terms of response. Final survival results are awaited. Clinical trial information: NCT04602078 . [Table: see text]

Management and Outcomes of Older Patients (Age ≥ 70 Years) with Advanced Soft Tissue Sarcoma and Role of Geriatric Assessment and Oncological Multidimensional Prognostic Index (Onco-MPI) in a Real-World Setting.

Background: Incidences of soft tissue sarcomas (STS) steadily increase with age. Yet, despite the high prevalence in advanced age, older patients (pts) are underrepresented in sarcoma clinical trials and evidence-based guidelines for chemotherapy are lacking. International oncological societies suggest using geriatric tools to evaluate older patients with cancer to optimise treatment indication. Comprehensive geriatric assessment (CGA) is a multidimensional assessment of older subjects, based on which pts can be classified as fit, vulnerable or frail. Onco-MPI (multidimensional prognostic index) is a CGA-based score which also considers tumour characteristics, classifying pts into three risk groups of death at one year: high-risk, intermediate-risk and low-risk. Methods: This is a single-centre retrospective study which aims at describing real-word management and outcomes of older pts with advanced stage STS and at assessing the ability of CGA and onco-MPI to predict survival in these pts. Consecutive pts with advanced stage STS aged 70 years or older and treated at the Istituto Oncologico Veneto from January 2009 to June 2020 were retrieved from a prospectively maintained database. Pts' demographics, CGA assessments and tumour characteristics were analysed. Statistical analysis was performed with R version 3.4.3 Results: Out of 101 pts, with a median age of 77 years, 76 received chemotherapy (75.3%), which was anthracycline-based for 46 pts (60.5%). Anthracyclines were used in a higher proportion in fit pts (58.9% fit vs. 45.1% vulnerable vs. 12.5% frail pts). Frail pts and pts in the onco-MPI high-risk group experienced a higher rate of chemotherapy-related toxicities. Median OS was 13.8 months (95% CI 11.3-17.7 months). According to CGA, the median OS was 19.53 months (95% CI 15.23-36.8) for fit pts, 12.83 months (95% CI 9.7-17.5) for vulnerable and 7.75 months (95% CI 2.73-30) for frail pts (p = 0.005). Onco-MPI confirmed a predictive value for 1-year survival with intermediate risk pts not reaching a median OS at 1 year, and high-risk pts having a median one-year OS of 11.5 months (95%CI 9.7-NA), p = 0.02. In multivariate analysis, onco-MPI and CGA were associated with survival (high risk onco-MPI: HR 5.5, 95%CI 1.25-24.7 p = 0.02; fitness at CGA HR 0.552 95% 0.314-0.973; p = 0.040) as well as chemotherapy use (HR 0.24, 95% CI 0.11-0.51, p < 0.005). Conclusions: Both CGA and onco-MPI retain prognostic value for survival in pts with metastatic STS. Pts frail/vulnerable at CGA and pts within the onco-MPI high risk category should be offered an oncogeriatric management approach in order to optimise treatment-related survival and reduce toxicity.

720 FRAILTY INFLUENCE ON PHYSICAL AND PSYCOLOGICAL OUTCOMES IN POST-CARDIAC SURGERY PATIENTS CARDIAC REHABILITATION, A SINGLE CENTER STUDY

Abstract Cardiac rehabilitation (CR) is a clinically and cost-effective intervention in post-cardiac surgery patients (PCSp). However the influence of patients frailty on clinical and psychological outcomes in these patients are not well-known. The aim of our work was to evaluate the effectiveness of a personalized rehabilitative therapy in PCSp divided using the Cumulative Illness Rating Scale (CIRS) in group A (393 low-frail pts, CIRS &amp;lt;3, 230 M, 65±3 yrs) and in a Group B (540 frail pts, CIRS &amp;gt;4, 379 M, 67±10)) evaluating pre and post-treatment the degree of autonomy recovery (Six-minute walking test SMWT, Barthel Index, BI) and the psychological behaviour (State-Trait Anxiety Inventory STAI-X1, Depression Questionaire QD-R). At admission the comparison between Group A vs B has shown: a greater loss autonomy in frail patients (BI scale A 51.7±1 vs B 28.7±14, p 0.005; SMWT A 245±25 m vs B 155±18 m, p 0.005)a greater impairment in psychological characteristics in frail patients (STAI-X1 A 18±9 vs B 20±4 p 0.028, QD/R A 3.6±2 vs B4.4±3 p0.001) At discharge after a similar period of rehabilitation (A 24.7±11.8 days vs B 25.6±10 days, p ns) we observed: a more evident improvement of degree of autonomy recovery in low-frail group ((BI scale A 77.7±18 vs B 67.7±19, p 0.001; SMWT A 485±18 m vs B 341±25m, p 0.001)a similar improvement in anxiety and depression characteristic in both groups (STAI-X1 A 17.8±2 vs B 17.4±4 p ns, QD/R A 3.1±2 vs B 3.4±2 p ns) Conclusions In our experience the frailty status does not affect the cardiac rehabilitation in post-cardiac surgery patients in term of ensuring adequate functional recovery (although reduced compared to low-frail patients) but with similar improvement in psychological behaviours.

Health-Related Quality of Life for Frail Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Daratumumab, Lenalidomide and Dexamethasone: Subgroup Analysis of MAIA Trial

Introduction: In the primary analysis of the phase 3 MAIA trial (NCT02252172), daratumumab, lenalidomide and dexamethasone (D-Rd) improved progression-free survival (PFS) in transplant-ineligible (TIE) patients (pts) with newly diagnosed multiple myeloma (NDMM) vs Rd. With longer follow-up (median: 56.2 months [mo]), D-Rd continued to demonstrate PFS benefit, conferred an overall survival benefit, induced deeper responses, and was associated with clinically meaningful improvements in patient-reported outcomes (PROs) vs Rd. The median age of these pts was 73 years with 43.6% of pts aged ≥75 years. Consistent with the overall population, in a frailty subgroup analysis (median age: 77 years), D-Rd also demonstrated deeper responses and PFS benefit vs Rd (not reached [NR] vs 30.4 mo; HR, 0.62; P = 0.003) in frail pts at a median follow-up of 36.4 mo. Although, D-Rd improved clinical outcomes in these elderly frail pts, little is known about health-related quality of life (HRQoL) outcomes. In frail pts, improving HRQoL and minimizing the risk of toxicity is paramount. Here, we assess PROs in the frail pts in the MAIA trial. Methods: Pts were randomized 1:1 to D-Rd or Rd until disease progression (PD) or unacceptable toxicity. Frailty assessment was performed on all randomized pts using age, Charlson Comorbidity Index, and baseline (BL) Eastern Cooperative Oncology Group performance status score. Based on this assessment, pts were categorized into frail and non-frail subgroups. PROs were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30). Questionnaires were completed at BL, on day 1 of cycles (Cyc) 3, 6, 9, and 12 for year 1, and every 6 mo thereafter until PD. Analyses were conducted on all pts with a BL and ≥1 post-BL PRO assessment. Meaningful thresholds for improvement and worsening were defined a priori based on published literature (≥10-point change). Treatment effect was assessed by a mixed-effects model for repeated measures. Time to first worsening was estimated using the Kaplan Meier method and Cox proportional hazards regression was used to compute hazard ratio (HR) and associated 95% confidence interval (CI) where worsening was defined using a distribution-based method. Results: In the MAIA trial, 737 pts were randomized (D-Rd, n=368; Rd, n=369). Of these, 341 pts were classified as frail (D-Rd, n=172; Rd, n=169,). At a median follow-up of 64.5 mo, frail pts treated with D-Rd reported greater improvements from BL vs Rd in EORTC QLQ-C30 Global Health Status (GHS) scores (Figure 1A) and physical functioning (LS mean change from BL for D-Rd at Cyc 12: 12.7 [9.0-16.3] vs Rd, 9.8 [5.9-13.7]) at several time points, with 39% of pts treated with D-Rd staying on treatment with PRO assessment at Cyc 48 vs 17% in the Rd group. Additionally, pts treated with D-Rd showed notably large reductions (≥20-point change) in pain symptoms over time and larger than that seen in pts treated with Rd (Figure 1B). No meaningful changes from BL were observed in fatigue symptoms for either treatment group. Results for emotional functioning, social functioning, and nausea and vomiting also numerically favored D-Rd at several time points. The median time to first improvement was numerically shorter with D-Rd vs Rd for GHS (D-Rd: 2.38 mo vs Rd: 4.67 mo), physical functioning (2.60 mo vs 4.65 mo), pain (2.07 mo vs 2.83 mo), and fatigue symptoms (2.04 mo vs 3.09 mo). The median time to first worsening was longest for physical functioning (D-Rd: 68.14 mo vs Rd: 39.62 mo; HR [95%CI] 0.66 [0.45-0.95]; P=0.023) and pain symptoms (D-Rd: NR vs Rd: 60.48 mo; 0.66 [0.44-1.00]; P=0.045). The median time to first worsening was longer with D-Rd vs Rd for GHS (D-Rd: 29.31 mo vs Rd: 21.62 mo; HR 0.91 [0.65-1.26]). The median time to first worsening for the other functional (emotional, social, role) and symptom (nausea and vomiting) scales numerically favored D-Rd vs Rd, except cognitive functioning and fatigue. Conclusions: D-Rd demonstrates clinical benefit in all pts, including frail pts. In addition, frail pts treated with D-Rd reported sustained improvements in global health (overall HRQoL) and physical functioning, with notable reduction in pain through the duration of therapy. Additionally, higher percentage of frail pts continued on D-Rd vs Rd. D-Rd regimen is not only clinically effective but also results in a sustained improvement in HRQoL for TIE frail pts with NDMM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Domiciliary Nursing Management for Patients Affected By Multiple Myeloma during Covid-19 Pandemia in the Viterbo Home Care Unit: Data Analysis from March 2020 to March 2022

Background Covid-19 pandemia constituted in the last two years a challenge in the management of frail patients (pts) with Multiple Myeloma (MM). The availability in the Viterbo province of a Domiciliary Hematologic Care Unit (DHCU) allowed a correct clinical assistance of our pts with MM during Covid-19 pandemia. Methods To evaluate the impact and efficacy of nursing management for frail MM pts followed by DHCU during Covid-19 pandemia, all nursing activities from 3/2020 to 3/2022 were analysed. Chemotherapies (CHT) allowed for nurse parenteral administration in MM pts were bortezomib and, more recently, daratumumab for subcutaneous injection. Results In the study period, 58 pts in 35 different municipalities of Viterbo province were followed by 4 nurses specifically dedicated to DHCU. Main features of the pts at DHCU admission are reported in the Table: at DHCU admission, 30 pts (51.8%) aged > 75 years. At beginning of the study period (08/03/2020), 17 pts (29.3%) were already followed by DHCU, while 41 pts (70.7%) entered DHCU assistance during the study period. Median distance from DHCU central site in Viterbo to pts house was 28 Km [Interquartile range (IQR) 20 - 38]: in particular, distance from DHCU was < 20 Km in 11 cases (19.0%), ≥ 20 < 40 Km in 33 (56.9%) and ≥ 40 Km in 14 (24.1%). A total number of 1637 nursing accesses was done in the whole period. According to the type of different procedures, 722 blood samples were performed, with a median number of 9 (IQR 4 - 15): in addition, there were 617 accesses for CHT administration (152 bortezomib-based cycles in 37 pts, 6 daratumumab-based cycles in 3 pts) and 298 accesses for other procedures (132 PICC medications, 114 therapies other than CHT, 29 assistances for transfusions, 17 assistances for marrow aspirates and 6 antigenic tests). In the study period, 5 pts (8.6%) developed Covid-19 infection. At the last follow-up (31/03/2022), 35 pts (60.3%) were alive and still in DHCU, 11 pts (19.0%) were alive and returned to Day-Hospital (DH) setting due to clinical improvement and 12 pts (20.7%) died while in domiciliary assistance. Conclusions Domiciliary nurse assistance during Covid-19 pandemia allowed to follow in a safer way compared to standard DH setting an important number of frail pts with MM, two/thirds of them in 1st active line of therapy. This peculiar type of nursing management should represent the best type of assistance for elderly and/or frail pts even beyond Covid-19 period of pandemia. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Daratumumab Carfilzomib Lenalidomide Dexamethasone Provides Effective Salvage for Functionally and Cytogenetically High-Risk Myeloma Patients, Except Those Expressing Module-1 Transcriptional Signature: Extended Follow-up from Kydar Multicenter Clinical/Translational Trial.

Background Myeloma patients (Pts) with resistance to a bortezomib-based induction therapy, either primary refractory or those relapsing early after completing induction, define a population of functional high-risk myeloma, shown to be associated with dismal prognosis. We designed a phase 2 clinical-translational trial to evaluate the safety and efficacy of a quadruple salvage regimen of carfilzomib (CFZ)/ lenalidomide (LEN)/dexamethasone (DEX) / daratumumab (DARA) (KRD-D) in myeloma Pts with functional high-risk (KyDaR, NCT04065789), and to identify molecular pathways of refractoriness based on transcriptional signatures associated with clinical resistance. Here we report final clinical data following 18-months (mo) study treatment and extended survival follow-up. Methods Forty-one newly diagnosed myeloma Pts treated with a bortezomib-containing induction regimen, who either: i) failed to achieve a minimal response after 2 cycles or a partial response (PR) after 4 cycles (cohort A), ii) had early relapse within 18 months from starting of therapy (cohort B) were enrolled to receive second line KRD-D treatment in eighteen 28-day (d) cycles (C) or until disease progression/unacceptable toxicity. CFZ: 56 mg/m2 IV days 1,8,15 (C 1-9), d 1,15 (C 10-18). LEN: 25 mg (Frail: 15mg) d1-21; Dex 40mg (Frail: 20mg) weekly; DARA: IV 16mg/Kg weekly (C 1-2), q14d (C 3-6), q28d. After 18 cycles, Pts continued to receive DARA/LEN. We applied longitudinally our calibrated protocol for single cell RNA sequencing (scRNA-seq) of myeloma plasma cells (Ledergor et al, Nat Med 2018) to identify transcriptional signatures associate with response or resistance, defined as PR or better (IMWG criteria) after 3 cycles. Primary endpoints were safety and tolerability. Secondary endpoints included overall response rate (ORR); progression free survival (PFS), and overall survival (OS). Results Forty-one Pts enrolled across 14 medical centers in Israel between June 2018-August 2019, patients had highly aggressive MM characteristics: 67% had intermediate/high risk and 30.5% had double hit FISH abnormalities, 39% had extramedullary disease, and 38% were frail. High expression of module-1 scRNAseq transcriptional signature associated with therapy resistance as previously described (Cohen YC et al, Nat Med 2021) was detected in 36%. At end-of study data cut-off (12NOV2021) the median follow-up was 30.7 mo (95% CI 26-35.3), and the median number of CFZ cycles administered was 10 (range 1-18). Nineteen Pts completed 18-months of KRD-D therapy. Reasons for early therapy discontinuation (n=22) included: disease progression (12), adverse event (AE, 6), consent withdrawal (3) and physician decision (1). All Pts had at least 1 treatment emergent AE (TEAEs), most were grade 1-2; There were 35 patients with TEAE grade ≥3, 4 (9.8%) patients discontinued study therapy due to AEs. Grade ≥3 TEAEs occurring in ≥10% of Pts included neutropenia (34%), thrombocytopenia (24%), sepsis (22%), pneumonia (19%) and musculoskeletal pain (12%); 4 patients died due to TEAEs (1 myocardial infarction, 3 sepsis). Durable and deep responses were achieved. ORR was 90% (37/41): near CR-stringent CR 22% / very good partial response 42% / PR 27%. Median duration of response was 25.6 mo (95% CI 11.5-39.7). Median PFS and OS were 15.4 and 28.2 months, respectively; 18-month PFS and OS were 49% and 57%, respectively. In univariable analysis, cohort (A vs B), age (≤70 vs >70) and high-risk cytogenetics (yes vs no) yielded similar OS. Over-expression of module-1 was highly predictive of poor PFS (3.8 mo vs not reached [NR], p=0.000006 and OS (13.8 mo vs NR, p=0.0003) [Fig1A]. A factorial analysis of module-1 X double-hit FISH showed the dominance of the former in prediction of OS [Fig 1B]. Frail Pts (IMWG criteria) had a median OS of 25 mo [95% CI 8.0-41.4] vs NR in intermediate/Fit Pts (p=0.07). Conclusions A cohort of functionally high-risk MM Pts, based on their resistance to an upfront bortezomib-based induction, were effectively salvaged by second line KRD-D quadruple regimen, achieving an ORR of 90% and durable responses. High expression of module-1 transcriptional signature, as discovered by scRNA-seq analysis was present in 36% of these Pts, and identified an ultra-high-risk population in which KRD-D provided inferior survival. Such patients may be considered for early experimental interventions such as novel immune-therapeutics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Bortezomib-Melphalan-Prednisone (VMP) Vs. Lenalidomide-Dexamethasone (Rd) in Transplant-Ineligible Real-Life Multiple Myeloma Patients: Updated Results of the Randomized Phase IV Real MM Trial

BACKGROUND. Bortezomib-melphalan-prednisone (VMP) and lenalidomide-dexamethasone (Rd) have represented standards of care for transplant-ineligible (NTE) newly diagnosed multiple myeloma (NDMM) patients (pts) until the recent introduction of daratumumab (Dara) in the frontline setting. However, no prospective randomized trial has directly compared VMP with Rd. Moreover, real-life older NTE pts are underrepresented in clinical trials, and only few data on safety and efficacy in this population are available. AIMS. We conducted a randomized multicenter phase IV trial (NCT03829371; funded by the Italian Medicine Agency AIFA - Independent Research) to compare safety and efficacy of the two standard regimens, VMP vs Rd, in an unselected real-life population of NTE NDMM pts. METHODS. NDMM pts ineligible for transplant due to age ≥65 years or comorbidities were randomized 1:1 to: 9 VMP cycles (42-day cycles, V: 1.3 mg/m2, days (dd) 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1-4 and dd 1, 8, 22, and 29, cycles 5-9; M: 9 mg/m2, dd 1-4; P: 60 mg/m2, dd 1-4) vs continuous Rd (28-day cycles, R: 25 mg, dd 1-21; d: 40 mg, dd 1, 8, 15, and 22) according to standard practice. Pts gave written informed consent and were enrolled regardless of performance status, comorbidities, renal function, or baseline laboratory values. Pts were stratified according to the International Myeloma Working Group (IMWG) frailty score and cytogenetic risk by fluorescence in situ hybridization [high risk if positive for del(17p), t(14;16), or t(4;14)]. The primary endpoint was progression-free survival (PFS) in the intention-to-treat (ITT) population. Key secondary endpoints included response rates, overall survival (OS), and safety. RESULTS. At the data cut-off (July 4, 2022), 231 pts were randomly allocated to receive VMP (n=114) or Rd (n=117). Baseline characteristics were evenly balanced between the two arms: median age was 77 (IQR 73-80) and 76 years (IQR 73-79); 49% vs 50% of pts were frail; 17% vs 19% pts had high-risk cytogenetics, respectively. After a median follow-up of 19 months, the median PFS in the ITT population was 29.6 vs 26.2 months with VMP vs Rd (hazard ratio [HR] 0.82, 95% CI 0.51-1.31, P=0.41; Figure - panel A). However, the HR was not constant over time: from 0.65 (95% CI 0.36-1.19, P=0.16) during the first year of treatment (suggesting a slight benefit of VMP vs Rd) to 1.37 (95% CI 0.65-2.86, P=0.40) after the first year of treatment (suggesting a slight benefit of continuous Rd therapy). The subgroup analysis according to cytogenetic risk showed a significant effect modification of the comparison VMP vs Rd in terms of PFS, with an HR=0.21 (95% CI 0.04-0.99) in the high-risk group vs an HR=1.24 (95% CI 0.70-2.18) in the standard-risk group (interaction P=0.036). No significant effect modification was observed in terms of age or frailty status. In the ITT population, the 2-year OS was 89% with VMP vs 75% with Rd (HR 0.53, 95% CI 0.26-1.07, P=0.08; Figure - panel B). No safety concerns were reported. The most frequent grade (G)3-4 adverse events (AEs) with VMP were thrombocytopenia (15%) and neuropathy (7%), while neutropenia (23%), infections (12%), and dermatologic toxicities (9%) were the most frequent G3-4 AEs observed in the Rd arm. Sixty-six percent of pts in the VMP and 59% in the Rd arms had ≥1 dose reductions of any drug, including 35% of pts in the VMP arm switching to once-weekly V before cycle 5. CONCLUSION. We confirmed the efficacy of VMP and Rd in an older real-life population of NTE NDMM pts including ~50% of frail pts. VMP and Rd were equally effective in standard-risk pts and in all frailty subgroups in terms of PFS. However, high-risk pts benefited more from VMP (HR 0.21), suggesting that the doublet Rd is suboptimal in this subgroup. Safety data were consistent with those previously reported. Of note, only one third of real-life pts were able to receive full-dose VMP or Rd therapy according to their schedule. Despite the limited follow-up, the difference in terms of OS between the two arms may be explained by the poor outcomes of patients failing lenalidomide-based treatments. Importantly, following a recent amendment, as of July 2022, enrolled pts will be randomized to Dara-VMP vs Dara-Rd. Decision-making and treatment selection will be further supported by a future analysis of this addition of Dara, based on patient and disease characteristics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal