Transplant-ineligible Research Articles

Comparison of Time to Next Treatment or Death Between Front-Line Daratumumab, Lenalidomide, and Dexamethasone (DRd) Versus Bortezomib, Lenalidomide, and Dexamethasone (VRd) Among Transplant-Ineligible Patients With Multiple Myeloma.

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

Frontline evaluation: Atezolizumab-bevacizumab versus lenvatinib for BCLC stage B hepatocellular carcinoma exceeding the up-to-seven criteria.

This study aimed to evaluate the efficacy and safety of atezolizumab combined with bevacizumab (Atez/Bev) compared to lenvatinib (LEN) as first-line systemic therapy for patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) exceeding the up-to-seven criteria threshold, who are typically unsuitable for transarterial chemoembolization (TACE). A retrospective analysis was conducted on 49 consecutive patients with HCC treated at Tokyo Metropolitan Komagome Hospital between May 2018 and October 2023. The patients were divided into two groups: the Atez/Bev group (21 patients) and the LEN group (28 patients). Eligibility criteria included Child-Pugh A classification, no prior systemic therapy, and ineligibility for resection, ablation, or transplantation. Treatment outcomes were assessed through periodic imaging and laboratory tests, evaluating OS, PFS, ORR, and disease control rate (DCR). Both groups demonstrated comparable baseline characteristics, with a median follow-up of 15.4 months. No significant difference was observed in OS between the Atez/Bev and LEN groups (median OS: 19.80 vs. 22.20 months, p = 0.763). The median PFS was 10.23 months for Atez/Bev and 7.20 months for LEN (p = 0.343). There were no statistically significant differences in ORR or DCR between the two groups. Common adverse events included elevated AST and ALT levels, with no significant difference in the overall rate of adverse events between the groups. Atez/Bev and LEN demonstrated comparable efficacy and safety as first-line systemic treatments for patients with BCLC stage B HCC exceeding the up-to-seven criteria. Both therapeutic options are viable for this population, though further large-scale prospective studies are required to confirm these findings.

Treatment and clinical outcomes of patients with acute myeloid leukemia in Finland 2010-2020: A retrospective analysis of electronic health records.

Our retrospective study (2010-2020) examined treatment patterns, outcomes, and healthcare resource utilization in Finnish acute myeloid leukemia (AML) patients. Data covered 153 patients diagnosed at Hospital District of Southwest Finland (HDSF) and 107 from other districts who underwent allogeneic stem cell transplantation (aSCT) at HDSF. Of the 153 patients, 56.2% received intensive chemotherapy (IC), while 43.8% deemed ineligible for IC received low-intensity therapies or best supportive care (BSC). Median overall survival for IC patients was 31.2 months, compared to 5.3 months for those under azacytidine and 1.2 months on BSC. Majority (57.5%) of patients over 60 with intermediate/high European leukemia network risk had poor outcomes with IC and couldn't proceed to aSCT. These patients carried the highest costs and hospital resource use per patient month. Most common reasons for transplant ineligibility after IC were refractory disease and infection. Our data provides a comprehensive view on AML treatment landscape from a period when the latest treatment advancements were not yet accessible. The data describes patient groups with poor prognosis and increased healthcare burden, emphasizing the need to improve treatment practices and identify better ways to get more patients to transplant, in a rapidly evolving treatment landscape.

Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial

CD38-targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) that are transplant ineligible (TI) and is considered the best standard of care (SOC). To improve current SOC, we evaluated the added value of weekly bortezomib (V) to isatuximab plus lenalidomide and dexamethasone (IsaRd versus Isa-VRd). This Intergroupe Francophone of Myeloma phase 3 study randomized 270 patients with NDMM that were TI, aged 65–79 years, to IsaRd versus Isa-VRd arms. The primary endpoint was a minimal residual disease (MRD) negativity rate at 10−5 by next-generation sequencing at 18 months from randomization. Key secondary endpoints included response rates, MRD assessment rates, survival and safety. The 18-month MRD negativity rates at 10−5 were reported in 35 patients (26%, 95% confidence interval (CI) 19–34) in IsaRd versus 71 (53%, 95% CI 44–61) in Isa-VRd (odds ratio for MRD negativity 3.16, 95% CI 1.89–5.28, P < 0.0001). The MRD benefit was consistent across subgroups at 10−5 and 10−6, and was already observed at month 12. The proportion of patients with complete response or better at 18 months was higher with Isa-VRd (58% versus 33%; P < 0.0001), as was the proportion of MRD negativity and complete response or better (37% versus 17%; P = 0.0003). At a median follow-up of 23.5 months, no difference was observed for survival times (immature data). The addition of weekly bortezomib did not significantly affect the relative dose intensity of IsaRd. Isa-VRd significantly increased MRD endpoints, including the 18-month negativity rate at 10−5, the primary endpoint, compared with IsaRd. This study proposes Isa-VRd as a new SOC for patients with NDMM that are TI. ClinicalTrials.gov identifier: NCT04751877.

All-oral triplet iberdomide, ixazomib, and dexamethasone in elderly patients with multiple myeloma at first relapse: Results of the IFM phase 2 study I2D.

7507 Background: The triplet combination daratumumab, lenalidomide and dexamethasone (DRd) and bortezomib, lenalidomide and dexamethasone (VRd) are to date the standard of care for patients with transplant ineligible (TI) newly diagnosed multiple myeloma (MM). Most TI patients therefore present with MM refractory to lenalidomide and daratumumab at first relapse and represent a difficult-to-treat population. Iberdomide is a novel oral cereblon E3 ligase modulator (CELMoD) that demonstrated promising activity in MM patients refractory to lenalidomide/pomalidomide. Here, we report efficacy and safety results of the oral triplet iberdomide, ixazomib and dexamethasone in elderly patients with MM at first relapse. Methods: The Intergroupe Francophone du Myélome (IFM) prospective, multicenter, phase 2 study I2D enrolled MM patients aged over 70 years at first relapse (NCT04998786).Patients received oral iberdomide (1.6 mg on day 1 to 21), ixazomib (3 mg on day 1,8,15) and dexamethasone (20 mg on day 1,8,15,22 on cycle 1-2 and 10 mg on day 1,8,15,22 on cycle 3-6) (28-day cycle) until disease progression or unacceptable toxicity. The primary endpoint was very good partial response (VGPR) rate. Results: Seventy patients were included from Dec 2021 to May 2023 in 19 IFM centers. Median age was 76. The International Myeloma Working Group (IMWG) frailty score was &gt;2 in 35 (50%) patients. In evaluable patients (54/70), cytogenetic analysis revealed del(17p) in 10 patients (18.5%) and t(4;14) in 8 (15%) patients. Based on inclusion criteria, all patients received 1 prior line of treatment, including lenalidomide in 87% (refractory, 74%) and daratumumab in 40% (refractory, 37%) of patients. Median time from MM diagnosis to study enrolment was 28 months. At data cut-off, 36 (51%) patients discontinued the study due to disease progression (n=30), adverse event (n=4) or death (n=2). After a median follow-up of 12 months, the overall response rate was 64%, including 33% VGPR. The median progression-free survival (PFS) was 13 months and the 12-month overall survival (OS) was 85% (77-95% 95% CI). In patients with MM refractory to both lenalidomide and daratumumab (n=26), the median PFS was 10 months. Overall, the triplet I2D was well tolerated. Most common non-hematologic adverse events (AE) were infection (30% of patients), peripheral neuropathy (20%), diarrhea (19%), and were mostly grade 1 or 2. Most common grade 3-4 treatment related AEs (&gt;5% of patients) were neutropenia (46%), thrombocytopenia (9%) and infection (8%). Four patients discontinued treatment due to a severe AE (cytopenia (n=3), skin rash (n=1). Conclusions: The oral tripletiberdomide, ixazomib and dexamethasone demonstrated a favorable efficacy / safety profile in elderly MM patients at first relapse, including in patients with lenalidomide and daratumumab refractory disease. Clinical trial information: NCT04998786 .

A phase 1/2 study of favezelimab in combination with pembrolizumab for heavily pretreated anti–PD-1–refractory classical Hodgkin lymphoma (cHL): An updated analysis.

7056 Background: PD-1 inhibitors are standard of care for relapsed or refractory (R/R) cHL, but patients (pts) often progress after anti–PD-1 therapy. The immune checkpoint receptor lymphocyte-activation gene 3 (LAG-3) is proposed to contribute to anti–PD-1 resistance. In a phase 1/2 study (NCT03598608) evaluating favezelimab (anti–LAG-3) plus pembrolizumab (anti–PD-1) for R/R hematologic malignancies, the combination provided antitumor activity and manageable safety in pts with heavily pretreated anti–PD-1–refractory cHL (cohort 2). Updated results after additional follow-up are presented. Methods: Eligible pts were aged ≥18 years with R/R cHL; prior treatment with or ineligibility for autologous stem cell transplantation or no response to salvage chemotherapy; an ECOG performance status of 0 or 1; and disease progression after ≥2 doses of anti–PD-1–based therapy and within 12 weeks of the last dose of anti–PD-1 therapy. The study comprised a safety lead-in (pembrolizumab 200 mg IV Q3W + favezelimab 200-mg starting dose, then dose escalation to 800 mg IV Q3W per a modified toxicity probability interval design) and a dose expansion phase (pembrolizumab + favezelimab at the established recommended phase 2 dose of 800 mg Q3W for ≤35 cycles). Primary end point was safety. ORR per IWG 2007 criteria by investigator review was a secondary end point. DOR and PFS per IWG 2007 criteria by investigator review and OS were exploratory. Results: Cohort 2 enrolled 34 pts. Median time from first dose to data cutoff (August 15, 2023) was 40.7 months (range, 20.4-54.8). Treatment-related AEs occurred in 28 pts (82%); the most common (≥15%) were hypothyroidism (18%), nausea (18%), and fatigue (15%). Grade 3 or 4 treatment-related AEs occurred in 6 pts (18%). Discontinuation due to treatment-related AEs occurred in 6 pts (18%). No deaths due to treatment-related AEs were reported. AEs of clinical interest occurred in 17 pts (50%); 2 pts (6%) had grade 3 events (encephalitis, hepatitis) and 1 pt (3%) had a grade 4 event (type 1 diabetes mellitus). ORR was 29% (10/34; 95% CI, 15-48), with 3 (9%) complete responses and 7 (21%) partial responses. ORR was 35% (6/17; 95% CI, 14-62) in pts with anti–PD-1 and 24% (4/17; 95% CI, 7-50) in pts with non–anti–PD-1 as most recent therapy. Median DOR was 21.9 months (range, 0.0+ to 26.1+) and an estimated 17% of responders remained in response at 24 months. Median PFS was 9.7 months (95% CI, 5.1-14.7); 24-month PFS rate was 21%. Median OS was 39.0 months (95% CI, 25.7-not reached); 24-month OS rate was 73%. Conclusions: After additional follow-up, favezelimab + pembrolizumab continued to demonstrate manageable safety and antitumor activity in pts with heavily pretreated anti–PD-1–refractory cHL. The phase 3 KEYFORM-008 study (NCT05508867) will evaluate a coformulation of favezelimab and pembrolizumab in pts with anti–PD-1–refractory cHL. Clinical trial information: NCT03598608 .

A phase 1/2 study of favezelimab in combination with pembrolizumab for anti–PD-1–naive relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL): An updated analysis.

7055 Background: PD-1 inhibitors such as pembrolizumab are an important treatment option for patients (pts) with R/R cHL, but treatment failure remains a significant challenge. Dual immune checkpoint blockade with a PD-1 inhibitor and a lymphocyte-activation gene 3 (LAG-3) inhibitor shows promise as a treatment option for R/R cHL. In a multicohort phase 1/2 study (NCT03598608) evaluating the anti–LAG-3 monoclonal antibody favezelimab in combination with pembrolizumab for R/R hematologic malignancies, pembrolizumab plus favezelimab demonstrated sustained antitumor activity and acceptable safety in the cohort of pts with anti–PD-1–naive R/R cHL (cohort 1). We present updated results from this cohort after additional follow-up. Methods: Eligible pts were aged ≥18 years with R/R cHL; prior treatment with or ineligibility for autologous stem cell transplantation or no response to salvage chemotherapy; no prior PD-1 inhibitor; and an ECOG PS of 0 or 1. The study comprised a safety lead-in (pembrolizumab 200 mg IV Q3W plus favezelimab 200-mg starting dose, then dose escalation to 800 mg IV Q3W using a modified toxicity probability interval method) and a dose expansion phase (pembrolizumab 200 mg Q3W plus favezelimab at the established recommended phase 2 dose of 800 mg Q3W for up to 35 cycles). Primary end point was safety. Objective response rate (ORR) per IWG 2007 criteria by investigator review was a secondary end point. Duration of response (DOR) and progression-free survival (PFS) per IWG 2007 criteria by investigator review and overall survival (OS) were exploratory. Results: Cohort 1 enrolled 30 pts. The median time from first dose to data cutoff (August 15, 2023) was 36.9 months (range, 29.4-48.6). Treatment-related adverse events (AEs) occurred in 27 pts (90%), of which the most common (≥20%) were hypothyroidism (27%), infusion-related reaction (23%), and fatigue (20%). Grade 3 or 4 treatment-related AEs occurred in 7 pts (23%). Five pts (17%) discontinued treatment due to treatment-related AEs. No deaths due to treatment-related AEs were reported. AEs of clinical interest occurred in 20 pts (67%); 3 pts (10%) had grade 3 events (colitis, pneumonitis, severe skin reaction) and 1 pt (3%) had a grade 4 event (hepatitis). The ORR was 83% (n = 25; 95% CI, 65-94); 11 pts (37%) had a complete response and 14 (47%) had a partial response. Median DOR was 17.0 months (range, 2.6-30.5), and an estimated 47% of responders remained in response at 24 months. Median PFS was 19.4 months (95% CI, 9.5-28.5), and the 24-month PFS rate was 46%. Median OS was not reached (NR; 95% CI, NR-NR), and the 24-month OS rate was 93%. Conclusions: With additional follow-up, favezelimab plus pembrolizumab continued to demonstrate sustained antitumor activity and manageable safety in pts with anti–PD-1–naive R/R cHL. Further studies to investigate this combination are warranted. Clinical trial information: NCT03598608 .

Clinical consensus on treatments for transplant-ineligible newly diagnosed multiple myeloma: double-blinded Delphi panel.

Aim: Obtain clinical consensus on factors impacting first-lineprescribing for transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM).Materials & methods: A double-blinded, modified Delphi panel was employed. USA-based hematologists/oncologists who treat TIE patients with NDMM were selected as expert panelists.Results: Consensus was reached that patient frailty, performance status, comorbidities, treatment efficacy, and adverse event profile affect first-line prescribing. All panelists agreed it is important to use themost efficacious treatment first; 88% of panelists considered daratumumab-containing regimens the most efficacious. Panelists agreed treatment should be continued until progression while benefits outweigh risk.Conclusion: Findings reinforce the importance of using themost efficacious regimen upfront for TIE NDMM, and nearly all panelists considered daratumumab-containing regimens the most efficacious treatment.

A Prognostic Survival Model Incorporating Patient-Reported Outcomes for Transplant-Ineligible Patients With Multiple Myeloma.

Developing prognostic tools specifically for patients themselves represents an important step in empowering patients to engage in shared decision-making. Incorporating patient-reported outcomes may improve the accuracy of these prognostic tools. We conducted a retrospective population-based study of transplant-ineligible (TIE) patients with multiple myeloma (MM) diagnosed between January 2007 and December 2018. A multivariable Cox regression model was developed to predict the risk of death within 1-year period from the index date. We identified 2356 patients with TIE MM. The following factors were associated with an increased risk of death within 1 year: age > 80 (HR 1.11), history of heart failure (HR 1.52), "CRAB" at diagnosis (HR 1.61), distance to cancer center (HR 1.25), prior radiation (HR 1.48), no proteosome inhibitor/immunomodulatory therapy usage (HR 1.36), recent emergency department (HR 1.55) or hospitalization (HR 2.13), poor performance status (ECOG 3-4 HR 1.76), and increasing number of severe symptoms (HR 1.56). Model discrimination was high with C-statistic of 0.74, and calibration was very good. To our knowledge, this represents one of the first prognostic models developed in MM incorporating patient-reported outcomes. This survival prognostic tool may improve communication regarding prognosis and shared decision-making among older adults with MM and their health care providers.

Abstract 2397: Double lung transplantation (DLT) in patients with stage IVA lung-limited non-small cell lung carcinoma (NSCLC): A case series

Abstract Introduction: Despite technological advances and expanded indications in lung transplantation, lung cancer constituted less than 0.1% of the lung transplantation over the past two decades. DLT may offer curative treatment for stage IVA NSCLC patients without extrapulmonary disease. We present a case series of consecutive NSCLC patients who underwent DLT. Methods: Patients treated with DLT were identified between 09/2021 and 09/2023 at Canning Thoracic Institute of Northwestern University. All patients had enrolled in the DLT registry aimed for lung-limited malignancies (DREAM) study (NCT05671887). Exclusion criteria include: presence of extrapulmonary disease and medical ineligibility for lung transplantation. All patients were followed up with computed tomography and tumor-informed ctDNA assay every 12 weeks. Results: Five patients with stage IVA NSCLC who underwent DLT were included. Three (60%) patients had invasive mucinous, and two (40%) had invasive non-mucinous adenocarcinoma histology. One of the two invasive non-mucinous patients had acinar, and the other had mixed lepidic, papillary, and acinar histology. Patients were aged 56-70; one (20%) was Asian, four (80%) were White, three (60%) were male, and two (40%) had a history of smoking. No patient had a past medical history of interstitial lung disease (ILD) or chronic obstructive pulmonary disease (COPD). All patients had high oxygen requirements before DLT due to cancer progression. Pre-transplant endobronchial ultrasound and evaluation of bilateral pneumonectomy lungs found no lymph node involvement (pN0). One patient had an epidermal growth factor receptor (EGFR) mutated cancer and but had failed relevant targeted therapy prior to transplant. All patients had disease progression on standard of care treatments with/without clinical trials. The indication for DLT was respiratory failure or refractory cancer for all patients. After DLT, one patient had a recurrence of the disease at 18 months with a 1cm solid nodule and was treated with stereotactic body radiotherapy (SBRT). Both original and recurrent tumors had invasive mucinous adenocarcinoma histology, negative PD-L1 expression, and the same JAK3 c.2174C&amp;gt;T, P725L mutated clone. It suggests that the recurrence likely arose from the original cancer. Transplant rejection did not occur in any of the cases. Following the transplant, there was no requirement for oxygen therapy for any patient. All patients are alive with 25, 15, 6, 3, and 1-month posttransplant follow-up. Conclusion: Five patients underwent DLT successfully without significant complications. Notably, one patient (25 months post-transplant) experienced cancer recurrence 18 months post-transplant and was effectively treated with SBRT. Ongoing DREAM study will continue to investigate the role of DLT in stage IVA NSCLC patients (especially in pN0). Citation Format: Young Kwang Chae, Tarik Demir, Liam Il-Young Chung, Carolyn Moloney, Rade Tomic, Ankit Bharat. Double lung transplantation (DLT) in patients with stage IVA lung-limited non-small cell lung carcinoma (NSCLC): A case series [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2397.

Adjusted Indirect Treatment Comparison of Progression-Free Survival with D-Rd and VRd Based on MAIA and SWOG S0777 Individual Patient-Level Data.

Daratumumab plus lenalidomide and dexamethasone (D-Rd) and bortezomib plus lenalidomide and dexamethasone (VRd) are commonly used treatment combinations for transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). D-Rd and VRd demonstrated superior efficacy relative to lenalidomide and dexamethasone (Rd) in the MAIA and SWOG S0777 trials, respectively, but have not been compared directly in a head-to-head trial. Naïve comparisons of efficacy across the two trials may be biased because MAIA enrolled only TIE patients (median age 73years), whereas SWOG S0777 enrolled both TIE patients and transplant-eligible patients who chose to defer/refuse frontline stem cell transplantation (median age 63years). The present study compared progression-free survival (PFS) in TIE patients with NDMM treated with D-Rd versus VRd based on an adjusted indirect treatment comparison (ITC) that leveraged individual patient-level data from MAIA and SWOG S0777. Harmonized inclusion/exclusion criteria (including age ≥ 65years as a proxy for transplant ineligibility) and propensity-score weighting were used to balance the trial populations on measured baseline characteristics. After differences in trial populations were adjusted for, an anchored ITC was performed wherein within-trial PFS hazard ratios (HRs) for D-Rd versus Rd and VRd versus Rd were estimated and used to make indirect inference about PFS for D-Rd versus VRd. PFS HRs were 0.52 (95% confidence interval [CI] 0.41-0.67) for D-Rd versus Rd based on MAIA data, 0.88 (95%CI 0.63-1.23) for VRd versus Rd based on SWOG S0777 data, and 0.59 (95%CI 0.39-0.90) for the Rd-anchored ITC of D-Rd versus VRd. Sensitivity and subgroup analyses produced results consistent with the primary results. This anchored ITC demonstrated a greater PFS benefit for D-Rd versus VRd in TIE patients with NDMM. In the absence of head-to-head trials comparing D-Rd and VRd, the present trial may help inform treatment selection in this patient population.

Prognostic model for relapsed/refractory transplant-ineligible diffuse large B-cell lymphoma utilizing the lymphocyte-to-monocyte ratio.

We conducted a multi-institutional retrospective study in 100 transplant-ineligible (TI) patients with diffuse large B-cell lymphoma (DLBCL) that relapsed or progressed after first-line R-CHOP (or -like) therapy to develop a robust predictive model for TI relapsed/refractory (r/r) DLBCL, which has a heterogeneous but poor prognosis by currently available treatment modalities other than chimeric antigen receptor T-cell (CAR-T) therapy or bispecific antibodies. The median age at relapse or progression was 76years. The median progression-free survival (PFS) and overall survival (OS) from the first progression were 11.5months and 21.9months, respectively. Multivariate analysis identified low lymphocyte-to-monocyte ratio (LMR), elevated high lactate dehydrogenase, and elevated C-reactive protein at progression as independent predictors of OS. A predictive model based on these three factors, here designated as the Kyoto Prognostic Index for r/r DLBCL (KPI-R), successfully stratified their OS and PFS with statistical significance. In addition, event-free survival less than 24months for R-CHOP and low LMR were identified as significant predictive factors for non-response in any sequence of salvage therapy. We concluded that LMR is a bonafide predictor of treatment response and prognosis in patients with TI r/r DLBCL, and may be helpful in treatment decision-making.

Detailed cause of donor ineligibility in living donor kidney transplants: a retrospective, single-center cohort study

BackgroundLiving kidney donors are evaluated to determine their physical and psychological suitability for transplantation and ensure their safety. During this process, we frequently encounter cases where a donor is found to be ineligible. In this study, we surveyed donors who are ineligible for transplantation at our hospital to educate patients, their families, and medical staff regarding transplantation in the future. MethodsWe examined the proportion of ineligible donors among 237 potential donors who visited our hospital between January 2002 and March 2022. Data were collected retrospectively from electronic medical records and evaluated from various aspects such as age, body mass index, medical history, medications, and renal function. ResultsThe mean age at presentation was 55.5 years, the male-to-female ratio was 1:1.6, and no significant difference was found between the ineligible and eligible donor groups. The transplant ineligibility rate was 23.6%, and the categories were for medical, backout, immunologic, and recipient-related reasons, in descending order. Furthermore, a low glomerular filtration rate (GFR) was the most common cause of medical cases. ConclusionMany patients were judged ineligible because of lifestyle-related diseases such as low GFR, diabetes mellitus, and obesity. Therefore, thorough patient education should be conducted using these data as a reference to reduce the number of donors ineligible because of lifestyle-related diseases.

Comparison of Time to Next Treatment or Death between Front-Line Daratumumab, Lenalidomide, and Dexamethasone (DRd) and Bortezomib, Lenalidomide, and Dexamethasone (VRd) in Transplant Ineligible Patients with Multiple Myeloma

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

Outcomes of Transplant-Eligible and Transplant-Ineligible Patients with Mantle Cell Lymphoma in Ontario, Canada

Background The frontline treatment of patients with symptomatic mantle cell lymphoma (MCL) requiring treatment varies in practice. In Ontario, Canada, transplant-eligible (TE) patients have been treated with chemoimmunotherapy followed by autologous stem cell transplant (ASCT). In 2013, R-CHOP alternating with R-DHAP prior to ASCT replaced R-CHOP alone as standard of care based on the European MCL Younger trial (Hermine JCO 2022). Although this regimen improves progression-free survival, there remains concern about its toxicity. For transplant-ineligible (TI) patients, the standard of care has evolved over time. Evidence in support of bendamustine-rituximab (BR) efficacy in indolent lymphoma resulted in its increased use in TI patients with MCL over the last decade. However, real-world data are lacking on toxicities of this regimen compared to other chemoimmunotherapy. We aimed to characterize survival and healthcare utilization outcomes of patients with MCL using current treatment approaches. Methods We conducted a retrospective population-based study of patients with MCL using healthcare administrative databases from Ontario, Canada, from 2005 to 2020. Patients were defined as TE if they were less than 70 years old at the time of treatment initiation, and received either R-CHOP or R-CHOP/R-DHAP. Patients were defined as TI if they were 70 years or greater at the time of treatment initiation, and treated with BR or other forms of chemoimmunotherapy. The primary outcome was 5-year overall survival (OS), from the time of first treatment to death or end of the study period. Secondary outcomes were toxicities of treatment and healthcare utilization. Cox regression analyses were used to assess the impact of demographic and treatment variables on OS. Results A total of 918 patients with MCL were included in this study; 426 were TE and 492 TI. For TE patients, 254 were treated with R-CHOP, and 172 with R-CHOP/R-DHAP. The median age of patients in both groups was 60 years (range 36-70 years, p=0.37). Patients treated with R-CHOP alone were followed for a mean of 6.01 years, and patients treated with R-CHOP/R-DHAP for a mean of 3.38 years. Maintenance rituximab (MR) was used in 70.5% of patients treated with R-CHOP and 77.3% of patients treated with R-CHOP/R-DHAP (p=0.12). ASCT was received by 53.5% of patients treated with R-CHOP and 83.7% of patients treated with R-CHOP/R-DHAP (p&amp;lt;0.01). 5-year OS of patients treated with R-CHOP/R-DHAP was 70.5% vs 62.0% for patients treated with R-CHOP regardless of transplant status ( Figure 1A hazard ratio [HR] 0.75, 95% CI 0.51-1.10). Of the 270 patients who received ASCT within 1 year of treatment initiation, survival was not impacted by prior receipt of R-CHOP alone or R-CHOP/R-DHAP (HR for R-CHOP/R-DHAP vs. R-CHOP 0.76, 95% CI 0.42-1.39). A higher proportion of patients treated with R-CHOP/R-DHAP required hospital admissions for fever, infection, neutropenia, and renal toxicity, compared to R-CHOP alone ( Table 1). There was no difference between regimens in the number of patients requiring emergency department (ED) visits between regimens (p=0.39). 492 TI patients were included; 303 treated with BR and 189 treated with other regimens, most commonly R-CHOP (n=62) or R-CVP (n=108). The median age of patients in both groups was 77 years (range 71-94 years, p=0.17), and there was no significant difference in comorbidities (p=0.23). MR was more commonly used after BR compared to historical regimens (72.6% vs. 54.5%, p&amp;lt;0.01). 5-year unadjusted OS of patients treated with BR was 40.3% and 27.5% for patients treated with R-CHOP/R-CVP ( Figure 1B), with significantly lower mortality with the use of BR (HR 0.68, 95% CI 0.51-0.89). After adjusting for age, sex, comorbidities, and MR, this was no longer significant (HR 0.86, 95% CI 0.65-1.14). MR use was associated with significantly lower mortality (HR 0.33, 95% CI 0.24-0.44). More patients treated with BR had hospital admissions for neutropenia and febrile neutropenia ( Table 1). Conclusion In this large population-based study of patients with MCL, R-CHOP/R-DHAP prior to ASCT showed a trend toward improved 5-year OS, though not significant. For TI patients, BR resulted in superior OS compared to other regimens with similar rates of toxicities, however this was not significant after adjusting for use of MR, suggesting other regimens followed by MR may be a reasonable alternatives.

Daratumumab Bortezomib and Dexamethasone in Transplant Ineligible Newly Diagnosed Elderly Myeloma Patients - a Trial By Asian Myeloma Network

Background: Transplant ineligible (TI) newly diagnosed Multiple Myeloma (NDMM) patients have inferior outcomes compared to that of a transplant population. This led to investigation of therapies with novel mechanisms of action to improve outcomes in this group. MAIA and ALCYONE studies have showed impressive outcomes in this group of patients. However, significant toxicities are a concern when delivering multiple anti-myeloma drugs concurrently in a continuous schedule in elderly patients. In this context, the efficacy and safety of Daratumumab, Bortezomib (finite) and dexamethasone in NDMM remains unknown. Aims: In this study, we investigated the combination of Daratumumab Bortezomib (in a finite schedule), and dexamethasone (DVd) followed by Daratumumab as maintenance in transplant ineligible TI NDMM patients from Asia (NCT03695744). Methods: This is a prospective, open-label, single-arm, phase 2 study of TI NDMM patients conducted by Asian Myeloma Network across three hospitals in Singapore. The primary end point was overall response rate. Secondary end points included progression free survival, overall survival, toxicity &amp; safety, duration of response, minimal residual disease (MRD) and sustained MRD negativity. The study was approved by SingHealth Centralised IRB (CIRB No 2018/2730). Patients with confirmed diagnosis of MM, fulfilling inclusion / exclusion criteria were enrolled after signing informed consent. Patients received IV daratumumab 16mg/kg weekly in weeks 1-9, Q3 weekly from weeks 10 to 24 and Q4 weekly from week 25 onwards. Subcutaneous Bortezomib 1.3mg/m 2 and Dexamethasone 40mg (20mg for patients &amp;gt;75 years old) once weekly were administered for 9 months, followed by daratumumab maintenance until progression or toxicity. Response assessments were as per IMWG criteria and serial QOL data was also collected. Regular safety reviews were performed from recruitment of first patient by an independent committee. Here we report the protocol specified interim analysis of safety and efficacy end points. Results: From Oct 2019 till Sep 2021, we enrolled 27 patients. Median age was 74.3 years (range 70.5 to 79.2 years; 13/27 patients were &amp;gt;75years). 13 male and 14 were female patients. Ethnic distribution was 20 Chinese, 3 Malay, 3 Indian and 1 Others. ECOG performance status was 0 in 5(19%), 1 in 16(59%) and 2 in 6(22%) patients respectively. 11(41%) and 6(22%) patients belonged to Stage II and III ISS respectively. 14(52%) patients had CrCl &amp;lt;60ml/Min. 26(96%) patients experienced any grade adverse event with 17 experiencing a grade 3/4 event. Most common adverse events were infections, gastrointestinal disorders, peripheral neuropathy, and infusion related reactions. All grade and grade 3/4 AEs were relatively low, particularly haematological, given the absence of drugs known to cause significant myelotoxicity. Detailed AEs and SAEs are tabulated in Table 1. Three patients have died, of which one was due to a treatment related infection, while two others were unrelated (1 - suicide secondary to known mental illness, 1 - accidental fall &amp; cervical spine injury). At data cut off (15 Oct 2022), 26 out of 27 patients had a response with 4(14.8%) sCR, 3 (11.1%) CR, 14 (51.9%) VGPR and 5 (18.5%) PR (1 missing assessment) giving an ORR of 96.3%. Median duration on Daratumumab was 16.3 mos and Bortezomib was 8 mos. 6 patients (22.2%) have experienced disease progression. With a median follow-up of 17.6 months, the 18-month progression free survival and overall survival were 65.4% &amp; 89% respectively (median PFS and OS not estimable). Follow-up is on-going and we aim to report long-term survival, FISH/ cytogenetic &amp; MRD results, toxicity and QOL data in future. Conclusion: DVd with Bortezomib in a finite schedule and Daratumumab maintenance achieved highly efficacious responses in elderly TI NDMM. Though this is a small study, toxicity rates here compare favorably to that noted in larger Phase 3 studies with quadruplets (Alcyone) and continuous triplet regimen as in the MAIA study. Whilst using novel agents like CD38 monoclonals upfront clearly improves responses and survival, minimizing toxicities without compromising efficacy by careful limitation of long-term concurrent exposure to multiple anti-myeloma drugs in an elderly population could help improve safety and quality of life. DVd could be an effective alternative in some elderly TI NDMM patients.

Subgroup Analyses of Progression-Free Survival from the Phase 3 Octans and Alcyone Studies in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Bortezomib, Melphalan, and Prednisone with or without Daratumumab

Introduction:Daratumumab, a human IgGκ monoclonal antibody targeting CD38, has shown clinical efficacy in combination with standard-of-care regimens in patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) significantly improved clinical outcomes vs bortezomib, melphalan, and prednisone (VMP) in phase 3 studies in Asian patients (OCTANS) and a global population (ALCYONE) with transplant-ineligible (TIE) NDMM. Here, we present subgroup analyses of progression-free survival (PFS) by measurable residual disease (MRD) and cytogenetic risk status from OCTANS and ALCYONE. Methods: Eligible patients from OCTANS (NCT03217812) and ALCYONE (NCT02195479) had a diagnosis of NDMM and were TIE due to age or comorbidities. Patients were randomized to receive up to nine 42-day cycles of VMP (bortezomib 1.3 mg/m 2 SC twice weekly in Cycle 1 and weekly in Cycles 2-9, and melphalan 9 mg/m 2 and prednisone 60 mg/m 2 orally on Days 1-4 of each cycle) or D-VMP (VMP + daratumumab 16 mg/kg IV weekly in Cycle 1, every 3 wk in Cycles 2-9, and every 4 wk thereafter until disease progression or unacceptable toxicity). MRD negativity (10 -5) was assessed by multi-parameter flow cytometry in OCTANS and next-generation sequencing in ALCYONE. Cytogenetic risk was assessed by FISH or karyotype testing. Results:A total of 220 Asian patients were randomized (D-VMP, n = 146; VMP, n = 74) in OCTANS, and 706 global patients were randomized (D-VMP, n = 350; VMP, n = 356) in ALCYONE. With a median follow-up of 41.2 mo (range, 0.0-59.9) in OCTANS, the median PFS was 38.7 mo with D-VMP and 19.2 mo with VMP (HR, 0.35; 95% CI, 0.23-0.52; P &amp;lt;0.0001). With a median follow-up of 40.1 mo (range, 0.0-52.1) in ALCYONE, the median PFS was 36.4 mo with D-VMP and 19.3 mo with VMP (HR, 0.42; 95% CI, 0.34-0.51; P &amp;lt;0.0001). The rates of overall and sustained MRD negativity were higher with D-VMP vs VMP. In OCTANS, the MRD-negativity rate was 40.4% with D-VMP vs 10.8% with VMP ( P &amp;lt;0.0001), and more patients in the D-VMP group had sustained MRD negativity lasting ≥12 mo (24.7% vs 1.4%; P &amp;lt;0.0001) and ≥18 mo (15.1% vs 1.4%; P = 0.0008). Similarly, in ALCYONE, the MRD-negativity rate was 28.3% with D-VMP vs 7.0% with VMP ( P &amp;lt;0.0001), with more patients in the D-VMP group having sustained MRD negativity lasting ≥12 mo (14.0% vs 2.8%; P &amp;lt;0.0001) and ≥18 mo (8.9% vs 1.7%: P &amp;lt;0.0001). In both studies, longer PFS was observed for patients who achieved MRD negativity vs those who did not within each treatment group; however, the PFS benefit observed for D-VMP vs VMP was maintained irrespective of MRD status ( Figure). In multivariate analyses, achievement of sustained MRD negativity lasting ≥12 mo was associated with longer PFS vs MRD negativity &amp;lt;12 mo in both OCTANS (HR, 0.23; 95% CI, 0.09-0.62; P = 0.004) and ALCYONE (HR, 0.13; 95% CI, 0.06-0.32; P &amp;lt;0.0001). No other factors showed a significant association with PFS in the multivariate analysis for OCTANS; other factors associated with longer PFS in ALCYONE included age &amp;lt;75 vs ≥75 y (HR, 0.38; 95% CI, 0.20-0.75; P = 0.005) and ISS disease stage I vs II (HR, 0.20; 95% CI, 0.05-0.86; P = 0.03). Data from OCTANS and ALCYONE were pooled for an analysis of PFS by cytogenetic risk subgroup (D-VMP, n = 496; VMP, n = 430). D-VMP prolonged median PFS vs VMP in patients with standard cytogenetic risk (not estimable vs 18.9 mo; HR, 0.33; 95% CI, 0.26-0.42) and high cytogenetic risk (25.6 vs 18.9 mo; HR, 0.54; 95% CI, 0.41-0.71), defined by the presence of t(4;14), t(14;16), del(17p), t(14;20), gain(1q21), and/or amp(1q21). Median PFS was also longer with D-VMP vs VMP for patients with gain and/or amp(1q21) (31.9 vs 18.9 mo; HR, 0.45; 95% CI, 0.32-0.63), 1 high-risk cytogenetic abnormality (HRCA; 24.4 vs 19.3 mo; HR, 0.62; 95% CI, 0.44-0.86), and ≥2 HRCA (28.2 vs 17.5 mo; HR, 0.36; 95% CI, 0.20-0.63). Conclusions:In this subgroup analysis of OCTANS and ALCYONE, the prolonged PFS observed with D-VMP vs VMP in the overall study populations was maintained irrespective of the achievement of MRD negativity or the presence of high cytogenetic risk. In addition, the rates of MRD negativity and sustained MRD negativity were higher with D-VMP vs VMP, and achievement of these deep responses translated into longer PFS, consistent with a prior pooled analysis of the MAIA and ALCYONE studies. These results further support the use of daratumumab in combination with VMP in both Asian and global patients with TIE NDMM.

An Updated Analysis of Ocular Adverse Events and Vision-Related Functioning in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Belantamab Mafodotin, Lenalidomide, and Dexamethasone in the Phase 1/2 Belard Trial

Introduction Belantamab mafodotin (belamaf; GSK2857916) is a B-cell maturation antigen-binding antibody-drug conjugate approved as a monotherapy in pretreated patients (pts) with relapsed/refractory multiple myeloma. Ocular adverse events (OAEs), manifesting as visual acuity changes, ocular symptoms, and corneal findings, are common with belamaf and the main reason for dose modifications (dose reduction, dose holds) or treatment discontinuation. In this descriptive analysis, we evaluate the OAEs and their impact on daily functioning in transplant ineligible (TI) pts with newly diagnosed multiple myeloma (NDMM), treated with an extended dosing schedule of belamaf in combination with lenalidomide and dexamethasone (Rd) in the phase 1/2 BelaRd study. Methods BelaRd (NCT04808037) is an open-label, phase 1/2 study conducted in Greece, aiming to enroll 66 TI NDMM pts. The study is comprised of 2 Parts: Part 1 evaluates the safety/clinical activity of three different belamaf doses (2.5/1.9/1.4 mg/kg) plus Rd and establishes the recommended phase 2 dose (RP2D). Part 2 further investigates the safety/efficacy of RP2D in two Groups and evaluates two different sets of guidelines for the management of OAEs. In Part 1, belamaf is initially administered q8w and, depending on toxicity, dosing may be adjusted to q12w. Ocular assessments include best corrected visual acuity (BCVA), using Snellen chart and manifest refraction, and corneal exam using slit lamp microscopy. Ocular symptoms are classified by Common Terminology Criteria for Adverse Events v5.0, while dry eye disease severity and vision-related functioning is assessed with the patient-reported questionnaire Ocular Surface Disease Index (OSDI). In Part 1 of the study, severity of corneal events is assessed with the Keratopathy Visual Acuity scale. This descriptive analysis presents the OAEs in all Part 1 pts over an extensive follow-up period (data cut-off: 05 June 2023). Results Thirty-six pts were included in this analysis, who were followed up for a median of 20.3 months (range 3.2-26.8). At baseline, all pts had ocular comorbidities. Among 216/244/201 BCVA assessments in cohorts 2.5/1.9/1.4 mg/kg, a meaningful BCVA decline (BCVA &amp;lt;20/50) with at least 3 lines drop in the better seeing eye, was observed in 21 (10%)/24 (10%)/17 (8%) of the assessments, while BCVA ≤20/200 with at least 3 lines drop in the better seeing eye was noted in only 2 (1%)/3 (1%)/8 (4%), with a median time to resolution of 1 month. The most frequently reported ≥Gr 3 ocular symptom was decreased vision, observed in 11 (5%)/ 8 (3%)/ 7 (3%) of the assessments, while ≥Gr3 keratopathy was noted in &amp;lt; 2% of assessments across all cohorts. Regarding OSDI, from 202/234/196 responses received, the number of “all/most” of the time worst responses in the ocular symptoms category were 6 (3%)/6 (3%)/8 (4%), while the respective proportions in the Activities of Daily Living category (ADL) were 6 (3%)/4 (2%)/3 (2%). In terms of missed doses due to OAEs, among 129/138/119 planned belamaf infusions, the number of skipped doses were 53 (41%)/48 (35%)/32 (27%). The overall response rate was 100%, no disease progression was observed over a median follow-up of 20.3 months, and 30 (83%) patients achieved at least VGPR while 19 (53%) achieved at least CR, with a median time to first response of 1 month. Conclusions Over a prolonged follow-up period, the belamaf-Rd triplet, with the extended dosing schedule for belamaf, had a minimal impact in vision-related functioning, as the ‘all/most’ of the time worst answers in the ADL category of OSDI was ≤3% across all cohorts. Furthermore, the frequency of clinically relevant impairment in vision was low, as a meaningful BCVA decline was observed in &amp;lt;10% of assessments, with a rapid time to resolution. Finally, the treatment combination induced rapid, deep and durable responses across all dose levels, with no PD observed. In conclusion, this novel extended belamaf schedule nearly eradicates the risk for clinically relevant ocular toxicity and impact on ADL, without any compromise in clinical activity, suggesting it may be a valid option in the upfront treatment of this frail, elderly and difficult-to-treat pt population.

Evaluation of a Novel Method for the Assessment of Ocular Adverse Events and Associated Functional Impact in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Belantamab Mafodotin, Lenalidomide, and Dexamethasone in the Phase 1/2 Belard Trial

Introduction Belantamab mafodotin (belamaf; GSK2857916), an antibody-drug conjugate targeting B-cell maturation antigen, has shown promising efficacy and a favorable tolerability profile in the treatment of multiple myeloma. Ocular adverse events (OAEs), manifesting as visual acuity changes, ocular symptoms, and corneal findings, are common with belamaf and the main reason for dose modifications (dose reduction, dose holds) or treatment discontinuation. Keratopathy and Visual Acuity (KVA) scale was used in most belamaf trials, including the pivotal DREAMM-2, to guide belamaf dose modifications. KVA grading is dependent on an ophthalmologist consultation prior to belamaf administration. Herein, we evaluate a novel approach to guide belamaf dosing in transplant ineligible (TI) patients (pts) with newly diagnosed multiple myeloma (NDMM), treated with an extended dosing schedule of belamaf in combination with lenalidomide and dexamethasone (Rd) in the phase 1/2 BelaRd study. Methods BelaRd (NCT04808037) is an open-label, phase 1/2 study conducted in Greece, aiming to enroll 66 TI NDMM pts. Part 1 evaluated the safety/tolerability of three belamaf doses (2.5/1.9/1.4 mg/kg) plus Rd in 36 pts and established that the recommended phase 2 dose (RP2D) is 1.9 mg/kg, initially administered q8w and, depending on toxicity, adjusted to q12w. Part 2 investigates the safety/efficacy of RP2D in Groups A and B, comprised of 15 pts each, and evaluates two different sets of guidelines for the management of OAEs. In Group A, belamaf dosing is guided by the KVA scale; in Group B, dose modifications are determined by the pts' responses on ocular symptoms and their impact on activities of daily living (ADL), captured by the Vision Related Anamnestic (VRA) tool, and by the presence of ≥Grade (Gr) 3 KVA events (BCVA reduced/corneal findings). VRA is a novel, 9-item physician administered questionnaire designed to assess the frequency of ocular symptoms and their impact on vision-related activities. Ocular exams include Snellen best corrected visual acuity (BCVA) and slit lamp corneal evaluation, while ocular symptoms are classified by CTCAE v5.0. Herein, we present the OAEs and the clinical activity of the treatment combination for both Groups of Part 2 (cut-off date 05/06/2023). Results By the cut-off date, twenty-four pts [median age: 75.5 years; male: 16 (66.7%)] had received ≥ 1 belamaf dose in Part 2 and were still on treatment. At baseline, most pts had ocular comorbidities. The median belamaf administrations and number of cycles reached were 3.0/2.0 and 6.5/5.5, for Groups A and B, respectively. A meaningful BCVA decline (BCVA &amp;lt;20/50) with at least 3 lines drop in the better seeing eye, was noted in 5/52 (9.6%) and 5/45 (11.1%) assessments, while BCVA ≤20/200 with at least 3 lines drop was noted in 1/59 (1.7%) and 2/51 (3.9%), respectively. Overall, no ≥Gr 3 ocular symptoms were observed, while the most frequent ≥Gr 2 ocular symptom was dry eye (57/110, 51.8%); also, no ≥Gr3 keratopathies were recorded. Among 66/59 VRA assessments, ocular symptoms and ADL impairment, manifesting for &amp;gt;50% of the time (substantial time) in the last 24 hours prior to belamaf administration, were noted in 2 (3.0%)/9 (15.3%) and 2 (3.0%)/7 (11.9%), respectively. Importantly, numerically similar proportions of KVA events and skipped belamaf doses were noted in both Groups (Table 1). Furthermore, although the sample size of the present analysis does not allow conclusions for the VRA test characteristics, it is notable that in all assessments where eyesight difficulties were reported for substantial time, ≥Gr2 KVA events were also recorded, suggesting a potential association between VRA responses and KVA events, that warrants further investigation. Finally, in terms of clinical activity, for the 19 response-evaluable pts (≥2 efficacy assessments), at a median follow-up of 7.4 months the ORR was 90%/100% in Groups A and B (PR/VGPR: 30%/60%; 66.7%/33.3%) with no disease progression observed. Conclusions In this preliminary descriptive analysis, the VRA tool was safe and effective in informing belamaf dose adjustments in the extended dosing schedule. Recruitment in Part 2 is ongoing and, as data accumulates, future analyses will provide further insight on the potential association of the VRA tool with KVA events, which may eliminate the need for an ophthalmic exam prior to belamaf dosing.

A Prognostic Model Integrating Circulating Clonal Plasma Cells into R-ISS and PET-CT Based Tumor Burden in Transplant-Ineligible Multiple Myeloma

Introduction: Circulating clonal plasma cell (cCPC) is an easily obtained and non-invasive biomarker in multiple myeloma (MM), providing distinct prognostic information from the revised-international staging system (R-ISS). However, its prognostic relevance has been investigated primarily in transplant-eligible and clinical trial settings. Consequently, there is limited data on the impact of cCPC on outcomes and optimal cut-off values in transplant-ineligible (TIE) MM patients. Moreover, appropriate combinations to refine risk stratification, such as tumor burden measured by positron emission tomography-computed tomography (PET-CT), have yet to be fully explored. Methods: We performed a retrospective analysis on newly diagnosed TIE-MM patients with available peripheral blood (PB) flow cytometry (FCM) and PET-CT data from 2011 to 2021. Patients with primary plasma cell leukemia (n=8), defined as &amp;gt;5% monoclonal plasma cells in PB, were excluded from the study. Quantification of cCPC was performed using 6-color (2011-2016) or 8-color (2017-2021) FCM staining for CD19, CD56, CD38, CD138, cytoplasmic κ, and cytoplasmic λ to confirm monoclonality (Beckman Coulter, USA), which required at least 150000 mononuclear cell counts with the detectable limit at 0.01% (10 -4) based on previous reports (Gonsalves et al). Tumor burden was assessed by calculating total lesion glycolysis (TLG) using the following formula: the mean standardized uptake value (SUV) multiplied by the total tumor volume with an absolute SUV &amp;gt;2.5, using Metavol Software (Hokkaido University, Japan). Receiver operating curve analysis with the Youden index was employed to determine the optimal cutoff for predicting 2-year progression-free survival (PFS) and 5-year overall survival (OS). The predictive performance of R-ISS, cCPC, and TLG alone, along with their combinations, was compared using Harrell's concordance index (c-index). Results: 114 patients with TIE-MM were analyzed. The median age was 78 years (interquartile range [IQR] 73-83). The number of patients classified as R-ISS Ⅰ, Ⅱ, and Ⅲ was 12 (10.5%), 82 (71.9%), and 20 (17.5%), respectively. Most patients (85.1%) received proteasome inhibitor-based induction remission therapy. cCPCs were detectable in 90 patients (80.7%), with a median level of 6 ×10 -4 (IQR 1-22). Regarding tumor burden, 73 patients (64%) had at least one fluorodeoxyglucose avid lesion with a median TLG of 34.7 (IQR 0-268). cCPC levels were significantly correlated with CPC in bone marrow (R =0.24, P =0.01) but not with TLG (R =-0.01, P =0.88) and involved free light chain levels (R =0.07, P =0.41). The optimal cut-off values in predicting 2-year PFS and 5-year OS were 9 and 10 ×10 -4 for cCPC, and 325 and 343 for TLG, respectively. For simplicity, we classified &amp;gt;10 ×10 -4 for cCPC and &amp;gt;300 for TLG as high-risks. Notably, approximately two-thirds of the patients (62.3%) had at least one high-risk feature (Figure 1). Both high cCPC and TLG showed significant associations with worse OS and PFS (5-year OS rate: cCPC high vs. low, 40.2% vs. 69.3%; TLG high vs. low, 38% vs. 64.5%; 2-year PFS rate: cCPC high vs. low, 45.7% vs. 69.1%; TLG high vs. low, 46.4% vs. 64% all P &amp;lt; 0.05). These factors retained prognostic significance after adjustment for R-ISS on multivariate analysis. Finally, we constructed a novel predictive model integrating RISS, cCPC, and TLG. This model discriminated OS among patients with 0 (5-year OS rate, 80% [95% confidence interval 68.4%-93.6%]), 1 (50.5% [37.7%-67.7%]), and ≧2 factors (29% [13.3%-63.5%], P &amp;lt;0.001, Figure 2). The c-index was the highest (0.651) in this combined model compared to the single use of these risk factors (0.585, 0.594, and 0.569). Conclusions: We demonstrated the prognostic impact of cCPC, which is independently associated with R-ISS and TLG, on real-world TIE-MM patients. The new prediction model, integrated with these different clinical and biological features, may provide robust outcome discrimination.