Prior Transplant Research Articles

AT-101 Enhances the Antitumor Activity of Lenalidomide in Patients with Multiple Myeloma.

Bcl-2 and Mcl-1 proteins play a role in multiple myeloma (MM) cell survival, for which targeted inhibitors are being developed. AT-101 is an oral drug, which disrupts Bcl-2 and Mcl-1 function, impedes mitochondrial bioenergetic processes and induces apoptosis in MM cells. When combined with lenalidomide and dexamethasone (Rd), AT-101 significantly reduced tumor burden in an in vivo xenograft model of MM. These data provided rationale for a phase I/II study to establish the effective dose of AT-101 in combination with Rd (ARd regimen) in relapsed/refractory MM. A total of 10 patients were enrolled, most with high-risk cytogenetics (80%) and prior stem cell transplant (70%). Three patients were lenalidomide-refractory, 2 were bortezomib-refractory and 3 were daratumumab-refractory. The ARd combination was well tolerated with most common grade 3/4 adverse events being cytopenia's. The overall response rate was 40% and clinical benefit rate was 90%. The median progression free survival was 14.9 months (95% CI 7.1-NE). Patients responsive to ARd showed a decrease in Bcl-2:Bim or Mcl-1:Noxa protein complexes, increased CD8+ T and NK cells and depletion of T and B-regulatory cells. The ARd regimen demonstrated an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM prompting further investigation in additional patients.

Post-cardiac surgery fungal mediastinitis: clinical features, pathogens and outcome

ObjectivesThe occurrence of mediastinitis after cardiac surgery remains a rare and severe complication associated with poor outcomes. Whereas bacterial mediastinitis have been largely described, little is known about their fungal etiologies. We report incidence, characteristics and outcome of post-cardiac surgery fungal mediastinitis.MethodsMulticenter retrospective study among 10 intensive care units (ICU) in France and Belgium of proven cases of fungal mediastinitis after cardiac surgery (2009–2019).ResultsAmong 73,688 cardiac surgery procedures, 40 patients developed fungal mediastinitis. Five were supported with left ventricular assist device and five with veno-arterial extracorporeal membrane oxygenation before initial surgery. Twelve patients received prior heart transplantation. Interval between initial surgery and mediastinitis was 38 [17–61] days. Only half of the patients showed local signs of infection. Septic shock was uncommon at diagnosis (12.5%). Forty-three fungal strains were identified: Candida spp. (34 patients), Trichosporon spp. (5 patients) and Aspergillus spp. (4 patients). Hospital mortality was 58%. Survivors were younger (59 [43–65] vs. 65 [61–73] yo; p = 0.013), had lower body mass index (24 [20–26] vs. 30 [24–32] kg/m2; p = 0.028) and lower Simplified Acute Physiology Score II score at ICU admission (37 [28–40] vs. 54 [34–61]; p = 0.012).ConclusionFungal mediastinitis is a very rare complication after cardiac surgery, associated with a high mortality rate. This entity should be suspected in patients with a smoldering infectious postoperative course, especially those supported with short- or long-term invasive cardiac support devices, or following heart transplantation.

The key role of hepatology providers in optimizing reproductive care in patients with liver disease: A call to action.

The key role of hepatology providers in optimizing reproductive care in patients with liver disease: A call to action.

An appraisal ofneostigmine versus sugammadex for neuromuscular blockade reversal in patients with aprior heart transplant.

Heart transplant recipients present unique perioperative challenges for surgery. Specifically, autonomic system denervation has significant implications for commonly used perioperative drugs. This study investigates neuromuscular blocking antagonists in this population when undergoing subsequent non-cardiac surgery. A retrospective review was performed for the period 2015-2019 across our health care enterprise. Patients with previous orthotopic heart transplant and subsequent non-cardiac surgery were identified. A total of 185 patients were found, 67 receiving neostigmine (NEO) and 118 receiving sugammadex (SGX). Information of patient characteristics, prior heart transplant, and subsequent non-cardiac surgery was collected. Our primary outcome was the incidence of bradycardia (heart rate < 60 bpm) and/or hypotension (mean blood pressure (MAP) < 65 mmHg) following neuromuscular blockade reversal. Secondary outcomes included need of intra-operative inotropic agents, arrhythmia, cardiac arrest, hospital length of stay (hLOS), ICU admission, and death within 30 postoperative days. In unadjusted analysis, no significant differences were found between the two groups in change in heart rate [0 (-26, 14) vs. 1 (-19, 10), P = 0.59], change in MAP [0 (-22, 28) vs. 0 (-40, 47), P = 0.96], hLOS [2 days (1, 72) vs. 2 (0, 161), P = 0.92], or intraoperative hypotension [4 (6.0%) vs. 5 (4.2%), OR = 0.70, P = 0.60] for NEO and SGX respectively. After multivariable analysis, the results were similar for change in heart rate ( P = 0.59) and MAP ( P = 0.90). No significant differences in the incidence of bradycardia and hypotension were found in the NEO versus SGX groups. NEO and SGX may have similar safety profiles in patients with prior heart transplant undergoing non-cardiac surgery.

Maternal and pregnancy outcomes following heart transplantation in the United States

Improvement in survival following heart transplantation has led to increasing numbers of recipients contemplating pregnancy, but data on outcomes are limited. We used a large national dataset to describe outcomes of deliveries in the U.S. complicated by prior heart transplantation.

Population-Based Analysis of Nonsteroidal Anti-inflammatory Drug Prescription in Subjects With Chronic Kidney Disease

Pain is a prevalent symptom experienced by patients with chronic kidney disease (CKD) and appropriate management of pain is an important element of comprehensive care. Nonsteroidal anti-inflammatory drugs (NSAID) are known to be nephrotoxic in persons with CKD. This study examined the pattern of NSAID prescribing practices in a population based-cohort of patients with CKD. Retrospective cohort study using linked population-based health care data. Entire province of Alberta, Canada. All adults in Alberta with eGFR defined CKD G3 or greater between 2009 and 2017 were included. CKD was defined using at least 2 outpatient serum creatinine (SCr) greater than 90 days apart; the date of second SCr measurement was used as index date. We determined the incidence of hyperkalemia using the peak serum potassium. Prescription drug information was obtained from the Pharmaceutical Information Network (PIN) database. All patients were followed from the index date until March 31, 2019, with a minimum follow-up of 2 years. Prescription drug information and the follow-up laboratory testing of serum creatinine and serum potassium were obtained. Patients with kidney failure defined as eGFR < 15 mL/min per 1.73 m2, receiving chronic dialysis, or prior kidney transplant at baseline were excluded. A total of 170 574 adults (mean age 76.3; 44% male) with CKD were identified and followed for a median of 7 years; 27% were dispensed at least 1 NSAID prescription. While there was a trend toward fewer prescriptions in patients with more advanced CKD (P < .001), 16% of those with CKD G4 were prescribed an NSAID. Primary care providers provided 79% of the prescriptions. Among NSAID users, 21% had a follow-up serum creatinine (SCr) within 30 days of the index prescription. Data collected were from clinical and administrative databases not created for research purposes. The study cohort is limited to subjects who sought medical care and had a serum creatinine measurement obtained. Measurement of NSAID use is limited to those who were dispensed a prescription, over-the-counter NSAIDs use is not captured. Despite guidelines advocating cautious use of NSAIDs in patients with CKD, this study indicates that there is a discrepancy from best practice recommendations. Effective strategies to better support and educate prescribers, as well as patients, may help reduce inappropriate prescribing and adverse events.

Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen.

Hereditary transthyretin (ATTRv) amyloidosis is a rare, severe, progressive, debilitating, and ultimately fatal disease caused by systemic deposition of transthyretin (TTR) amyloid fibrils. ATTRv amyloidosis occurs in both males and females. Eplontersen (ION-682884), a ligand-conjugated antisense oligonucleotide designed to degrade hepatic TTR mRNA, is being evaluated for the treatment of ATTRv amyloidosis with polyneuropathy (ATTRv-PN) in the phase 3, international, multicenter, open-label NEURO-TTRansform study (NCT04136184). To describe the study population of this pivotal trial, here we report the baseline characteristics of patients enrolled in the NEURO-TTRansform study. Patients eligible for NEURO-TTRansform were 18-82years old with a diagnosis of ATTRv-PN and Coutinho stage 1 (ambulatory without assistance) or stage 2 (ambulatory with assistance) disease; documented TTR gene variant; signs and symptoms consistent with neuropathy associated with ATTRv; no prior liver transplant; and New York Heart Association (NYHA) functional class I or II. The NEURO-TTRansform study enrolled 168 patients across 15 countries/territories (North America, 15.5%; Europe, 38.1%; South America/Australia/Asia, 46.4%). At baseline, the study cohort had a mean age of 52.8years, 69.0% of patients were male, and 78.0% of patients were White. The V30M variant was most prevalent (60.1% of patients), and prevalence varied by region. Overall, 56.5% and 17.3% of patients had received previous treatment with tafamidis or diflunisal, respectively. A majority of patients (79.2%) had Coutinho stage 1 disease (unimpaired ambulation) and early (before age 50) disease onset (53.0%). Time from diagnosis to enrollment was 46.6 (57.4) months (mean [standard deviation]). Most patients had a baseline polyneuropathy disability (PND) score of I (40.5%) or II (41.1%), and the mean modified Neuropathy Impairment Score + 7 (mNIS + 7) was 79.0. The recruited population in the ongoing NEURO-TTRansform study has global representation characteristic of contemporary clinical practice. ClinicalTrials.gov identifier NCT04136184.

1844. Mortality associated with Stenotrophomonas maltophilia bloodstream infection in patients with leukemia

Abstract Background Patients with leukemia are disproportionately vulnerable to infections caused by S. maltophilia and mortality approaches 100% in patients with hemorrhagic pneumonia. Trimethoprim-sulfamethoxazole (SXT) is the drug of choice for treatment of infections caused by S. maltophilia however allergies, toxicity, and resistance may preclude its use. We sought to characterize clinical outcomes of patients with leukemia and S. maltophilia bloodstream infection (BSI). Methods Patients with leukemia are disproportionately vulnerable to infections caused by S. maltophilia and mortality approaches 100% in patients with hemorrhagic pneumonia. Trimethoprim-sulfamethoxazole (SXT) is the drug of choice for treatment of infections caused by S. maltophilia however allergies, toxicity, and resistance may preclude its use. We sought to characterize clinical outcomes of patients with leukemia and S. maltophilia bloodstream infection (BSI). Results Ninety-six patients with leukemia and S. maltophilia BSI were identified. The most common diagnosis was acute myeloid leukemia (60%); 31% had prior stem cell transplant. The most common single identified source was respiratory (31%) followed by central venous catheter (CVC, 26%). A single clear source was unable to be identified in 33%.Overall 14-day mortality was 31%. After excluding eleven patients who died within 24 hours, most patients received SXT (72%), followed by ceftazidime (40%), tigecycline (TGC, 40%), and minocycline (26%). SXT was associated with reduced mortality (hazard ratio [HR] 0.15, 95% confidence interval [CI] 0.05 – 0.44, p &amp;lt; 0.01) while TGC was associated with increased mortality (HR 3.13, 95% CI 1.00 – 9.73, p = 0.05). All patients who died were neutropenic at baseline and none had a CVC infection. Conclusion S. maltophilia BSI is associated with high mortality in patients with leukemia, particularly those with neutropenia at baseline. CVC infection alone was not associated with mortality. SXT is associated with reduced mortality relative to other antimicrobials. Alternative agents should be used with caution in these vulnerable patients. Disclosures Samuel L. Aitken, PharmD, MPH, Entasis Therapeutics: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|Melinta: Grant/Research Support|Shionogi: Advisor/Consultant Pablo C. Okhuysen, MD, AstraZeneca: Stocks/Bonds|Beam Therapeutics: Stocks/Bonds|Biontech: Stocks/Bonds|Deinove: Grant/Research Support|Ferring: Advisor/Consultant|Glaxo Smith Kleine: Stocks/Bonds|Johnson and Johnson: Stocks/Bonds|Melinta: Grant/Research Support|Merck Sharp &amp; Dohme Corp: Grant/Research Support|Moderna: Stocks/Bonds|Napo Pharmaceuticals: Advisor/Consultant|Napo Pharmaceuticals: Grant/Research Support|Novavax: Stocks/Bonds|Pfizer: Stocks/Bonds|Summit: Advisor/Consultant|Summit: Grant/Research Support.

Evaluation of cell collection efficiency in non-mobilized adult donors for autologous chimeric antigen receptor T-cell manufacturing.

Data about collection efficiency 1 (CE1), which takes into account blood cell counts before and after collection, thus providing a more accurate estimate, in the collection of autologous T lymphocytes by apheresis for chimeric antigen receptor (CAR) T-cells remain scarce. We evaluated donor- and procedure-related characteristics that might influence the CE1 of lymphocytes. We retrospectively reviewed all mononuclear cell (MNC) collections) performed for CAR T-cell manufacturing in our institution from May 2017 to June 2021 in adult patients. Age, gender, weight, total blood volume (TBV), prior haematopoietic cell transplant, diagnosis, days between last treatment and apheresis, pre-collection cell counts, duration of apheresis, TBV processed, vascular access, inlet flow and device type were analysed as potential factors affecting CE1 of lymphocytes. A total of 127 autologous MNC collections were performed on 118 patients diagnosed with acute lymphoblastic leukaemia (n=53, 45%), non-Hodgkin lymphoma (n=40, 34%), multiple myeloma (n=19, 16%), and chronic lymphocytic leukaemia (n=6, 5%). The median CE1 of lymphocytes was 47% (interquartile range: 32%-65%). In multiple regression analysis, Amicus device was associated with higher CE1 of lymphocytes (p=0.01) and lower CE1 of platelets (p < 0.01) when compared with Optia device. The knowledge of the MNC and lymphocyte CE1 of each apheresis device used to collect cells for CAR T therapy, together with the goal of the number of cells required, is essential to define the volume to be processed and to ensure the success of the collection.

Shoulder arthroplasty following solid organ transplant: A systematic review and meta-analysis

IntroductionThe purpose of this study is to report a systematic review and meta-analysis of solid organ transplant (SOT) patients undergoing shoulder arthroplasty to compare functional and radiographic outcomes, demographics, and complications with non-transplant patients. MethodsStudies were included if they examined patients undergoing shoulder arthroplasty in the setting of prior solid organ transplantation and included post operative range of motion, patient-reported outcomes, complications, or revisions. Studies were excluded if they were national database analyses or lacked clinical data. Pubmed, MEDLine, Scopus, and Web of Science were queried using relevant search terms in July 2022. Data was pooled, weighted, and a paired t-test and chi-square analysis was performed. ResultsThere were 71 SOT and 159 non-SOT shoulders included in the study. The most common indication for surgery was avascular necrosis (n = 26) in the solid organ transplant group and osteoarthritis (n = 60) in the non-SOT group. Forward elevation, external rotation, ASES, and VAS pain scores improved significantly in both cohorts following surgery. There was no significant difference in age at surgery (p-value = 0.20), postoperative forward elevation (p-value = 0.08), postoperative external rotation (0.84), and postoperative ASES scores (p-value = 0.11) between the two cohorts. VAS pain scores were significantly lower in the SOT cohort (p-value<0.01). The risk of death was significantly higher in the SOT group (p-value<0.01). but the rate of overall complications (p = 0.47), surgical complication (p-value = 0.79), or revision surgery (p-value = 1.00) was not significantly different between the two cohorts. ConclusionShoulder arthroplasty is a safe, effective option in patients following solid organ transplant. There is not an increased risk of adverse outcomes, and SOT patients had comparable range of motion and patient-reported outcomes when compared to their non-SOT peers. Level of evidenceIII.

Novel therapeutic approach to slow down the inflammatory cascade in acute/subacute spinal cord injury: Early immune therapy with lipopolysaccharide enhanced neuroprotective effect of combinational therapy of granulocyte colony-stimulating factor and bone-marrow mesenchymal stem cell in spinal cord injury.

Bone-marrow mesenchymal stem cells (BM-MSCs) have not yet proven any significant therapeutic efficacy in spinal cord injury (SCI) clinical trials, due to the hostile microenvironment of the injured spinal cord at the acute phase. This study aims to modulate the inflammatory milieu by lipopolysaccharide (LPS) and granulocyte colony-stimulating factor (G-CSF) to improve the BM-MSCs therapy. For this purpose, we determined the optimum injection time and sub-toxic dosage of LPS following a T10 contusion injury. Medium-dose LPS administration may result in a local anti-inflammatory beneficial role. This regulatory role is associated with an increase in NF-200-positive cells, significant tissue sparing, and improvement in functional recovery compared to the SCI control group. The second aim was to examine the potential ability of LPS and LPS + G-CSF combination therapy to modulate the lesion site before BM-MSC (1 × 105 cells) intra-spinal injection. Our results demonstrated combination therapy increased potency to enhance the anti-inflammatory response (IL-10 and Arg-1) and decrease inflammatory markers (TNF-α and CD86) and caspase-3 compared to BM-MSC monotherapy. Histological analysis revealed that combination groups displayed better structural remodeling than BM-MSC monotherapy. In addition, Basso-Beattie-Bresnahan (BBB) scores show an increase in motor recovery in all treatment groups. Moreover, drug therapy shows faster recovery than BM-MSC monotherapy. Our results suggest that a sub-toxic dose of LPS provides neuroprotection to SCI and can promote the beneficial effect of BM-MSC in SCI. These findings suggest that a combination of LPS or LPS + G-CSF prior BM-MSC transplantation is a promising approach for optimizing BM-MSC-based strategies to treat SCI. However, because of the lack of some methodological limitations to examine the survival rate and ultimate fate of transplanted BM-MSCs followed by LPS administration in this study, further research needs to be done in this area. The presence of only one-time point for evaluating the inflammatory response (1 week) after SCI can be considered as one of the limitations of this study. We believed that the inclusion of additional time points would provide more information about the effect of our combination therapy on the microglia/macrophage polarization dynamic at the injured spinal cord.

Clinical Activity of Anti-PD-1 Therapy Following CD30 CAR-T Cell Therapy in Relapsed Hodgkin Lymphoma

Background: Anti-CD30 chimeric antigen receptor (CD30.CAR) T-cell therapy has been studied in heavily pretreated relapsed/refractory (r/r) classic Hodgkin lymphoma (cHL) patients with an objective response rate (ORR) of 62% and complete response (CR) rate of 51% (Ramos et al, JCO, 2020). Despite high response rates, disease progression has been observed, with a 1-year PFS of 36%. The anti-PD-1 antibodies nivolumab and pembrolizumab have both been studied in phase II studies in patients with r/r cHL with ORR ranging between 65-87% and median progression free survival (PFS) ranging from 13-15 months. Limited data is available regarding the clinical benefit of anti-PD-1 therapies following CD30.CAR-T cell therapy and the potential mechanism of response in patients with prior anti-PD-1 exposure. Methods: We followed and analyzed the clinical outcome of 10 patients with r/r HL who progressed after CD30.CAR-T cell therapy at the University of North Carolina at Chapel Hill and subsequently received anti-PD-1 therapy to treat relapsed disease. Clinical responses in follow up were determined per local radiologist assessment. Expansion and persistence of CD30.CAR-T cells in vivo was determined by quantitative PCR from peripheral blood samples. Results: Between October 2016 and November 2019, patients were treated with either CD30.CAR-T cells (9 patients) or CD30.CCR4.CAR-T cells (1 patient) on one of three clinical trials (NCT02690545, NCT02663297, NCT03602157). The median age of patients was 30 years (range, 24-51 years). The median number of prior lines of therapy was 8 (range, 5-16). Eight patients had a prior autologous stem cell transplant, and six patients had a prior allogeneic stem cell transplant. The best response to CAR-T cell therapy was a CR in 5 patients, partial response (PR) in 1 patient, and stable/progressive disease in 4 patients. At the time of progression following CD30.CAR-T cell therapy, patients were offered standard of care anti-PD-1 therapy. Eight patients were treated with nivolumab, and 2 patients were treated with pembrolizumab based on decision of the treating physician. The median time from CAR-T cell therapy to anti-PD-1 therapy was 171 days (range, 56-858 days). Seven of the 10 patients had prior anti-PD-1 exposure before CAR-T cell therapy. All 10 patients had an objective response to anti-PD-1 therapy after CAR-T cells, with a best response of CR in 7 patients and PR in 3 patients. Four of the 6 patients who had a PR to anti-PD-1 therapy prior to CAR-T cell treatment, achieved CR with anti-PD-1 re-challenge afterwards. At the time of the last follow up, 8 patients remain in an ongoing response, lasting over 1 year in 7 and over 3 years in 3 patients. The median PFS was not reached in this cohort (Fig 1A). Five patients stopped anti-PD-1 therapy after CAR-T cell therapy (4 related to toxicity of therapy, 1 for ongoing durable response). At the time of data collection, with a median follow up of 3.6 years (range, 1.7-4.7 years), all patients were still alive. Longitudinal peripheral blood samples were available in 3 of the 10 patients. All 3 patients with longitudinal samples demonstrated expansion and/or persistence of CD30.CAR-T cells following anti-PD-1 therapy (Fig 1B). Patient #9 and #5 had impressive expansion of CD30.CAR-T cell signals shortly after start of anti-PD-1 therapy. Patient #1 had detectable PCR signals in the peripheral blood until at least 1 year after CD30.CAR-T cell infusion; however, sample timepoints were not available to assess for expansion of CD30.CAR-T cell signals shortly after anti-PD-1 therapy. Conclusion: To our knowledge, this is the largest cohort of patients with r/r cHL who have received anti-PD-1 therapies after CD30.CAR-T cell treatment. Clinical efficacy appears strong, with high response rates and durable remissions observed even if most patients had prior exposure to anti-PD-1 therapy. All patients with no prior anti-PD-1 exposure experienced durable remissions. This study is the first to describe CD30.CAR-T expansion following anti-PD-1 therapy. While further analysis is warranted to assess for CD30.CAR-T functionality after anti-PD-1 exposure, our data suggest that anti-PD-1 therapy may rescue CD30.CAR T cells, supporting further investigations in patients with cHL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of a Validated Composite Comorbidity Score on Outcomes in Patients Treated with CAR T-Cell Therapy for Diffuse Large B Cell Lymphoma (DLBCL): A Multicenter Real-World Evidence (RWE) Study

Introduction: Chimeric Antigen Receptor T-cell therapy (CART) has dramatically improved outcomes for patients (pts) with relapsed/refractory (r/r) DLBCL, but the majority of pts still have poor outcomes due to progressive disease and toxicities. Tools quantifying frailty and comorbidities have not been verified in large patient cohorts. The Cumulative Illness Rating Scale (CIRS) is a comprehensive tool that has been found to predict outcomes in various B cell malignancies. We used a machine learning algorithm to rank the prognostic impact of specific comorbidities measured by CIRS on progression-free survival (PFS) in DLBCL pts undergoing leukapheresis for CART in a multicenter learning cohort (LC; Shouse et al, ASH 2021). In this study, we establish that these comorbidities also predict overall survival (OS) and verify their prognostic significance in a separate validation cohort (VC). Methods: We conducted a retrospective RWE analysis of pts with r/r DLBCL who underwent leukapheresis for CART at 10 academic centers. CIRS was assessed at the time of T-cell collection and calculated per Salvi (2008). High comorbidity burden was defined using a published cutoff of CIRS score ≥7. PFS and OS were measured from T-cell collection. Random survival forest (RSF) modeling of PFS and OS was repeatedly applied to random subsets of the LC to determine the most important CIRS categories and comorbidity levels in the presence of known prognostic factors (IPI at diagnosis, concurrent indolent lymphoma, age, ECOG performance status, number of prior therapies, prior transplant, number of medications, cell of origin subtype, complex karyotype, MYC rearrangement by FISH, and MYC+BCL2/BCL6 rearrangement). Cox proportional hazards models were fit to quantify the association between survival and significant pt features. Associations between comorbidities and CART adverse events were evaluated with Fisher's exact test. Results: We analyzed data from 577 pts. The median CIRS score was 7 (range, 0-25) with 54% (n=309) having CIRS ≥7. The median PFS was 11 months (95% CI: 8 - 15) and OS 30 months (95% CI: 23 - NA), with a median follow-up of 20 months. Although CIRS ≥7 was significantly associated with inferior PFS (HR=1.26) and OS (HR=1.35) in univariable analysis, it did not remain significant in multivariable models. According to RSF variable importance and node splits, key CIRS categories which adversely impacted OS were respiratory, upper GI, renal, and hepatic. 9% of pts had a score of ≥3 in at least one of the above comorbidities, which we designated Severe4. When accounting for other significant variables, Severe4 was independently associated with inferior PFS (HR=2.45, p<0.001) and OS (HR=2.30, p<0.001) in the LC. This finding was recapitulated in a single-center VC of 218 patients. In this cohort, median follow-up was 35 months, median age 61 years, median 3 prior therapies, ECOG 0-1 in 74%. As in the LC, axicabtagene ciloleucel was the predominant CART (93%). A CIRS comorbidity score of ≥3 in any of the Severe4 categories was found in 16% of pts. Severe4 remained independently associated with inferior PFS (HR=1.84, p=0.003) and OS (HR=1.82, p=0.007) in the VC (Figure). Pts with Severe4 also had a higher rate of grade ≥3 CRS (16% vs 6%; p=0.013), while development of grade ≥3 ICANS was associated with CIRS ≥7 (26% vs 12%; p<0.001). Conclusions: In this large RWE study, we demonstrate that the presence of comorbidity within the Severe4 composite index had prognostic significance for OS in CART recipients for r/r DLBCL. Importantly, Severe4 was validated in a separate cohort. Severe4 is predictive of severe CRS and CIRS ≥7 is predictive of severe ICANS. The underlying mechanism leading to this observation is an area of active investigation. Given these results, CIRS evaluation and Severe4 should be calculated prior to CART in DLBCL to identify those at highest risk for morbidity and mortality and to counsel pts about their expected risk. These results may be product specific given the enrichment of axi-cel patients and may need additional verification with other products. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Exploratory Analysis of Factors Influencing Efficacy and Safety of Camidanlumab Tesirine: Data from the Open-Label, Multicenter, Phase 2 Study of Patients with Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL)

Introduction: Despite most patients with cHL being cured with standard therapies, a proportion of patients are refractory or relapse after first- and second-line treatments (1L/2L), including stem cell transplantation, and there are limited treatment options available after failure of brentuximab vedotin (BV) and PD-1 blockade. Camidanlumab tesirine (Cami) is an antibody-drug conjugate comprising an anti-CD25 monoclonal antibody conjugated through a cleavable linker to a pyrrolobenzodiazepine (PBD) dimer. Cami has shown notable single-agent anti-tumor activity and manageable toxicity in the Phase 2 trial of patients with R/R cHL (Carlo-Stella et al, Hemasphere 2022;6:102-103). Objectives: To assess the clinical response and safety of Cami by subgroups based on demographics, known risk factors impacting outcomes in patients with R/R cHL, and factors with potential relevance to Cami's mechanism of action. Methods: This analysis was based on the open-label, multicenter, Phase 2 study of Cami monotherapy in patients with R/R cHL after ≥3 prior lines of therapy (NCT04052997). Cami was administered (30-minute infusion) on day 1 of each 3-week cycle at 45 µg/kg for 2 cycles, then 30 µg/kg for subsequent cycles. Subgroup analyses (data cutoff: March 16, 2022) were conducted (Table 1). Efficacy outcomes included the overall response rate (ORR) and median duration of response (mDOR); statistical significance was assessed by comparison of 95% confidence intervals. Safety was assessed by incidence of treatment emergent adverse events (TEAEs). Results: There were no significant differences in efficacy outcomes between demographic subgroups based on age or sex (Table 1). The ORR was similar for patients who were refractory or relapsed after 1L therapy (72.4% vs 72.2%). Despite the higher number of patients who were refractory after last line therapy versus those who relapsed, the ORR was not significantly different between the two groups (68.2% vs 78.4%). The response to Cami did not depend on the prior response to PD-1 inhibition or the time since the last PD-1 inhibitor use. The ORR was similar for patients who were refractory to PD-1 inhibition or relapsed (66.2% vs 75.8%) and for patients who were treated with Cami ≤4 months and >4 months since the last PD-1 inhibitor (69.0% vs 71.7%). No statistically significant differences in the ORR were observed based on the number of prior lines of therapy, prior HSCT, or region. However, the complete response rate (CRR) for patients who received prior HSCT was 41.9% vs 18.6% in patients without HSCT; the mDOR was 13.73 months in patients with prior HSCT vs 5.85 in patients without prior HSCT. Median DOR was similar between North American (NA) and European (EU) patients (13.77 months vs 13.73 months). However, NA patients had improved CRR vs EU patients (44.6% vs 23%), and differences were more pronounced in NA vs EU patients with prior HSCT (52.4% vs 28.1%). Cami's tolerability was similar across most subgroups. The safety profile of Cami was similar in older compared with younger patients, as indicated by similar incidences of TEAEs overall, grade ≥3 TEAEs, and groupings by system organ class. The incidence of any grade TEAEs was similar between NA and EU patients (100% vs 98.4%). Patients with prior HSCT had more grade ≥3 TEAEs vs those without prior HSCT (73% vs 58.1%). Conclusions: Evidence from preliminary subgroup analyses suggests that response to Cami was independent of age, sex, and response to and timing of last PD-1 inhibitor. Differences in Cami's safety and efficacy were noted by prior transplant and region. Although a difference in CRR was observed between NA and EU, this did not result in a difference in mDOR or ORR between the two regions. These preliminary analyses should be interpreted with caution as subgroups were small and limited in statistical comparison. Exploratory analyses to identify predictive markers of GBS/polyradiculopathy observed in Cami trials are ongoing and results will be also presented. These results suggest that Cami shows antitumor activity across patient subgroups, including heavily pretreated and older patients. Funding: ADC Therapeutics SA; medical writing: CiTRUS Health Group. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes with Panobinostat in Heavily Pretreated Multiple Myeloma Patients

Background: Multiple myeloma remains a largely incurable disease despite major advances in therapy. Panobinostat (pano) is an oral pan histone-deacetylase (HDAC) inhibitor which improves outcomes when added to bortezomib and dexamethasone for multiple myeloma in early relapse and even re-sensitizes myeloma to proteasome inhibitors. In 2021, the FDA withdrew pano from the US market but it is still utilized to this day in Europe. Notwithstanding, this drug remains a viable option for patients who have progressed beyond many of our standard therapies. Here, we report the use of pano-based combinations at an academic medical center in a heavily pretreated population. Methods: We retrospectively analyzed 105 patients who were treated with pano for multiple myeloma at The Mount Sinai Hospital between October 2012 and October 2021. We reviewed baseline demographics, treatment characteristics including the doses of pano used and the agents it was combined with, as well as safety, tolerability, and efficacy. The objective response rate (ORR) and clinical benefit rate (CBR) will be reported along with 95% exact confidence intervals (CI). The outcomes of duration of response (DOR), progression free survival (PFS), and overall survival (OS) will be estimated using the method of Kaplan-Meier. The confidence interval for the median DOR, PFS, and OS times will be constructed based on the method of Brookmeyer and Crowley. Results: In total, 105 patients were treated with pano of whom 56.8% were female with a median age of 65 (range 37-87). Patients were heavily pretreated with a median of 6 prior lines of therapy, with 70.5% of them having had prior transplants, and over half (53.3%) being triple class refractory. Fifty-four percent had high-risk cytogenetics. The 20 mg dose of pano was most commonly used (64.8%), followed by the 10 mg (22.9%) and 15 mg (11.4%) doses, and pano was generally used as part of a triplet (61.0%) or quadruplet (30.5%) combination. Pano was combined with steroids along with a 3rd and sometimes 4th drug, most commonly with lenalidomide, pomalidomide, carfilzomib, and daratumumab in descending order of utilization. The most common grade 3+ toxicities were hematologic, primarily neutropenia (34.3%), thrombocytopenia (27.6%), and anemia (19.1%), while the most common non-hematologic grade 3+ toxicity was fatigue in 15.2% of patients. Of the 101 response evaluable patients, ORR was 23.8% (95% CI 16.0%-33.1%) with a median DOR of 7.3 months (95% CI 3.7-15.7 months; range 0.4-20.9 months), while the CBR was 35.2% (95% CI 26.2%-45.2%). The patients had a median PFS of 3.3 months (95% CI 2.1-4.2 months) and OS of 19.1 months (95% CI 15.9-30.5 months). Conclusion: Pano-based combination therapies were well-tolerated and yielded modest response and clinical benefit rates in heavily pretreated patients. Over half of the patients in this cohort were triple class refractory. Immunomodulators (IMiDs) were most frequently combined with pano to attain these results, although, to date there are no randomized trials demonstrating benefit with these combinations. As a convenient oral option with a unique mechanism of action, pano may play an important role in recapturing responses in patients who have relapsed beyond standard therapies. The utility of pano in combination with IMiDs, in particular, warrants further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Anti-Leukemic Activity of STRO-002 a Novel Folate Receptor-α (FR-α)-Targeting ADC in Relapsed/Refractory CBF2AT3-GLIS2 AML

BACKGROUND: CBF2AT3-GLIS2 (CBF/GLIS) oncogenic fusion is the underlying genomic cause of "RAM" phenotype AML, a megakaryoblastic subtype exclusively seen in infants and young children. CBF/GLIS AML is a highly refractory and uniformly fatal subtype of AML with limited response to conventional chemotherapy. We have demonstrated that FR-α, a known target in ovarian cancer, is expressed in CBF/GLIS AML cells and this expression is causally linked to the fusion oncogene. STRO-002 is currently under clinical investigation for the treatment of relapsed/refractory ovarian and endometrial cancer (NCT03748186). Preclinical studies have tested and confirmed the potent in vitro and in vivo anti-leukemia activity of STRO-002 in CBF/GLIS AML cell lines and xenograft models (Le et al. ASH 2021). Based on these compelling preclinical pharmacology observations, Sutro Biopharma evaluated patients on a case-by-case basis for consideration of a single patient IND (compassionate use) program for pediatric patients with CBF/GLIS AML. METHODS: Key criteria for consideration of STRO-002 were CBF2AT3-GLIS2 oncogenic fusion and FR-α expression by flow cytometry in AML sample. Key exclusion criteria were co-existent acute/uncontrolled infection and compromised organ function (pulmonary, hepatic, renal, etc). Between August 2021 and July 2022, 16 patients received STRO-002. Median age at treatment was 2 years (range 6 months-7 years). Median number of prior therapies was 3 (range 1-8). Eight patients had relapsed after stem cell transplant (SCT) and the remaining 8 had primary refractory (induction failure) or relapsed AML. RESULTS: In the 16 patients treated, 10 received STRO-002 as monotherapy, and 6 received combination with chemotherapy (fludarabine/cytarabine, decitabine, methotrexate (MTX), or dasatinib). All 16 pts were evaluable for response, best observed response included 7 CRs with 6 MRD negative remissions. Of these CRs, 3 occurred after monotherapy and 4 with combination therapy: MTX/fludarabine/cytarabine (n = 1), decitabine/DLI (n = 1), fludarabine/cytarabine/G-CSF (n = 1) and dasatinib/DLI (n = 1). The remaining 9 patients had stable disease or transient decrease in disease burden. Of the 7 patients who achieved a CR, 4 proceeded to SCT, 2 are receiving DLI and 1 will receive consolidation therapy. Ten (63%) of the 16 evaluable patients are alive and the other 6 died of progressive disease. Follow-up is limited for the surviving patients. Of note were 6 patients who achieved an MRD negative CR, two with primary refractory disease, and four who had relapsed after an allogeneic SCT. These six patients with significant disease had deep response to STRO-002 with MRD negative remission. One patient had a rapid decline in marrow blasts and had no evidence of disease by flow after 3 single agent every other week (QOW) doses of STRO-002. A second patient had a similarly rapid response to single agent STRO-002 with clearance of all detectable disease after a second QOW dose of STRO-002. ANC for both patients one week after last dose of STRO-002 was >1000. These patients were consolidated with allogeneic stem cell transplant or with DLI. STRO-002 was generally well tolerated. Collection and review of treatment-emergent AEs (TEAEs) is ongoing. Treatment-related events ≥ grade 3 included neutrophil count decreased (n = 3), platelet count decreased (n = 3), anemia (n = 2), WBC decreased (n = 2), hyperbilirubinemia (n = 1), bacteremia (n = 1), febrile neutropenia (n = 1), urticaria (n = 1), generalized edema (n = 1), aspartate aminotransferase elevation (n = 1), alanine aminotransferase elevation (n = 1). CONCLUSIONS: STRO-002 has promising activity in relapsed/refractory CBF2AT3-GLIS2 AML, a disease that tends to be highly refractory to all standard-of-care (SOC) therapies. Further, STRO-002 is well tolerated as a monotherapy agent and in combination with SOC therapies. Patients with low tumor burden were more likely to achieve CR and transition to SCT, DLI and CAR-T. Deep molecular and flow cytometric remission was achieved in a cohort of patients. Patients with primary refractory disease (no prior transplant), 1-3 prior lines of therapy, low disease burden, or without extramedullary disease appeared to have a more potent response to STRO-002. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The CAR-Hematotox Score Identifies Patients at High Risk for Hematological Toxicity, Infections and Poor Clinical Outcomes Following Brexucabtagene Autoleucel in Relapsed/Refractory Mantle Cell Lymphoma

Background: Hematological toxicity and infectious complications drive the toxicity burden of CD19 CAR-T. We recently developed the CAR-HEMATOTOX (HT) score - a validated risk-stratification system of hematotoxicity, infections, and clinical outcomes in LBCL patients (Rejeski et al. Blood 2021/JITC 2022). The score integrates parameters associated with pre-CAR-T hematopoietic reserve (e.g. ANC, hemoglobin, platelet count) and inflammation (e.g. CRP, ferritin). Whether the HT score is of prognostic utility in relapsed/refractory mantle cell lymphoma (R/R MCL) remains unstudied. Methods: In this multicenter retrospective study, we characterized the influence of the HT score on toxicity and survival in 78 patients receiving standard-of-care brexucabtagene autoleucel (brexu-cel) across seven international sites. Patterns of hematopoietic recovery were defined as quick recovery vs. intermittent recovery vs. aplastic as previously described (Rejeski et al. Blood 2021). The duration of severe neutropenia was assessed as the total cumulative days with an ANC<500/µl between days 0-60. Early infection events (day 0-90) were defined as bacterial, viral or fungal based on microbiologic data or as a clinical syndrome of infection (e.g. pneumonia, cellulitis, cystitis) based on retrospective chart review. Severe (Grade ≥3) infections were defined as requiring intravenous anti-infectives and/or hospitalization. Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS) were compared using the log-rank test. Results: The study cohort comprised a representative cohort of R/R MCL patients treated in a real-world setting: median age was 68 (range 49-89), median ECOG PS was 1, median LDH was 217 U/L (interquartile range 171-289 U/L), and patients had received a median of 3 prior treatment lines (IQR 2-4). Of note, 28% of patients had received a prior autologous stem cell transplant (ASCT) and >90% were BTKi exposed. The rate of severe (grade ≥3) CRS and ICANS was 2.6% and 27%, respectively. Tocilizumab was applied in 82% of patients, while glucocorticoids were used in 64% of all cases. Across all patients, the median duration of severe neutropenia was 8 days (IQR 5-15). The distribution of neutrophil recovery phenotypes was: 30% quick, 46% intermittent, and 24% aplastic. The cumulative 90-day incidence of any-grade and severe infections was 37% and 17%, respectively. The median CAR-HEMATOTOX score was 1 (IQR 1-3), including 42 HTlow (Score 0-1) and 36 HThigh (Score ≥2) patients. When comparing risk groups, we noted higher serum LDH levels in HThigh patients(median 261 vs. 209 U/L, p=0.07).In terms of toxicity, the incidence of severe CRS and ICANS was comparable between both groups. However, the duration of neutropenia was significantly increased in HThigh patients compared to their HTlow counterparts (15 vs. 7 days, p<0.001). Moreover, the proportion of patients displaying an aplastic phenotype of neutrophil recovery, defined by continuous severe neutropenia ≥14 days, was markedly increased in the HThigh group (53 vs. 0%, p<0.0001, Fig. 1A). This translated into a higher rate of severe infectious complications in the HThighgroup (28% vs. 7%, p=0.03), including 3 life-threatening (all bacterial), and 2 fatal infections (1 bacterial, 1 fungal).Notably, a high HT score was associated with markedly inferior PFS (median 7.5 months vs. not-reached, p=0.0006, Fig. 1B) and OS (median 15.3 months vs. not-reached, p=0.0004). Comparing the HThigh vs. HTlow groups, we observed 1-year PFS of 73% vs. 38% and 1-year OS of 88% vs. 51%. Conclusions: Taken together, these findings underline the importance of pre-CAR-T bone marrow reserve and systemic inflammation in driving immunotoxicity after CD19 CAR-T therapy. Importantly, they validate the utility of the HT score to risk-stratify patients for hematotoxicity, severe infections and poor survival outcomes prior to brexu-cel infusion. The score can be used to aid clinical decision-making concerning anti-infective prophylaxis and early or prophylactic G-CSF use. Considering that ASCT represents a mainstay of frontline MCL therapy, the HT score may also guide the use of stem cell rescue (obtained at time of remission) for the patients developing severe CAR-T-related aplasia. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chimeric Antigen Receptor-T (CAR-T) Cell Therapy Targeting BCMA in Patients with Prior Allogeneic Transplantation (allo-HCT) in Relapsed and/or Refractory Multiple Myeloma (RRMM)

Chimeric Antigen Receptor-T (CAR-T) Cell Therapy Targeting BCMA in Patients with Prior Allogeneic Transplantation (allo-HCT) in Relapsed and/or Refractory Multiple Myeloma (RRMM)

Clinical Outcomes of CD19 CAR-T-Cell Therapy with Axi-Cel in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) with and without Prior Autologous Stem Cell Transplant

Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common form of aggressive non-Hodgkins lymphoma, accounting for up to 40% of cases. Long term remission is achieved in 50-60% of the patients with rituximab and anthracycline based treatment, but the remaining patients will have either primary refractory or relapsed disease. Prior to the advent of CAR-T-cell therapy, salvage chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) was the standard of care for these cases of relapsed or refractory (r/r) disease. For those who relapse post ASCT, options are limited and outcome was dismal. With the results of recent pivotal studies, CAR-T-cell therapy is now offered in patients who are not ASCT candidates and for those who relapse after ASCT. The phenotype of patients who proceed to CAR-T without ASCT is possibly different than those who are able to achieve a clinical response and then proceed to ASCT. While numerous trials have compared the clinical outcomes of ASCT and CAR-T, few have investigated outcomes of CAR-T in previously transplanted versus transplant naïve patients. Wang et al. demonstrated a potential benefit for sequential ASCT and CAR-T in 14 patients with r/r DLBCL, with a median PFS of 14.82 months. Our study compared the clinical outcomes of previously transplanted and transplant naïve patients with r/r DLBCL who received axi-cel (Yescarta) CD19 CAR-T therapy at our center between 2018-2021. Methods Data was collected on 99 patients who received first axi-cel CAR-T therapy at our center for r/r DLBCL between 2018-2021. Of these patients, 84 were transplant naïve and 15 had received prior ASCT. We examined the rate of relapse/progression after CAR-T. Overall survival (OS) was defined as time from date of CD19 CAR-T therapy to death, censored at last known alive. Progression-free survival (PFS) was defined as time from date of CD19 CAR-T therapy to time of disease recurrence or death from any cause, censored at last known alive. Non-relapsed mortality (NRM) was defined as death without relapse or progression. Results 63 patients (64%) were alive as of end of study date. Median follow-up time was 1.70 years (95% CI: 1.54-2.07) for all patients, 1.63 years (95% CI: 1.50-1.99) for transplant naïve patients, and 2.21 (95% CI: 1.09-not reached) for previously transplanted patients. 90-day disease response to CAR-T (CR, PR, SD and PD) was not different for transplant naïve vs. previously transplanted patients (P=0.444). Median OS was not reached for either transplant naïve or previously transplanted patients, with 2-year OS rates of 60% (95% CI: 50-73%) vs. 66% (95% CI: 43-100%) for previously transplanted patients (P=0.23). Median PFS was 0.51 years for transplant naïve patients and not reached for previously transplanted patients, with 2-year PFS rates of 44% (95% CI: 34-56%) for transplant naïve and 56% (95% CI: 33-92%) for previously transplanted patients (P=0.16). 2-year cumulative incidence of relapse or progression was 43% (95% CI: 33-54%) for transplant naïve and 33% (95% CI: 8-58%) for previously transplanted patients (P=0.43). 2-year NRM was 12% (95% CI: 5-20%) for transplant naïve and 11% (95% CI: 0-33%) for previously transplanted patients (P=0.44). In multivariate analysis, bridging therapy, elevated LDH >600 at the time of lymphodepleting chemo, and grade 3 and 4 CRS were associated with worse OS; platelets <75,000 at the time of lymphodepleting chemo, grade 3 and 4 CRS and elevated LDH >600 were associated with worse PFS. There was no difference in the incidence of high grade CRS and neurotoxicity, ICU transfer rate, cytopenias and length of hospitalization between the 2 groups. Conclusions This study showed no significantly significant differences in the OS, PFS, relapse/progression and NRM of r/r DLBCL patients who received CD19 CAR-T-cell therapy (axi-cel) with or without prior ASCT. Other factors such as bridging therapy, elevated LDH and high grade CRS were associated with worse OS. We conclude that prior ASCT does not appear to adversely affect the outcomes of CAR-T-cell therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Elranatamab, a BCMA Targeted T-Cell Engaging Bispecific Antibody, Induces Durable Clinical and Molecular Responses for Patients with Relapsed or Refractory Multiple Myeloma

Introduction: Multiple myeloma (MM) is a plasma cell dyscrasia characterized by expression of B-cell maturation antigen (BCMA). Elranatamab (PF-06863135), a bispecific antibody that targets BCMA and CD3 on T-cells, activates and redirects the T-cell mediated immune response against MM. This clinical trial, MagnetisMM-1 (NCT03269136), is the ongoing Phase 1 first-in-human study evaluating the safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of elranatamab for patients (pts) with relapsed or refractory MM. Methods: Elranatamab was administered subcutaneously (SC) at doses from 80 to 1000µg/kg either weekly or every 2 weeks. Treatment-emergent adverse events (TEAEs) were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (v4.03), whereas cytokine release syndrome (CRS) was assessed by criteria of the American Society for Transplantation and Cellular Therapy. PK, cytokines, lymphocyte subsets, and soluble BCMA were analyzed over time. Clinical response was assessed by criteria of the International Myeloma Working Group (IMWG). Minimal residual disease (MRD) was assessed by next generation sequencing at a sensitivity of 1×10-5 in accordance with IMWG criteria. Results: A total of 55 pts received single-agent elranatamab SC at a dose ≥215μg/kg as of 22-Jun-2022. Median age was 64 (range 42-80) years, and 27% of pts were Black/African American or Asian. Median number of prior regimens was 5 (range 2-14), 91% were triple-class refractory, 69% had prior stem cell transplantation, 29% had high cytogenetic risk, and 24% received prior BCMA-targeted therapy. The most common TEAEs regardless of causality included CRS, neutropenia, anemia, injection site reaction, and lymphopenia. With pre-medication and a single priming dose (600µg/kg or 44mg), the overall incidence of CRS at the recommended dose (1000µg/kg or 76mg) was 67% and limited to Grade 1 (33%) or Grade 2 (33%), with no events Grade 3 or higher. Elranatamab exposure was dose dependent. Cytokine increases occurred with the first dose and were reduced by pre-medication. Soluble BCMA decreased with disease response, elranatamab therapy was associated with increased peripheral T-cell proliferation, and median time to response was 36 days (range 7-262). With a median follow-up of 12.0 months (range 0.3-29.0) and including only IMWG confirmed responses, the objective response rate (ORR) was 64% (95% CI 50-75%) with 56% of pts (31/55) achieving very good partial response (VGPR) or better and 38% of pts (21/55) achieving complete response (CR) or better. Among 13 pts with prior BCMA-directed therapy (antibody drug conjugate, chimeric antigen receptor T-cell therapy, or both), 54% (7/13) achieved response including 46% (6/13) with VGPR or better. For responders (n=35), the probability of being event-free at 12 months was 59% (95% CI 39-74%) and the Kaplan-Meier estimate for median duration of response was 17.1 months (95% CI 10.6-NE). Single-agent elranatamab induced durable clinical and molecular responses, and 100% (12/12) of evaluable pts with confirmed CR or better achieved MRD negativity at a sensitivity of 1×10-5 including 2 pts with MRD negativity and ongoing stringent CR beyond 2 years. Conclusions: Elranatamab induced durable clinical and molecular responses for pts with relapsed or refractory MM. The ORR was 64% with more than half of these pts (38%) achieving CR or better, and 100% of evaluable pts achieved MRD negativity. Together with emerging data from pivotal studies MagnetisMM-3 (NCT0469359) and MagnetisMM-5 (NCT05020236), these results support further development of elranatamab for patients with MM.