Fonseca, Rafaël

AbstractBackgroundThe prognosis in patients with advanced cardiac amyloidosis (CA) remains poor.ObjectivesWe sought to describe survival post heart transplantation (HT) in amyloid compared with non‐amyloid recipients, highlight waitlist times within the new allocation system across three Organ Procurement and Transplantation Network (OPTN) regions, and describe multiorgan transplantation (MOT) in hereditary amyloidosis.MethodsThis is a retrospective review of end‐stage CA patients who underwent HT at Mayo Clinic from January 2007 to December 2020. Wait time was compared in the new versus old OPTN allocation era starting December 18, 2018 by Wilcoxon rank sum test. All‐cause mortality for those with and without CA was compared using Kaplan–Meier estimates with log rank analysis, censoring December 16, 2022.ResultsFifty‐five patients with CA underwent HT between 2007 and 2020, 8 light chain amyloidosis (AL) (14.5%), 28 hereditary transthyretin (ATTRv) (50.9%), 17 wildtype transthyretin (ATTRwt) (30.9%), and 2 hereditary apolipoprotein A1 (AApoA1) amyloidosis patients (3.6%). No significant difference in overall survival post‐transplant was seen in amyloid compared with non‐amyloid (p = 0.816). Median time to HT was shorter in the new system, 45 days (IQR 24, 78) versus 174 days (IQR 76.5, 483.5), p = 0.006. There was a decline in MOT in hereditary amyloidosis over time with the concomitant rise in disease‐targeted therapies.ConclusionsHT survival in CA patients was similar to non‐amyloid patients. The new allocation system benefits this cohort with shorter wait times. There is less MOT in hereditary amyloidosis with increased utilization of disease‐targeted therapy.

PURPOSE Teclistamab is initiated with a step-up dosing (SUD) schedule to mitigate the risk of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Early teclistamab users commonly received SUD in a hospital setting. This study aimed to evaluate safety and health care resource utilization (HRU) in real-world patients with multiple myeloma who initiated teclistamab SUD in an outpatient setting. METHODS This was a retrospective study using Mayo Clinic's electronic medical records from October 26, 2022, to October 31, 2023. Patient characteristics were summarized for all patients treated with teclistamab and separately for patients who started SUD outpatient. SUD pattern, safety, HRU, and post-SUD dosing schedule were described in patients with complete SUD. RESULTS At data cutoff, 65 patients received ≥1 teclistamab dose, including 58 patients who initiated SUD outpatient (median age, 69.2 years; male, 63.8%; White, 89.7%). Among 57 patients who completed SUD in an outpatient setting, all received premedications on the days of teclistamab administrations per label recommendation; 18 (31.6%) developed CRS (13 grade 1, four grade 2, and one grade 4) and two developed ICANS (one each with grade 2 and 4). All CRS and ICANS resolved with supportive care and all patients continued treatment. Eighteen patients were admitted to the hospital for CRS treatment, with a median CRS-related hospital stay of 2 days per admission. Most (60%) doses during SUD required <1 hour clinic time between administration and checkout. Post-SUD, clinic time for treatment doses decreased to <30 minutes for most doses (82%). CONCLUSION Outcomes of this study support outpatient administration as a safe and feasible option for teclistamab SUD to potentially reduce HRU and improve patient experiences.

Introduction Talquetamab (Tal) is a bispecific antibody therapy approved for patients with relapsed/refractory multiple myeloma (MM), targeting both GPRC5D x CD3 receptors. Clinical studies demonstrate that Tal creates deep and durable responses, but less is known about the patient experience. This study aimed to explore the experiences of patients from the patient and physician perspectives to help understand what to expect with this first-in-class novel therapy. Methods This qualitative study consisted of two components. First, patients with documented use of Tal were identified and recruited through the HealthTree Cure Hub. Individual patients then took part in 2-hour, semi-structured virtual interviews. Patients were asked to discuss their experiences 1-2 months prior to starting Tal and 4-5 months after beginning therapy. Patients discussed GPRC5D-related symptoms (including oral, skin-related, and nail-related symptoms), overall impact, and satisfaction. Participants were US adults diagnosed with MM who took Tal for at least 4 months, either in a clinical trial or commercial setting. Interviews were conducted February-April 2024. Second, patients and physicians gathered in a facilitated roundtable discussion to review findings and generate ideas for symptom management. The roundtable lasted 2.5 hours and took place in Chicago, IL in May 2024. Results Eight men and 4 women (n=12) aged 52-79 years participated in the interviews. Interviewed participants were mostly white (84%) and college-educated (84%). Seven (58%) received Tal in a clinical trial, and 9 were still receiving Tal. Roundtable participants included 3 patients (2 male, 1 female; all white and college educated), and 3 physicians with Tal experience. In the interviews, patients reported high overall satisfaction, with most (75%) rating their satisfaction an 8 or higher on a 10-point scale. Satisfaction was largely driven by the effectiveness of therapy, with all reporting clinical improvements in their MM disease. Patients reported improvements in their energy/strength and decreased fatigue. They also reported increased physical activities and ability to work, volunteer, or engage in hobbies. Physicians affirmed these findings as consistent with their observations and noted they are also very satisfied with Tal. Oral symptoms such as distorted taste/loss of taste and dry mouth were common with varying severity. Although all interviewees (n=12) reported taste symptoms (typically starting within the first month of therapy), five said their symptoms fully improved (3 after 1 year on treatment, and 2 after stopping treatment), and 4 experienced partial recovery. Ten lost weight, but most (92%) maintained adequate nutrition. Patients and physicians suggested coping strategies including diet modifications, use of strong flavors (e.g., spices, cinnamon), monitoring weight, prioritizing adequate calories, using mouthwashes/lozenges, drinking water while eating, taking small bites, and consuming foods that are easier to swallow. They also noted that it is important to educate patients on expected symptoms before starting the treatment. Skin- and nail-related symptoms were also common but less impactful on quality of life. All patients (n=12) experienced skin- and nail-related symptoms, but most considered these symptoms mild. Skin-related symptoms such as dry skin and skin exfoliation occurred once and typically lasted 1-2 months. Nail symptoms were primarily cosmetic, and the duration varied. Suggested management strategies include skin moisturizers, nail thickeners/hardeners, keeping nails short, and wearing protective gloves. Physicians noted it's helpful to reassure patients that nail loss is not harmful. Overall, GPRC5D-related symptoms were not treatment-limiting, and no patients had to miss a dose due to these symptoms. Patients perceived these symptoms as bearable but noted the treatment was effective at controlling the disease. Conclusions This study described patient experiences and reflected how patients perceive the benefit/risk profile of talquetamab. Symptoms were perceived as bearable and high satisfaction scores were driven by strong clinical effectiveness. Patients and physicians agreed that real-world feedback from patients, practical tips, and management strategies are vitally important for patients and physicians using this novel therapy.

Background: Venetoclax (Ven), a BCL2 inhibitor, has shown promising responses in multiple myeloma (MM) patients with t(11;14) and/or BCL2 expression. However, consistent benefit in clinical trials remain elusive. This report evaluates the efficacy and safety of Ven combination therapies, including in the non-t(11;14) subgroup, and examines the impact of secondary cytogenetic abnormalities (SGA) on outcomes. Methods: This retrospective study included multiple myeloma (MM) patients without concurrent AL amyloidosis treated with Ven-based combinations at Mayo Clinic sites from January 2015 to December 2023. FISH data was collected at diagnosis and before venetoclax initiation to assess SGAs. Refractoriness was defined by progression on or within 60 days of stopping treatment. Patients refractory to at least one proteasome inhibitor (PI), immunomodulatory drug (ImiD), and anti-CD38 antibody were considered triple-class refractory (TCR). Ven combinations were grouped as: Daratumumab/CD38 antibody (Dara)-Ven based if received Dara ± other drugs, PI-Ven-based without Dara, Ven-dexamethasone (Ven-d), and other combinations (Ven-Misc). BCL2 expression in patients without t(11;14) was determined by immunohistochemistry (IHC). Progression-free survival (PFS) was calculated from treatment initiation to disease progression or last follow-up. Results: We included 232 patients in this study. The median age at diagnosis of MM was 62 years (range 32-87), and the median age at initiation was 68 years (range 35-89). The median time from diagnosis of MM to initiation of Ven was 55 months (95% CI 28, 89 months), and the median follow-up from initiation of Ven-based treatment was 17.2 months (95% CI: 14, 22). Patients had received a median of 3 lines (IQR 4-6); 65% (n=152) of patients were TCR, 71% (n=163) had received autologous stem cell transplant and 7% (n=16) patients had received prior immune effector therapy prior to initiation of Ven-based therapy. The majority (83%, n=190) of the patients harbored a t(11;14); in the patients without t(11;14), a BCL2 expression by IHC was tested in 18 patients and positive in 17 patients. The most common Ven-based combinations included: Dara-Ven-d (19%, n=44), PI-Ven-d (30.2%, n=70), Ven-d (48.3%, n=112), Ven-misc (2.6%, n=6). The overall response rate for the entire cohort was 57% [64% for t(11;14) and 26% for non t(11;14), p&lt;0.0001]. The median PFS for the entire cohort was 9.5 months (95% CI 8.5,13), and the duration of response was 18 months (95% CI 15.2-23.3). The median PFS was 11.8 months (95% CI 9.5-16.7) for patients harboring a t(11;14) compared to 2.9 months (95% CI 1.8, 8.4) for patients without a t(11;14), p&lt;0.0001. Among the non-t(11;14) cohort with BCL2 expression, the median PFS was 1.8 months (95% CI: 1.2-4.2). Among the 190 patients with t(11;14), 18% (34/190) harbored deletion 17p and 32% (60/193) harbored a 1q gain/amplification (referred hereforth as 1q21+) at initiation of Ven-based therapy. In the cohort of patients with t(11;14), the presence of either del17p or 1q21+ (n=85/190) was associated with a significantly inferior PFS [median PFS 8.2 months (95% CI: 5.5,13)] vs. 15.1 months (95% CI: 11.6, 22), p=0.03. At the last follow-up,42 patients had ongoing treatment with ven-based combination. Most common reasons for discontinuation were progression (77% N=140), adverse effect (12%, n=22), patient/provider preference(9%, n=17); 2% (n=4) patients died without progression (3 infection, 1 unclear). The most commonly utilized maximum dose of venetoclax was 400 mg (42%); 15% (n=35) of patients required a dose reduction, and 23% (n=54) received a ramp-up. Tumor lysis syndrome was not noted in any patient. Infectious complications were noted in 23% (n=52). The estimated median OS from initiation of ven-based Rx was 34 months (95%CI 25-47). The estimated median OS for patients without a t(11;14) was 6.2 months (95% CI: 3.3-11.3) compared to 46 months (31.4-54.1), p&lt;0.0001. In the t(11;14) subgroup, the 18-month OS rate was 79% for patients without 1q21+/del17p vs. 50% for patients with a 1q21+/del17p (p=0.002). Conclusion: Venetoclax-based regimens represent an important treatment option for patients harboring a t(11;14). The PFS in patients with BCL2 expression without t(11;14) was poor suggesting lack of efficacy of venetoclax-based regimens for that subgroup. Presence of concurrent del17p and/or 1q21+ with t(11;14) portends an inferior PFS.

BACKGROUND ELRA is a humanized, BCMA/CD3 bispecific antibody. In the phase 2 registrational MagnetisMM-3 (MM-3) trial, SC ELRA given as 2 step-up priming doses (12 mg on day 1 and 32 mg on day 4 of cycle 1) followed by 76 mg QW in patients (pts) with RRMM naive to BCMA-directed therapy resulted in an ORR of 61.0%. With a median follow-up of 28.4 mos, the median DOR, PFS, and OS were not reached (NR; 2-year rate, 66.9%), 17.2, and 24.6 mos, respectively. Overall, 56.3% of pts had CRS (grade 2, 14.3%; no grade ≥3). Most events occurred after doses 1 (44.5%), 2 (20.2%), and 3 (5.9%); 0.8% (1 pt) had CRS with doses ≥4. Recurrent CRS occurred in 15.1% of pts. The phase 1/2 MagnetisMM-9 (MM-9; NCT05014412) study is examining an alternative priming regimen and longer dosing intervals of ELRA. Here, we present updated MM-9 results. METHODS In MM-9, pts with RRMM and disease refractory to ≥1 IMiD drug, ≥1 PI, and ≥1 anti-CD38 antibody were given SC ELRA as step-up priming doses of 4 and 20 mg on Day 1 and Day 4 of Cycle 1, respectively. After the priming doses, ELRA 76 mg was given QW for the next 6 cycles (Part 1) or for 1 cycle followed by 116 (dose level 1 [DL1]) or 152 (dose level 2 [DL2]) mg Q2W for the next 5 cycles (Part 2A). After 6 cycles, the dosing frequency was decreased from QW to Q2W (Part 1) or from Q2W to Q4W (Part 2) in pts who achieved ≥PR lasting ≥2 months. The recommended phase 2 dose from Part 2A (152 mg, DL2) was evaluated in Part 2B (dose expansion). The primary endpoint for both parts is grade ≥2 CRS rate per ASTCT criteria during Cycle 1. Secondary endpoints include evaluation of efficacy and adverse events. Data cutoff: February 13, 2024. RESULTS Overall, 85 pts (median age, 64.0 y) were treated with ELRA. The majority (72.9%) of pts had R-ISS stage I/II disease (23.5% with R-ISS stage III); 31.8% had high-risk cytogenetics. Median number of prior lines of therapy was 5.0 (range, 1-12). The median treatment duration was 8.6, 2.9, 1.4, and 3.3 mos, in Part 1, Part 2A DL1, Part 2A DL2, and Part 2B, respectively. Median follow-up for pts overall (n=85), in Part 1 (n=33), Part 2A DL1 (n=12), Part 2A DL2 (n=11), and Part 2B (n=29) was 10.4, 23.3, 16.5, 15.2, and 9.3 mos, respectively. Overall, the ORR was 58.8%. For pts in Part 1, Part 2A DL1, Part 2A DL2, or Part 2B, ORR was 66.7%, 58.3%, 36.4%, and 58.6%, respectively; median DOR was NR (9-mo rate: 86.4%), 10.8 mos (9-mo rate: 80.0%), NR (9-mo rate: 100.0%), and NR (9-mo rate: 84.8%); median PFS was 17.1 (9-mo rate: 62.8%), 11.6 (9-mo rate: 50.9%), 1.6 mos (9-mo rate: 40.0%), and NR (9-mo rate: 57.1%); median OS was NR (9-mo rate: 75.8%), 17.4 mos (9-mo rate: 66.7%), NR (9-mo rate: 60.0%), and NR (9-mo rate: 72.4%), respectively. For pts in Part 1, Part 2A DL1, Part 2A DL2, and Part 2B, grade ≥2 CRS rates during Cycle 1 were 15.2%, 16.7%, 27.3%, and 6.9%, respectively. For pts in Part 1, Part 2A DL1, Part 2A DL2, and Part 2B, CRS rates were 30.3%, 33.3%, 36.4%, and 24.1% after dose 1, 27.3%, 25.0%, 36.4%, and 24.1% after dose 2, 15.2%, 33.3%, 27.3%, and 20.7% after dose 3, 6.1%, 8.3%, 0%, and 3.4% after dose 4, and 6.1%, 16.7%, 9.1%, and 0% after doses ≥5. Recurrent CRS occurred in 18.2%, 33.3%, 18.2%, and 17.2% of pts in Part 1, Part 2A DL1, Part 2A DL2, and Part 2B. The most common (&gt;60%) TEAEs (any grade/grade ≥3) were hematologic TEAEs (Part 1, 75.8%/75.8%; Part 2A DL1, 83.3%/83.3%; Part 2A DL2, 81.8%/81.8%; Part 2B, 79.3%/69.0%), infections (Part 1, 78.8%/48.5%; Part 2A DL1, 83.3%/66.7%; Part 2A DL2, 72.7%/63.6%; Part 2B, 62.1%/37.9%), and CRS (Part 1, 60.6%/0%; Part 2A DL1, 83.3%/0%; Part 2A DL2, 90.9%/9.1%; Part 2B, 48.3%/0%). Grade 5 TEAEs not including PD were infection (n=4), fall (n=1), subdural hematoma (n=1), and food poisoning (n=1). CONCLUSIONS The 4/20 mg step-up priming regimen and alternative dosing schedules in MM-9 resulted in similar efficacy vs the step-up regimen used in the registrational MM-3 study (12/32 mg). Responses were durable with encouraging PFS and OS with the alternative step up and longer dosing schedule. While the overall safety signals with the alternative step up regimen are similar to those seen with MM-3, the CRS profile differed with more CRS events after each subsequent dose and a higher prevalence of recurrent CRS. Thus, the optimal ELRA step-up regimen remains 12/32 mg from the original regimen in the MM-3 study. In addition, these early results suggest that reducing the dose frequency of ELRA may not compromise efficacy.

Introduction: With improving overall survival among MM patients, there is an increasing need to both understand the absolute risk and identify risk factors for developing a second primary malignancy (SPM). Understanding these risk and potential modulation factors may help guide decisions regarding treatment options, monitoring surveillance strategies, and patient counselling. Furthermore, understanding this baseline SPM risk will help contextualize the future SPM risk associated with newer therapeutics, including chimeric antigen receptor therapies. Thus, we conducted a population-based study with following objectives: 1) to evaluate the rate and distribution of SPMs, and 2) to identify risk factors including a history of prior malignancy associated with an increased risk of SPMs in patients with MM. Methods: We conducted a retrospective population-based study using data from Institute for Clinical Evaluative Sciences (ICES), an administrative database that captures all health records in the publicly funded health care system in Ontario, Canada. Adult patients treated for newly diagnosed MM between 2007-2022 were identified using ICD-O-3 code 9732/3 (MM). The list of secondary cancers (excluding non-melanoma skin cancers) were identified from pathology codes maintained in the Cancer Care Ontario Registry. Additional risk factors were also collected including a history and type of any pre-existing cancer (at least 1 year prior to MM diagnosis), treatment details including history of autologous stem cell transplantation (ASCT) and lenalidomide usage. The Kaplan-Meier method was used to estimate the median overall survival (OS). We estimated the cumulative incidence of secondary cancer accounting for death as a competing risk. To identify the association of prognostic factors on the risk of developing a SPM, we performed competing risks regression and estimated the subdistribution hazard ratios (sHR) accounting for death as a competing risk. Results: A total of 12123 patients . The median age at diagnosis was 70 (IQR 61-77) years, 6860 (57%) of our cohort had a male sex. In our 4511 (37%) received at least one ASCT, 8062 (67%) were lenalidomide exposed and 6917 (57%) were cyclophosphamide exposed at any time post MM diagnosis, and 3017 (16%) received oral melphalan based induction regimens. The median follow up for cohort was 4.53 (95% CI 4.4-4.7) years. A total of 2079 patients (17%) had a prior cancer diagnosis at least 1 year prior to their MM diagnosis. Of these patients, 665 (32%) had received chemotherapy and 553 (27%) had received radiation to treat their prior malignancy. The three most common prior cancers were: prostate cancer (25%), breast cancer (13%) and heme malignancies (4%).The median time from diagnosis of a prior malignancy to MM diagnosis was 6.4 (IQR 2.04-13.26) years. A total of 1070 (8.8%) of the cohort developed a SPM. The cumulative incidence of SPM post MM diagnosis, accounting for death as a competing risk, was 3.7% at 2 years, 7.6% at 5 years, and 11.5% at 10 years. The three most common SPMs were hematologic (21%), prostate (7%), and lung (7%) cancer. The three most common hematological SPMs were acute myeloid leukemia (37%), B-acute lymphoblastic leukemia (16%), and myelodysplastic syndrome (19%). The median OS following after any SPM diagnosis was 1.64 (95% CI 1.36-1.92) years, was 1.85 (95% CI 1.54-2.28) years for patients that developed a non-hematologic SPM, and was 1.05 (95% CI 0.88-1.40) years for patients that developed a hematologic SPM. Conclusion: This study represents one of the largest real-world cohort studies examining the rates, risk factor and outcomes of MM patients developing secondary cancers. We show that a prior malignancy diagnosis increased the risk of SPM after adjusting for ASCT and lenalidomide exposure, sex, and age at MM diagnosis. These data are important for patients and physicians to understand the risks associated with treatment of MM.

Introduction: Although not formally approved for the treatment of multiple myeloma (MM), the BCL2 inhibitor venetoclax (ven) has shown promising activity in patients (pts) with MM whose disease harbors t(11;14). The randomized BELLINI trial (VenVd vs Vd in unselected MM pts, Kumar Lancet Oncol 2020) demonstrated improved PFS, especially in the 35 patients with t(11;14) [HR 0.11], although worse OS in the intention to treat population due to increased treatment related mortality. The subsequent CANOVA trial (Vendex vs Pomdex in MM pts with t(11;14), Mateos IMS 2023) failed to show a PFS benefit (median PFS 9.9 mo vs 5.8 mo, p=0.237), leaving an uncertain future for ven in myeloma, despite the biological rationale and clinical activity. We therefore analyzed real world physician practice patterns using off-label ven for MM in the US. Methods: This retrospective observational study used data from the US nationwide Flatiron Health electronic health record (EHR)-derived de-identified longitudinal database. The Flatiron Health database contains structured and unstructured data curated via technology-enabled abstraction from approx. 280 cancer clinics and 800 unique sites of care. We included all patients in the Flatiron Health database with multiple myeloma (ICD-9 203.0x or ICD-10 C90.0x, confirmed with clinical review) who had received ven as part of any line of MM treatment. This included patients who commenced ven between 2016-2024. The primary endpoint was time to next treatment or death (TTNT) from ven initiation, with overall survival (OS) from ven initiation as the key secondary endpoint, both of which were estimated using the Kaplan-Meier method. Outcomes were compared using Cox proportional hazards model, using R v 4.3.0. Results: We included 208 patients who received ven for MM. They had a median of three prior lines of therapy (range 0-12), a median age of 67 years (Range 34-85 yrs), and 59% were male. Race/ethnicity breakdown was: Non-Hispanic White: 136 pts (72.7%), Black 36 (19.3%), Hispanic 10 (5.3%), Asian 5 (2.7%), other/unknown 21 (10.1%). Most had commercial insurance (188 pts, 91.3%) and 108 pts (52%) were cared for in academic settings while 100 (48%) were in community settings. ECOG performance status was 0 in 50 pts (24%), 1 in 80 pts (38.5%), ≥2 in 31 pts (14.9%) and unknown in 47 (22.6%). ISS Stage was I in 42 pts (20.2%), II in 43 pts (20.7%), III in 52 pts (25.0%) and unknown in 71 (34.1%). 148 pts had t(11;14) (71.2%), while 25 pts did not (12%) and 35 pts had unknown t(11;14) status (16.8%). Most pts received ven as part of a triplet combination (106 pts, 51%), followed by doublets (39, 18.8%; 21 ven+dex and 18 ven+non-dex doublet), quads (38, 18.3%), as a single agent (17, 8.2%) or in other combinations such as with multi-agent cytotoxic chemotherapy or in addition to quadruplet therapy (8, 3.9%). Most common first ven-containing regimens used were VenDd (34 pts), VenKd (31), VenVd (25), Vendex (21), VenDVd (13), VenDKd (7). Ven was used as part of ≥2 different regimens in 20 patients, in 10 of whom those regimens were non-consecutive. Median TTNT was 10.2 months (mo) in all comers, 12 mo in pts with t(11;14), 3.4 mo in pts without t(11;14) and 7.6 mo in pts with unknown t(11;14) status. Median OS was 27.6 mo in all comers, 30.5 mo in pts with t(11;14), 8.1 mo in pts without t(11;14) and 27.9 mo in pts with unknown t(11;14) status. Pts with t(11;14) receiving ven had a significantly longer TTNT than those without t(11;14) [median 12 mo vs 3.4 mo, HR 0.59, 95%CI 0.42-0.84, p=0.003]. and a significantly longer OS [median 30.5 mo vs 8.1 mo, HR 0.58, 95% CI 0.38 - 0.89, p=0.012]. Discussion: We evaluated US ven prescribing patterns in 208 pts with MM in the largest real world study of ven in MM to date. While it was mostly used in pts with t(11;14) (71%), there was occasional use in pts without t(11;14), and it was used in a wide variety of combination regimens. Ven achieved meaningful TTNT in some patients and both TTNT and OS were greater in pts with t(11;14) than those without. This suggest that despite mixed data from clinical trials, clinicians are using ven for MM patients in practice and further data is required to optimize its use and understand its best combination treatment partners in MM.

Introduction: CARTITUDE-4 is a phase 3 randomized controlled trial (RCT) assessing the efficacy and safety of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in patients with relapsed and refractory multiple myeloma (RRMM) with one to three prior line(s) of therapy that included an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI), and who are refractory to lenalidomide. Based on the latest reported results from CARTITUDE-4, cilta-cel demonstrated superiority over PVd and DPd on progression-free survival (PFS), overall survival (OS) and response rates (overall response rate [ORR], very good partial response [VGPR] or better, and complete response [CR] or better [CR or better]). In 2023, an initial analysis was performed to compare the efficacy outcomes between all apheresed patients from the cilta-cel arm in CARTITUDE-4 vs doublet (Pd and Kd) and daratumumab-based triplet (DKd and DVd) therapy regimens in the same target population using available patient level data. Data from an updated prespecified data-cut of CARTITUDE-4 with median follow-up of 34 months became available, allowing for an updated assessment of the comparative efficacy, including OS, between cilta-cel and these treatment regimens. Methods: Individual patient data were collected from the CARTITUDE-4 (cilta-cel), CASTOR (DVd), CANDOR (DKd and Kd), and APOLLO (Pd) RCTs, from which patients who met CARTITUDE-4 eligibility criteria were identified. As no patients in the comparative trials had prior treatment with anti-CD38, patients with prior exposure to anti-CD38 therapies in the cilta-cel cohort were excluded. Key prognostic baseline covariates including refractory status, ISS stage, presence of extramedullary disease (EMD), and time to progression on prior line, were adjusted for using inverse probability of treatment weighting (IPTW), with average treatment effect in the treated weights. Differences in baseline characteristics were assessed using standardized mean differences. PFS, OS and response rates (ORR, ≥VGPR and ≥CR) were compared between cilta-cel versus the comparator regimens. Relative efficacy for PFS and OS was estimated with Hazard ratios (HRs) and 95% confidence intervals (CIs) using weighted Cox proportional hazards regression. Response endpoints were analyzed using weighted logistic regression estimating response rate ratios (RRs) and 95% CIs. Sensitivity analyses using alternative statistical approaches and including additional covariates were explored. Results: After the exclusion of 53 patients with prior exposure to an anti-CD38 therapy, 155 patients in the cilta-cel arm remained, and were compared to patients treated with DVd (n=44), DKd (n=98), Kd (n=46) and Pd (n=92) who met the CARTITUDE-4 inclusion criteria. Baseline covariates were well balanced across the cohorts after IPTW. Patients from the cilta-cel arm showed significant improvements in PFS versus all comparators, with adjusted HRs ranging from 0.21 vs DVd to 0.58 vs DKd (all p ≤0.01). Also, OS was significantly longer for cilta-cel versus all other regimens, with adjusted HRs ranging between 0.31 vs Pd to 0.55 vs DKd (all p ≤0.05). While comparative estimates for ORR and VGPR did not change versus the previously reported results, the relative benefit for cilta-cel versus other regimens further increased on deeper levels of response, with adjusted RR for ≥CR from 2.71 vs DKd to 31.47 vs Pd (all p≤0.001). Treatment with DKd consistently yielded the best results out of all comparator regimens but results were still significantly in favor of cilta-cel. Results of cilta-cel benefit were generally consistent across sensitivity analyses. Conclusions: Results from this updated analysis confirm the previously observed significant superiority of PFS and response outcomes of cilta-cel, whilst showing significant OS benefit compared to commonly used treatment regimens for this patient population. These findings provide valuable information to support cilta-cel as a highly effective treatment for RRMM patients who received 1-3 prior lines of therapy, including a PI and IMiD, and who are refractory to lenalidomide, particularly in countries where standard of care may be different from DPd/PVd.

Introduction The major primary genetic events in multiple myeloma (MM) include translocations of immunoglobulin heavy chain (IgH) and a hyperdiploidy (HRD) karyotype (Kuehl, 2002). The main drivers of pathogenesis in HRD MM are unknown (Fonseca, 2003), therefore further research is needed in this subgroup. Translational research in HRD MM has relied on analysis of genomic and transcriptomic alterations, however changes at the genome and transcriptome level do not always correlate directionally with protein abundance. Because proteins are considered the main and final effectors of most cellular processes, proteogenomics can improve our understanding of the drivers of HRD MM. We employed it here to identify potential biomarkers in HRD MM and determine whether any given trisomy may lead to a selective advantage. Methods: Protein and mRNA were extracted from CD138+ cells from 47 HRD MM and 14 t(11;14) MM samples. RNA-seq data was processed using MAPR-Seq pipeline using default parameters and gene-wise raw counts were extracted for each sample. Proteomics data was processed using Specranaut and protein-wise intensities were extracted for each sample. A generalized linear model configured with negative binomial distribution was used to analyze gene-wise count data in edgeR software. Genes with an adjusted p-value of &lt;=0.05 were considered significantly differentially expressed. Protein intensity data were normalized using trimmed mean of M-values and log2 transformed. A generalized linear model configured with Gaussian distribution was used to compare protein intensities between the groups. Proteins with an adjusted p-value &lt;= 0.05 were considered significantly differentially expressed. Two separate rank lists for protein and mRNA data were generated for pathway analysis. Results When comparing our small cohort of HRD MM patient samples to those with t(11;14) MM, out of approximately 16,600 total transcripts and 9,700 proteins evaluated we identified approximately 2,100 significantly variant transcripts and 500 significantly variant proteins in HRD MM. GSEA pathway analysis of the transcriptome and proteome revealed significantly upregulated translational and ribosomal processing pathways in HRD MM. Transcriptional MYC target pathways were also significantly upregulated. RNAseq revealed significantly higher expression of MYC (Rank 24.5, p=5.3E-6) in HRD MM. It is known that patients with t(11;14) MM have increased expression of CCND1 (Kuehl and Bergsagel, 2012). As expected, we found that the HRD MM subgroup had significantly lower expression of CCND1 compared to the t(11;14) MM subgroup (Rank -79.9, p=2.8E-21) and this was also true at the protein level (Rank -21.7, p=2.2E-5). The most significantly abundant protein in the HRD MM subgroup compared to t(11;14) MM was BAHD1, which is a protein that targets H3K27me3 and recruits transcriptional co-repressors (Fan, 2020). BAHD1 has been shown to repress erythroid genes and may recruit HDAC5, which plays a role in osteoblast differentiation (Rank 72.3, p=2.9E-20; Xu, 2021). The second most abundant protein in HRD MM was CKS2, which binds to the catalytic subunit of cyclin-dependent kinases (CDKs) and therefore positively regulates cell proliferation, invasion, and migration and has been shown to be implicated in tumor progression in several solid tumors (Rank 72.3, p=2.9E-20; You, 2015). TRIM proteins promote tumorigenesis and cancer development. TRIM14 mediates cancer development through mediating the JAK/STAT, PI3K/AKT, NFkB, and p53 pathways and was found to be significantly higher in HRD MM (Rank 70.6, p=9.0E-20; Huang, 2022). We also found increased protein abundance of LAMP5 in HRD MM (Rank 20.1, p=6.0E-5). LAMP5 may play an important role in MM progression and has been shown to be highly expressed in patients with mixed-lineage leukemia and is associated with a poor prognosis (Wang, 2023; Gracia-Maldonado, 2022). We identified many proteins (not all discussed here) that have not been well described in HRD MM and thus may be biomarkers/targets of disease pathogenesis of this subgroup. Conclusion Proteins are the final effectors of most cellular processes. Proteogenomics can improve our understanding of the drivers of HRD MM. Using a proteogenomic approach we identified proteins that may lead to selective advantage and/or pathogenesis of trisomies in HRD MM.

Introduction The tumor ecosystem in multiple myeloma (MM) involves complex interactions among various cell types, including clonal plasma cells (PCs) and immune cells. Previous research has indicated that the bone marrow (BM) microenvironment's metabolite and lipid profiles differ between MM patients and those with precursor conditions. This study aims to explore if differences in cell composition, metabolic phenotype of clonal PCs, and the spatial organization of various cell types are linked to the early versus late progression of high-risk smoldering MM (SMM) to MM. Methods We identified high-risk SMM patients using the IMWG 20-2-20 criteria, focusing on early progressors (EP), who progressed to MM within one year, and later progressors (LP), who progressed after more than four years. Using a high-dimensional single-cell spatial imaging platform, CODEX (CO-Detection by indEXing), we identified clonal PCs and immune cell types as well as their metabolic phenotypes at the single-cell level, in paired FFPE BM samples at SMM diagnosis and at the time of progression to MM. Our validated panel included markers such as CD3e, CD4, CD8, CD14, CD20, CD31, CD38, CD45, CD66a, CD68, CD138, HLA-DR, ASCT2, pNRF2, GLUT1, LDHA, ATPA5, CPT1A, and Citrate synthase. We employed single-cell segmentation, artifact cleanup, signal thresholding, and spatial analysis. Repeated measure models accommodated multiple regions of interest (ROIs) per patient and accounted for potential intrapatient correlation, while Poisson models estimated incidence rate ratios (RR) of cell types. Spatial statistical models evaluated cell type segregation and integration at the time of SMM diagnosis. Results Single cell events were acquired from 6 unique SMM patients who had paired FFPE BM samples from the time of their SMM diagnosis and at the time of their progression to MM. There were 3 EP SMM patients (Time to Progression (TTP):8, 8, 10 mos) and 3 LP SMM patients (TTP: 51, 58, 117 mos). The median number of single cell events identified per patient slide sample was 104,390 (Range: 24,357 - 314,877). We identified 8 main cell types: PCs, CD4+ T-cells, CD8+ T-cells, B-cells, granulocytes, Monocyte/Macrophages and two groups of other immune cells. The PCs and the remainder of the non-PCs were further classified based on the expression of the following metabolic markers: ASCT2 (Glutamine importer), CPT1A (Fatty acid metabolism), GLUT1 (Glucose importer), LDHA (Glycolysis), Citrate synthase and ATPA5 (Oxidative Phosphorylation). There was a higher RR of granulocytes (RR 2.1, CI 1.6-2.8, p&lt;0.001) in EP compared to LP samples at the time of SMM diagnosis, but a lower RR of CD4 T cells (RR 0.40, CI 0.3-0.6, p&lt; 0.001). Focusing on metabolic phenotypes of the PCs, we observed higher incidence RR of most metabolic markers: ASCT2 (RR=1.77; p=0.032), ATPA5 (RR=1.25; p&lt;0.001), CPT1a (RR=2.42; p=0.015), and LDHA (RR 2.13; p&lt;0.001) in EP compared to LP samples at the time of SMM diagnosis. However, GLUT1 had a lower incidence RR in EP patients (RR=0.79; p&lt;0.001). The same modeling for non-PCs at the time of SMM diagnosis yielded higher expression of LDHA (RR=1.98; p&lt;0.001) and ASCT2 (RR=3.3; p=0.002). Using the x and y coordinates and the corresponding phenotype classifications, we performed spatial statistical modeling based on spatial point processes to generate aggregated measures of how different types of cells of interest interacted. CD4 T cells were more isolated in LPs compared to EPs (p =0.046). Segregation indices for PCs and CD4 T cells indicated that they were more integrated/collocated in EPs. Granulocytes were more isolated in EPs although the difference was not as pronounced (p= 0.07). PCs were more integrated with granulocytes (p=0.06) and B cells (p=0.07) in LP patients. Further analyses of paired samples at the time of progression to MM will be reported at the time of the presentation. Conclusion This study is the first to provide whole-slide, single-cell, spatial proteomic characterization of clonal PCs and immune cells in the FFPE BMs of high-risk SMM patients with varying progression times to MM. Distinct metabolic pathway markers in clonal PCs and their spatial relationships with immune cell subsets are closely associated with the risk of progression to MM. These findings illuminate the complex interactions between the metabolic states of clonal PCs and their spatial orientation relative to immune cells in the pathogenesis of MM.