Kastritis, Efstathios

Introduction: Talquetamab (Talq) is a GPRC5D targeting bispecific antibody recently approved for the treatment of relapsed refractory multiple myeloma (MM) based on the MonumenTAL-1 study. Real World Evidence (RWE) is needed to understand the safety and efficacy of Talq in patients treated outside of a clinical trial as they may have different outcomes and toxicities. Here we report outcomes of 118 patients treated with Talq. Methods: Patients treated with standard-of-care Talq were included. Data was collected through a retrospective chart review from 01/2023 until 7/2024 from 7 International Myeloma Foundation (IMF) associated MM academic centers. Results: 118 patients were included in the analysis. The median age was 64, 37% had HR disease, 22% had EMD at presentation. The median LOT was 6, median number of immunotherapies before TAL was 2 (range 1,4) and 71% received prior BCMA therapy. 72% were triple refractory and 44% were penta refractory. 25% (n=60) would not have been eligible for TAL clinical trial due to exclusion criteria and15% had an ECOG of 2 or greater. 18% (n=97) received TAL as an outpatient and the median number of hospital days was 9 (0,37) for inpatients. CRS during Step up Dose (SUD) 1 was present in 30% Gr 1 (57%), Gr2 (11%), Gr 3 (6%), CRS during SUD 2 was present in 31%, Gr 1 (65%), Gr 2 (11%), CRS during SUD 3 when administered was present in 14% , Gr 1 (82%), Gr 2 (6%) and with first full dose was 12% , Gr 1 (71%), unknown (29%). ICANS occurred in 6% (7/97), Gr 1 (14%), Gr 2 (29%), Gr 3 (14%) and unknown in 43% there was no evidence of HLH. Skin toxicity was present in 62% of patients (n=105/118) with 4% needing dose interruptions and presented as rash (20%), dryness (42%) and itching (20%). Nail toxicity was present in 20% (n=65/118), with 9% needing dose interruptions. Dysgeusia was present in 51% (n=97/118), with 10% needing dose interruptions. Oral toxicity manifest as stomatitis (10%), glossitis (1%), ulcerations (2%), dry mouth (27%), was present in 34% (n=61/118), with 12.5% needing dose interruptions. Infections were present in 34% (n=82/118) and CMV reactivation in 23% while only 1 patient needed treatment for CMV. The Overall Response Rate (ORR) was 64.9% with a VGPR rate or higher of 43.3% in this population. Updated efficacy data including PFS will be reported at the time of presentation Conclusions: This is the first largest RWE of the safety and efficacy of Talq in a heavily pretreated population with a high prior BCMA exposure. The ORR is consistent with a prior study by Jakubowiak et al which showed an ORR OF 65.7% after prior T cell engagers. The safety profile - CRS, ICANS, skin and oral toxicities was similar to the MonumenTAL study, CMV reactivation was higher and this may be related to treatment with prior immunotherapies and should be monitored in the future. This report shows that Talq has a similar safety and efficacy profile in the real world when sequenced after prior BCMA therapies.

Introduction: Acute kidney injury (AKI) due to cast nephropathy is a medical emergency that leads to a diagnosis of myeloma in less than 3% of cases, but up to 30% of patients develop kidney impairment during the course of their disease. Currently, studies aiming to identify parameters that correlate with kidney function recovery and response to myeloma are limited due to small sample size or single center reports. We have therefore initiated an international collaboration and collected a large number patients (pts) from 16 participating centers. Objectives: To assess the impact of pts and disease characteristics and treatment-specific factors on renal outcome and overall survival and to validate the IMWG criteria for renal response in pts with cast nephropathy and newly diagnosed MM. Patients and Methods: Three-hundred forty-three pts (median age: 65.5 range 35-93 yrs) with newly diagnosed MM and an eGFR <40ml/min/1.73m2 have been selected from 704 pts that had been enrolled in the database hosted by RedCap. Eligibility criteria were a diagnosis of AKI due to cast nephropathy diagnosed either by kidney biopsy (n=119) or on clinical criteria (AKI in the setting of involved free light chain concentration of ≥500 mg/L), newly diagnosed multiple myeloma, >2 cycles of therapy, time and type of therapy, best eGFR and best myeloma response available. Results: Median follow up was 36.9 months. Myeloma therapy resulted in renal CR, and PR as defined by the IMWG criteria in 131 (38.2%) and 57 (16.6%) pts, respectively, 54 (15.7%) and 82 (23.9%) pts had minor response or no response, respectively. Nineteen (5.5%) pts were not classifiable by the IMWG response criteria (pts with eGFR 15-<30, with increase to eGFR to ≥30-<40). An eGFR of >60, ≥30-<60, ≥15-<30, and <15ml/min was achieved by 131 (38.2%), 112 (32.7%), 67 (19.5%), and 33 (9.6%) pts respectively. Myeloma response (≥VGPR) correlated significantly with renal response (≥PRrenal) (OR 1.64, CI 1.05-2.56, p=0.03) and with OS compared to no myeloma response (median 89.7 vs. 39.7 months, HR 2.12, CI 1.55-2.89, p<0.0001). A >50% reduction in FLCs from baseline to treatment cycle 2 (OR 5.92, CI 2.15-19.23, p=0.001) and cycle 3 (OR 5.25, CI 2.15-19.25, p=0.006) were strongly associated with renal response Median OS was 69.6 months (CI 55.4-89.7). Forty-three pts died within the first 12 months of treatment and additional 146 during further FU. Pts with a best GFR of >15ml/min had a significantly longer OS compared to those with GFR <15ml/min (median: 77.9 vs 31.9 months, HR 1.85, CI 1.16-2.94, p=0.01). The comparison of survival of pts with different renal response groups and with the best eGFR showed no statistically significant difference (log rank p=0.1, long rank p=0.057, respectively). Other factors that correlated with longer OS were bortezomib-based therapy (77.9 vs. 44.0 months, HR 1.59, CI 1.05-2.38, p=0.03), M-protein isotype with κ as compared to l light chain type (84.9 vs. 51.4 months, HR 1.47, CI 1.09-2.00, p=0.013), and higher hemoglobin (HR 1.16, CI 1.06-1.26, p=0.001). In contrast, hypercalcemia which was noted in 101 (29.4%) pts (HR 1.10, CI 1.03-1.18, p=0.005), ISS stage III vs. I-II (57.8 vs. 126.2 months, HR 2.26, CI 1.22-4.17, p=0.009), and ECOG status 3+4 vs. 2 vs. 0+1 (24.4 vs. 44.6 vs. 103 months, HR 2.83, CI 2.15-3.74, p<0.0001) were associated with shorter OS. Hypercalcemia, correlated with renal response (OR 1.27, CI 1.12-1.44, p=0.0002), and best eGFR ≥46.4 ml/min (median dichotomized) (OR 1.28, CI 1.14-1.46, p<0.0001). 119 (34.7%) pts required initial dialysis, OS was significantly longer in those who achieved best eGFR levels of >15ml/min. (77.6 vs 31.9 months, HR 0.54, CI 0.34-0.86, p=0.01); 64 (53%) pts discontinued dialysis. Conclusion: Myeloma response correlated with renal response as defined by IMWG criteria. A >50% reduction in FLCs from baseline to treatment cycle ≥2 was strongly associated with renal response. OS was longer in pts with renal response, in pts receiving bortezomib-based therapy, and in pts with kappa light chain M-proteins. Hypercalcemia was frequent (29.4%), and associated with higher renal response rate and best eGFR, but shorter OS. Pts on dialysis who achieved eGFR >15ml/min had better survival. Fast diagnostic work up, rapid treatment initiation and achieving significant myeloma response (≥VGPR) is essential to prevent irreversible kidney damage. Including novel immunotherapies may further improve outcome.

Summary: While the current approach to precursor hematologic conditions is to “watch and wait,” this may change with the development of therapies that are safe and extend survival or delay the onset of symptomatic disease. The goal of future therapies in precursor hematologic conditions is to improve survival and prevent or delay the development of symptomatic disease while maximizing safety. Clinical trial considerations in this field include identifying an appropriate at-risk population, safety assessments, dose selection, primary and secondary trial endpoints including surrogate endpoints, control arms, and quality-of-life metrics, all of which may enable more precise benefit–risk assessment.

Abstract Amyloid light-chain (AL) amyloidosis is a rare, typically fatal disease characterized by the accumulation of misfolded immunoglobulin light chains (LCs). Birtamimab is an investigational humanized monoclonal antibody designed to neutralize toxic LC aggregates and deplete insoluble organ-deposited amyloid via macrophage-induced phagocytosis. VITAL was a phase 3 randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of birtamimab + standard of care (SOC) in 260 newly diagnosed, treatment-naive patients with AL amyloidosis. Patients received 24 mg/kg IV birtamimab + SOC or placebo + SOC every 28 days. The primary composite end point was the time to all-cause mortality (ACM) or centrally adjudicated cardiac hospitalization ≥91 days after the first study drug infusion. The trial was terminated early after an interim futility analysis; there was no significant difference in the primary composite end point (hazard ratio [HR], 0.826; 95% confidence interval [CI], 0.574-1.189; log-rank P = .303). A post hoc analysis of patients with Mayo stage IV AL amyloidosis, those at the highest risk of early mortality, showed significant improvement in the time to ACM with birtamimab at month 9 (HR, 0.413; 95% CI, 0.191-0.895; log-rank P = .021). At month 9, 74% of patients with Mayo stage IV AL amyloidosis treated with birtamimab and 49% of those given placebo survived. Overall, the rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were generally similar between treatment arms. A confirmatory phase 3 randomized, double-blind, placebo-controlled clinical trial of birtamimab in patients with Mayo stage IV AL amyloidosis (AFFIRM-AL; NCT04973137) is currently enrolling. The VITAL trial was registered at www.clinicaltrials.gov as #NCT02312206.

PURPOSE Binary cardiac response assessment using cardiac biomarkers is prognostic in light chain amyloidosis. Previous studies suggested four-level cardiac responses using N-terminal prohormone of brain natiuretic peptide improves prognostic prediction. This study was designed to validate graded cardiac response criteria using N-terminal prohormone of brain natiuretic peptide/brain natiuretic peptide. PATIENTS AND METHODS This retrospective, multicenter study included patients with light chain amyloidosis who achieved at least a hematologic partial response (PR) and were evaluable for cardiac response. Four response criteria were tested on the basis of natriuretic peptide response depth: cardiac complete response (CarCR), cardiac very good partial response (CarVGPR), cardiac PR (CarPR), and cardiac no response (CarNR). Response was classified as best response and at fixed time points (6, 12, and 24 months from therapy initiation). The study primary outcome was overall survival. RESULTS 651 patients were included. Best CarCR, CarVGPR, CarPR, and CarNR were achieved in 16%, 26.4%, 22.9%, and 34.7% of patients, respectively. Patients in cardiac stage II were more likely to achieve CarCR than patients in cardiac stage IIIA and IIIB (22% v 13.5% v 3.2%; P < .001). A deeper cardiac response was associated with a longer survival (5-year overall survival 93%, 79%, 65%, and 33% for CarCR, CarVGPR, CarPR, and CarNR, respectively; P < .001). Fixed time-point analyses and time-varying covariates Cox regression analysis, to minimize survivorship bias, affirmed the independent survival advantage of deeper cardiac responses. Four-level response performed better than two-level response as early as 12 months from therapy initiation. CONCLUSION Graded cardiac response criteria allow better assessment of cardiac improvement compared with the traditional binary response system. The study re-emphasizes the importance of early diagnosis, which increases the likelihood of deep cardiac responses.

SummaryThe severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐associated coronavirus disease 2019 (COVID‐19) is primarily manifested as a respiratory tract infection, but may affect and cause complications in multiple organ systems (cardiovascular, gastrointestinal, kidneys, haematopoietic and immune systems), while no proven specific therapy exists. The challenges associated with COVID‐19 are even greater for patients with light chain (AL) amyloidosis, a rare multisystemic disease affecting the heart, kidneys, liver, gastrointestinal and nervous system. Patients with AL amyloidosis may need to receive chemotherapy, which probably increases infection risk. Management of COVID‐19 may be particularly challenging in patients with AL amyloidosis, who often present with cardiac dysfunction, nephrotic syndrome, neuropathy, low blood pressure and gastrointestinal symptoms. In addition, patients with AL amyloidosis may be more susceptible to toxicities of drugs used to manage COVID‐19. Access to health care may be difficult or limited, diagnosis of AL amyloidosis may be delayed with detrimental consequences and treatment administration may need modification. Both patients and treating physicians need to adapt in a new reality.

Abstract Background: Treatment of multiple myeloma has evolved considerably in the past few years with availability of several news drugs as well as increasing use of multidrug combinations. These changes have no doubt led to the improved survival seen among patients with MM. We have previously shown that outcomes of patients intolerant or refractory to one of the IMiDs and bortezomib had a poor outcome. Since that time, other drugs of the same class as well as new classes of drugs have been introduced for the treatment of MM. We designed this retrospective study to estimate the outcomes in patients with relapsed myeloma, who have become refractory to the current generation IMiDs and proteasome inhibitors. Patients and Methods: Patients with relapsed multiple myeloma who have received at least 3 prior lines of therapy, is refractory to both an IMiD (lenalidomide or pomalidomide) AND a proteasome inhibitor (bortezomib or carfilzomib), and has been exposed to an alkylating agent were identified from multiple centers. The time patients met the above criteria was defined as T0, and details of all treatment regimens before and after T0 were collected using electronic CRFs. The study was approved by the IRB at the respective centers. Results: 543 patients were enrolled in this study; median age was 62 years (31-87) and 61% were males. Patients were enrolled from centers in North America (n=181), Europe (n=318), and Asia Pacific (n=44). Patients were diagnosed between 2006 and 2014, the median duration between diagnosis of myeloma and study entry (T0) was 3.1 years (0.3 to 9). The median (95% CI) estimated follow up from diagnosis and from T0 were 61 (57, 66) months and 13 (11, 15) months respectively. The median number of lines of therapy prior to T0 was 4 (3-13), 48% had a prior transplant. The median OS from T0 for the entire cohort was 13 (11, 15) months. For these 462 patients, the median number of recorded regimens was 2 (1-9). The overall response and the depth of response to each line of treatment following T0 are as shown in the table. The median (95% CI) PFS and OS from T0 was 5 (4, 6), and 15.2 (13, 17), respectively. The overall survival for the 81 patients with no treatment post T0 was only 2.1 months. In a multivariate analysis, duration from diagnosis to T0, ISS stage III and number of lines of therapy were all associated with inferior PFS, as well as OS, and in addition, serum creatinine>2 mg/dL at T0 also predicted inferior OS. Conclusions: The study provides the expected outcome following development of myeloma that is refractory to a PI and an IMiD. The outcomes of these patients appear to be better than we had seen historically in patients refractory/ intolerant to bortezomib and IMiDs, highlighting the increased treatment options available for these patients. However, there is decreasing response rate to sequential regimens highlighting the development of drug resistance. The data provides a bench mark for comparison of new therapies that are being evaluated in this disease. Table Table. Disclosures Dimopoulos: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kastritis:Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Terpos:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria. Hillengass:Sanofi: Research Funding; Novartis: Research Funding; Amgen: Consultancy, Honoraria; BMS: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. Leleu:TEVA: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; LeoPharma: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Pierre Fabre: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Honoraria. Oriol:Janssen: Honoraria, Other: Expert board committee; Amgen: Honoraria, Other: Expert board committee. Cavo:Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vij:Shire: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy; Karyopharma: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding. Lokhorst:Genmab: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. van de Donk:Amgen: Research Funding; Janssen: Research Funding; BMS: Research Funding; Celgene: Research Funding. Mark:Onyx: Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ludwig:Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; BMS: Speakers Bureau; Janssen: Speakers Bureau. Jagannath:Novartis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Merck: Consultancy. Usmani:Array: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Dytfeld:Janssen Poland: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Moreau:Novartis: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau. Lee:Amgen: Membership on an entity's Board of Directors or advisory committees. Shustik:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. de la Rubia:Celgene: Consultancy; Bristol Myers: Consultancy; Amgen,: Consultancy; Janssen: Consultancy. Durie:Takeda: Consultancy; Amgen: Consultancy; Janssen: Consultancy.