Husnain, Muhammad

Summary CD19 chimeric antigen receptor T‐cell (CAR‐T) therapy is a pivotal part of the treatment algorithm for large B‐cell lymphoma (LBCL) in the second‐ and third‐line settings based on numerous clinical trials. However, these studies included very few patients with a diagnosis of high‐grade B‐cell lymphoma, not otherwise specified (HGBCL‐NOS) and it is unclear if outcomes are similar to those observed with more common LBCL histologies. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we identified 111 HGBCL‐NOS patients who received CAR‐T therapy. The cytokine release syndrome (CRS) rate was 74% (7.7% grade 3+), median onset was 4 days (1–17) and immune effector cell‐associated neurotoxicity syndrome rate was 45.2% (22.6% grade 3+), median onset was 7 days (1–17). At 2 years post‐CAR‐T infusion, the probability of overall survival and progression‐free survival were 41.6% and 28.7% respectively. The 2‐year non‐relapse mortality and relapse/progression were 3.1% (95% confidence interval [CI]: 0.6–7.6) and 68.1% (95% CI: 57.9–77.6) respectively. Our analysis illustrates that patients with HGBCL‐NOS represent a particularly difficult group to treat, even with CAR‐T therapy. We observed that one third of patients achieved a durable response; however, the overall results were less favourable, with lower overall response rate, overall survival and progression‐free survival as compared to published reports on LBCL.

ABSTRACTBackgroundThe treatment landscape for multiple myeloma continues to evolve. Recently, the addition of anti‐CD38 monoclonal antibodies (mAbs) to the triplet regimen, comprising a proteasome inhibitor, an immunomodulatory agent, and a steroid, for transplant‐eligible newly diagnosed multiple myeloma (TENDMM) has shown promising results.AimsTo evaluate the overall efficacy and safety of quadruplet therapy with an anti‐CD38 mAb compared to a triplet regimen.MethodsA systematic search of Medline, Scopus, and EMBASE databases from inception to July 2024 identified relevant randomized controlled trials (RCTs). Efficacy and safety outcomes were derived using random‐effects meta‐analysis. Summarized outcomes include hazard ratios (HR) for progression‐free survival (PFS) and overall survival (OS), odds ratios (OR) for response rates, measurable residual disease (MRD) negativity rate, and grade 3 or higher adverse events (G ≥ 3 AEs).ResultsFive RCTs involving 2963 patients were included. A statistically significant PFS was observed for quadruplet therapy when compared to the triplet regimen (HR 0.44; 95% Confidence Interval [CI] 0.35–0.56). PFS benefit was consistent for the standard risk (SR) group (HR 0.38; 95% CI 0.27–0.52) and high risk (HiR) group (HR 0.62; 95% CI 0.41–0.92). No statistically significant benefit was observed for OS (HR 0.55; 95% CI 0.28–1.08). A statistically significant benefit was observed for the overall response rate (OR 1.77; 95% CI 1.02–3.06) and MRD negativity rate (OR 2.67; 95% CI 1.79–3.99). No significant differences were observed for G ≥ 3 AE (OR 1.21; 95% CI 0.92–1.58), lymphopenia (OR 1.09; 95% CI 0.62–1.89), and anemia (OR 1.06; 95% CI 0.83–1.37). However, a significantly increased risk was observed for all‐grade thrombocytopenia (OR 1.64; 95% CI 1.37–1.97), neutropenia (OR 2.24; 95% CI 1.67–3.02) and infections (OR 1.88; 95% CI 1.07–3.31).ConclusionQuadruplet therapy demonstrated a favorable efficacy and safety profile, with consistent benefit across subgroups. The findings support its potential as the new standard of care for TENDMM.

e19534 Background: Immunomodulatory drugs, proteasome inhibitors plus dexamethasone are the standard triplet induction regimen for TENDMM. We analyzed the efficacy of adding either anti-CD38 monoclonal antibodies (mAbs) or anti-SLAMF7 antibody to the triplet therapy. Methods: Ovid MEDLINE, EMBASE and published abstracts were systematically searched from each database’s inception through 01-31-2024 to identify II/III trials assessing quadruplet therapy versus triplet therapy in TENDMM patients. Hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS), odds ratios (OR) for overall response rates (ORR), measurable residual disease (MRD) negativity rate (with sensitivity of 10 -5) and grade 3 or higher treatment-related adverse events (G≥3 TRAE) were summarized using random effects meta-analysis via inverse variance approach. Additional subgroup analyses based on the cytogenetic risk were performed. P-value of interaction (Pint ) < 0.1 was pre-specified as statistically significant for the difference between the two groups. Results: 3806 studies were screened and seven trials were included with a total of 3546 patients. Four trials (2303 patients) assessed the addition of anti-CD-38 mAbs and three (1243 patients) assessed anti-SLAMF7 mAb, elotuzumab to the triplet regimen. Quadruplet therapy significantly improved PFS as compared to triplet (HR: 0.63; 95% CI: 0.43-0.92), and the PFS benefit was also observed in standard risk group (HR 0.5; 95% CI 0.2-0.9); however, results were insignificant for high-risk group (HR 0.8; 95% CI 0.62-1.93). No significant OS benefit was observed (HR: 0.79; 95% CI 0.49–1.26); however, data for three trials (CASSIOPEIA, DSMM XVII, PERSEUS) is immature, with longer-term follow-up ongoing. Quadruplet therapy showed significant results for very good partial response or better (OR: 1.7; 95% CI 1.2-2.36), stringent complete response (OR: 1.74; 95% CI 1.27-2.07) and complete response or better (OR: 1.91; 95% CI 1.19-3.06). MRD rate shows benefit with quadruplet therapy (OR: 2.59; 95% CI 2.22-3.01). Improved MRD rate was also observed for high-risk (OR 2.13; 95% CI 1.4-3.2) and standard-risk group (OR 2.58; 95% CI 1.68-3.94). Secondary analysis for efficacy of anti-CD38 mAbs showed benefit for PFS (HR: 0.44; 95% CI: 0.35-0.56), ORR (OR: 1.77;95% CI: 1.02-3.06), and MRD (OR: 2.98; 95% CI 1.8-4.8). G ≥3 TRAE did not significantly differ between the groups (OR: 1.05; 95% CI 0.97-1.12). However, quadruplet therapy showed significant risk of infection (OR: 1.2; 95% 1.05-1.35) and thrombocytopenia (OR: 1.41; 95% CI 1.24-1.59). Conclusions: Quadruplet therapy improved PFS, ORR, and MRD rates compared to triplet regimen and has demonstrated promising benefits to be considered the new standard of care for TENDMM patients.

Introduction The optimal maintenance regimen by prognostic categories remains unclear in newly diagnosed multiple myeloma (NDMM) patients undergoing autologous stem cell transplant (ASCT). Therefore, we conducted a systematic review and network meta-analysis (NMA) to assess the comparative effectiveness of novel agents by different prognostic groups. Methods A comprehensive systematically structured literature search was conducted to identify phase II/III randomized controlled trials (RCTs) evaluating maintenance therapies in post-transplant NDMM patients and reporting data by subgroups including but not limited to international staging system (ISS), and cytogenetic risk. High cytogenetic risk (HCR) and standard cytogenetic risk (SCR) were defined in accordance with the eligible trials. Main outcomes of interest were overall survival (OS) and progression-free survival (PFS). Precomputed hazard ratios (HR) with 95% CI were pooled using an inverse variance approach. A frequentist network meta-analysis was conducted. P-score (PS) were used to assess relative rankings of the treatments and were interpreted in congruency with pairwise estimates. Higher ranks indicated better efficacy. Results This NMA included six RCTs with 4119 participants and six unique treatment arms. In patients with SCR, the combination of carfilzomib, lenalidomide, and dexamethasone (KRd) improved PFS when compared to lenalidomide (Len; HR: 0.44; 95% CI: 0.24-0.81), daratumumab (Dara; 0.27; 0.13-0.55), ixazomib (Ixa; 0.26; 0.13-0.53), and no maintenance therapy (0.17; 0.09-0.32). Similarly, KR improved PFS compared to lenalidomide (Len; 0.56; 0.33-0.96), daratumumab (Dara; 0.34; 0.18-0.65), ixazomib (Ixa; 0.33; 0.17-0.63), and no maintenance therapy (0.21; 0.12-0.38). There was no statistically significant difference between KRd and KR. KRd was ranked as potentially the most efficacious treatment (rank 1) followed by KR (rank 2), Len (rank 3), Dara (rank 4), and Ixa (rank 5) for improving PFS in SCR. In patients with HCR, KRd (0.35; 0.14-0.92), KR (0.32; 0.15-0.67), Dara (0.43; 0.25-0.73), and Len (0.48; 0.35-0.64) improved PFS when compared to no maintenance therapy. No other significant differences were observed in HCR patients. KR was ranked as potentially the most efficacious treatment followed by KRd (rank 2), Dara (rank 3), Len (rank 5), and Ixa (rank 5) for PFS in HCR patients. In patients with ISS-I/II, KRd and KR improved PFS when compared to Dara (KRd vs. Dara - 0.32; 0.16-0.65, KR vs Dara - 0.50; 0.26-0.94), and Ixa (KRd vs. Ixa - 0.22; 0.11-0.45, KR vs Ixa - 0.35; 0.18-0.65). KRd, not KR, improved PFS when compared to Len (0.41; 0.22-0.76). Rankings were consistent with those observed in SCR patients. No significant differences were observed among mixed treatment comparisons for ISS-III patients. Limited number of trials reporting OS precluded formal assessment. Conclusions The current data suggest that KRd and KR may delay disease progression regardless of risk category. Overall survival data is still emerging and, if consistent, may influence clinical practice. We maintain a living meta-analysis to incorporate new evidence constantly.

Background CV mortality has been recognized as the preventable cause of death in most cancers. However, there is a scarcity of data exploring CV mortality in adults diagnosed with leukemia. Hence, understanding the timing, and quantifying the magnitude of CV mortality can facilitate strategies to reduce the burden of mortality in these patients. Methods Surveillance, Epidemiology, and End Results (SEER) database (2004-2018) was queried to obtain CV mortality (defined as deaths due to heart diseases, hypertension, cerebrovascular diseases, atherosclerosis, and aortic aneurysm and dissection) in adults (&gt;18 years of age) diagnosed with leukemias including acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Standardized mortality ratios (SMRs) were calculated. SMR was defined as the observed deaths from each category divided by the expected number of deaths in the age-matched US population for the same period. SMR &gt;1 indicated increased while &lt;1 indicated decreased mortality. SMR was presented by latency periods of &lt;2, 2-5, and &gt;5 years after the initial diagnosis of leukemias and stratified by age (&lt;50 years, 50-70 years, &gt;70 years), race (White, Black, Asian/Pacific Islander, Native American), ethnicity (Hispanic, Non-Hispanic), and marital status (married vs single/divorced/widowed). Results This analysis included 120,193 leukemia patients. Of which, 61,763 had lymphocytic leukemia and 58,430 were diagnosed with myeloid leukemia. In overall population, a significant increase in mortality was observed in adults diagnosed with leukemia (SMR: 1.34, 95% CI: 1.27-1.40). The risk of CV death was highest &lt;2 years of initial diagnosis (1.94, 1.87-2.01) as compared to the population who died 2-5 years (1.17, 1.11-1.23) and &gt;5 years (1.07, 1.01-1.14) after the initial diagnosis. In terms of different subgroups, patients aged &lt;50 years observed the highest risk of CV mortality within &lt; 2 years (9.35, 6.54-13.38) compared to patients aged 50-70 years (2.73, 2.45-3.04), and aged &gt;70 years (1.80, 1.73-1.88). Similarly, regarding race, Asians/Pacific islanders had the highest risk of CV mortality (4.41, 3.70-5.26) followed by Blacks (2.58, 2.26-2.94), and Whites (1.85, 1.78-1.92) within &lt;2 years of initial diagnosis. There was a significant increase in observed mortality in Hispanic (2.83, 2.47-3.23) as well as in non-Hispanic (1.90, 1.83-1.97) population within &lt;2 years of initial diagnosis. However, the magnitude was relatively higher in Hispanic as compared to non-Hispanics. The risk of CV death was observed to be higher in single/divorced/widowed patients (2.30, 2.00-2.20) compared to those who were married (1.81, 1.71-1.91). The CV mortality risk remained consistent for all subtypes of leukemias (ALL, CLL, AML and CML) in overall patient population and among subgroups of interest over different latency periods of &lt;2, 2-5, and &gt; 5years after the initial diagnosis. Small sample size in Native Americans precluded any meaningful statistics. Conclusions: Risk of CV mortality among adults with leukemia is observed to be highest among younger (&lt;50 years), Asians, Hispanics, and single/divorced/widowed patients, especially within 2 years of initial diagnosis. A risk-adapted approach may be warranted for cardiovascular care in these patients. Targeted cardio-oncological strategies should be aimed at improving CV mortality in patients who are at the highest risk of death.

e24078 Background: The addition of anti-CD38 mAbs, daratumumab and isatuximab, to standard anti-myeloma regimens have drawn scrutiny towards long-term safety concerns, including the risk of SPMs. ICARIA-MM study reported SPMs in 3.9% patients (pts.) in the Isatuximab, pomalidomide and dexamethasone (Isa-Pd) arm compared to 0.7% in the Pd arm. We hypothesized that exposure to anti-CD38 mAbs could potentially increase risk of SPMs due to prolonged immunosuppression. An assessment of this association is warranted, given the improved life expectancy and growing prevalence of pts. with MM. Methods: We performed a meta-analysis on data obtained from RCTs published between January 2005 and April 2022 that compared anti-CD38 mAb-based regimens to other standard anti-myeloma regimens (control) in pts. with newly diagnosed or relapsed/refractory (r/r) MM. Total number of SPMs (including categories) were extracted for pts. in both groups. Malignant melanomas were included under solid SPM category. Binary outcome data were analyzed using fixed-effect Peto method. Treatment effect estimates were expressed as odds ratio (OR) and 95% confidence interval (CI). I2 > 50% indicated substantial heterogeneity. Results: 10 RCTs involving 4980 pts. were included, with 2824 (57%) and 2156 (43%) pts. randomized to the anti-CD38 mAb and control arms, respectively (Table). Overall, 191 and 112 SPMs were reported in the anti-CD38 mAb and control arms, respectively. At a median follow-up of 35.3 months, anti-CD38 mAb exposure was associated with an increased risk of developing SPMs compared to control (6.8% vs. 5.2%; OR: 1.53 [95% CI: 1.20-1.95]; I2= 0%). Non-melanoma cutaneous cancers were the most common, and higher in the anti-CD38 mAb vs. control arms (92 versus 47; OR: 1.77 [95% CI: 1.25-2.51]; I2= 0%). The increase in solid cancers (including melanoma) (OR: 1.28 [95% CI: 0.85-1.95]) and hematologic SPMs (OR: 1.86; [95% CI: 0.81-4.27] was not significant. On sensitivity analysis, the total number of SPMs were higher in the anti-CD38 mAb arm vs. control arm, regardless of the presence of immunomodulatory drugs in combination regimen. Conclusions: This meta-analysis shows an increased risk of SPMs in pts. with MM exposed to daratumumab or isatuximab, particularly that of non-invasive cutaneous tumors. This association should be further investigated in real-world settings using large databases. [Table: see text]

e19502 Background: Inconsistent results observed in recent trials (ZUMA-7, TRANSFORM, BELINDA) assessing chimeric antigenic receptor T (CAR-T) cell therapy in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) prompted a meta-analysis to assess the available evidence and to compare the effectiveness of different CAR-T products. Methods: MEDLINE and EMBASE were searched to identify full-text or abstract publications of phase 3 randomized controlled trials (RCTs) assessing CAR-T in patients with R/R DLBCL compared to standard of care (SOC). Efficacy outcomes included event-free survival (EFS), progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and complete response (CR). CR rates were also compared between CAR-T and patients in SOC arm who received autologous stem-cell transplantation (ASCT). Safety outcomes included grade > 3 any adverse events (AE), cytokine release syndrome (CRS) and neurological toxicity (NT). A DerSimonian-Laird random-effects meta-analysis was conducted to pool effect estimates. Freeman-Tukey transformation method was used to estimate pooled proportion (PP) of safety events specific to CAR-T. Mixed treatment comparisons were computed using a frequentist network meta-analysis approach. Results: Of 1803 studies identified, three RCTs with 865 patients were included. Meta-analysis showed significant improvement in EFS (HR: 0.51; 95% CI: 0.27-0.97; I2: 92%), PFS (HR: 0.47; 95% CI: 0.37-0.60; I2: 0%) with CAR-T compared to SOC. OS was not significantly different between the two groups (HR 0.76; 95% CI: 0.56 to 1.03; I2: 29%). Higher objective response (RR: 1.49; 95% CI: 1.13-1.97; I2: 81%), and CR rates (RR: 1.55; 95% CI: 1.07-2.24; I2: 79%) were observed with CAR-T compared to SOC. However, CAR-T was associated with lower CR when compared to patients who underwent ASCT (RR: 0.65; 95% CI: 0.46-0.90; I2: 89%). The safety profile was not different between CAR-T and SOC. The incidences of grade ≥3 CRS (PP: 4.19; 95% CI: 1.60-7.80; I2: 57%) and grade ≥3 NT (PP: 7.57; 95% CI: 0.20-22.6; I2: 95%) were low. Mixed treatment comparisons showed significant EFS benefit with liso-cel (rank 1: HR: 0.37; 95% CI: 0.22-0.61) and axi-cel (rank 2: HR: 0.42; 95% CI: 0.29-0.61) compared to tisa-cel (rank 3). No significant differences were observed among different CAR-T products for PFS or OS improvement. The safety profile of CAR-T products was comparable with tisa-cel (rank 1) being the safest. Conclusions: CAR-T therapy, as a second line treatment, appears to be effective in achieving higher response rates and delaying the disease progression compared to SOC in R/R DLBCL. However, given lack of OS benefit coupled with lower response rates when compared to patients who received ASCT, we should exercise caution in adopting CAR-T as second line therapy for all patients with R/R DLBCL.

BackgroundDespite routine evaluation of cytogenetics in myeloma, little is known regarding the impact of high‐dose therapy (HDT) consolidation on overall survival (OS) or progression‐free survival (PFS) in patients who have high‐risk cytogenetics. The authors performed a meta‐analysis of randomized controlled trials (RCTs) to assess the heterogeneity of HDT efficacy according to cytogenetic risk.MethodsAll RCTs in patients who had newly diagnosed myeloma from 2000 to 2021 that compared upfront HDT versus standard‐dose therapy (SDT) consolidation were included. The primary objective was to assess the difference in HDT efficacy between standard‐risk and high‐risk cytogenetics in terms of the OS or PFS log(hazard ratio) (HR). The pooled OS and PFS HR was calculated according to cytogenetic‐risk subgroup using a random‐effects model, and heterogeneity (I2) (the percentage of total observed variability explained by between‐study differences) was assessed using an interaction test.ResultsAfter screening 3307 citations, 6 RCTs were included for PFS analysis, and 4 were included for OS analysis. The median follow‐up ranged from 3.1 to 7.8 years. The pooled OS HR for HDT versus SDT consolidation in patients with standard‐risk and high‐risk cytogenetics was 0.90 (95% confidence interval [CI], 0.70‐1.17; I2 = 0%) and 0.66 (95% CI, 0.45‐0.97; I2 = 0%), respectively. The difference in HDT efficacy in terms of OS between standard‐risk and high‐risk patients was statistically significant in favor of the high‐risk group (P for interaction = .03). The pooled PFS HR for HDT versus SDT was 0.65 (95% CI 0.56‐0.76; I2 = 0%) versus 0.52 (95% CI, 0.33‐0.83; I2 = 55%), respectively. The difference in HDT efficacy in terms of PFS between standard‐risk and high‐risk patients was not significant (P for interaction = .25).ConclusionsThe magnitude of OS benefit with upfront HDT is cytogenetics‐dependent. Patients with high‐risk cytogenetics should preferably receive upfront rather than delayed HDT consolidation.Lay Summary Upfront autologous stem cell transplantation improves overall survival in patients with newly diagnosed myeloma harboring high‐risk cytogenetics.