Introduction: The risk of second primary malignancies (SPMs) has emerged as a growing clinical concern in patients with multiple myeloma (MM) who currently achieve prolonged survival. The reported cumulative incidence of SPMs in MM has varied greatly depending on patient characteristics, treatment and stringency of follow up. we sought to estimate the incidence of SPM in a large MM population followed long-term in a single center and identify risk factors for SPM, including genetic aberrations. Methods: This retrospective cohort study includes patients (pts) with MM who initiated first-line Rx at Memorial Sloan Kettering Cancer Center, excluding patients who did not continue care at MSK beyond induction and transplant, and those internally referred to avoid selection bias inherent to a cancer center. The primary objective is to estimate the cumulative incidence of SPM following Rx start, excluding non-invasive skin cancers or recurrence of prior known malignancies, and explore risk factors for SPM. Secondary objectives are: (1) To evaluate associations between MM and specific SPMs; (2) To analyze overall survival (OS) of pts with SPM. The Kaplan-Meier method estimated median OS. Cumulative incidence of SPM was calculated with death as a competing risk. Cause-specific Cox models estimated hazard ratios for SPM risk, accounting for competing risks, and landmark analysis assessed the association between SPM development and OS. Results: We included 1,476 patients with a median follow-up of 5.7 years. The median OS for all pts is 15.6 years (95% CI, 14.1–Not reached); (5-year OS: 83.8% (95% CI, 81.6%-86%) and 10-year OS: 65.5% (95% CI, 61.6%-69.7%). Median age at start of Rx is 64 years (IQR, 57–71). 54% are male. Racial distribution includes 72% Caucasian, 15% African American, 5% Asian, and 8% others. A smoking history is present in 37%, history of other malignancy prior to MM diagnosis in 18%, and a first-degree family history of cancer in 56%. The isotype is IgG (61%), IgA (21%), and IgD (1%), and light chain only (17%) with ISS stages I, II, and III in 48%, 34%, and 18%. High-risk cytogenetic features at diagnosis include gain/amp 1q (28%), del17p (10%), t(4;14) (7%), and t(14;16) (2%). 238 patients acquired additional cytogenetic abnormalities during follow up. Induction Rx included VRD (29%), KRD (20%), DVRD (16%), DKRD (8.1%), VCD (4.2%), and others (22.7%). ASCT occurred in 55%, and CAR-T cell Rx in 7%. The 5- and 10-year estimated cumulative incidence of all-SPMs is 8.8% (95% CI, 7.3–11%) and 20% (95% CI, 17–23%), respectively (Heme-SPMs in 1.7% and 5.8%, and solid-SPMs in 7.1% and 13%, 5 and 10 years respectively). The median number of lines of therapy prior to SPM is 1 (IQR 1–2). In those patients with SPM, the median time to SPMs after start of Rx is 3.7 years (IQR 1.8–6.7): 5.5 years (IQR 3–7.8) in Heme-SPM and 3 years (IQR 1.5-6.2) in Solid-SPM. Heme-SMPs (n=42) include MDS 42%, ALL 28%, AML 11%, NHL 9%, MPD 7%, and LGL 2%. Solid-SPMs (n=129) include prostate 17%, GU 14%, lung 14%, melanoma 12%, breast 9%, GI 9% and other cancers 24%. Although univariate analysis showed a trend toward increase in all-SPM risk for patients with prior malignancy (HR 1.43, 95% CI 0.99–2.1) and male sex (HR 1.3, 95% CI 0.98–1.8); and association of heme-SPM risk with ASCT (HR 2.0, 95% CI 0.99–3.8), multivariable model, adjusted for significant univariable factors, identified age 55–65 (HR 1.7, 95% CI 1.1–2.8), age ≥65 (HR 2.1, 95% CI 1.3–3.4), Caucasian race (HR 1.6, 95% CI 1.0–2.7), and smoking history (HR 4.7, 95% CI 1.7–13) as independent predictors of SPM. The median OS after SPM diagnosis was 3.0 years (95% CI 2.3–NA) for Heme-SPMs and 12.1 years (95% CI 6–NA) for solid-SPMs. Conclusions: Acknowledging the limitations inherent to a tertiary referral cancer center and related biases, this study shows in pts with MM, the 5 and 10-year estimated cumulative incidence of SPM after start of MM Rx, is 8.8% and 20%, respectively. Notably, 18% of patient also have prior malignancies diagnosed prior to MM. Patients who developed solid SPMs demonstrated particularly favorable overall survival, probably due to early detection. Older age, Caucasian race, and smoking history were significant risk factors for developing SPM. Analysis of cytogenetics and MSK Impact sequencing analysis remains in progress and will be reported.

Background: CAR T-cell therapy (CAR-T) results in a unique spectrum of toxicities, affecting morbidity, mortality, and quality of life. Traditionally, immunotoxicities like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are studied independently. However, the overall toxicity landscape of CAR-T is complex and interdependent, with patterns that remain incompletely understood. To address this, we mapped early CAR-T toxicities day-by-day across multiple dimensions to understand their biological and clinical implications. Study Design: This international multicenter observational study included 558 adult patients treated with standard-of-care CD19 or BCMA CAR-T therapies for relapsed/refractory B-cell malignancies (77% B-NHL, 7% B-ALL, 16% multiple myeloma). The product breakdown was: axi-cel (39%), tisa-cel (22%), liso-cel (17%), cilta-cel (9%), ide-cel (7%), brexu-cel (6%). A team of trained investigators evaluated four major toxicity domains daily, from lymphodepletion until 30 days post-infusion. CRS (1) and ICANS (2) were graded according to ASTCT criteria. Infections (3) were clinically or microbiologically defined and graded per Hill et al., Blood 2018. Hematotoxicity grades (4) were derived computationally using serial neutrophil counts (EHA/EBMT ICAHT grading). Results: We comprehensively reviewed over 20,000 patient days, resulting in 80,352 unique toxicity datapoints. To quantify the overall burden of toxicity at a patient-level, we first devised a cumulative toxicity index (CTI) reflecting the aggregated severity and duration of the four major toxicity domains. Across all patients, the median CTI was 23 (IQR 10-51). We identified product-specific variations of CTI. Among CD19 CAR-T products, brexu-cel had the highest CTI, followed by axi-cel, tisa-cel and liso-cel (45 vs. 27 vs. 24 vs. 18, p=0.003). For BCMA CAR-T products, cilta-cel and ide-cel had a comparable CTI (17 vs. 14, p=0.6). Next, we employed a topographical imaging approach to visualize patient-level toxicity profiles across four dimensions of toxicity and time. Visual inspection revealed complex interactions between these five elements, which are challenging to interpret directly. To elucidate these complexities, we applied an unsupervised learning technique-latent trajectory class analysis (Hart & Fei et al., Biometrics 2020)-to the longitudinal toxicity data, focusing on the large B-cell lymphoma cohort (n=384). We identified three distinct toxicity phenotypes: low-tox (LT), mid-tox (MT), and high-tox (HT). The LT phenotype (n=175) was characterized by mild-to-moderate CRS, short duration of cytopenias, rare and mild ICANS, and notably, the absence of infectious complications. The MT phenotype (n=134) exhibited similar rates of CRS and ICANS, but showed longer and deeper cytopenias, and an increased infection signal throughout the first 30 days. The hallmark of the HT phenotype (n=75) was protracted and severe toxicity across all four domains. In terms of CTI, we noted a gradual increase with each phenotype (L/M/HT: 10 vs. 37 vs. 85, p<0.001). Cytokine profiling revealed divergent inflammatory signatures among the toxicity phenotypes, with the HT phenotype showing upregulation of IL-6, IL-10, and TNF-α. The newly defined phenotypes were strongly linked to morbidity and mortality. HT patients were hospitalized longer (L/M/HT: 12 vs. 15 vs. 22 days, p<0.001), required more ICU admissions (4% vs. 5% vs. 47%, p<0.001), and had increased non-relapse mortality (1-year NRM: 3.7% vs. 4.4% vs. 12.6%, p=0.003). Notably, HT patients showed inferior PFS (1-year PFS 53% vs. 47% vs. 30%, p<0.001) and OS (1-year OS, 78% vs. 70% vs. 52%, p<0.001). In a multivariable Cox regression model accounting for age, pre-lymphodepletion LDH levels and product, the toxicity phenotype was independently associated with both PFS (HT vs. LT: HR 2.0, p=0.003) and OS (HT vs. LT: HR 1.7, p=0.007). Conclusions: Leveraging over 80,000 longitudinal data points from a large, deeply annotated international cohort, we developed a new metric, the Cumulative Toxicity Index (CTI), to quantify the main toxicity burden in CAR-T patients. Additionally, employing an unsupervised approach, we defined biologically distinct and prognostically relevant toxicity phenotypes, underlining that CAR-T toxicities should be understood as more than the sum of their parts.

Introduction: Infections cause significant morbidity among relapsed refractory multiple myeloma (RRMM) patients receiving chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies (BsAbs). Real-world infection data in patients receiving commercial BsAbs and CAR T-cell therapy as standard of care are lacking and necessary to understand risk factors for serious infections, guiding treatment choices, and management strategies. Methods: This isa retrospective single-center study of infectious complications in RRMM patients during treatment with commercial CAR T-cell therapy, idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel), and BsAbs, including teclistamab, elranatamab, or talquetamab between 8/1/2023-6/1/2024. Infections were graded in accordance with Common Terminology Criteria for Adverse Events v5.0. Patients received antiviral and PJP prophylaxis per standardized institutional guidelines. The primary endpoint was rate of total and serious infections (grade ≥3). Secondary objectives included time to first infection and impact of baseline characteristics on infectious complications. Results: A total of 119 patients (55% Female, 68% Caucasian, 19% Black) were included; 69 treated with BsAbs and 50 treated with CAR T-cells. The BsAb group was older (median age 70 vs 66; p=0.041), had more prior lines of therapy (median 6 vs 5; p=0.01), a greater proportion of high-risk cytogenetics (61% vs 20%; p<0.001), a greater proportion of extramedullary disease (43% vs 12%; p<0.001), a lower baseline median hemoglobin (8.8 vs 11.40 g/dL; p<0.001), and a lower baseline median IgG (432 vs 592 mg/dL; p=0.028). Baseline ECOG, neutrophils, lymphocytes, and platelets were similar. Median follow-up was 3.7m (0.13-11.3m) for BsAbs and 5.3m (1.15-10.25m) for CAR T-cells. Overall, 173 infections were reported with 106 amongst 46 (67%) BsAb patients and 67 amongst 26 (52%) CAR T-cell patients. Upper respiratory tract infections were the most common infections amongst both BsAb and CAR T-cell patients (39% and 49%). The BsAb group had a higher proportion of bacterial infections compared to the CAR T-cell group (49% vs 26%), but a lower proportion of viral infections, (47% vs 60%). Fungal infections were uncommon with 4 reported in the BsAb group and 1 in the CAR T-cell group. Recurrent infections (≥2) were more common in the BsAb group (43% vs 28%). A total of 55 serious infections, not including grade 5, were reported with 43 amongst 28 (41%) BsAb patients and 12 amongst 7 (14%) CAR T-cell patients. Grade 5 infections occurred in 5 BsAb patients and 1 CAR T-cell patient. Recurrent serious infections were more common in the BsAb group (20% vs 6%). In a multivariable analysis, CAR T-cell therapy was associated with a lower rate of serious infections (incidence rate ratio [IRR]: 0.25, 95% CI 0.12-0.51;p<0.001). Male sex (IRR: 3.02 95% CI: 1.70-5.57; p<0.001) was also associated with an increased rate of serious infections. The estimated cumulative incidence of first infection was higher in the BsAb group at day 30 (42% vs 24%) and day 90 (57% vs 40%). Estimated cumulative incidence of first serious infection was also higher in the BsAb group at day 30 (23% vs 6%) and day 90 (31% vs 10%). In a multivariable analysis, CAR T-cell therapy was associated with a longer time to first serious infection (HR 0.33, 95% CI 0.13-0.87; p=0.019). Male sex was associated with a shorter time to first serious infection (HR 2.95, 95% CI 1.40-6.21; p=0.003). There were no differences in infection incidence or time to first infection between ide-cel or cilta-cel nor were there differences seen between BCMA-targeted BsAbs, teclistamab and elranatamab, and GPRC5D-targeted talquetamab. Baseline thrombocytopenia (<100k), neutropenia (ANC<1000), lymphopenia (ALC<500), and hypogammaglobulinemia (IgG<400) were not associated with infection incidence or time to first infection. Conclusion: Infections were common amongst RRMM patients treated with commercial BsAbs and CAR T-cell therapy. In a real-world setting with standardized antimicrobial prophylaxis, BsAbs were associated with a higher incidence of total, serious, and recurrent infections which occurred earlier during treatment. The BsAb group had more high-risk features and more severe anemia at baseline likely contributing to infection incidence. Longer follow-up with more patients and extended analysis will be presented at the meeting.

Background: MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a key component of the CARD11-BCL10-MALT1 (CBM) complex, which activates the classical NF-κB pathway. JNJ-67856633, a highly selective protease inhibitor of CBM-mediated NF-κB signaling, has demonstrated potent anti-lymphoma activity preclinically in vitro and in vivo. Aims: To present results from a phase 1, first-in-human dose escalation study (NCT03900598) of JNJ-67856633 in patients (pts) with R/R B-NHL and CLL. Methods: Eligible pts were those aged ≥18 years with R/R B-NHL or CLL (per WHO/iwCLL criteria), Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1, and with ≥1 or 2 lines of therapy (LOT). Dose escalation was supported by a modified continual reassessment method to identify recommended phase 2 dose (RP2D). Pts in dose-finding cohorts received JNJ-67856633 orally at doses between 50 mg and 600 mg once daily. Loading doses (LD) were explored to accelerate steady-state exposure of JNJ-67856633: 2 LD using capsules at 400 mg once daily for 14 days followed by 300 mg once daily, and 300 mg twice daily for 7 days followed by 300 mg once daily. Similar LD were used for the tablet formulation. Results: At a clinical cutoff of January 22, 2023, 109 pts with R/R B-NHL or CLL received JNJ-67856633 (n=89, capsules; n=20, tablets). Median age was 70.0 years (range 20-89) and 64% were male. Over half the pts had ≥4 prior LOT. Median duration of treatment was 10.3 weeks (range 0.57-176.29). The most common histology was diffuse large B-cell lymphoma (DLBCL) (n=65; [59.6%]). Treatment-emergent AEs were reported in 97.2% of pts (Table). Hyperbilirubinemia was observed in 44.0% of pts and was taken into consideration when selecting the RP2D. Dose limiting toxicities were reported in 5 pts (400 mg, Grade 3 [G3] hyponatremia; 600 mg, G2 bradycardia; 300 mg, G3 febrile neutropenia; 400 mg LD, G3 renal failure; 300 mg LD, G3 acute renal failure); 4 pts continued with same dosing and 1 pt had dose reduction. Maximum-administered dose was 600 mg once daily and maximum-tolerated dose was not reached. Based on the toxicity profile, RP2D was 300 mg once daily and LD 300 mg. No new safety signals were observed with both formulations at different LD. Preliminary pharmacokinetic (PK) data showed that JNJ-67856633 is rapidly absorbed, with a median Tmax (time to reach maximum drug concentration) ranging from 2-5 hours, and slowly eliminated at doses of 50 mg to 600 mg. JNJ-67856633 accumulated approximately 8-fold upon multiple dosing. When administering the 50 mg capsule, steady-state exposure increased in an approximately dose proportional manner as the dose increased from 50 mg to 400 mg. Exposures were comparable between tablet doses of 200 mg or 240 mg and a capsule dose of 300 mg. Overall response rate (ORR) at the RP2D (n=36) was 27.8% (complete response, n=4 [11.1%]; partial response, n=6 [16.7%]). Responses were observed across indolent and aggressive histologic subtypes. Summary/Conclusion: Preliminary data from this first-in-human MALT1 inhibitor (JNJ-67856633) phase 1 dose escalation study indicates that it has a manageable hematological and non-hematological safety profile. JNJ-67856633 has demonstrated clinical activity in indolent and aggressive lymphomas. LD may be associated with a higher ORR and is further explored in expansion cohorts. The safety and efficacy results from this dose escalation study supported targeting MALT1 in pts with R/R B-NHL and CLL, and further evaluation of JNJ-67856633 in expansion cohorts.Keywords: Phase I, Non-Hodgkin’s lymphoma, relapsed/refractory, Chronic lymphocytic leukemia

Patients with DLBCL achieving complete metabolic response (CMR) after initial treatment with R-CHOP generally have a favourable prognosis; however, there are no established prognostic biomarkers for relapse in these patients. Soluble interleukin-2 receptor (sIL-2R) levels at diagnosis are prognostic factors in patients with DLBCL. However, the significance of post-treatment sIL-2R levels is unclear. To determine the significance of post-treatment serum sIL-2R levels on subsequent relapse and survival, we retrospectively analysed 485 patients with newly diagnosed DLBCL who received R-CHOP treatment and achieved CMR. The cumulative incidence of relapse (CIR) was significantly higher in patients with elevated post-treatment sIL-2R levels than in those with normal sIL-2R levels (five-year CIR; 38.8% vs. 12.8%). The prognostic value remained significant in multivariable analysis (hazard ratio, 2.30; p < 0.001). Five-year progression-free survival (49.0% vs. 83.5%) and overall survival (61.7% vs. 91.6%) rates were lower in patients with elevated post-treatment sIL-2R levels than in those with normal sIL-2R levels ( p < 0.001 for both). In patients with newly diagnosed DLBCL who achieved CMR after R-CHOP treatment, the post-treatment serum sIL-2R level was an independent prognostic marker of subsequent relapse and survival.

A 58-year-old man with a 6-year history of successful radiation of solitary plasmacytoma of iliac, humeral, and femoral bone with minimal marrow involvement developed progressive pain in his foot during walking. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) (Picture 1) revealed multiple foot bone lesions and gallbladder tumors, and serum free kappa light chain had increased to 1,537 mg/L gradually with an elevated kappa/lambda ratio, although the plasma cell count in bone marrow was 1.5% and liver function test findings, CEA, and CA19-9 were normal. Based on endoscopic ultrasound and magnetic resonance imaging (Picture 2), both gallbladder cancer and plasmacytoma were suspected. Pathology after cholecystectomy revealed plasmacytoma with kappa light chain positivity (Picture 3, 4). The patient achieved complete response, and the pain disappeared with bortezomib-lenalidomide-dexamethasone followed by autologous stem cell transplantation. Plasmacytoma in the gallbladder is extremely rare, with 12 cases found in the literature, and it is difficult to distinguish from cancer based on imaging (1, 2). A diagnosis requires a biopsy.

Introduction: MALT1 is a key component of the CARD11-BCL10-MALT1 (CBM) complex, which activates the classical NF-κB pathway. JNJ-67856633 (JNJ-6633), a highly selective protease inhibitor of CBM-mediated NF-κB signaling, demonstrated potent anti-lymphoma activity in preclinical models. Here, we present results from a phase 1 dose escalation study of JNJ-6633 in patients (pts) with R/R B-NHL and CLL. Methods: Pts were ≥18 years with R/R B-NHL or CLL (per WHO/iwCLL criteria), ECOG PS ≤1, and ≥1 or 2 lines of therapy (LOT). Dose escalation was supported by a modified continual reassessment method to identify recommended phase 2 dose (RP2D). Pts received oral 50–600 mg JNJ-6633 once daily (QD). Loading doses (LD) were explored to accelerate steady-state exposure of JNJ-6633: 2 LD using capsules at 400 mg QD for 14 days followed by 300 mg QD, and 300 mg twice daily for 7 days followed by 300 mg QD. Similar LD were used for tablets. Results: At a clinical cutoff of 22 January 2023, 109 pts with R/R B-NHL or CLL received JNJ-6633 (n = 89, capsules; n = 20, tablets). Median duration of treatment was 10.3 weeks (range 0.57–176.29). Most common histology was diffuse large B-cell lymphoma (n = 65 [59.6%]). Treatment-emergent AEs were reported in 97.2% pts (Table). Hyperbilirubinemia was observed in 44% of pts and taken into consideration when selecting RP2D. Dose limiting toxicities were reported in 5 pts (400 mg, Grade 3 [G3] hyponatremia; 600 mg, G2 bradycardia; 300 mg, G3 febrile neutropenia; 400 mg LD, G3 renal failure; 300 mg LD, G3 acute renal failure); 4 pts continued with same dosing and 1 pt had dose reduction. Maximum-administered dose was 600 mg QD and maximum-tolerated dose was not reached. Based on toxicity profile, RP2D was 300 mg QD and LD 300 mg. No new safety signals were observed with both formulations at different LD. Preliminary pharmacokinetic data showed JNJ-6633 is rapidly absorbed (median Tmax, range 2–5 h), slowly eliminated at 50–600 mg doses, and accumulated ∼8-fold upon multiple dosing. Steady-state exposure of 50 mg capsule increased in an approximately dose proportional manner as the dose increased from 50 to 400 mg. Exposures were comparable between tablet doses of 200 or 240 mg and a capsule dose of 300 mg. Overall response rate (ORR) at RP2D (n = 36) was 27.8% (complete response, n = 4 [11.1%]; partial response, n = 6 [16.7%]). Responses were observed across indolent and aggressive histologic subtypes. Conclusions: Preliminary data from this phase 1 dose escalation study of JNJ-6633 indicates it has a manageable hematological and non-hematological safety profile. JNJ-6633 demonstrated clinical activity in indolent and aggressive lymphomas. LD may be associated with higher ORR and is further explored in expansion cohorts. Safety and efficacy results from this dose escalation study supported targeting MALT1 in pts with R/R B-NHL and CLL and further evaluation of JNJ-6633 in expansion cohorts. Encore Abstract—previously submitted to EHA 2023 The research was funded by: Janssen Pharmaceuticals Keywords: chronic lymphocytic leukemia (CLL), molecular targeted therapies, non-Hodgkin (pediatric, adolescent, and young adult) No conflicts of interests pertinent to the abstract.

Ξ − atomic X-ray spectroscopy is one of the most useful methods for investigation of the Ξ-nucleus strong interaction. A serious problem in the measurement is the significant background coming from in-flight Ξ − decay. For the first Ξ − atomic X-ray spectroscopy experiment, a novel method of identifying stopped Ξ − events using nuclear emulsion was developed to reject background photons from in-flight Ξ − decay. We succeeded in reducing the background to 1/170 by this method employing coincidence measurements using the nuclear emulsion and X-ray detectors.

A high-resolution measurement method based on X-ray microscopy was developed to analyze double-strangeness hypernuclear events with a complex topology in a nuclear emulsion. In a feasibility study performed on $$\alpha $$ -decay events in emulsions, the resolution of the X-ray microscopy in the focal plane was found to be 0.2  $$\upmu {\mathrm{m}}$$ , which shows an improvement by $$\sim 2.4$$ times to that of the optical microscopy used for conventional analysis. The extent to which the emulsion underwent modification as a result of X-ray irradiation was also evaluated. The modification mainly occurred in the form of a change in its thickness; however, this affection was adequately small to perform X-ray imaging if the duration of the irradiation was sufficiently short. Stereo imaging with X-ray microscopy improved the resolution by $$\sim 2.5$$ times to 0.28  $$\upmu {\mathrm{m}}$$ along the optical axis compared with the depth of field of the optical microscope, 0.7  $$\upmu {\mathrm{m}}$$ . We applied the developed method to the study of a double-strangeness hypernuclear event. The uncertainty on the position of the vertex point and the binding energy of the $$\Xi ^-$$ and $$^{14}$$ N system was improved from 3  $$\upmu {\mathrm{m}}$$ to 0.04  $$\upmu {\mathrm{m}}$$ and $$\pm 3$$  MeV to $$\pm 0.86$$  MeV, respectively. The binding energy was deduced to be $$-1.23 \pm 0.86~{\mathrm{MeV}}$$ , and this result indicates that a $$\Xi ^-$$ atomic state is produced in the observed event.

Although outcomes of transformed diffuse large B-cell lymphoma (DLBCL) from follicular lymphoma (FL) were improved using rituximab-combined immunochemotherapy, the efficacy of subsequent rituximab maintenance (RM) remains unclear. We retrospectively analyzed the prognoses of 519 patients with de novo DLBCL and 62 patients with concurrent DLBCL and FL (concurrent-DLBCL/FL). Progression-free survival (PFS) was shorter in patients with concurrent-DLBCL/FL than in de novo DLBCL (p=.030). Twenty-four patients with concurrent-DLBCL/FL received RM after induction therapy, and they achieved better OS and PFS (p=.010 and p<.001, respectively) with lower risk of relapse (p<.001) than the non-RM group. Moreover, concurrent-DLBCL/FL showed better subsequent OS and PFS after recurrence than de novo DLBCL (p=.0083 and p=.0044, respectively). Our study indicates that in the face of a high relapse rate, concurrent-DLBCL/FL is manageable and benefits from RM.

The clinical outcome of 576 patients with diffuse large B-cell lymphoma treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) without vincristine omission/reduction, and with vincristine omission/reduction was compared retrospectively. Vincristine had little impact on overall survival in most cases; however, excessive dose omission/reduction possibly reduces the effectiveness of R-CHOP therapy. Background: The R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) is the standard therapy for patients with diffuse large B-cell lymphoma (DLBCL). However, vincristine is sometimes omitted or reduced owing to side effects. Materials and Methods: We retrospectively reviewed newly diagnosed patients with DLBCL with R-CHOP-like chemotherapy in our institute from January 2005 to February 2018 to investigate whether the omission/reduction of vincristine reduced the efficacy of the treatment. We compared the overall survival (OS) with and without the omission/reduction of vincristine from the R-CHOP regimen. Results: A total of 576 cases were reviewed, and vincristine was omitted/reduced in 50 (9%) patients. The 4-year OS with and without vincristine omission/reduction for relative dose intensity < 80%, 50%, and 25% was 70% versus 82% (P =.035), 70% versus 82% (P = .085), and 53% versus 82% (P = .0007). In a multivariate analysis, adjusting for international prognostic index risk factors, a statistically significant, poor OS was indicated in the patients with relative dose intensity < 25%. Conclusions: Excessive dose omission/reduction of vincristine might lead to a substantial loss of efficacy of R-CHOP therapy. (C) 2020 The Author(s). Published by Elsevier Inc.

Primary pancreatic lymphomas are extremely rare, accounting for 0.1–0.5% of malignant lymphomas and about 0.2% of primary pancreatic tumors. They occur most commonly in the pancreatic head of elderly males, with diffuse large B-cell lymphoma being the most common subtype. Primary pancreatic follicular lymphoma is the most commonly reported primary pancreatic indolent lymphoma, accounting for 9–14% of primary pancreatic lymphomas. We report two cases of primary pancreatic follicular lymphoma treated with obinutuzumab, a second-generation humanized anti-CD20 monoclonal antibody, and bendamustine. One was diagnosed by endoscopic ultrasound-guided fine-needle aspiration, while the other required laparoscopic lymph node sampling to reach a diagnosis. Both achieved complete response with induction therapy and opted for maintenance therapy with obinutuzumab. We also conducted a literature review of primary pancreatic follicular lymphoma cases reported over the last 30 years.

Peripheral T-cell lymphoma (PTCL) is a group of aggressive lymphomas commonly treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Progression-free survival at 24 months (PFS24) constitutes a survival predictor for some lymphomas but has not been examined in Asian populations. We retrospectively investigated whether PFS24 was predictive of survival outcomes after CHOP treatment in 73 Japanese patients with PTCL. Patients without PFS24 had shorter median subsequent overall survival (OS) (20.2 vs. 121.0 months, p < 0.001) and shorter median subsequent progression-free survival (5.0 vs. 17.1 months, p = 0.03). Patients without PFS24 had worse overall (62.5% vs. 100%) and complete response rates (45.8% vs. 96.0%) (both p < 0.001). PFS24 absence (hazard ratio: 3.34, p = 0.004) and poor performance status (hazard ratio: 3.17, p = 0.04) were independently predictive of shorter OS. These findings suggest that PFS24 is predictive of survival after CHOP treatment in Japanese patients with PTCL.

Background High-risk cytogenetic abnormality (CA) influences the prognosis of multiple myeloma (MM) even in the era of novel agents. However, prognostic heterogeneity could exist in MM patients with high-risk CA and additional cytogenetic aberrations are possibly correlated with worse outcomes. We conducted a retrospective study in patients with MM with high-risk CA to evaluate whether the outcomes are different in each high-risk group and whether the existence of additional chromosomal abnormalities would lead to poor outcomes. Method Patients with newly diagnosed MM (NDMM) in our institute between February 2006 and December 2020 were enrolled in this retrospective cohort. We analyzed only patients who were treated with novel agents including proteasome inhibitor and/or immunomodulatory drugs. All of cytogenetic abnormalities were analyzed from bone marrow samples. In this cohort, we defined high-risk CA as del(17p), t(4;14), t(14;16), and/or 1q21 gain, all of which were identified using FISH analysis. We surveyed additional chromosomal aberrations using G-banding testing. Complex chromosomal abnormality was defined as three or more chromosomal aberrations accompanying with at least one structural aberration. The survival was calculated by the Kaplan Meier method, and statistical analysis was performed by the Log-rank test. Factors affecting OS and PFS were evaluated using Cox proportional hazard model. Results We analyzed 36 MM patients who had high-risk CA at initial diagnosis. Twelve patients had del(17p), 16 had t(4;14), four had 1q21 gain, and four had more than one high-risk CA; two patients with t(4;14) and 1q21 gain, one with del(17p) and 1q21 gain and one with del(17p), t(4;14), and 1q21 gain. G-banding testing showed that patterns of complex chromosomal abnormality were found in nine patients. No significant differences in progression-free survival (PFS) and overall survival (OS) were seen between each high-risk CA group. The tendency of shorter PFS and OS was observed in patients with concurrent complex chromosomal karyotype than patients with no additional chromosomal aberrations. Furthermore, we found that the existence of complex cytogenetic abnormality by G-banding was correlated with poor PFS by multivariate analysis (hazard ratio 4.01, 95% confidence interval 1.35–11.9, p = 0.012). In addition, seven of nine MM patients with complex chromosomal karyotype had concurrent plasmacytoma. Conclusion Although the limitation of retrospective study design and the small sample size exists, our findings indicate that the coexistence of complex chromosomal abnormality, probably which reflects aggressive disease status like extraosseous or extramedullary disease, could be associated with poor prognoses of MM patients with high-risk CA. High-risk cytogenetic abnormality (CA) influences the prognosis of multiple myeloma (MM) even in the era of novel agents. However, prognostic heterogeneity could exist in MM patients with high-risk CA and additional cytogenetic aberrations are possibly correlated with worse outcomes. We conducted a retrospective study in patients with MM with high-risk CA to evaluate whether the outcomes are different in each high-risk group and whether the existence of additional chromosomal abnormalities would lead to poor outcomes. Patients with newly diagnosed MM (NDMM) in our institute between February 2006 and December 2020 were enrolled in this retrospective cohort. We analyzed only patients who were treated with novel agents including proteasome inhibitor and/or immunomodulatory drugs. All of cytogenetic abnormalities were analyzed from bone marrow samples. In this cohort, we defined high-risk CA as del(17p), t(4;14), t(14;16), and/or 1q21 gain, all of which were identified using FISH analysis. We surveyed additional chromosomal aberrations using G-banding testing. Complex chromosomal abnormality was defined as three or more chromosomal aberrations accompanying with at least one structural aberration. The survival was calculated by the Kaplan Meier method, and statistical analysis was performed by the Log-rank test. Factors affecting OS and PFS were evaluated using Cox proportional hazard model. We analyzed 36 MM patients who had high-risk CA at initial diagnosis. Twelve patients had del(17p), 16 had t(4;14), four had 1q21 gain, and four had more than one high-risk CA; two patients with t(4;14) and 1q21 gain, one with del(17p) and 1q21 gain and one with del(17p), t(4;14), and 1q21 gain. G-banding testing showed that patterns of complex chromosomal abnormality were found in nine patients. No significant differences in progression-free survival (PFS) and overall survival (OS) were seen between each high-risk CA group. The tendency of shorter PFS and OS was observed in patients with concurrent complex chromosomal karyotype than patients with no additional chromosomal aberrations. Furthermore, we found that the existence of complex cytogenetic abnormality by G-banding was correlated with poor PFS by multivariate analysis (hazard ratio 4.01, 95% confidence interval 1.35–11.9, p = 0.012). In addition, seven of nine MM patients with complex chromosomal karyotype had concurrent plasmacytoma. Although the limitation of retrospective study design and the small sample size exists, our findings indicate that the coexistence of complex chromosomal abnormality, probably which reflects aggressive disease status like extraosseous or extramedullary disease, could be associated with poor prognoses of MM patients with high-risk CA.

Maintenance ± consolidation or continuous therapy is considered a standard of care for both transplant–eligible and –ineligible patients with multiple myeloma (MM). However, long-term benefits of such therapy have not yet been clarified in the context of clinical practice. To clarify the efficacy of maintenance/continuous approach, we retrospectively analyzed the cohort data of newly diagnosed MM patients by propensity-score matching based on age, gender, revised International Staging System (R-ISS) stage, and implementation of transplantation to reduce the bias due to confounding variables. Among 720 patients, 161 were identified for each of the maintenance and no maintenance groups. Maintenance/continuous therapy employed immunomodulatory drugs (n = 83), proteasome inhibitors (n = 48), combination of both (n = 29), or dexamethasone alone (n = 1). Progression-free survival (PFS) was significantly prolonged in the maintenance group compared with the no maintenance group (median 37.7 and 21.9 months, p = 0.0002, respectively). Prolongation of PFS was observed in both transplanted and non-transplanted patients (p = 0.017 and p = 0.0008, respectively), with standard risk (p < 0.00001), R-ISS stage I (p = 0.037) and stage II (p = 0.00094), and those without obtaining complete response (p = 0.0018). There was no significant benefit in overall survival (OS), but it tended to be better in the maintenance group in non-transplanted patients. Regarding the treatment pattern, the substitution or addition of drugs different from the induction therapy and the combination with immunomodulatory drugs and proteasome inhibitors appeared to be more beneficial for PFS but not OS. These results support the benefit of current maintenance/continuous approach in routine clinical practice in the management of MM.

Multiple myeloma (MM) is still extremely difficult to cure, and new therapeutic drugs are needed. We recently found that integrin β7 is constitutively activated in MM cells, and chimeric antigen receptor (CAR) T cells targeting activated integrin β7 have a significant anti-MM effect. In this study, we performed flow cytometry analysis of the expression of activated integrin β7 in bone marrow cells from 137 symptomatic MM patients. In 60/137 (44%) MM patients, activated integrin β7 was detected in most MM cells (> 80% of MM cells were in the positive gate). Activated integrin β7 was highly expressed in MM cells even in heavily treated patients. It also showed high expression in many CD38lo/−CD138−CD19+B cells, which reportedly include clonotypic B cells, in the bone marrow of MM patients. Taken together, these results suggest that CAR T-cell therapy targeting activated integrin β7 has the potential to benefit many patients with relapsed or refractory MM.

Background A classification tree was used to analyze background factors for granulocyte colony-stimulating factor (G-CSF) preparation selection for febrile neutropenia (FN) prophylaxis in Japanese patients with non-Hodgkin B-cell lymphoma receiving the first R-CHOP cycle. Methods This was a subanalysis of the retrospective observational study STOP FN in NHL 2 (UMIN000029534). Patient characteristics, changes in neutrophil count, incidence and severity of neutropenia, and risk factors for dose reduction/delay of R-CHOP were assessed by G-CSF formulation. Results Among 234 patients in cycle 1, 25.6% received no G-CSF preparation, 52.1% received daily G-CSF, and 22.2% received pegfilgrastim. Pegfilgrastim use was most frequent among patients aged ≥ 80 years, while that of daily G-CSF was most frequent in patients with lymphocyte count (LC) < 1000 cells/μL. Changes in neutrophil count were more marked with pegfilgrastim compared with daily G-CSF and no G-CSF. Relevant factors for G-CSF preparation selection in the first R-CHOP cycle were age ≥ 80 years and LC < 1000 cells/μL; for chemotherapy dose reduction were FN onset in cycle 1 and female sex; and for dose delay was hemoglobin (< 12 g/dL). After cycle 2 and onward, pegfilgrastim use increased markedly (72.6%) compared with cycle 1 (22.2%), with significantly greater proportions continuing pegfilgrastim use and switching from daily G-CSF. Conclusion Relevant factors for G-CSF preparation selection were age ≥ 80 years and LC < 1000 cells/μL. The use of pegfilgrastim increased markedly after cycle 2. These results may be useful for selecting appropriate G-CSF preparations in the first R-CHOP cycle. Trial registration UMIN000029534; registered on 13 October 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000033733 .

Multiple myeloma has been known as an incurable disease; however, since the approval of bortezomib in Japan in 2006 as the treatment for relapsed and refractory multiple myeloma, novel agents such as immunomodulatory drugs (IMIDs) and antibodies have been introduced one after another. Hence, progression-free survival and overall survival rates have markedly improved, regardless of the transplantation indication, and we have entered an era of a possible cure. Now that long-term survival can be expected, some clinical issues exist: 1) when to start treatment, 2) what regimen to choose for initial treatment, 3) how to continue treatment including maintenance therapy, 4) what to do for supportive care, and 5) what to choose for relapse treatment. The answers to these questions should be revised year-by-year according to the evidence from new clinical trials. This paper will discuss the current state of knowledge based on the latest evidence on treatment strategies for patients with myeloma who are ineligible for transplantation.

The central nervous system (CNS) relapse in patients with diffuse large B cell lymphoma (DLBCL) is fatal as there are no effective rescue treatments. To test if the presence of the MYD88 L265P mutation is a prognostic factor for secondary CNS relapse, we carried out the digital PCR analysis of 134 samples from patients with DLBCL at diagnosis. The MYD88 L265P mutations were detected in 22 (16.4%) patients, particularly in those with a non-GC subtype, CD5-positive, high absolute monocyte count, extra-nodal lymphoma, and B symptoms. Nine patients showed low signal in digital PCR but were deemed positive for the MYD88 L265P mutation by the nested allele-specific PCR. The remaining 103 patients were negative according to the results of both the PCR analyses. With a median follow-up period of 64 months, the carriers of MYD88 L265P mutation exhibited inferior CNS relapse-free survival at 5 years (53.2% versus 96% and 100%, respectively, P < 0.001) with a significant effect of the mutation demonstrated by the multivariate analysis (hazard ratio 5.1; 95% CI 1.2-22.9, P = 0.02). This suggests that the MYD88 L265P mutation plays a critical role in the progression of DLBCL to CNS.