Comparison of infectious complications with BCMA-directed therapies in multiple myeloma.

B-cell-maturation-antigen (BCMA)-directed therapies are highly active for multiple myeloma, but infections are emerging as a major challenge. In this retrospective, single-center analysis we evaluated infectious complications after BCMA-targeted chimeric-antigen-receptor T-cell therapy (CAR-T), bispecific-antibodies (BsAb) and antibody-drug-conjugates (ADC). The primary endpoint was severe (grade ≥3) infection incidence. Amongst 256 patients, 92 received CAR-T, 55 BsAb and 109 ADC. The incidence of severe infections was higher with BsAb (40%) than CAR-T (26%) or ADC (8%), including grade 5 infections (7% vs 0% vs 0%, respectively). Comparing T-cell redirecting therapies, the incidence rate of severe infections was significantly lower with CAR-T compared to BsAb at 1-year (incidence-rate-ratio [IRR] = 0.43, 95%CI 0.25-0.76, P = 0.004). During periods of treatment-emergent hypogammaglobulinemia, BsAb recipients had higher infection rates (IRR:2.27, 1.31-3.98, P = 0.004) and time to severe infection (HR 2.04, 1.05-3.96, P = 0.036) than their CAR-T counterparts. During periods of non-neutropenia, CAR-T recipients had a lower risk (HR 0.44, 95%CI 0.21-0.93, P = 0.032) and incidence rate (IRR:0.32, 95% 0.17-0.59, P < 0.001) of severe infections than BsAb. In conclusion, we observed an overall higher and more persistent risk of severe infections with BsAb. Our results also suggest a higher infection risk during periods of hypogammaglobulinemia with BsAb, and with neutropenia in CAR-T recipients.

Prognostic impact of corticosteroid and tocilizumab use following chimeric antigen receptor T-cell therapy for multiple myeloma.

Despite being the mainstay of management for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), there is limited data regarding the impact of tocilizumab (TCZ) and corticosteroids (CCS) on chimeric antigen receptor (CAR) T-cell efficacy in multiple myeloma (MM). The present study aims to evaluate the prognostic impact of these immunosuppressants in recipients of BCMA- or GPRC5D-directed CAR T cells for relapsed/refractory MM. Our retrospective cohort involved patients treated with commercial or investigational autologous CAR T-cell products at a single institution from March 2017-March 2023. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), complete response rate (CRR), and overall survival (OS). In total, 101 patients (91% treated with anti-BCMA CAR T cells and 9% treated with anti-GPRC5D CAR T cells) were analyzed. Within 30 days post-infusion, 34% received CCS and 49% received TCZ for CRS/ICANS management. At a median follow-up of 27.4 months, no significant difference in PFS was observed between CCS and non-CCS groups (log-rank p = 0.35) or between TCZ and non-TCZ groups (log-rank p = 0.69). ORR, CRR, and OS were also comparable between evaluated groups. In our multivariable model, administering CCS with/without TCZ for CRS/ICANS management did not independently influence PFS (HR, 0.74; 95% CI, 0.36-1.51). These findings suggest that, among patients with relapsed/refractory MM, the timely and appropriate use of CCS or TCZ for mitigating immune-mediated toxicities does not appear to impact the antitumor activity and long-term outcomes of CAR T-cell therapy.

Comparison of Infectious Complications with BCMA-directed Therapies in Multiple Myeloma.

B-cell-maturation-antigen (BCMA)-directed therapies are highly active for multiple myeloma, but infections are emerging as a major challenge. In this retrospective, single-center analysis we evaluated infectious complications after BCMA-targeted chimeric-antigen-receptor T-cell therapy (CAR-T), bispecific-antibodies (BsAb) and antibody-drug-conjugates (ADC). The primary endpoint was severe (grade ≥ 3) infection incidence. Amongst 256 patients, 92 received CAR-T, 55 BsAb and 109 ADC. The incidence of severe infections was higher with BsAb (40%) than CAR-T (26%) or ADC (8%), including grade 5 infections (7% vs 0% vs 0%, respectively). Comparing T-cell redirecting therapies, the incidence rate of severe infections was significantly lower with CAR-T compared to BsAb at 1-year (incidence-rate-ratio [IRR] = 0.43, 95%CI 0.25-0.76, P = 0.004). During periods of treatment-emergent hypogammaglobulinemia, BsAb recipients had higher infection rates (IRR:2.27, 1.31-3.98, P = 0.004) and time to severe infection (HR 2.04, 1.05-3.96, P = 0.036) than their CAR-T counterparts. During periods of non-neutropenia, CAR-T recipients had a lower risk (HR 0.44, 95%CI 0.21-0.93, P = 0.032) and incidence rate (IRR:0.32, 95% 0.17-0.59, P < 0.001) of severe infections than BsAb. In conclusion, we observed an overall higher and more persistent risk of severe infections with BsAb. Our results also suggest a higher infection risk during periods of hypogammaglobulinemia with BsAb, and with neutropenia in CAR-T recipients.

Prognostic value of post-treatment serum soluble interleukin-2 receptor in newly diagnosed diffuse large B-cell lymphoma patients who achieved complete metabolic response following R-CHOP therapy.

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.

Propensity-score matched analysis of the efficacy of maintenance/continuous therapy in newly diagnosed patients with multiple myeloma: a multicenter retrospective collaborative study of the Japanese Society of Myeloma.

BACKGROUND: 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. PURPOSE: 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. FINDINGS: 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. CONCLUSION: These results support the benefit of current maintenance/continuous approach in routine clinical practice in the management of MM.

[Treatment strategies for longer life of patients with transplant-ineligible multiple myeloma].

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.

Pancreatic follicular lymphoma: a report of two cases and literature review.

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.

Expression of activated integrin ß7 in multiple myeloma patients.

Multiple myeloma (MM) is still extremely difficult to cure, and new therapeutic drugs are needed. We recently found that integrin ß7 is constitutively activated in MM cells, and chimeric antigen receptor (CAR) T cells targeting activated integrin ß7 have a significant anti-MM effect. In this study, we performed flow cytometry analysis of the expression of activated integrin ß7 in bone marrow cells from 137 symptomatic MM patients. In 60/137 (44%) MM patients, activated integrin ß7 was detected in most MM cells (> 80% of MM cells were in the positive gate). Activated integrin ß7 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 ß7 has the potential to benefit many patients with relapsed or refractory MM.

Factors for the optimal selection of granulocyte colony-stimulating factor preparations and predictors for R-CHOP dose reductions/delays among patients with non-Hodgkin B-cell lymphoma (STOP FN in NHL 2 subanalysis).

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 .

Rituximab maintenance improves outcomes of transformed diffuse large B-cell lymphoma: a retrospective study of 519 cases with de novo diffuse large B-cell lymphoma and 62 cases with concurrent diffuse large B-cell lymphoma and follicular lymphoma.

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.

Progression-free survival at 24 months as a predictor of survival outcomes after CHOP treatment in patients with peripheral T-cell lymphoma: a single-center validation study in a Japanese population.

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.

Impact of Omission/Reduction of Vincristine From R-CHOP in Treatment of DLBCL.

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.

The clonal evolution during long-term clinical course of multiple myeloma.

Somatic gene mutations related to acceleration disease and clonal evolution in multiple myeloma strongly influence severe clinical outcomes. In this study, we traced the transition of somatic mutations during the clinical course of myeloma patients over a long-term follow-up period (8.5 year average). Seven myeloma cases treated with immuno-chemotherapy at our institution were analyzed with clinical courses and the results of FISH and G-band analyses. Furthermore, the target sequences in regard to 121 genes, related to driver mutations or acceleration of disease in myeloma, were performed using bone marrow myeloma samples by next-generation sequencing, Ion Proton™ System. We detected a relationship between an increase in the dominant mutated gene (e.g., TP53, DIS3, FAM46C, KDM6B, and EGR1) and poor prognosis. In particular, clonal escalation of the TP53 mutation could not be overcome by any treatment. The selection of a combination treatment conducted in conjunction with the monitoring of gene mutations is appropriate for long-term survival. Our data demonstrate that long-term follow-up of somatic gene mutations during the clinical course of myeloma is helpful in the development of an effective treatment strategy.

MYD88 L265P mutation detected by digital PCR as a prognostic factor in patients with diffuse large B-cell lymphoma in rituximab era.

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.

Insignificance of surveillance imaging in patients with diffuse large B-cell lymphoma who achieved first complete remission: a retrospective cohort study.

The aim of this study was to evaluate the value of scheduled imaging for patients who achieved first complete remission after CHOP-like chemotherapy plus rituximab. In this retrospective cohort study, we included 759 patients newly diagnosed with de novo diffuse large B-cell lymphoma (DLBCL) at the Cancer Institute, Japanese Foundation for Cancer Research. Relapsed patients were divided into two groups based on method of diagnosis: clinical symptoms (symptom group, n = 57) or scheduled imaging (imaging group, n = 27). Our primary goal was to compare overall survival and relapse-free survival between the two groups. No significant difference in outcomes was found between the symptom and imaging groups. Median overall survival [7.5 years; 95% confidence interval (CI) 4.0-9.7 vs. 9.1 years; 95% CI 2.7 to not reached; P = 0.747), and median relapse-free survival (1.8 years; 95% CI 1.4-2.5 vs. 2.4 years; 95% CI 1.2-4.4; P = 0.108). Surveillance imaging in patients with DLBCL who achieved first complete remission did not demonstrate an advantage in terms of overall survival or relapse-free survival.

Incidence and risk factors for febrile neutropenia in Japanese patients with non-Hodgkin B cell lymphoma receiving R-CHOP: 2-year experience in a single center (STOP FN in NHL 2).

BACKGROUND: Myelosuppressive chemotherapy-induced febrile neutropenia (FN) is a life-threatening condition. Patients receiving granulocyte colony-stimulating factors (G-CSF) have shorter duration of neutropenia, faster recovery from fever, and shorter duration of antibiotics use. Most strategies for FN prevention using daily G-CSF and pegfilgrastim are based on overseas studies. Data on Japanese patients were lacking; thus, we previously determined the incidence of FN in non-Hodgkin B cell lymphoma (B-NHL) patients at our center. Here, we aimed to gain additional insights into pegfilgrastim use in this population. METHODS: This single-center, retrospective, observational study (STOP FN in NHL 2) enrolled patients with B-NHL who underwent a regimen comprising rituximab and CHOP therapy over a 2-year period (January 2015-June 2017). The incidence of FN in cycle 1 of chemotherapy, risk factors for FN development, and use of daily G-CSF and pegfilgrastim were evaluated. RESULTS: We evaluated 239 patients: 61 patients did not receive G-CSF and 178 received G-CSF. The incidence of FN was 10.5% (95% confidence interval [CI] 6.9-15.1%) in cycle 1 and 13.0% (95% CI 9.0-17.9%) in all cycles. The FN incidence was significantly lower (P = 0.0008) in patients receiving daily G-CSF and pegfilgrastim than patients not receiving G-CSF. Significant risk factors for FN were age ≥ 65 years, albumin < 3.5 g/dL, hemoglobin < 12 g/dL, and no prophylaxis with daily G-CSF/pegfilgrastim during cycle 1. CONCLUSIONS: The incidence of FN in cycle 1 and in all cycles and the identified risk factors were similar with those we previously reported; thus, our results validate previous findings. TRIAL REGISTRATION: UMIN000029534.

Bortezomib, lenalidomide, and dexamethasone in transplant-eligible newly diagnosed multiple myeloma patients: a multicenter retrospective comparative analysis.

The combination of bortezomib, lenalidomide, and dexamethasone (VRD) is used as induction treatment in multiple myeloma; however, the optimum schedule for this regimen remains controversial. In this retrospective study, we compared the efficacy and tolerability of twice-weekly VRD (twVRD) and modified VRD-lite in transplant-eligible myeloma patients. Fifty-five patients (median age 61 years) were included; 22 received twVRD (bortezomib [1.3 mg/m2 on days 1, 4, 8, and 11] and lenalidomide [25 mg/body on days 1-14] over 21-day cycles) and 33 received modified VRD-lite (bortezomib [1.3 mg/m2 on days 1, 8, 15, and 22) and lenalidomide [15 mg/body on days 2-7, 9-14, 16-21] over 28-day cycles). Overall response, very good partial response, and complete response rates after VRD were 96.4%, 45.5%, and 20.0%, respectively (median follow-up period, 17.7 months). The 1-year progression-free survival (PFS) and overall survival rates were 95.8% and 98.2%, respectively. The response rate and PFS were similar between the groups, regardless of cytogenetic risk and age. The incidence of peripheral neuropathy ≥ grade 2 and thrombocytopenia ≥ grade 3 was higher in the twVRD group (27.2% vs. 0.0%, P = 0.003 and 27.2% vs. 0.0%, P = 0.003). In conclusion, modified VRD-lite had similar efficacy with, but better tolerability than, twVRD in transplant-eligible patients.

Initial Experience of Pembrolizumab Therapy in Japanese Patients With Metastatic Urothelial Cancer.

BACKGROUND/AIM: Pembrolizumab was approved as second-line treatment for patients with metastatic urothelial cancer (UC) in Japan. We performed a retrospective pilot study to assess the potency of pembrolizumab treatment in Japan. PATIENTS AND METHODS: The medical records of 40 consecutive Japanese patients with metastatic UC who started pembrolizumab between January and October 2018 were reviewed and statistically analyzed to clarify the efficacy and safety of the drug. RESULTS: The objective response rate, median progression-free survival period, and median overall survival period were 20.6%, 4.1 months and 10.0 months, respectively. Multivariate analysis indicated the presence of liver metastasis, worse performance status (≥2), and higher C-reactive protein as factors predictive of shorter OS. CONCLUSION: We demonstrated for the first time, a comparable efficacy and safety profile of pembrolizumab for Japanese patients with metastatic UC, as in the KEYNOTE-045 study. The results indicate the features of pembrolizumab therapy in the current Japanese clinical practice.