Multiple myeloma is an incurable hematologic malignancy; however, survival outcomes have improved with the introduction of proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. As autologous transplantation remains the standard therapy, transplant eligibility determines the treatment strategy for newly diagnosed myeloma. Quadruplet first-line regimens were approved in 2025 and became the standard of care regardless of transplant eligibility, improving clinical outcomes. Minimal residual disease (MRD) has been identified as a surrogate marker for survival, and MRD negativity is increasingly being adopted as the primary endpoint in clinical trials. Autologous transplantation is associated with higher MRD negativity rates, but its necessity for patients who achieve MRD negativity may be open to debate. Furthermore, ongoing clinical trials are comparing autologous transplantation with CAR-T cell therapy and incorporating BCMA-targeted immunotherapies, including bispecific antibody drugs, into post-transplant maintenance therapy. This review summarizes treatment strategies for newly diagnosed myeloma in the era of quadruplet combination therapy.
Treatment of relapsed or refractory multiple myeloma (MM) has advanced substantially with the introduction of chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibody therapy targeting B-cell maturation antigen (BCMA). CAR-T therapy induces high complete response rates and deep minimal residual disease negativity after a single infusion. In a subset of patients, remission persists beyond completion of therapy, making treatment-free intervals an achievable therapeutic objective in MM. In contrast, BCMA-directed bispecific antibody therapy can be administered without manufacturing delay and provides rapid and durable responses. It also reduces the cumulative treatment burden by enabling outpatient management and extended dosing intervals. Despite these advances, clinically relevant challenges remain. Sustained T-cell activation may result in hypogammaglobulinemia and increased susceptibility to infections, while antigen loss and T-cell exhaustion represent key mechanisms of relapse. Careful monitoring of immune reconstitution and appropriate infection prophylaxis are therefore essential components of MM management. Future therapeutic strategies should emphasize optimal treatment sequencing, evaluation of fixed-duration approaches, and development of multi-antigen targeting platforms to overcome resistance. Achieving durable remission while preserving functional capacity and improving quality of life has become an important goal in the treatment of MM.
Idecabtagene vicleucel (ide-cel) is effective for relapsed/refractory multiple myeloma (RRMM), but real-world data in Japan are limited. We retrospectively analyzed 11 patients with RRMM who received ide-cel at our institution. The median age at infusion was 67 years (range, 54-71), and the median number of prior lines of therapy was 4 (range, 3-6). At best response, the overall response rate was 90.0%, with a complete response rate of 60.0%. With a median follow-up of 530 days (range, 198-1,032) among survivors, the 1-year overall survival and progression-free survival rates were 90.9% and 71.6%, respectively. Cytokine release syndrome (CRS) occurred in all patients, including one fatal grade 5 event. Analysis of peripheral blood chimeric antigen receptor T-cell (CAR-T) kinetics showed a trend toward better progression-free survival in patients with greater expansion from day0 to day28. Although the efficacy of ide-cel for RRMM in our cohort was comparable to that in previous reports, the management of severe CRS remains a challenge. Further investigation in a larger cohort is required to establish predictive factors for safety and efficacy in Japanese clinical practice.
To address the challenges of regional collaboration in the treatment of hematologic malignancies, we conducted a prospective clinical study of a healthcare communication platform (Dr2GO®) designed to ensure seamless continuity of care by streamlining inter-hospital transfer coordination. By the end of 2024, nineteen patients were enrolled across the four participating institutions. The most frequently used clinical pathway was vaccination after allogeneic hematopoietic stem cell transplantation (7 cases). The median time from the referral request by the hub hospital to confirmation by the community institution was 15 hours. Among the cases requested during regular working hours, 83% were confirmed within 30 minutes. The median duration of pathway continuation was 9.5 months, with a continuation rate of 78.9%. In a survey, 75% of respondents reported faster medical coordination. During the study period, 26 chat entries were recorded, with a median of one entry per patient. These findings suggest that the Dr2GO®-based electronic clinical pathway both facilitates rapid transfer coordination and efficient information sharing, while potentially reducing physician workload and promoting task shifting.
This review outlines the clinical significance of comprehensive genomic profiling (CGP) in patients with hematopoietic failure, including severe unexplained cytopenia. Since March 2025, Japanese National Health Insurance has covered CGP for hematologic malignancies and related disorders, facilitating a genome-based precision medicine approach that complements conventional clinical approaches, including morphologic and cytogenetic analyses. In bone marrow failure phenotypes, CGP supports differentiation of aplastic anemia from myelodysplastic syndromes and related diseases by evaluating genetic alterations. In addition to diagnosis, CGP contributes to prognostic stratification and evaluation of inherited bone marrow failure syndromes, which may present with minimal extra-hematologic features. However, accurate interpretation of CGP results requires not only understanding the genetic pathology of each disease, but also awareness of the characteristics of the CGP and the pitfalls specific to hematopoietic diseases (such as clonal hematopoiesis) and discussions with an expert panel. This review aims to facilitate the interpretation of CGP results to optimize clinical management for patients with hematopoietic failure.
The prognosis of multiple myeloma (MM) has improved dramatically over the past two decades with the introduction of proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, and, more recently, immune-based therapies such as chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies. Quadruplet regimens are now used in the frontline setting, enabling deeper responses and long-term survival, and even making functional cure a realistic goal for some patients. Nevertheless, MM remains a relapsing disease, and outcomes of triple-class-exposed (TCE) patients are still poor. While novel immunotherapies have significantly improved outcomes in relapsed or refractory MM, their extremely high costs may threaten the sustainability of healthcare systems, particularly in countries with universal health coverage, such as Japan. Cost-effectiveness analysis (CEA) using quality-adjusted life years (QALYs) provides a quantitative framework to evaluate the value of high-cost therapies. In this review, we summarize recent advances in immunotherapy for MM and discuss the cost-effectiveness of these therapies based on clinical trials, real-world data, and modeling studies. We also present our own analyses of daratumumab-based quadruplet induction and anti-BCMA CAR-T therapy. Finally, we discuss future strategies to balance innovation and sustainability, including patient selection, subgroup-based treatment optimization, and minimal residual disease-guided treatment discontinuation.
Epcoritamab, a subcutaneous CD3×CD20 bispecific antibody, has shown high efficacy in relapsed or refractory large B-cell lymphoma (R/R LBCL). However, treatment options are limited for patients who fail to achieve durable remission after immune-based therapy. Here, we describe a case of refractory diffuse large B-cell lymphoma in an 87-year-old woman who achieved long-term remission through concurrent epcoritamab and radiotherapy. During the fifth cycle of third-line epcoritamab therapy, positron emission tomography/computed tomography revealed persistent fluorodeoxyglucose-avid lesions in the spleen and mediastinum. Volumetric modulated arc therapy of 36 Gy in 18 fractions was administered to both sites while continuing epcoritamab (administered during the sixth cycle for the splenic lesion and during the thirteenth and fourteenth cycles for the mediastinal lesion). The combined therapy resulted in complete metabolic response without significant adverse events, and the patient remains in remission beyond 27 treatment cycles. In this case, we obtained durable remission by adding radiotherapy for localized lymphoma refractory to epcoritamab. The absence of cross-resistance between radiotherapy and systemic chemotherapy supports the rationale for local irradiation as a complementary approach to bispecific antibody therapy. This combination may represent a feasible and well-tolerated option for elderly or heavily pretreated patients with localized refractory disease.
In the 5th edition of the WHO classification, Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (EBV+ nTNKL) is a newly defined, poor-prognosis disease originating from cytotoxic T cells. Here, we report a rare case of lymphoma arising in immune deficiency/dysregulation with an immunophenotype of EBV+ nTNKL that emerged during treatment for follicular lymphoma (FL). A 71-year-old woman was diagnosed with FL grade 3A and received chemotherapy with rituximab. Despite treatment, the disease relapsed repeatedly. During follow-up, she presented with fever and lymphadenopathy. An axillary lymph node biopsy revealed a diffuse proliferation of abnormal lymphocytes expressing CD3, CD4, TIA-1, granzyme B, and EBER, consistent with the EBV+ nTNKL immunophenotype. CHOP therapy was administered; however, disease control proved difficult, and the patient died 5 weeks after diagnosis. This case exemplifies a rare occurrence of EBV-associated lymphoma arising during the course of B-cell lymphoma. Our experience underscores that rapid clinical deterioration (e.g., fever, hepatosplenomegaly, or B symptoms) during the course of FL should prompt consideration of EBV-associated lymphoma in the differential diagnosis, alongside histologic transformation. Further case reports and molecular analyses should help improve diagnostic accuracy and establish treatment strategies for this rare and aggressive disease.
Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of relapsed/refractory hematologic malignancies, achieving remarkable response rates in B-cell acute lymphoblastic leukemia and lymphomas. However, treatment responses and toxicities vary substantially among patients, necessitating the establishment of robust predictive biomarkers for optimal patient stratification and treatment personalization. This review systematically categorizes key factors affecting CAR-T therapy efficacy into tumor-intrinsic and T cell-intrinsic components. Tumor-intrinsic factors include tumor burden, antigen expression heterogeneity, and immunosuppressive components within the tumor microenvironment, such as regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and inhibitory cytokines (e.g., TGF-β and IL-10). T cell-intrinsic factors encompass memory T cell subset composition, particularly central memory and stem cell memory populations, CAR expression density and transduction efficiency, polyfunctional cytokine production profiles, mitochondrial function and metabolic fitness, and expression of immune checkpoint molecules. Recent technological advances in single-cell RNA sequencing, comprehensive proteomics, and high-dimensional immunophenotyping combined with machine learning algorithms enable increasingly precise biomarker identification and predictive modeling. Integration of these multidimensional biomarkers into unified prediction models holds substantial promise for personalizing therapy, enhancing efficacy while minimizing adverse events, and ultimately achieving durable remission in patients receiving CAR-T therapy.
Allogeneic hematopoietic stem cell transplantation is the only curative treatment for myelofibrosis. However, the high risk of non-relapse mortality and the difficulty of finding an HLA-matched sibling donor are obstacles, given the advanced age at disease onset. Here, we report four cases of transplantation from an HLA-haploidentical donor using post-transplant cyclophosphamide (PTCy-haplo) in three recipients with primary (n=1) and secondary (n=2) myelofibrosis. The median age was 52 years, and one patient had received JAK2 inhibitor therapy prior to transplantation. The sources were bone marrow and peripheral blood stem cells (two cases each); myeloablative conditioning was used in two cases. Neutrophil engraftment was achieved in all cases (median 19 days); however, prolonged G-CSF administration (median 44 days) was required, and platelet engraftment was delayed (median 68 days). Two patients survived without relapse, with observation periods of 3.5 and 8 years, respectively. One patient relapsed 17 months after the first transplantation and died of pneumonia 49 days after second PTCy-haplo. These findings suggest that PTCy-haplo is a feasible option for patients with myelofibrosis; however, the risk of delayed hematopoietic recovery should be noted.
A 62-year-old man was referred to our hospital for leukocytosis with an increase (25.5%) of plasma cell-like cells in the peripheral blood. M-protein was not detected, and no deviation of the κ/λ ratio of free light chain was observed. Bone marrow biopsy showed increased plasma cell-like cell counts; however, immunohistochemical staining was positive only for CD138, and negative for both κ and λ chains. Non-secretory multiple myeloma (MM) was diagnosed based on morphological findings, although differential diagnosis from lymphoplasmacytic lymphoma was difficult. After remission induction treatment, the patient underwent autologous peripheral blood stem cell transplantation and relapsed one year later. The disease was refractory to various chemotherapies. To support the diagnosis, next-generation sequencing was performed on a bone marrow sample obtained at relapse. The analysis showed multiple mutations in driver genes (IRF4, TRAF2 and TRAF3) and 1q gain, which are characteristic of MM. These mutations are associated with a poor prognosis, which is consistent with the clinical course of the present case. This case highlights the potential utility of next-generation sequencing in diagnosis and therapeutic decision-making for MM.
The patient was a 37-year-old woman with immune thrombocytopenia (ITP) diagnosed at age 9. Steroids and splenectomy were ineffective, but high dose intravenous immunoglobulin therapy (IVIG) resulted in a transient increase in platelets. Platelet counts remained at 10,000 and 30,000/µl, so eltrombopag was started; however, the platelet count remained the same. In July 2023 (age 35 years), fostamatinib was started in combination with prednisolone 4 mg/day and eltrombopag 50 mg/day. In the first week, the platelet count rose to 126,000/µl, but then decreased; by the eighth week, it had fallen to 8,000/µl. When eltrombopag was changed to romiplostim, the platelet count generally exceeded 50,000/µl. Discontinuation of fostamatinib was attempted, but the platelet count fell to 29,000/µl. Upon resumption of fostamatinib, the platelet count stabilized again. In post-splenectomy chronic ITP patients with a long history of disease, responsiveness to IVIG indicates a high likelihood of response to fostamatinib, which has the same mechanism of action via Fc receptor inhibition. Combining fostamatinib with romiplostim, which promotes platelet production, may be beneficial due to their complementary mechanisms of action.
Hyperfibrinolysis-related bleeding is well recognized in conditions such as the acute phase of trauma, disseminated intravascular coagulation with hyperfibrinolysis, and acute promyelocytic leukemia. In contrast, whether primary hyperfibrinolysis can directly cause bleeding in the absence of an underlying disorder has not been sufficiently investigated, largely due to the lack of an established disease concept and the limited availability of reliable functional assays. Congenital deficiencies of individual fibrinolysis inhibitors-such as plasminogen activator inhibitor-1 (PAI-1) deficiency, α2-plasmin inhibitor (α2-PI) deficiency, and thrombomodulin (TM) disorders leading to impaired activation of thrombin-activatable fibrinolysis inhibitor (TAFI)-are extremely rare but are known to result in severe bleeding manifestations. Based on functional assessment assays for these conditions, we have proposed a novel disease entity, "bleeding disorders caused by hyperfibrinolysis," and established diagnostic criteria. This entity was designated in Japan as an intractable disease (No. 347), effective April 2025. This review outlines the clinical significance and diagnostic framework of this disorder and highlights the potential contribution of fibrinolytic dysfunction to bleeding disorder of unknown cause (BDUC).
Fibrin-associated large B-cell lymphoma is an extremely rare subtype of LBCL, characterized by distinctive pathological findings and symptoms, and is generally considered to follow an indolent clinical course. Here we report a case of fibrin-associated large B-cell lymphoma arising in association with an incidentally discovered left atrial myxoma, which has remained in remission with surgical resection alone. The patient was an 84-year-old woman. In September 2023, a routine preoperative chest X-ray performed prior to surgery for osteoarthritis of the shoulder revealed an abnormal shadow. Subsequent echocardiography demonstrated an intracardiac mass in the left atrium, and the patient was referred to our cardiology department. Echocardiography at our hospital revealed a pedunculated mass attached to the atrial septum, consistent with a diagnosis of left atrial myxoma. The mass measured approximately 80 mm and prolapsed between the left atrium and ventricle. Given the risk of obstruction, urgent surgical resection was performed. Histopathological examination of the resected specimen confirmed the diagnosis of fibrin-associated large B-cell lymphoma, and the patient was subsequently referred to the hematology department. A systemic workup revealed no evidence of additional disease. She has remained disease-free without any further therapy.
We report a rare case of JAK2 V617F-positive essential thrombocythemia (ET) followed by BCR::ABL1-positive chronic myeloid leukemia (CML) in a 47-year-old woman. Dasatinib induced deep molecular remission; however, persistent thrombocytosis required hydroxyurea. The persistence of the JAK2 V617F mutation despite BCR::ABL1 suppression suggests distinct clonal populations. This case underscores the importance of vigilance for secondary myeloproliferative neoplasms (MPNs) and clonal evolution when a new hematologic phenotype emerges in a patient with an established MPN. The coexistence of JAK2 V617F and BCR::ABL1 mutations is exceedingly rare and presents significant diagnostic and therapeutic challenges.
A 62-year-old man was diagnosed with JAK2 mutation positive essential thrombocythemia (ET) after developing cerebral infarction. He was treated with anagrelide and aspirin, with anagrelide increased to 5.5 mg/day, but platelet count remained around 700,000/µl. In July 2024, he presented to the emergency department with abdominal pain and vomiting. CT angiography showed a large gastric intramural hematoma as well as pseudoaneurysm from the right gastroepiploic artery. Following transcatheter arterial embolization, his symptoms improved, the hematoma decreased in size, and his condition stabilized. Gastric intramural hematoma is an extremely rare condition, often secondary to factors like anticoagulant therapy. Reports of cases diagnosed after resection of a suspected tumor highlight the importance of accurate diagnosis. Although thrombosis prevention is crucial in ET, anagrelide is associated with a higher risk of bleeding events than other therapies. To our knowledge, this is the first reported case of gastric intramural hematoma associated with ET and anagrelide.
POEMS syndrome is a rare multisystemic disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell dyscrasia, and skin changes. Markedly elevated serum vascular endothelial growth factor (VEGF) levels play a crucial role in its pathogenesis. Recent genomic studies have identified specific mutational patterns in the immunoglobulin lambda light chain gene (e.g., IGLV1-40 or IGLV1-44), providing new insights into the unique biology of POEMS syndrome. For clinical diagnosis, the Japanese diagnostic criteria are highly practical and accurate, designating polyneuropathy, monoclonal plasma cell proliferation, and elevated serum VEGF levels (>1,000 pg/ml) as mandatory major criteria. Treatment strategies are determined based on eligibility for autologous stem cell transplantation (ASCT). For eligible patients, high-dose melphalan followed by ASCT is the standard of care, yielding significant neurological improvement and favorable long-term survival. In contrast, for transplant-ineligible patients or as induction therapy before ASCT, novel agents such as thalidomide, lenalidomide, and bortezomib have demonstrated clinical efficacy. Serum VEGF levels serve as an essential biomarker that sensitively reflects disease activity and treatment response, making them indispensable for monitoring during follow-up. This review provides a comprehensive overview of recent advances in the pathogenesis, diagnostic refinements, and latest therapeutic strategies for POEMS syndrome based on recent scientific evidence.
Platelet function is regulated by numerous molecules, and congenital abnormalities of these molecules result in a variety of congenital platelet function disorders. Among these, Glanzmann thrombasthenia (GT), caused by a congenital deficiency or molecular abnormality in GPIIb-IIIa (αIIbβ3), and Bernard-Soulier syndrome (BSS), caused by a congenital deficiency or molecular abnormality in the GPIb-IX-V complex, are representative disorders that manifest as severe bleeding tendency from infancy. GT and BSS are diagnosed mainly by flow cytometry of membrane glycoproteins in addition to conventional light transmission aggregometry. Platelet transfusions are indicated for bleeding refractory to standard hemostatic measures, and recombinant factor VIIa (rFVIIa) has been shown to be effective in GT. rFVIIa has conventionally been used in GT patients refractory to platelet transfusion due to alloantibody production, but is now available in Japan regardless of alloantibody status or platelet transfusion refractoriness. rFVIIa should be considered especially in patients at risk of alloantibody production due to platelet transfusion.
A 26-year-old man presented in 2002 with petechiae, hemolytic anemia, and thrombocytopenia, raising suspicion for thrombotic thrombocytopenic purpura (TTP). His condition improved with plasma exchange, fresh frozen plasma (FFP) transfusion, and prednisolone. He was diagnosed with thrombotic microangiopathy and subsequently experienced multiple relapses, all treated successfully with FFP transfusion and prednisolone. During the sixth relapse in December 2018, a marked reduction in ADAMTS13 activity was detected, confirming the diagnosis of TTP. At the ninth relapse in June 2022, ADAMTS13 inhibitor testing was negative, and congenital TTP was considered as a differential diagnosis. However, repeated testing at another institution confirmed the presence of ADAMTS13 inhibitor, leading to the final diagnosis of immune-mediated TTP. After rituximab therapy, ADAMTS13 inhibitor became undetectable, and the patient has remained in remission for three years. This clinical course is atypical for immune-mediated TTP, as recurrent relapses were successfully managed with FFP transfusion and short-term prednisolone. This case provides important insights into the diagnosis and management of immune-mediated TTP.
Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by endothelial injury resulting from dysregulated activation of the alternative complement pathway. Clinical outcomes have markedly improved since the anti-complement agent eculizumab, an anti-C5 monoclonal antibody, became available in 2013. However, no established diagnostic method directly assesses complement activation for definitive diagnosis. In practice, diagnosis relies on the evaluation of pathogenic variants in complement-related genes as predisposing factors and on the exclusion of other diseases that can cause TMA. Consequently, distinguishing aHUS from secondary TMA can sometimes be clinically challenging. In particular, secondary TMA associated with hypertensive emergencies or pregnancy may overlap with aHUS, requiring careful diagnostic consideration. In recent years, several novel anti-complement agents have been developed. In addition to therapies targeting the terminal complement pathway downstream of C5, agents that act on the proximal complement cascade are also under development, and further clinical evidence on these strategies is awaited.