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Objective This study compared the tumor burden and prognostic impact of total diffusion volume (tDV) and total lesion glycolysis (TLG) in the same patients with newly diagnosed multiple myeloma (NDMM) simultaneously. We also examined the relationship between these imaging tumor volumes (TVs) and plasma cell (PC) TV in bone marrow (BM) specimens. Methods We retrospectively reviewed the data of 63 patients with newly diagnosed multiple myeloma (NDMM) from April 2016 to March 2018. tDV was calculated from whole-body diffusion-weighted imaging and TLG was calculated from the average standard uptake value and the metabolic tumor volume, respectively. Cellularity of BM hematopoietic tissue and the percentage of BM PCs were used as a reference of PC volume in the BM. Results The Spearman correlation coefficient between tDV and TLG was moderate (ɤs = 0.588, p < 0.001) when PET false-negative patients were excluded. There were positive correlations between the BM plasma cell volume (BMPCV) and the imaging TVs (ɤs = 0.505, vs. tDV; and 0.464, vs. TLG). Patients with high tDV and high TLG, as determined by the receiver operating characteristic curve, had worse survival; moreover, patients with both high tDV and high TLG showed the worst prognosis (median progression-free and overall survival: 13.2 and 28.9 months, respectively). Conclusions Although tDV and TLG each reflected the total TV, in several cases, tDV and TLG were discrepant due to the biological features of each MM. It is important to use both modalities for complementary assessment of total tumor burden and biological characteristics in MM. Key Points • Total diffusion volume (tDV) and total lesion glycolysis (TLG) reflect the total tumor volume and have prognostic value in patients with multiple myeloma (MM). • tDV and TLG could assess MM from different biological perspectives and should be considered for each patient individually.

We evaluated anti-spike protein antibody (anti-S) production in 130 hematopoietic stem cell transplant (HSCT) recipients who received the coronavirus disease-2019 vaccine. Sixty-five received allo-HSCT and 65 received auto-HSCT. Disease-specific treatments were being administered to 43.1% of allo-HSCT and 69.2% of auto-HSCT patients. Seropositivity was observed in 87.7% of allo-HSCT and 89.2% in auto-HSCT patients. Anti-S antibody production was significantly impaired in auto-HSCT patients compared with controls (178U/mL [0.4–4990.0] vs. 669 U/mL [40.3–4377.0], p < 0.001), but not in allo-HSCT patients (900 U/mL [0.4–12,893.0] vs. 860 U/mL [40.3–8988.0], P = 0.659). Clinically relevant anti-S antibody levels (> 264 U/mL) were achieved in 59.2% of patients (76.9% in allo-HSCT and 41.5% in auto-HSCT). The main factors influencing the protective level of the antibody response were the CD19 + cell count and serum immunoglobulin G levels, and these were significant in both allo-HSCT and auto-HSCT patients. Other factors included time since HSCT, complete remission status, use of immunosuppressive drugs, and levels of lymphocyte subsets including CD4, CD8 and CD56 positive cells, but these were only significant in allo-HSCT patients. Allo-HSCT patients had a relatively favorable antibody response, while auto-HSCT patients had poorer results.

CD38 expression on myeloma cells is a critical factor affecting the early response to the anti‐CD38 antibody daratumumab. However, factors affecting CD38 expression in untreated multiple myeloma are not fully elucidated. In this study, we found that CD38 expression was significantly lower in myeloma patients with the translocation t(11;14)‐associated immature plasma cell phenotype, and particularly in those expressing B–cell‐associated genes such as PAX5 and CD79A. CD138, a representative marker of plasmacytic differentiation, was also significantly lower in these patients, suggesting that CD38 expression may be associated with the differentiation and maturation stages of myeloma cells. Furthermore, the BCL2/BCL2L1 ratio, a response marker of the BCL2 inhibitor venetoclax, was significantly higher in patients with the immature phenotype expressing B–cell‐associated genes. The BCL2/BCL2L1 ratio and CD38 expression were significantly negatively correlated. We also confirmed that patients with translocation t(11;14) expressing B–cell‐associated genes were indeed less sensitive to daratumumab‐mediated direct cytotoxicity but highly sensitive to venetoclax treatment in ex vivo assays. Moreover, all‐trans‐retinoic acid, which enhances CD38 expression and induces cell differentiation in myeloma cells, reduced B‐cell marker expression and the BCL2/BCL2L1 ratio in myeloma cell lines, leading to reduced efficacy of venetoclax. Venetoclax specifically induces cell death in myeloma with t(11;14), although why patients with translocation t(11;14) show BCL2 dependence is unclear. These results suggest that BCL2 dependence, as well as CD38 expression, are deeply associated with the differentiation and maturation stages of myeloma cells. This study highlights the importance of examining t(11;14) and considering cell maturity in myeloma treatment strategies. Here, we show that the expression of CD38 and BCL2 dependence are associated with the differentiation/maturation stage of myeloma cells. Indeed, myeloma patients with the t(11;14)‐associated immature phenotype, especially those expressing B–cell‐related genes, showed significantly lower CD38 levels and higher BCL2 dependence. Our data may reveal factors affecting CD38 expression in untreated myelomas, and explain why t(11;14) myelomas are BCL2 dependent and susceptible to venetoclax.

This study investigated the clinical significance of loss of spleen visualization (LSV) on whole-body diffusion-weighted imaging (WB-DWI) in patients with multiple myeloma (MM). The WB-DWI of 96 patients with newly diagnosed MM (NDMM) and 15 patients with smoldering MM (sMM) were retrospectively reviewed. LSV was observed in 56 patients with NDMM (58.3%) and 1 patient with sMM (6.7%). Patients with NDMM with LSV had a higher median infiltration of bone marrow plasma cells (80.0% vs. 50.0%, p  < 0.001) and median total diffusion volume (median; 540.2 vs. 137.0 mL, p  = 0.003) than patients without LSV. Patients with LSV had a lower spleen-to-spinal cord ratio (0.36 vs. 0.96, p  < 0.001) and worse 2-year overall survival (OS) (84.6% vs. 100%, p  = 0.032). Patients who did not recover spleen visualization during treatment had a worse prognosis, even when they obtained very good partial response (median progression-free survival: 13.2 months). Spleen histopathological findings revealed higher cellularity and diffuse myeloma cell infiltration in a patient with LSV and splenic amyloidosis without extramedullary hematopoiesis in a patient without LSV. Therefore, LSV indicates worse prognosis for patients with MM, even when the patient responds to treatment. Further studies are warranted to clarify the immunological role of spleen in MM.

Patients with lymphoma are at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); therefore, evaluation of SARS-CoV-2 vaccination efficacy is essential. We conducted a prospective observational study to monitor the antibody response in 500 patients with lymphoma after SARS-CoV-2 vaccination. Antibody levels increased in a stepwise manner after the first and second dose of the vaccine. After completion of the two-dose series, anti-S antibody was negative in 109 patients (21.8%), and below clinically protective levels (anti-S ≥ 264 U/mL) in 236 patients (47.2%). The median anti-S titers at 0–6 months, 7–12 months, 13–24 months, and 24 months after treatment completion were 0.4 U/mL, 3.8 U/mL, 270 U/mL, and 650 U/mL, respectively. Multivariate analysis showed that receiving the vaccine < 6 months since completing treatment, white blood cell count < 5050/μL, percentage of CD19 + cells < 10%, CD4 + cells < 27%, immunoglobulin (Ig) A < 195 mg/dL, IgM < 50 mg/dL, serum soluble interleukin 2 receptor > 600 U/mL, and presence of lymphoma cells in the peripheral blood were significantly correlated with anti-S < 264 U/mL. Lymphoma patients had variably impaired antibody response to the SARS-CoV-2 vaccine. We identified various factors to predict COVID-19 vaccine effectiveness in lymphoma patients that may help tailoring possible vaccine boosters.

Stringent complete response (sCR) is defined as a deeper response than complete response (CR) in multiple myeloma. Whether achieving sCR correlates with better survival remains controversial. We evaluated the outcomes in patients with intact immunoglobulin multiple myeloma (IIMM) and light chain multiple myeloma (LCMM) who achieved a very good partial response (VGPR) or better. Multicolour flow cytometry was used to assess the depth of response. LCMM patients with sCR had significantly lower measurable residual disease (MRD) levels than those with CR (median MRD: 7.9 × 10 –4 vs. 5.6 × 10 –5 , P  < 0.01). Nonetheless, no significant difference was observed in MRD levels across the responses in groups of patients with IIMM (VGPR vs. CR: 3.5 × 10 –4 vs. 7.0 × 10 –5 , P  = 0.07; CR vs. sCR: 7.0 × 10 –5 vs. 5.4 × 10 –5 , P  = 0.81. In accordance with MRD levels, the median overall survival of patients with sCR was significantly longer (sCR, CR, VGPR; not reached, 41 months, and 58 months, respectively; VGPR vs. CR, P  = 0.83; CR vs. sCR, P  = 0.04) in LCMM, but not in IIMM (sCR, CR, VGPR; not reached, 41 months, and not reached, respectively; VGPR vs. CR, P  = 0.59; CR vs. sCR; P  = 0.10). Our results show that sCR represents a deeper response that correlates with longer survival in patients with LCMM, but not IIMM.

Chylous effusion is associated with lymphatic obstruction or leakage in mediastinal or abdominal lymph nodes, and is a rare but troublesome complication in patients with malignant lymphomas. Although there is no standard of care, it is often treated with simultaneous chemotherapeutic and non-chemotherapeutic interventions. Here, we describe the cases of five patients with lymphoma-associated chylothorax with the aim of clarifying an effective treatment strategy. All patients achieved a partial response or better for lymphoma. All patients underwent interventional radiology (IVR) procedures, including lymphangiography (LAG) and thoracic duct embolization (TDE). Complete resolution of chylothorax was eventually achieved by IVR procedures or pleurodesis in all patients. No patients experienced serious adverse events related to LAG/TDE. Treatment of chylous effusion required months for most patients (range: 0.2–4.8 months). Our data suggest that a combination of chemotherapy and LAG/TDE is effective for refractory lymphoma-related chylous effusion.

We conducted a prospective, three-center, observational study in Japan to evaluate the prevalence of seropositivity and clinically protective titer after coronavirus disease 2019 vaccination in patients with plasma cell dyscrasia(PCD). Two-hundred sixty-nine patients with PCD [206 symptomatic multiple myeloma (MM)] were evaluated. Seropositivity was observed in 88.7% and a clinically protective titer in 38.3% of MM patients, both of which were significantly lower than those of healthy controls. Patients receiving anti-CD38 antibodies had much lower antibody titers, but antibody titers recovered in those who underwent a wash-out period before vaccine administration. Older age (≥65), anti-CD38 antibody administration, immunomodulatory drugs use, lymphopenia (<1000/μL), and lower polyclonal IgG (<550 mg/dL) had a negative impact for the sufficient antibody production according to multivariate analysis. Patients with clinically protective titer had a significantly higher number of CD19+ lymphocytes than those with lower antibody responses (114 vs. 35/μL, p = 0.016). Our results suggested that patients with PCD should be vaccinated, and that the ideal protocol is to temporarily interrupt anti-CD38 antibody therapy for a “wash-out” period of a few months, followed by a (booster) vaccine after the B-cells have recovery.

Epstein-Barr virus (EBV) reactivation can occur following allogenic hematopoietic stem cell transplantation (allo-HSCT). However, the clinical characteristics and outcomes of EBV-viral load are not well known. Thus, we retrospectively analyzed the clinical features and prognostic impact of the EBV viral load in 121 allo-HSCT recipients from our hospital. EBV DNA quantification was performed in whole blood after transplantation. Patients were grouped based on whether EBV DNA quantification reached > 1000 copies/mL during follow-up (N = 50) or not (N = 71). Patients with EBV > 1000 EBV copies/mL were relatively more common in the groups with graft versus host disease (GVHD) prophylaxis including ATG, haploidentical donor type, peripheral blood as a donor source, and acute GVHD II–IV. The 20-month OS and DFS were not significantly different between patients with < 1000 EBV copies/mL and patients with > 1000 EBV copies/mL (20-month OS, 56.0% vs. 60.6%; p = 0.503, 20-month DFS, 50.0% vs. 57.7%; p = 0.179). Immunosuppressant (ISS) dose reduction was achieved after the maximum increase in EBV in 41/50 (82%) patients. Additionally, 30/50 (60%) patients achieved a 50% dose reduction or no restarting of ISS within 3 months of the maximum EBV increase. Among cases wherein EBV DNA quantification reached > 1000 copies/mL, those that achieved rapid dose reduction of ISS tended to have longer overall survival (“not reached” vs 5.4 months, p < 0.001) and disease-free survival (88.4 months vs 5.3 months, p < 0.001) than those in patients who did not. Our data highlight the importance of rapid ISS reduction in post-transplant EBV reactivation.

Abstract Objectives To demonstrate the clinical features and prognostic impact of cyclin D1 positivity in patients with amyloid light chain amyloidosis (AL). Methods We consecutively included 71 patients diagnosed with AL with cyclin D1 positivity between February 2008 and January 2022. t(11;14) was examined through interphase fluorescence in situ hybridization using bone marrow cells. Results The median age of the patients was 73 years, and 53.5% were male. The underlying diseases included symptomatic multiple myeloma, smoldering multiple myeloma, Waldenström macroglobulinemia, and monoclonal gammopathy of undetermined significance, representing 33.8%, 26.8%, 2.8%, and 36.6%, respectively. The prevalence of cyclin D1 and t(11;14) was 38.0% and 34.7%, respectively. Higher frequency of light chain paraprotein type was seen in cyclin D1–positive patients with AL than in cyclin D1–negative patients (70.4% vs 18.2%). The median overall survival (OS) of patients with AL with and without cyclin D1 expression was 18.9 months and 73.1 months, respectively (P = .019). Early death occurred in 44.4% of cyclin D1–positive patients and 31.8% of cyclin D1–negative patients. Moreover, 83.3% of cyclin D1–positive patients and 21.4% of cyclin D1–negative patients died of cardiac causes. Conclusions Cyclin D1 immunohistochemistry accurately identified patients with t(11;14). Cyclin D1–positive patients had significantly inferior OS compared with cyclin D1–negative patients.