Kentaro Narita

In multiple myeloma (MM), defining tumor burden is difficult because systemic bone marrow disease and focal lesions often show different levels of activity. We analyzed 352 newly diagnosed patients. We used bone marrow plasma cell percentage (BMPC) quantified from whole slide images, MRI-total diffusion volume (TDV), PET-metabolic tumor volume (TMTV), and serum sBCMA levels. In patients with complete datasets, Principal Component Analysis (PCA) and unsupervised clustering were used to classify patients into four phenotypes based on two factors: physical tumor volume (based on BMPC, TDV and TMTV) and sBCMA levels. Among all markers evaluated, sBCMA showed the strongest and most consistent prognostic association, independent of imaging-defined tumor volume. The four phenotypes were: Dual-High (high volume / high sBCMA), Sero-dominant (low volume / high sBCMA), Macro-dominant (high volume / low sBCMA), and Dual-Low (low volume / low sBCMA). Elevated sBCMA, rather than tumor volume, was the primary determinant of early treatment failure; the Sero-dominant and Dual-High groups showed similar 12-month progression-free survival despite markedly different tumor volumes. The Macro-dominant phenotype represented a state of "spatial sequestration," characterized by extensive imaging-defined tumor burden that remained anatomically confined without hematogenous dissemination or extramedullary spread. In this phenotype, the prognostic impact of Gain(1q21) was not significant, whereas it was strongly associated with inferior survival in the Sero-dominant phenotype. MM outcomes are determined by the interaction between physical tumor volume and sBCMA levels. This multimodal classification provides a rational framework for risk stratification.

Random skin biopsy (RSB) is essential for diagnosing intravascular large B-cell lymphoma (IVLBCL), but previous clinical prediction models have shown limited performance. This study developed and internally validated predictive models for RSB positivity using data from a single center with 181 Japanese patients who underwent RSB and positron emission tomography-computed tomography (PET-CT) between 2006 and 2024. Three models were evaluated: clinical (lactate dehydrogenase [LDH] and hypoxia), PET-CT (maximum standardized uptake values [SUVmax] of the lymph nodes, lungs, and adrenal glands), and combined (LDH and SUVmax of the lymph nodes, lungs, and nose). The combined model showed superior discriminative power compared to the clinical model. All models demonstrated good calibration. Decision curve analysis revealed higher net benefits for PET-CT and combined models. These findings suggest incorporating PET-CT improves patient selection for RSB in the diagnosis of IVLBCL, and external validation in larger cohorts is needed.

We evaluated serum soluble B-cell maturation antigen (sBCMA) levels in 67 Waldenström macroglobulinemia (WM) patients, healthy controls, and individuals with IgM-MGUS, IgM-multiple myeloma, other B-cell neoplasms, and reactive hypergammaglobulinemia. WM patients had higher sBCMA levels (median 100 ng/mL) compared to healthy controls (41.4 ng/mL, p < 0.001). Symptomatic WM patients had a higher level of sBCMA than asymptomatic patients (133 vs 73.8 ng/mL, p < 0.001). Asymptomatic WM did not progress to symptomatic disease when sBCMA was in MGUS level (<65 ng/mL). There was strong correlation between bone marrow CD20+ cell counts and sBCMA levels (ρ = 0.73), while serum IgM levels showed weaker correlation (ρ = 0.55). sBCMA levels demonstrated parallel changes with IgM levels when assessing treatment efficacy. Notably, IgM flares following rituximab administration or plasma exchanges had a minimal impact on sBCMA levels. These findings suggest that sBCMA is a decent biomarker of tumor burden, offering a reliable predictor of clinical outcomes in WM patients.

Summary: Multiple myeloma (MM) with chromosome 1q21 gain/amplification (1q+) has been reported to respond poorly to daratumumab. We aimed to explore the mechanism of daratumumab resistance in 1q+ MM. Our findings revealed significantly lower CD38 expression in patients with 1q+ MM than in those with 1q wild type (WT) MM. Next, we focused on the interleukin‐6 receptor (IL6R) located in the 1q21 region because a previous report shows that interleukin‐6 (IL‐6) reduces CD38 expression via the IL‐6/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway activation in MM. Indeed, IL6R expression was significantly higher in 1q+ MM than in 1q WT MM. We verified that the 1q+ human myeloma cell lines (HMCLs) expressed higher IL6R levels than the 1q WT HMCLs. IL‐6 treatment induced CD38 downregulation in both the 1q+ HMCLs and primary bone marrow (BM) samples but not in their 1q WT HMCLs and BM samples. IL‐6 also resulted in the upregulation of phosphorylated STAT3 in 1q+ HMCLs but not in the 1q WT HMCLs. Furthermore, inhibition of the IL‐6/JAK/STAT pathway by treatment with ruxolitinib or tocilizumab restored CD38 expression in the 1q+ HMCLs and BM samples. These findings elucidate the mechanisms underlying daratumumab resistance in 1q+ MM and provide insights for future therapeutic strategies.

Soluble B-cell maturation antigen (sBCMA) is elevated on multiple myeloma (MM) cells. We investigated whether sBCMA levels correlated with other myeloma tumor volume indicators and its utility in monitoring oligosecretory/nonsecretory (O-S/Non-S) MM. In 115 patients with newly diagnosed MM, sBCMA was compared with M-protein levels, bone marrow plasma cells (BMPCs), circulating tumor cells (CTCs), and total diffusion volume (tDV; estimated by whole-body diffusion-weighted magnetic resonance imaging) at diagnosis. sBCMA levels increased significantly with International Staging System stage, chromosome 1q21 gain/amplification, and CTC levels. sBCMA also correlated strongly with %BMPC (r = 0.65) and moderately with tDV (r = 0.55) and paraprotein levels (involved immunoglobulin in IgG and IgA subtypes, r = 0.44 and 0.4; involved free light-chain levels in light-chain-only MM, r = 0.61, all P < .05). Longitudinal changes in sBCMA were consistent with disease status in both 17 O-S/Non-S and other secretory MM cases. Furthermore, sBCMA levels increased as early as 6 months prerelapse in almost all O-S/Non-S relapsed patients. Thus, sBCMA correlates strongly with total tumor volume in MM, as assessed using different modalities. We suggest that sBCMA is useful, not only for monitoring responses in patients with O-S/Non-S MM but also for early relapse detection and prediction.

We aimed to improve prognostic predictors in patients with transplant-ineligible multiple myeloma (TIE-MM) by combining baseline circulating clonal tumor cells (CTCs) and positron emission tomography/computed tomography (PET/CT) findings. The factors associated with prognosis were retrospectively investigated in 126 patients with TIE-MM who underwent CTC quantification by multiparameter flow cytometry and PET/CT at the initial presentation. The total lesion glycolysis (TLG) level was calculated using the Metavol software. The median percentage of CTC was 0.06% (range, 0%-4.82%), and 54 patients (42.9%) demonstrated high CTC levels. High CTC levels were associated with significantly poorer progression-free survival (PFS, 2-year 43.4% vs 68.1%; P < .001) and overall survival (OS, 5-year 39.0% vs 68.3%; P < .001). Similarly, high TLG levels significantly worsened the PFS (2-year, 41.2% vs 67.6%; P = .038) and OS (5-year, 37.7% vs 63.1%; P = .019). The multivariate analyses showed that Revised International Staging System (R-ISS) III, high CTC and TLG levels, and complete response were significant prognostic factors for PFS and OS. A novel predictive model was constructed using CTCs, TLG, and R-ISS III. The patients were stratified into 3 groups according to the number of risk factors, revealing an extremely high-risk group with a 2-year PFS of 0% and a 5-year OS of 20%. Patients without any high-risk features had better prognosis, with a 2-year PFS of 78.6% and a 5-year OS of 79.5%. The combination of CTCs and volumetric assessment of PET/CT at diagnosis augments the existing stratification systems and may pave the way for a risk-adapted treatment approach.