Citations

The bone marrow immune microenvironment (BMME) is a critical factor in multiple myeloma (MM) pathogenesis. Despite higher incidence of MM among self-identified African Americans, the relationship between African genetic similarity and the BMME remains unclear. We present the largest analysis to date assessing the impact of Ancestry on the BMME in myeloma (N=320, including 64 with ≥50% African genetic similarity, AFR-High) leveraging our recently generated Immune Atlas. AFR-High was associated with enrichment of late T-effector cells, driven by rare cytotoxic CD4⁺ T cells, suggesting a distinct adaptive BMME. AFR-High exhibited expansion of late-differentiated adaptive NK cells with high cytotoxic GNLY and GZMH expression. AFR-High depicted reduced CD14⁺ monocytes, increased CD16⁺ non-classical monocytes, and expansion of macrophage-like monocyte populations with enrichment of metabolic adaptation, efferocytosis and phagocytic clearance programs, and immunoregulatory pathways. These findings reveal a shift from an innate inflammatory immune landscape toward adaptive cytotoxic and immunoregulatory remodeling associated with African genetic similarity in MM.

Background. Negative pressure wound therapy promotes wound healing through fluid removal, edema reduction, and mechanical contraction. A novel thermoplastic elastomer (TPE) dressing has been developed to improve exudate evacuation and reduce tissue ingrowth, but its effect on wound contraction compared with reticulated open cell foam (ROCF) remains unclear. Objective. To compare the degree of wound contraction with the TPE dressing, ROCF, or no filler at different wound depths and negative pressure settings in a porcine explant model. Materials and Methods. The effect of the materials or lack thereof on wound contraction was investigated at 2 wound depths (shallow, deep) and 3 negative pressure settings (−50 mm Hg, −80 mm Hg, and −125 mm Hg). Wound width was measured at 3 standardized locations before and during therapy. Univariable and multivariable linear regression analyses were performed to identify factors associated with contraction. Results. A total of 810 measurements were obtained. Both the TPE dressing and ROCF demonstrated statistically significantly greater contraction than no filler. In deep wounds, greater contraction was noted with the TPE dressing compared with ROCF. Higher negative pressure and increased wound depth were independently associated with greater contraction. Absolute differences in contraction between dressings were small (<3 mm across all conditions). Conclusion. The TPE dressing provides equivalent or greater wound contraction compared with ROCF, particularly in deep wounds, without impairing macrodeformation. Given the small magnitude of differences, the clinical relevance of this finding likely depends on additional factors, which should be evaluated in future in vivo studies.

ABSTRACT Negative pressure wound therapy relies on suction, commonly set to −125 mmHg, to evacuate wound fluid, but dysvascular and pressure injuries often respond unpredictably. Newton's third law indicates that negative pressure applies an equal and opposite contact pressure on the wound surface, and this study quantified this contact pressure across dressing types, wound configurations and suction levels. Using a porcine explant model, central and peripheral contact pressure measurements were obtained beneath black reticulated open cell foam, white foam and a novel thermoplastic elastomer dressing across plexiglass, intact skin, shallow and deep wounds under −50, −75 and −125 mmHg. Contact pressure increased proportionally with negative pressure, and multivariable modelling demonstrated that dressing type, wound type and suction level significantly influenced pressure, with negative pressure explaining most of the variance (0.77 and 0.68). Thermoplastic elastomer at −50 mmHg in deep wounds produced the lowest contact pressure, whereas black reticulated open cell foam and white foam at −125 mmHg generated elevated contact pressures of approximately +125 to +195 mmHg. These findings show that black reticulated open cell foam at conventional −125 mmHg can create hypoperfusion conditions, whereas thermoplastic elastomer consistently produces the lowest pressures and may enhance perfusion at lower suction levels, offering a physiologic explanation for improved clinical outcomes in dysvascular and pressure injuries treated with reduced negative pressure.

Abstract Multiple myeloma is a malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment (IME). To investigate immune correlates of treatment response and disease progression, we conducted multi-omics profiling including CD138neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138pos bulk RNA and whole-genome sequencing from 209 samples. In longitudinal analyses, interferon-γ signaling associated with markers of impaired T-cell memory after autologous stem cell transplant, whereas naïve B-cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48; P = 2.3e−4). At disease progression, multiple myeloma cells upregulated cancer–testis antigens (CTAg) and immune effector genes, with concurrent B-cell depletion, enrichment of myeloid-derived suppressor cell expression, and phenotypic T-cell exhaustion. These findings highlight dynamic immune–tumor interactions, identifying naïve B-cell reconstitution as a biomarker of durable response and CTAgs as potential targets for high-risk disease at progression. Significance: Longitudinal profiling of multiple myeloma and the IME revealed dynamic immune–tumor interactions across the disease course. Altered expression in CD8+ T cells limited memory phenotype after transplant, whereas naïve B-cell recovery associated with sustained treatment response. At progression, CTAg expression associated with immunosuppression, revealing novel mechanisms of immune dysregulation.

Abstract Introduction: Multiple Myeloma (MM) is a complex hematologic malignancy, where patients often display one or more potentially high risk cytogenetic alterations associated with poor outcomes. Traditional high risk cytogenetics events in myeloma, such as NSD2 t(4;14) translocations, gain of 1q21, or deletion of 17p13, have often been studied in isolation, but emerging evidence suggests the combination of these high risk alterations has a greater negative prognostic impact than any on their own. This has been recently reflected in risk stratification guidelines from IMS and IMWG, which consider certain events, such as t(4;14), as high risk only in combination with gain of 1q21 or deletion of 1p32. Still, the mechanisms through which multi-hit high risk events disrupt the microenvironment and promote poor outcomes remains unclear. We hypothesize that myelomas with multiple high risk alterations remodel the immune environment to promote tumor progression and immune escape. Methods: To study the role of multi-hit high risk cytogenetics on the immune microenvironment, we analyzed CD138-bone marrow aspirate single-cell RNA sequencing (scRNAseq) data from 337 newly diagnosed MM patients from the MMRF CoMMpass study, generated as part of the Immune Atlas initiative. Cytogenetic alterations for these patients were derived from whole-genome and whole-exome sequencing of CD138+ bone marrow aspirates from the MMRF CoMMpass cohort. Patients were classified as multi-hit high-risk MM if they exhibited either (i) two high-risk cytogenetic events, including NSD2 t(4;14), MAF t(14;16), del(17p13), or (ii) one high-risk event with gain of 1q21. Results: Based on cytogenetic information, 33 patients in the Immune Atlas cohort were classified as 'multi-hit’ high-risk, while 34 patients had only a single high-risk alteration. These multi-hit high risk patents displayed significantly worse progression free survival compared to standard risk patients, adjusting for age, therapy, and ASCT (HR=2.34, p&lt;7.2e-5), while single-hit patients showed a non-significant trend towards worse outcomes (HR=1.51, p=0.071). The most frequent multi-hit risk event in the cohort was NSD2 t(4;14) in combination with 1q21, observed in 23 patients. Compositional analysis of the immune populations in the scRNAseq data revealed that relative to both standard and single-hit high risk patients, multi-hit high risk patients displayed significant reductions in IFN-I stimulated CD4+ and CD8+ T cell populations, marked by decreased expression for antiviral response markers such as ISG15, XAF1, and IFI44L. Enrichment of inflammatory CD16+ non-classical monocytes was also observed. Further analysis of the most frequent multi-hit risk event, NSD2 with 1q21, revealed distinct enrichment of late-activated cytotoxic HLA+ CD8+T cells and cytotoxic CD4+.T cells. Neither alteration was observed in patients with single-hit NSD2 or 1q21. Further analysis on the interactions between high risk events revealed distinct transcriptomic profiles dependent on the high risk events involved, particularly in multi-hit events involving mutations or deletions of TP53 or gain of 1q21. Reduction in IFN-I signaling across various immune populations was primarily restricted to multi-hit risk events involving gain of 1q21. Conversely, patients with biallelic loss of TP53 displayed significant enrichment of these same IFN-I populations. Given this contrast in IFN-I signaling spanning multiple immune subtypes, we hypothesized that the malignant myeloma cells might similarly display altered IFN-I activity. Utilizing CD138+ myeloma bulk RNA sequencing data from CoMMpass, we found that IFN-I response scores strongly correlated between paired scRNA immune and bulk RNAseq tumor datasets (R2: 0.75, p=1.63e-32). Across 660 patients with bulk RNAseq and cytogenetic data, we confirmed significant reductions in IFN-I response scores in tumor cells in multi-hit high risk involving 1q21, and significant enrichment in those with complete loss of TP53 relative to standard-risk MM. Conclusions: Overall, we do observe that MM patients with multiple high risk cytogenetic alterations display distinct immunologic traits relative to standard risk or single-hit high risk patients in addition to significantly worse outcomes. Furthermore, we find variability in the immune alterations observed based on the cytogenetic events involved, further illustrating the heterogeneity in how MM shapes the immune microenvironment.

BACKGROUND Septic facet cysts are a rare phenomenon reported in the literature among immunocompromised hosts and may require operative intervention for appropriate source and symptomatic control. OBSERVATIONS A 70-year-old male with a past medical history of immunoglobulin A lambda smoldering myeloma degenerative lumbar disease who presented with low back and radicular lower extremity pain was found to have a left L4–5 septic facet cyst with extension to the epidural space. Intraoperative cultures were positive for Nocardia species. Staging workup revealed progression to high-risk-profile multiple myeloma. LESSONS Patients with septic facet cysts may require operative intervention for appropriate source control. Nocardia spine infections and septic facet cysts are rare and require investigation of preexisting risk factors and any potential underlying immunocompromise. https://thejns.org/doi/10.3171/CASE25220

OBJECTIVES: To compare whether femoral version more closely mirrors the contralateral femur or a population norm estimate of 15 degrees of anteversion. METHODS: Design: Radiologic observational study. Setting: Level I Trauma Center. Patient Selection Criteria: Patients with no history of anatomy-altering femoral injury who underwent bilateral lower extremity computed tomography scans. Outcome Measures and Comparisons: Computed tomographies were analyzed to measure femoral version on each side. The asymmetry in femoral version between left and right in each patient (interfemoral rotational variance [IRV]) was recorded. The difference of each femur's version from a proposed population mean of 15 degrees of anteversion was also recorded. RESULTS: A total of 219 patients with a mean femoral version of 14.9 degrees ± 10.5 degrees of anteversion were included. Mean IRV was 5.3 degrees, compared with 8.2 degrees of mean variation from the population norm of 15 degrees of anteversion (P < 0.001). Five percent of patients had IRV >15 degrees compared with 15% that had femoral rotation >15 degrees from the population mean of 15 degrees (P < 0.001). CONCLUSIONS: In the setting of a comminuted diaphyseal femur fracture, knowledge of the appropriate target for restoration of rotational alignment is critical. This radiologic cohort study found that on average, femoral version more closely mirrors an individual patient's contralateral femur as opposed to a population norm of 15 degrees of anteversion.

Despite significant improvements in survival of patients with multiple myeloma (MM), outcomes remain heterogeneous, and a significant proportion of patients experience suboptimal outcomes. Importantly, traditional prognostic factors based on data from patients treated with older therapies no longer capture prognosis accurately in the contemporary era of novel triplet or quadruplet therapies. Therefore, risk stratification requires refinement in the context of available and investigational treatment options in routine practice and clinical trials, respectively. The current identification of high-risk MM (HRMM) in routine practice is based on the Revised International Staging System, which stratifies patients using a combination of widely available serum biomarkers and chromosomal abnormalities assessed via fluorescence in situ hybridization. In recent years, a substantial body of evidence concerning additional clinical, biological, and molecular/genomic prognostic factors has accumulated, along with new MM risk stratification tools and consensus reports. The International Myeloma Society, along with the International Myeloma Working Group, convened an Expert Panel with the primary aim of revisiting the definition of HRMM and formulating a practical and data-driven consensus definition, based on new evidence from molecular/genomic assays, updated clinical data, and contemporary risk stratification concepts. The Panel proposes the following Consensus Genomic Staging (CGS) of HRMM which relies upon the presence of at least one of these abnormalities: (1) del(17p), with a cutoff of >20% clonal fraction, and/or TP53 mutation; (2) an IgH translocation including t(4;14), t(14;16), or t(14;20) along with 1q+ and/or del(1p32); (3) monoallelic del(1p32) along with 1q+ or biallelic del(1p32); or (4) β2 microglobulin ≥5.5 mg/L with normal creatinine (<1.2 mg/dL).

Abstract Multiple myeloma (MM) is an incurable malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment. To investigate immune factors driving treatment response and resistance, we conducted multi-omics profiling including CD138 neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138 pos bulk RNA and whole-genome sequencing from 209 samples. Longitudinal analyses revealed that interferon gamma signaling impairs T cell memory after autologous stem cell transplant, while naïve B cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48, p = 2.3e -4 ). At disease progression, MM cells upregulated cancer-testis antigens and immune effector genes, with concurrent B cell depletion, enrichment of myeloid-derived suppressor cell genes in monocytes, and T cell exhaustion. These findings highlight dynamic immune-tumor interactions, identifying naïve B cell reconstitution as a biomarker of durable response, and cancer-testis antigens as potential targets for high-risk disease at progression. Statement of Significance Longitudinal profiling of multiple myeloma and the immune microenvironment revealed dynamic immune-tumor interactions across the disease course. Dysfunctional CD8⁺ T cells limited memory formation post-transplant, while naïve B recovery associated with sustained treatment response. At progression, cancer-testis antigen expression associated with immunosuppression, revealing novel mechanisms of immune escape.

Introduction Induction therapy (Tx) followed by ASCT and lenalidomide (LEN) maintenance is the standard of care in transplant-eligible pts with NDMM. Pts who have suboptimal response after front-line ASCT, however, have an increased risk of progression or death. Ide-cel demonstrated significantly improved median progression-free survival (PFS) and overall response rate (ORR) vs standard regimens in KarMMa-3 in pts with early-line triple-class-exposed relapsed and refractory multiple myeloma (MM). KarMMa-2 (NCT03601078) is a multicohort, phase 2, multicenter trial evaluating the efficacy and safety of ide-cel in several MM disease settings; cohort 2c includes pts with NDMM who achieved &lt; very good partial response (VGPR) after front-line ASCT. An extended follow-up analysis (median follow-up of 39.4 months) of cohort 2c was presented at ASH 2023 (Dhodapkar M, et al. ASH 2023; P2101). Here, we report results with 55.4 months of median follow-up and additional data on pts who received LEN maintenance at the investigator's discretion. Methods Adult pts with NDMM who received ≥ 3 cycles of induction Tx (proteasome inhibitor, immunomodulatory agent, dexamethasone), and had &lt; VGPR 70-110 days after ASCT (single/tandem) were eligible. Pts received a single ide-cel infusion (150-450 × 106 chimeric antigen receptor-positive T cells) and could receive maintenance Tx post-infusion at investigator discretion. The primary endpoint was complete response rate (CRR); secondary endpoints included ORR, duration of response (DOR), PFS, overall survival (OS), safety, cellular kinetics, and patient-reported outcomes on health-related quality of life (HRQoL). Minimal residual disease (MRD) negativity (sensitivity, 10-5), an exploratory endpoint, is also reported. Results At data cutoff (June 28, 2024), with a median follow-up of 55.4 (range, 51.4-59.5) months, all 31 pts treated with ide-cel were alive; 28 (90.3%) remained in follow-up and 3 (9.7%) discontinued due to disease progression or withdrawal by pt. Eight pts received LEN maintenance after ide-cel at the investigator's discretion. Among all 31 ide-cel-treated pts, CRR and ORR were 80.6% and 87.1%, respectively. Among the 8 pts who received LEN maintenance, CRR and ORR were 75.0% and 100.0%, respectively. Median DOR, PFS, and OS were not reached; 36-month event-free rates were 81.5%, 76.8%, and 100.0%, respectively. Of the 8 pts who received LEN maintenance after ide-cel infusion, none experienced disease progression. At 36 months, MRD negativity was confirmed in 12/18 (66.7%) evaluable pts; all 12 achieved ≥ CR. Since last data cutoff, 1 pt with MRD-negative MM changed to MRD-positive at 36 months, and 1 pt who had previously achieved MRD negativity was indeterminate at 36 months. Among the 6 evaluable pts who received LEN maintenance, 3/6 (50.0%) achieved MRD negativity at 36 months. There were no new safety signals nor reports of parkinsonism or Guillain-Barré syndrome since the previous data cutoff. In the 8 pts who received LEN maintenance, 6 (75.0%) experienced grade 3/4 AE, most commonly neutropenia, and 1 (12.5%) experienced grade 3/4 infection on or after LEN maintenance. All 8 pts were still receiving LEN at data cutoff. Robust CAR+ T cell expansion was observed in 31 pts, with higher expansion in pts with ≥ CR vs &lt; CR. Following ide-cel treatment, HRQoL improved and disease symptoms were stable over time (assessed by European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Core Questionnaire and EORTC Quality of Life Multiple Myeloma Module 20 Questionnaire). More than 75% of pts had improved or stable global health status/QoL by month 3. Conclusions With extended follow-up, ide-cel continued to demonstrate deep, durable responses in pts with &lt; VGPR to front-line ASCT. No new safety signals were observed and no deaths were reported. Data in a small group of pts in cohort 2c showed that ide-cel followed by LEN maintenance extended disease control. Pts who received LEN maintenance did not experience disease progression regardless of MRD status. Stable or improved HRQoL was observed after ide-cel treatment. Overall, ide-cel continued to show a favorable clinical benefit-risk profile in NDMM after ASCT. The phase 3 KarMMa-9 study (NCT06045806), currently recruiting, will compare ide-cel followed by LEN maintenance vs LEN maintenance alone in pts with NDMM after suboptimal response to ASCT.