Three-dimensional telomere profiling predicts risk of progression in smoldering multiple myeloma.

Smoldering multiple myeloma (SMM) is a precursor stage that precedes multiple myeloma (MM). SMM is heterogenous with nearly 40% of patients progressing to MM in the first 5 years. The high rate of progression of SMM patients highlights the need for early intervention, which underscores the importance of identifying SMM patients with the highest risk of progression. Several risk stratification models showed utility in identifying high-risk SMM patients; however, these systems showed limited sensitivity. To date, identifying high-risk SMM patients remains an important clinical need. In this study, we present the 3-dimensional telomere profiling as a structural biomarker capable of stratifying SMM patients as a function of genomic instability. Quantifying telomere dysfunction using the TeloView technology showed utility in risk stratification of cancer patients, particularly hematological malignancies. In this study, we analyzed 168 SMM patients. We report an AUC in ROC analysis of 0.8 using a subset of the patients as a training dataset. We then conducted a blind validation on a different cohort and demonstrated a positive predictive value of 85% and negative predictive value of 73%, with sensitivity and specificity of 83% and 76%, respectively. We examined the correlation between the TeloView prediction and the 20-2-20 scoring system, and cytogenetic abnormalities. We report a correlation of 53% with the 20-2-20 scores and over 60% correlation with cytogenetic abnormalities. The result of this study presents the telomere profiling as an effective biomarker able to stratify SMM patients to their respective risk groups with high sensitivity and specificity.

Long-term tributyltin exposure alters behavior, oocyte maturation, and histomorphology of the ovary due to oxidative stress in adult zebrafish.

Tributyltin (TBT), an organotin endocrine-disrupting substance, is recognized as one of the important toxic environmental pollutants. The present study was carried out to investigate the toxic effects of TBT on behavior and the ovary of adult zebrafish with a focus on oxidative stress markers and oocyte maturation. Adult zebrafish were exposed to three different concentrations (125, 250, and 500 ng/L of water) of TBT for 28 days. TBT exposure produced a concentration-dependent negative effect on the body weight and behavior (anxiety-like symptoms) of adult zebrafish. Alterations in the activity of superoxide dismutase (SOD) and catalase (CAT), the total antioxidant capacity of ovarian tissue by the highest exposure level of TBT resulted in lipid peroxidation as indicated by increased malondialdehyde (MDA) level. The numbers of early-vitellogenic oocytes were significantly increased in zebrafish exposed to TBT as low as 125 ng/L. However, the numbers and size of fully-grown (mature) oocytes were significantly reduced in the highest exposure group only. Correlation between the MDA level and pre-vitellogenic oocytes in the 500 ng/L group indicated that lipid peroxidation prevented the maturation of pre-vitellogenic oocytes. TBT exposure produced significant histological changes in the ovary as evidenced by disturbed maturation of oocytes. In conclusion, TBT adversely affected the maturation of oocytes in zebrafish ovary through oxidative stress-mediated mechanisms.

Correlation between the middle phalanx of the third finger skeletal maturation staging system and insulin-like growth factor-1 levels among Indian children - A 3-year longitudinal study.

INTRODUCTION: Tracking insulin-like growth factor-1 (IGF-1) level alongside the middle phalanx of the third finger (MP3) staging modification could provide valuable insights into the relationship between hormonal factors and skeletal maturation during different stages of growth. Longitudinal studies indeed play a crucial role in understanding these complex relationships over time, allowing for a more comprehensive assessment of how IGF-1 might serve as a marker for pubertal growth stages. METHODOLOGY: The present longitudinal prospective cohort study was done among 26 boys and 26 girls. For each child, once in every 6 months for 3 years, blood samples (to estimate IGF-1 level) and X-rays of the left hand middle finger were taken. DRG IGF-1 600 Human Enzyme-Linked Immunosorbent Assay kit was used for the quantitative measurement of IGF1 from serum. The MP3 stages of the middle phalanx of the middle finger were evaluated using a modified MP3 system. The collected data were subjected to suitable descriptive and inferential statistics. RESULTS: The mean IGF1 levels were significantly higher in girls compared to boys across all the stages of MP3 skeletal maturity indicators. However, in both boys and girls, IGF-1 levels showed increasing trends from Stage F to H where it peaked and showed deceleration to Stage I (P < 0.05). CONCLUSION: The observed increase in serum IGF-1 levels during pubertal stages, followed by a decline in late puberty, aligning with the stages of skeletal maturation, suggests a close relationship between hormonal changes and bone development.

Outcomes of patients with multiple myeloma refractory to standard dose vs low dose lenalidomide.

Refractoriness to lenalidomide is an important factor determining the choice of therapy at first relapse in multiple myeloma (MM). It remains debatable if resistance to lenalidomide varies among MM refractory to standard doses vs low dose maintenance doses. In this study, we assessed the outcomes with subsequent therapies in patients with MM refractory to standard dose vs low dose lenalidomide. We retrospectively reviewed all patients with MM at our institution who received first line therapy with lenalidomide containing regimens, and assessed progression free survival (PFS) and overall survival for these patients for second line therapy, and with lenalidomide retreatment. For second line therapy, we found no difference in the PFS between standard dose refractory and low dose refractory groups (median PFS 14 months vs 14 months, p = 0.95), while the PFS for both these groups was inferior to the not refractory group (median PFS 30 months, p < 0.001 for both pairs). Similar trends were seen among these groups on lenalidomide retreatment, and on multivariable analysis. These data suggest that refractoriness to lenalidomide is not dose dependent, and definition of lenalidomide refractoriness should not depend on the dose of lenalidomide to which the disease was considered refractory.

Once-weekly versus twice-weekly bortezomib in newly diagnosed multiple myeloma: a real-world analysis.

Induction regimens for multiple myeloma (MM) commonly include bortezomib, which has typically been administered twice weekly despite studies demonstrating comparable efficacy and less peripheral neuropathy (PN) with once-weekly bortezomib. We aimed to analyze the real-world prevalence and efficacy of once-weekly versus twice-weekly bortezomib regimens in newly diagnosed MM. We analyzed 2497 US patients aged 18-70 years treated with commercial first-line bortezomib using nationwide Flatiron Health electronic health record-derived data, including 910 (36.4%) patients who received twice-weekly and 1522 (63.2%) who received once-weekly bortezomib. Once-weekly bortezomib use increased over time, from 57.7% in 2017 to 73.1% in 2022. Multivariate analysis identified worsened performance status and more recent year of diagnosis with higher odds of receiving once-weekly bortezomib. Real-world progression-free survival (median 37.2 months with once-weekly versus 39.6 months with twice-weekly, p = 0.906) and overall survival (medians not reached in either cohort, p = 0.800) were comparable. PN rates were higher in patients receiving twice-weekly bortezomib (34.7% versus 18.5%, p < 0.001). In conclusion, once-weekly bortezomib is clearly associated with similar efficacy and fewer toxicities compared to twice-weekly bortezomib. Our findings support once-weekly bortezomib as a standard-of-care regimen for newly diagnosed patients with MM.

Patient-Reported Adverse Events and Early Treatment Discontinuation Among Patients With Multiple Myeloma.

Importance: There is substantial interest in capturing cancer treatment tolerability from the patient's perspective using patient-reported outcomes (PROs). Objective: To examine whether a PRO question, item 5 from the Functional Assessment of Cancer Therapy-General General Physical Wellbeing Scale (GP5), was associated with early treatment discontinuation (ETD) due to adverse events. Design, Setting, and Participants: This prospective survey study was conducted from February to April 2023. Among participants in the ECOG-ACRIN E1A11 trial (a phase 3, parallel design trial conducted between 2013 and 2019), patients with newly diagnosed multiple myeloma were randomized to receive bortezomib (VRd) or carfilzomib (KRd) plus lenalidomide and dexamethasone as induction therapy. The GP5 item was administered at baseline (pretreatment) and at 1 month, 2.8 months, and 5.5 months postbaseline. Eligible participants included patients with newly diagnosed multiple myeloma treated at community oncology practices or academic medical centers in the US. Exposures: GP5 response options were "very much," "quite a bit," "somewhat," "a little bit," and "not at all." Responses at each assessment while undergoing treatment (1 month, 2.8 months, and 5.5 months) were categorized as high adverse event bother (ie, "very much," and "quite a bit") and low adverse event bother (ie, "somewhat," "a little bit," or "not at all"). In addition, change from baseline to each assessment while undergoing treatment was calculated and categorized as worsening by 1 response category and 2 or more response categories. Main Outcome and Measure: ETD due to adverse events (yes vs no) was analyzed using logistic regression adjusting for treatment group, performance status, gender, race, and disease stage. Results: Of the 1087 participants in the original trial, 1058 (mean [SD] age 64 [9] years; 531 receiving VrD [50.2%]; 527 receiving KRd [49.8%]) responded to item GP5 and were included in the secondary analysis. A small proportion (142 patients [13.4%]) discontinued treatment early due to AEs. For those with high adverse-effect bother, GP5 while undergoing treatment was associated with ETD at 1 month (adjusted odds ratio [aOR], 2.20; 95% CI, 1.25-3.89), 2.8 months (aOR, 3.41; 95% CI, 2.01-5.80), and 5.5 months (aOR, 4.66; 95% CI, 1.69-12.83). Worsening by 2 or more response categories on the GP5 was associated with ETD at 2.8 months (aOR, 3.02; 95% CI, 1.64-5.54) and 5.5 months (aOR, 5.49; 95% CI, 1.45-20.76). Conclusions and Relevance: In this survey study of the E1A11 trial, worse GP5 response was associated with ETD. These findings suggest that simple assessment of adverse-effect bother while receiving treatment is an efficient way to indicate treatment tolerability and ETD risk.

Bailout Options for Intra-operative Implant and Instrumentation Related Incidents and Complications During Arthroscopic Knee Surgery-A Retrospective Study.

Background: Arthroscopic knee procedures are one amongst the common surgical interventions for problems in the knee. It is technically more demanding than an open procedure and is associated with several potential complications. During arthroscopy procedures, several technical challenges may arise, and even experienced surgeons may encounter new issues. However, careful attention to the surgical technique can help prevent or resolve them. Methodology: The study was conducted on all patients who underwent knee arthroscopy procedure during study period. We recorded details of the implants used and any unexpected situations related to them, as well as how they were managed. Instrumentation-related parameters such as screwdriver issues, radiofrequency ablator issues, scope damages, shaver complications, probe complications, and meniscus suture passing devices were also assessed. Results: In total, there were 12 (3.73%) implant and instrument-related incidents and complications, of which 5 (1.55%) were implant-related and 7 (2.17%) were instrument related. Among the instrumentation-related incidents and complications, two (0.62%) were screwdriver breakage incidents, two (0.62%) were radiofrequency ablator-related incidents, one was arthroscopic probe (0.31%) related incident, one (0.31%) was meniscus suture passing device related complication and one (0.31%) was arthroscope related incident. Conclusion: Surgeons must be ready to anticipate and effectively manage any technical difficulties that may arise during the procedure, maintaining composure in the face of unexpected challenges and guiding the team. In most cases, incidents can be addressed intra operatively and may not have long-term effects on patient outcomes. It is crucial to have multiple implant and instrument backup options available for successful surgery.

Periosteum-Augmented Soft-Tissue Graft for Anterior Cruciate Ligament Reconstruction.

Soft-tissue grafts are an option for anterior cruciate ligament reconstruction. One of the major drawbacks of soft-tissue grafts is the delay in the osteointegration and ligamentization of the implanted graft. Enveloping the ends of the graft with periosteum sleeves can hasten the osteointegration process and help in quicker rehabilitation of the patient. This article describes a simple and unique way to augment the soft-tissue graft with periosteum for anterior cruciate ligament reconstruction.

Mode of progression in smoldering multiple myeloma: a study of 406 patients.

The approach to patients with high-risk smoldering multiple myeloma (SMM) varies among clinicians; while some advocate early intervention, others reserve treatment at progression to multiple myeloma (MM). We aimed to describe the myeloma-defining events (MDEs) and clinical presentations leading to MM diagnosis among SMM patients seen at our institution. We included 406 patients diagnosed with SMM between 2013-2022, seen at Mayo Clinic, Rochester, MN. The 2018 Mayo 20/2/20 criteria were used for risk stratification. Median follow-up was 3.9 years. Among high-risk patients who did not receive treatment in the SMM phase (n = 71), 51 progressed by last follow-up; the MDEs included: bone lesions (37%), anemia (35%), hypercalcemia (8%), and renal failure (6%); 24% met MM criteria based on marrow plasmacytosis (≥60%) and/or free light chain ratio (>100); 45% had clinically significant MDEs (hypercalcemia, renal insufficiency, and/or bone lesions). MM diagnosis was made based on surveillance labs/imaging(45%), testing obtained due to provider suspicion for progression (14%), bone pain (20%), and hospitalization/ED presentations due to MM complications/symptoms (4%). The presentation was undocumented in 14%. A high proportion (45%) of patients with high-risk SMM on active surveillance develop end-organ damage at progression. About a quarter of patients who progress to MM are not diagnosed based on routine interval surveillance testing.

Superior detection rate of plasma cell FISH using FACS-FISH.

OBJECTIVES: Fluorescence in situ hybridization (FISH) for plasma cell neoplasms (PCNs) requires plasma cell (PC) identification or purification strategies to optimize results. We compared the efficacy of cytoplasmic immunoglobulin FISH (cIg-FISH) and fluorescence-activated cell sorting FISH (FACS-FISH) in a clinical laboratory setting. METHODS: The FISH analysis results of 14,855 samples from individuals with a suspected PCN subjected to cytogenetic evaluation between 2019 and 2022 with cIg-FISH (n = 6917) or FACS-FISH (n = 7938) testing were analyzed. RESULTS: Fluorescence-activated cell sorting-FISH increased the detection rate of abnormalities in comparison with cIg-FISH, with abnormal results documented in 54% vs 50% of cases, respectively (P < .001). It improved the detection of IGH::CCND1 (P < .001), IGH::MAF (P < .001), IGH::MAFB (P < .001), other IGH rearrangements (P < .001), and gains/amplifications of 1q (P < .001), whereas the detection rates of IGH::FGFR3 fusions (P = .3), loss of 17p (P = .3), and other abnormalities, including hyperdiploidy (P = .5), were similar. Insufficient PC yield for FISH analysis was decreased between cIg-FISH and FACS-FISH (22% and 3% respectively, P < .001). Flow cytometry allowed establishment of ploidy status in 91% of cases. In addition, FACS-FISH decreased analysis times, workload efforts, and operating costs. CONCLUSIONS: Fluorescence-activated cell sorting-FISH is an efficient PC purification strategy that affords significant improvement in diagnostic yield and decreases workflow requirements in comparison with cIg-FISH.

Predictors and Impact of Timing of Disease Progression Following Primary Therapy in Multiple Myeloma.

In multiple myeloma (MM) significant variation in progression-free survival (PFS) and overall survival (OS) is observed. We examined the outcomes of 1557 MM patients stratified into short (<2 years), medium (between 2 and 5 years) and long (>5 years) PFS. Short PFS occurred in 758 patients (48.7%), medium in 561 patients (36.2%), and long in 238 patients (15.3%). Median post-progression PFS was 9.2 months (95% CI: 8.1-11.0) in the short PFS and 33.1 months (95% CI: 29.0-42.1; P < .001) in the long PFS group. Median post-progression OS was 26.6 months (95% CI: 23.9-29.8) in the short PFS and 87.8 months (95% CI: 71.3- NR; P < .001) in the long PFS. Worse survival in the short PFS was irrespective of high risk (HR) fluorescence in situ hybridization (FISH) features, defined as deletion 17p and/or translocation t(4;14), t(14;16), t(14;20). In a multivariable analysis short PFS was associated with HR FISH, extramedullary plasmacytoma, plasma cell labeling index ≥2% at diagnosis, nonimmunoglobulin G isotype, treatment without autologous stem cell transplantation and achieving less than very good partial remission. In conclusion, the duration of the PFS significantly influences survival, regardless of HR cytogenetic features. Therefore, it should be considered an important parameter for risk stratification in patients experiencing a relapse.

Smoldering Multiple Myeloma: Observation Versus Control Versus Cure.

Smoldering multiple myeloma (SMM) is an intermediate clinical stage in the spectrum of monoclonal plasma cell disorders. It represents a heterogeneous clinically defined condition in which some patients (approximately 50%) have monoclonal gammopathy of undetermined significance (premalignancy), and some (approximately 50%) have multiple myeloma (biologic malignancy). Using specific prognostic factors, patients with SMM, in whom malignant transformation has already likely occurred, can be identified. These patients are considered to have high-risk SMM. Patients with newly diagnosed high-risk SMM are candidates for early intervention with lenalidomide or lenalidomide plus dexamethasone for 2 years, or enrollment in clinical trials.

Muscle and fat composition in patients with newly diagnosed multiple myeloma.

Measures of muscle and adipose tissue mass have been associated with outcomes in several malignancies, but studies in multiple myeloma (MM) are inconsistent. The aim of this study was to evaluate the association between muscle and fat areas and radiodensity, and overall survival (OS) in patients with newly diagnosed MM. We included 341 patients diagnosed with MM from 2010-2019 who had an 18F-fluorodeoxyglucose positron emission tomography/computed tomography at diagnosis. A cross-sectional image at the third lumbar vertebrae was segmented into muscle and fat components. Median follow up was 5.7 years. There was no association between sarcopenia and baseline disease characteristics or OS. Low muscle radiodensity was associated with higher disease stage, anemia, and renal failure. OS was 5.6 vs. 9.0 years in patients with muscle radiodensity in the lower vs. middle/upper tertiles, respectively (P = 0.02). High subcutaneous adipose tissue (SAT) radiodensity was associated with higher stage, anemia, thrombocytopenia, hypercalcemia, renal failure, and high LDH. OS was 5.4 years vs. not reached in patients with SAT radiodensity in the upper vs. middle/lower tertiles, respectively (P = 0.001). In conclusion, sarcopenia was not associated with OS in MM patients. High SAT radiodensity and low muscle radiodensity were associated with advanced disease stage and adverse laboratory characteristics.

Late versus early response and depth of response are associated with improved outcomes in patients with newly diagnosed multiple myeloma enrolled in the TOURMALINE-MM2 trial.

Deeper responses are associated with longer survival in multiple myeloma (MM); however, limited data exist on the impact of response kinetics on outcomes. We investigated progression-free survival (PFS) and duration of response (DOR) by response depth and in early (best confirmed response 0-4 months; n = 424) versus late responders (best confirmed response >4 months; n = 281). Newly diagnosed patients enrolled in TOURMALINE-MM2 receiving ixazomib-lenalidomide-dexamethasone (IRd) (n = 351) or placebo-Rd (n = 354) were evaluated post hoc. Deeper responses were associated with longer PFS (complete response [CR] not reached [NR], very good partial response [VGPR] 37.2 months, partial response [PR] 16.4 months) and DOR (CR NR, VGPR 42.6 months, PR 15.4 months). Among patients with a PFS (n = 511) or DOR (n = 484) of ≥6 months who achieved ≥PR, median PFS was prolonged among late versus early responders receiving IRd (59.7 vs. 17.9 months) or placebo-Rd (56.6 vs. 12.4 months), as was median DOR (IRd, NR vs. 20.9 months; placebo-Rd, 58.2 vs. 11.7 months). While the treatment paradigm for newly diagnosed MM is treatment to progression, our findings suggest slowness of response to a proteasome inhibitor-immunomodulatory drug-steroid combination is not a negative predictor of outcome.

Mode of Progression in Smoldering Multiple Myeloma: A study of 406 patients.

The approach to patients with high-risk smoldering multiple myeloma (SMM) varies among clinicians; while some advocate early intervention, others reserve treatment at progression to multiple myeloma (MM). We aimed to describe the myeloma-defining events (MDEs) and clinical presentations leading to MM diagnosis among SMM patients seen at our institution. We included 406 patients diagnosed with SMM between 2013-2022, seen at Mayo Clinic, Rochester, MN. The 2018 Mayo 20/2/20 criteria were used for risk stratification. Median follow-up was 3.9 years. Among high-risk patients who did not receive treatment in the SMM phase (n=71), 51 progressed by last follow-up; the MDEs included: bone lesions(37%), anemia(35%), hypercalcemia(8%), and renal failure(6%); 24% met MM criteria based on marrow plasmacytosis (≥60%) and/or free light chain ratio (>100); 45% had clinically significant MDEs (hypercalcemia, renal insufficiency, and/or bone lesions). MM diagnosis was made based on surveillance labs/imaging(45%), testing obtained due to provider suspicion for progression(14%), bone pain(20%), and hospitalization/ED presentations due to MM complications/symptoms(4%). The presentation was undocumented in 14%. A high proportion (45%) of patients with high-risk SMM on active surveillance develop end-organ damage at progression. About a quarter of patients who progress to MM are not diagnosed based on routine interval surveillance testing.