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.

Sir Wilfred Thomason Grenfell: Medical Pioneer in Newfoundland and Labrador.

Stamp Vignettes focus on biographical details and accomplishments related to science and medicine, and not individual views and prejudices except where they had a major impact on the subject's life. The authors do not intend to imply any endorsement of such views when discussing a Stamp Vignette on Medical Science.

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.

A case of benign immunoglobulin D monoclonal gammopathy of undetermined significance with 26 years of follow-up.

The presence of a serum immunoglobulin D (IgD) monoclonal protein (M-protein) is seen in < 1% of patients with monoclonal gammopathies and is usually indicative of a malignant plasma cell disorder. Only a few cases of well-documented benign monoclonal gammopathy of undetermined significance (MGUS) of IgD subtype have been reported, and only 2 of those had over 5 years of follow-up at the time they were reported. Herein we describe longer-term follow-up of one of those 2 patients who has subsequently passed away from unrelated causes but never developed multiple myeloma or amyloidosis after 26 years of follow-up. Although IgD MGUS is extremely rare, this case confirms that presence of an IgD M-Protein is not always synonymous with a malignant plasma cell process.

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.

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.

MicroRNA and long non-coding RNA analysis in IgM monoclonal gammopathies reveals epigenetic influence on cellular functions and oncogenesis.

Not available.

Outcomes of patients with primary refractory multiple myeloma in the era of triplet and quadruplet induction therapy.

Patients with multiple myeloma (MM) who do not respond to initial therapy have worse outcomes than primary responders, and effective treatments are lacking in this population. However, the outcomes of primary refractory disease in the modern treatment era have not yet been studied. We reviewed patients with MM treated with triplet/quadruplet therapy at our institution to assess the incidence of primary refractory disease and the impact of salvage therapies in this population. We identified 1127 patients, of whom 1086 were evaluated for hematologic responses after 4 to 6 cycles. Of these, 93.3% (1013) had evidence of response, whereas 6.7% (73) had primary refractory disease. With a median overall survival (OS) of 51.3 months, patients with primary refractory disease had an increased risk of shorter survival in univariable and multivariable analyses (hazard ratio [HR], 3.5 [95% confidence interval (CI), 2.5-4.9]; HR, 4.3 [95% CI, 2.6-6.9], respectively). In the subgroup analysis of patients with primary refractory disease, those who received second-line autologous stem cell transplantation (ASCT) had increased second progression-free survival (20.9 vs 8.1 months; P < .01) and second OS (74.7 vs 31.3 months; P = .02) compared with patients who did not. We conclude that early progression remains a significant factor for shorter OS in the current era, and salvage ASCT could be the most beneficial option for this population.

Impact of cytogenetic abnormalities on the risk of disease progression in solitary bone plasmacytomas.

Most patients with solitary bone plasmacytomas (SBP) progress to multiple myeloma (MM) after definitive radiation therapy as their primary treatment. Whether the presence of high-risk (HR) cytogenetic abnormalities by fluorescence in situ hybridization (FISH) in the clonal plasma cells, obtained either directly from the diagnostic SBP tissue or the corresponding bone marrow examination at the time of diagnosis, is associated with a shorter time to progression (TTP) to MM is unknown. This study evaluated all patients diagnosed with SBP at the Mayo Clinic from January 2012 to July 2022. The presence of del(17p), t(14;16), t(4;14), or +1q (gain or amplification) by FISH in clonal plasma cells was defined as HR. A total of 114 patients were included in this cohort, and baseline FISH was available for 55 patients (48%), of which 22 were classified as HR (40%). The median TTP to MM for patients with SBP and HR FISH was 8 months (95% confidence interval [CI], 6.3-26) compared with 42 months (95% CI, 25-not reached [NR]) in patients with SBP without HR FISH (P < .001). In a multivariate analysis, only HR FISH was a significant predictor for shorter TTP to MM, independent of minimal marrow involvement and an abnormal serum free light chain ratio at diagnosis. Deletion (17p) and gain 1q abnormalities were the most common FISH abnormalities responsible for the short TTP to MM. Thus, assessing for HR FISH abnormalities in clonal plasma cells derived from either the diagnostic SBP tissue or the staging bone marrow examination of patients with newly diagnosed SBP is feasible and prognostic for a shorter TTP to MM.

Natural history, predictors of development of extramedullary disease, and treatment outcomes for patients with extramedullary multiple myeloma.

Extramedullary multiple myeloma (EMM) can present either at initial diagnosis (de novo) or at disease relapse (secondary) and confers an aggressive clinical course. Limited data exist for choosing the optimal therapy for EMM and this remains an area of unmet clinical need. After excluding paraskeletal multiple myeloma and primary plasma cell leukemia, we identified 204 (68%) patients with secondary EMM and 95 (32%) with de novo EMM between January 01, 2000 and 31 December, 2021. The median overall survival (OS) was 0.7 (95% CI: 0.6-0.9) years for secondary EMM and 3.6 (95%CI: 2.4-5.6) years for de novo EMM. The median progression-free survival (PFS) with initial therapy was 2.9 months (95% CI: 2.4-3.2 months) for secondary EMM and 12.9 months (95% CI: 6.7-18 months) for de novo EMM. Patients with secondary EMM treated with CAR-T therapy (n = 20) achieved a partial response (PR) or better in 75% with a median PFS of 4.9 months (3.1 months-not reached; NR). Patients with EMM treated with bispecific antibodies (n = 12) achieved a ≥ PR in 33%, with a median PFS of 2.9 months (95%CI: 2.2 months-NR). In a matched cohort, multivariate logistic regression analysis demonstrated younger age at diagnosis, 1q duplication, and t(4;14) at diagnosis of MM to be independent predictors of development of secondary EMM. Presence of EMM was independently associated with inferior OS in the matched cohorts for both de novo (HR 2.9 [95% CI: 1.6-5.4], p = .0007) and secondary EMM (HR 1.5 [95% CI: 1.1-2], p = .001).

Conditional survival in multiple myeloma and impact of prognostic factors over time.

Overall survival estimates from diagnosis are valuable for guiding treatment, but do not consider the years already survived. Conditional survival (CS) provides dynamic survival predictions over time. This study was conducted to estimate CS at 1-8 years from diagnosis and the impact of baseline prognostic factors on CS in multiple myeloma (MM) patients. This is a retrospective study including 2556 MM patients diagnosed between 2004 and 2019. CS (t | s) was defined as the probability of surviving t years given survival of s years. Median age was 64 years. Median follow-up was 6.2 years and median overall survival from diagnosis was 7.5 years. The 5-year CS estimates at s = 0, 1, 2, 3, and 5 years were 0.64, 0.61, 0.61, 0.61, and 0.58, respectively. On multivariate analysis, age ≥ 65 and proteasome inhibitor+immunomodulatory-based induction were associated with decreased survival and increased survival, respectively, retained at 5 years. The adverse impact of 1q gain/amplification, high-risk IgH translocation, and ISS-3 was significant at 1 and 3 years but not 5 years. Chromosome 17 abnormality was associated with decreased survival only at 1 year. Among MM patients, 5-year CS was stable at 1-5 years from diagnosis. The prognostic impact of high-risk cytogenetic factors decreased with additional years survived.

Artificial intelligence-enabled screening strategy for drug repurposing in monoclonal gammopathy of undetermined significance.

Monoclonal gammopathy of undetermined significance (MGUS) is a benign hematological condition with the potential to progress to malignant conditions including multiple myeloma and Waldenstrom macroglobulinemia. Medications that modify progression risk have yet to be identified. To investigate, we leveraged machine-learning and electronic health record (EHR) data to screen for drug repurposing candidates. We extracted clinical and laboratory data from a manually curated MGUS database, containing 16,752 MGUS patients diagnosed from January 1, 2000 through December 31, 2021, prospectively maintained at Mayo Clinic. We merged this with comorbidity and medication data from the EHR. Medications were mapped to 21 drug classes of interest. The XGBoost module was then used to train a primary Cox survival model; sensitivity analyses were also performed limiting the study group to those with non-IgM MGUS and those with M-spikes >0.3 g/dl. The impact of explanatory features was quantified as hazard ratios after generating distributions using bootstrapping. Medication data were available for 12,253 patients; those without medications data were excluded. Our model achieved a good fit of the data with inverse probability of censoring weights concordance index of 0.883. The presence of multivitamins, immunosuppression, non-coronary NSAIDS, proton pump inhibitors, vitamin D supplementation, opioids, statins and beta-blockers were associated with significantly lower hazard ratio for MGUS progression in our primary model; multivitamins and non-coronary NSAIDs remained significant across both sensitivity analyses. This work could inform subsequent prospective studies, or similar studies in other disease states.

Survival trends in young patients with Waldenström macroglobulinemia: Over five decades of experience.

Waldenström macroglobulinemia (WM) is a rare, indolent lymphoma, that predominately affects the elderly. We report the outcomes of young WM patients, evaluated over five decades, compared to their older counterparts, matched for the time of diagnosis. Between January 1, 1960 and October 31, 2013, 140 (11.8%) WM patients were ≤50 years of age at diagnosis in our database, and their estimated 10-year overall survival (OS) was 74%, with death attributable to WM in a higher proportion of patients compared to their older (≥65 years) counterparts (91% vs. 58%, p = .0001). Young patients were grouped into three cohorts based on the timing of the initiation of therapy: Group 1 (1960-1977, n = 12), Group 2 (1978-1995, n = 48), and Group 3 (1996-2013, n = 74). Among young patients, there was no disease-specific survival (DSS) difference across the three periods, [median DSS at 13 years (95% CI 5-23), 16 years (95% CI 14-22), and 15 years (95% CI 10-NR; p = .41), respectively]. However, DSS for the older cohort incrementally improved (Group 1, median 5.2 years, Group 2: 9.6 years, Group 3: 12 years; p = .05) over these periods. The estimated average years-of-life lost for the young cohort was 11.2 years from diagnosis, based on the expected survival for a normal age- and sex-matched population. Despite a protracted disease course, nearly all young patients succumb to their disease. In contrast to the improved survival of the elderly patient population, the evolving treatment strategies in WM have not impacted the outcome of young patients; however, the impact of Bruton tyrosine kinase inhibitors on this unique patient population remains to be determined.