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.

Thrombosis in multiple myeloma: Risk estimation by induction regimen and association with overall survival.

Lenalidomide-containing (R) triplet and quadruplet regimens are the standard of care for multiple myeloma (MM) and have been shown to increase the risk of thrombosis. The association between thromboembolism (TE) and survival in the novel multidrug era is not yet delineated. In this study, we evaluated the incidence of TE during the first year of MM diagnosis, its association with the type of induction regimen, and its impact on overall survival. We studied 672 newly diagnosed MM (NDMM) patients who received a triplet or quadruplet lenalidomide-based induction at the Mayo Clinic, Rochester. TE was diagnosed in 83 patients (12.4%). Of these, 56 (8.3%) had a deep venous thrombosis (DVT), 23 (3.4%) had a pulmonary embolism (PE) with or without the DVT, and 4 (0.6%) patients had a stroke. Carfilzomib-Rd (KRd) had the highest risk of TE (21.1%, 18/85), followed by quadruplets (11.1%, 5/45), bortezomib-Rd (9.6%, 51/531), and 0/11 (0%), treated with other lenalidomide-containing regimens. The difference in TE risk between KRd and the other regimens was statistically significant (OR = 2.6, p < .01). Nine patients developed a TE before being exposed to any treatment. Survival was significantly lower among patients that developed a TE (66 vs. 133 months, p < .01). The association of TE with reduced survival demonstrated in univariate analysis (HR = 2.2, 95% CI = 1.6-3.3) was maintained in the multivariable analysis adjusted for high-risk interphase fluorescence in situ hybridization (FISH), sex, age, receipt of an upfront transplant, the response at induction, and the International Staging System (ISS) (HR = 2.61, CI = 1.74-3.9). We conclude that TE is an important aspect of MM management, and effective management is especially relevant in the novel treatment era.

Molecular Clusters and Tumor-Immune Drivers of IgM Monoclonal Gammopathies.

PURPOSE: IgM monoclonal gammopathy of undetermined significance (MGUS) and Waldenström macroglobulinemia (WM) represent a disease spectrum with highly varied therapeutic management, ranging from observation to chemoimmunotherapy. The current classification relies solely on clinical features and does not explain the heterogeneity that exists within each of these conditions. Further investigation is warranted to shed light on the biology that may account for the clinical differences. EXPERIMENTAL DESIGN: We used bone marrow (BM) clonal CD19+ and/or CD138+ sorted cells, matched BM supernatant, and peripheral blood serum from 32 patients (7 MGUS, 25 WM) to perform the first multi-omics approach including whole-exome sequencing, RNA sequencing, proteomics, metabolomics, and mass cytometry. RESULTS: We identified three clusters with distinct pathway activation, immune content, metabolomic, and clinical features. Cluster 1 included only patients with WM and was characterized by transcriptional silencing of genes involved in cell cycle and immune response, enrichment of mitochondrial metabolism, infiltration of senescent T effector memory cells, and aggressive clinical behavior. Genetic/structural alterations of TNFAIP3 were distinct events of this cluster. Cluster 2 comprised both MGUS and WM patients with upregulation of inflammatory response, senescence and glycolysis signatures, increased activated T follicular helper and T regulatory cells, and indolent clinical behavior. Cluster 3 also included both MGUS and WM patients and exhibited intermediate features, including proliferative and inflammatory signaling, as well as glycolysis and mitochondrial metabolism. CONCLUSIONS: We have identified three distinct molecular clusters, suggesting a potential biologic classification that may have therapeutic implications.

Second- and third-line treatment strategies in multiple myeloma: a referral-center experience.

The treatment landscape for relapsed multiple myeloma (MM) has increased. In this study, we aimed to characterize 2nd (n = 1439) and 3rd (n = 1104) line regimens and compare the results between subgroups based on the year of treatment initiation (2nd line: 2003-2008, 2009-2015, 2016-2021; 3rd line: 2004-2009, 2010-2015, and 2016-2021). In both the second- and third- lines, we observed increasing use of novel agents (from 78 to 95% and from 77 to 95%, respectively) and triplet regimens (from 15 to 69% and from 21 to 71%, respectively). The most frequently used regimens in the last studied periods included lenalidomide-dexamethasone (RD; 14%), carfilzomib-RD (12%), and daratumumab-RD (10%) for the second-line, and daratumumab-pomalidomide-dexamethasone (11%) and daratumumab-RD (10%) for the third-line. The median time to the next treatment from second-line therapy has improved from 10.4 months (95% CI: 8.4-12.4) to 16.6 months (95% CI: 13.3-20.3; p < 0.001). The median overall survival from the first relapse increased from 30.9 months (95% CI: 26.8-183.0) to 65.8 months (95% CI: 50.7-72.8; p < 0.001). Over the last two decades, more patients were treated with newer agents and triplets for relapsed MM. The landscape of regimens has become more diverse, and survival after the first relapse is continually improving.

The impact of Post-Transplant doxycycline in AL amyloidosis - updated results after Long-Term follow up.

INTRODUCTION: The current treatment paradigm of AL amyloidosis lacks effective fibril-directed therapies. Doxycycline has been shown to have anti-fibril properties in preclinical models. In 2012, we reported that posttransplant prophylaxis with doxycycline was associated with improved survival compared to penicillin in patients with haematologic response. We provide here updated results after long-term follow up. METHODS: We included 553 patients who underwent transplant between July 24th, 1996, and June 24th, 2014. Doxycycline 100 mg daily was used for prophylaxis in patients with penicillin allergy; since 2013, doxycycline was used as the standard for prophylaxis. Prophylaxis was typically continued for a year after transplant. RESULTS: The median follow-up from transplant was 12.7 years. Doxycycline was used for prophylaxis in 33% of patients; the rest received penicillin. The median time to next treatment was 6.0 (95%CI; 4.4-8.8) years and 6.0 (95%CI; 4.9-7.1) years in the doxycycline and penicillin groups, respectively (p = .89). The median overall survival was 12.0 (95%CI: 11.0-19.6) years and 11.0 (95%CI: 9.6-12.7) years in the 2 groups, respectively (p = .17). There was a minimal trend towards improved survival with doxycycline among patients with ≥ very good partial response and among patients with organ response that was not statistically significant. CONCLUSION: After long-term follow-up, there is no clear evidence to support benefit of doxycycline in the post-transplant setting.

Sarcopenia identified by computed tomography imaging using a deep learning-based segmentation approach impacts survival in patients with newly diagnosed multiple myeloma.

BACKGROUND: Sarcopenia increases with age and is associated with poor survival outcomes in patients with cancer. By using a deep learning-based segmentation approach, clinical computed tomography (CT) images of the abdomen of patients with newly diagnosed multiple myeloma (NDMM) were reviewed to determine whether the presence of sarcopenia had any prognostic value. METHODS: Sarcopenia was detected by accurate segmentation and measurement of the skeletal muscle components present at the level of the L3 vertebrae. These skeletal muscle measurements were further normalized by the height of the patient to obtain the skeletal muscle index for each patient to classify them as sarcopenic or not. RESULTS: The study cohort consisted of 322 patients of which 67 (28%) were categorized as having high risk (HR) fluorescence in situ hybridization (FISH) cytogenetics. A total of 171 (53%) patients were sarcopenic based on their peri-diagnosis standard-dose CT scan. The median overall survival (OS) and 2-year mortality rate for sarcopenic patients was 44 months and 40% compared to 90 months and 18% for those not sarcopenic, respectively (p < .0001 for both comparisons). In a multivariable model, the adverse prognostic impact of sarcopenia was independent of International Staging System stage, age, and HR FISH cytogenetics. CONCLUSIONS: Sarcopenia identified by a machine learning-based convolutional neural network algorithm significantly affects OS in patients with NDMM. Future studies using this machine learning-based methodology of assessing sarcopenia in larger prospective clinical trials are required to validate these findings.

Risk factors for severe infection and mortality In patients with COVID-19 in patients with multiple myeloma and AL amyloidosis.

Patients with multiple myeloma (MM) have a lower efficacy from COVID-19 vaccination and a high rate of mortality from COVID-19 in hospitalized patients. However, the overall rate and severity of COVID-19 infection in all settings (including non-hospitalized patients) and the independent impact of plasma cell-directed therapies on outcomes needs further study. We reviewed the medical records of 9225 patients with MM or AL amyloidosis (AL) seen at Mayo Clinic Rochester, Arizona, and Florida between 12/01/2019 and 8/31/2021 and identified 187 patients with a COVID-19 infection (n = 174 MM, n = 13 AL). The infection rate in our cohort was relatively low at 2% but one-fourth of the COVID-19 infections were severe. Nineteen (10%) patients required intensive care unit (ICU) admission and 5 (3%) patients required mechanical ventilation. The mortality rate among hospitalized patients with COVID-19 was 22% (16/72 patients). Among patients that were fully vaccinated at the time of infection (n = 12), two (17%) developed severe COVID-19 infection, without any COVID-related death. On multivariable analysis, treatment with CD38 antibody within 6 months of COVID-19 infection [Risk ratio (RR) 3.6 (95% CI: 1.2, 10.5), p = .02], cardiac [RR 4.1 (95% CI: 1.3, 12.4), p = .014] or pulmonary comorbidities [RR 3.6 (95% CI 1.1, 11.6); p = .029] were independent predictors for ICU admission. Cardiac comorbidity [RR 2.6 (95% CI: 1.1, 6.5), p = .038] was an independent predictor of mortality whereas MM/AL in remission was associated with lower mortality [RR 0.4 (95% CI: 0.2-0.8); p = .008].

Deepening Responses after Upfront Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma in the Era of Novel Agent Induction Therapy.

High-dose melphalan followed by autologous stem cell transplantation (ASCT) remains the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). Achievement of complete response (CR) and minimal residual disease (MRD) negativity are associated with improved progression-free survival (PFS) and overall survival (OS). With superior triplet- and quadruplet-based induction regimens, a higher proportion of patients are achieving deep responses of at least a very good partial response (VGPR) or better. The probability of achieving different levels of deeper hematologic responses post-ASCT based on the pre-ASCT depth of response is less clear in the existing literature but would be of value to patients and providers in discussing the added benefit of ASCT. We assessed the rate of deepening the hematologic response with upfront ASCT in patients with NDMM, mainly to MRD-negative CR, based on the response achieved after induction therapy. We retrospectively reviewed 210 patients with NDMM who underwent upfront ASCT at Mayo Clinic Rochester between May 1, 2018, and July 31, 2019. In addition to the availability of next-generation flow cytometry (NGF) testing for MRD status, which yielded a sensitivity of 10-5, the more sensitive mass spectrometry-based assessment of peripheral blood (ie, MASS-FIX) for monoclonal proteins was used rather than conventional immunofixation. Pre-ASCT, 23 patients (11%) achieved MRD-negative CR, which increased to 66 patients (31%) post-ASCT. Of 187 patients not in MRD-negative CR pre-ASCT, 45 (24%) converted to MRD-negative CR. Patients with MRD-positive CR before ASCT had the highest rates of conversion to MRD-negative CR. HR cytogenetics did not impact rates of MRD-negative CR achievement post-ASCT irrespective of pre-ASCT IMWG response (P = 1.0). Overall, irrespective of IMWG response, 43 patients (20%) were MRD-negative pre-ASCT (19 in VGPR, 24 in CR or sCR), and 102 patients (49%) were MRD-negative post-ASCT (36 in VGPR, 66 in CR or sCR). Among 85 patients with VGPR post-ASCT, 36 achieved MRD negativity, of whom 8 (22%) progressed, whereas 49 had MRD-positive disease, of whom 24 (49%) progressed (P = .014). Upfront ASCT in patients with NDMM led to deeper responses, with 24% converting to MRD negative CR and more than doubling of the total rate of MRD negativity irrespective of IMWG response depth.

Insurance-based disparities impact survival outcomes in Waldenström macroglobulinemia within the United States.

Considerable healthcare resource utilization and financial burden have been associated with the treatment of WM; however, the impact of health insurance status on outcomes has not been previously reported. We conducted a National Cancer Database analysis of newly diagnosed cases of active WM between 2004 and 2017 to evaluate the impact of insurance status on outcomes. For patients <65 years old (n = 1249, male sex: 62.4%, median age: 58 years), significant insurance-based survival differences were observed on multivariable analysis; patients who were uninsured [n = 63; HR 3.11 (95%CI, 1.77-5.45), p < 0.001], on Medicaid [n = 87; HR 1.88 (95% CI, 1.01-3.48), p = 0.045], or on Medicare [n = 122; HR 2.78 (95%CI, 1.76-4.38), p < 0.001], had inferior survival compared to patients with private insurance (n = 977; reference). In patients ≥65 years, no insurance-based survival differences were found (p = 0.10). Overall, significant insurance-based outcome disparities exist in WM. Further work is desperately needed to systematically uncover and address these disparities.