Sher, Taimur

Background: Light chain (AL) amyloidosis is a rare and understudied plasma cell disorder. It is caused by abnormal misfolding of monoclonal immunoglobulin light chains, leading to extracellular deposition of amyloid, ultimately resulting in organ dysfunction and death. Since AL amyloidosis is uncommon, therapies are adapted from the more common plasma cell disorders like multiple myeloma. Daratumumab, a monoclonal antibody targeting CD38, was first tested in several prospective and retrospective studies in AL patients with relapsed refractory disease. The ANDROMEDA study (Kastritis E et al, NEJM 2021) established daratumumab in combination with CyBorD (Cyclophosphamide-Bortezomib-Dexamethasone) followed by daratumumab maintenance as the new standard of care compared to CyBorD alone for newly diagnosed patients. Consequently, daratumumab maintenance has become universally offered to all newly diagnosed AL amyloidosis patients. Notably, there was no second randomization before the initiation of maintenance therapy in ANDROMEDA. Hence, a critical question that remains is whether the superior efficacy observed in the investigational arm of the ANDROMEDA trial is solely a result of the addition of daratumumab during the induction phase or if the maintenance phase contributed to the favorable outcomes in the investigational arm. We hypothesize that a shorter duration of maintenance would prove non-inferior to the standard duration of daratumumab maintenance in patients with AL amyloidosis that have responded to Daratumumab-CyBorD induction. To answer this question we are conducting a pragmatic phase 2 randomized trial assessing the optimal duration of daratumumab maintenance in patients with AL amyloidosis who have responded to Daratumumab-CyBorD induction. Study Design, Patients and Methods: We use broadened eligibility criteria consistent with pragmatic trial design. The estimated total enrollment is up to 96 patients. The main eligibility criteria are patients with biopsy-proven AL Amyloidosis who have completed 6 cycles of Dara-CyBorD-based induction treatment and achieved an adequate response to induction (defined as hematological complete response (CR), hematological very good partial response (VGPR), or hematological partial response (PR) with at least one organ response). Patients in whom bortezomib and/or cyclophosphamide were omitted from induction due to toxicity concerns or adverse effects are allowed. The major exclusion criteria are patients who were concomitantly diagnosed with multiple myeloma based on International Myeloma Working Group (IMWG) criteria. This phase II, open-label, multicenter trial (NCT05898646) randomizes patients who have attained an adequate response to 6 cycles of Dara-CyBorD-based induction in a 1:1 ratio, using a dynamic allocation procedure that balances the marginal distributions of the stratification factors (age, cardiac stage, and t(11;14) status). Randomization is to either single-agent daratumumab maintenance of 6 cycles duration (experimental arm) or 18 cycles of daratumumab maintenance (control arm) (cycle = 28 days). Treatment is allowed to be given at a local facility After completing maintenance treatment, patients will follow up every 3 months for up to 36 months from registration. The primary endpoint of the trial is to evaluate the non-inferiority of a shorter (6 cycles) daratumumab maintenance measured by event-free survival (EFS) compared to the standard maintenance of 18 cycles in newly diagnosed AL amyloidosis who receive 6 cycles of daratumumab-CyBorD based induction. EFS in this study is defined as time from registration to any of the following events: hematological progression, organ progression, subsequent anti-plasma cell therapy in the absence of hematological progression but with persistent organ dysfunction or death, whichever occurs first. Secondary endpoints are depth of hematological and organ response, bone marrow measurable residual disease negativity rate, duration of response, quality of life, and survival. By investigating whether a shorter duration of maintenance is non-inferior to the standard duration, we aim to inform clinical practice and potentially reduce the toxicities associated with prolonged maintenance therapy, including hypogammaglobulinemia, recurrent infections, the need for intravenous gammaglobulin replacement, and financial toxicity.

Introduction: Overall outcomes have improved significantly for MM with a 5-year relative survival rate currently of >60%. With effective treatments, patients from all clinical strata and age groups are expected to have meaningful benefit, but despite excellent therapeutic advancements, some patients continue to have early mortality. We conducted this study to investigate factors associated with early mortality. Methods: The National Cancer Database (NCDB) was queried for adult patients with NDMM between 2004 and 2021. We excluded patients with multiple primary malignancies or lost to follow-up (unknown vital status or last contact). Early mortality was defined as death within 6 months from MM diagnosis. Patient demographics and socioeconomic factors available in NCDB were collected. Kaplan-Meier and multivariate Cox regression were used to evaluate the likelihood of early mortality in this large cohort of MM patients using multi-variate analysis. Results: Out of 255,579 eligible patients with MM, 35,302 (13.8%) died within the first 6 months of diagnosis and 108,534 (42.5%) died after the first 6 months of MM diagnosis. The early mortality cohort had significantly higher mean age at MM diagnosis (73.9 vs. 68.5 years, p<0.001) but no significant differences were noted for gender distribution. There was a statistically significant difference for racial/ethnic distribution (p=0.019), but the percentages were very similar among non-Hispanic White (69% vs 68.1%), non-Hispanic African American (18% vs 18.7%) and Hispanic patients (4.7% vs 4.8%). Patients in the early mortality cohort were less likely to be treated at academic institutions (28.4% vs 37.8%, p<0.001) and have significantly different distribution by insurance type (less likely to have private insurance; 17.3% vs. 30%, more likely to have Medicare; 72.1% vs. 58.7%, p<0.001) although overall insurance access was similar between the two groups (95.3% vs 95.2%, p=0.283). Early mortality was associated with higher morbidity scores as per the Charlson-Comorbidity Index (CCI) (p<0.001) and were more likely to have not received any treatment for MM (53.2% in early mortality group vs. 28.4% in late mortality, p<0.001). Early mortality was also associated with a lower literacy rate (high school graduation rate 21.2% vs. 19.7%, p<0.001) and lower household income (<$46,277; 19.1% vs. 17.7%, p<0.001). Conclusion: This large real-world analysis shows that despite therapeutic advances in recent years, there is a significant percentage of patients with NDMM in the U.S. who suffer from early mortality. There are several sociodemographic and economic factors that were found to be associated with early mortality, with some showing clear trends (older age, treatment facility type, insurance type, income, education, CCI), while others like racial differences were significant but somewhat ambiguous. Identifying and addressing these factors at diagnosis will help provide personalized care plans and minimize early mortality.

Abstract Multiple myeloma (MM) therapeutics have evolved tremendously in recent years, with significant improvement in patient outcomes. As newer treatment options are developed, stem cell transplant (SCT) remains an important modality that provides excellent disease control and delays the progression of disease. Over the years, SCT use has increased overall in the U.S., but two distinct gaps remain, including suboptimal use overall, and racial-ethnic disparities. We evaluated the National Cancer Database (NCDB) to study what sociodemographic factors might play a role within a given racial-ethnic group leading to disparate SCT utilization, such that targeted approaches can be developed to optimize SCT use for all. In nearly 112,000 cases belonging to mutually exclusive categories of non-Hispanic Whites (NHW), non-Hispanic Blacks (NHB), Hispanics, non-Hispanic Asians (NHA), and others, we found certain factors including age, comorbidity index, payor type, facility type (academic vs. community) and facility volume to be uniformly associated with SCT use for all the racial-ethnic groups, while gender was not significant for any of the groups. There were several other factors which had a differential impact on SCT utilization among the various race-ethnicity groups studied, including year of diagnosis (significant for NHW, NHB and Hispanics), income level (significant for NHW and Hispanics), literacy level (significant for NHW and NHB), and geographic location of the treatment facility (significant for NHW and NHA). The suboptimal SCT utilization overall in the U.S., suggests that there may be room for improvement for all, even including the majority NHW, while we continue to work on factors that lead to disparities for the traditionally underserved populations. This study helps identify sociodemographic factors that may play a role specifically in each group and paves the way to devise targeted solutions such that resource utilization and impact can be maximized.

SummaryThis phase II study evaluated time‐limited (24 cycles) treatment with ibrutinib and ixazomib in newly diagnosed (NDWM; n = 9) and relapsed/refractory (RRWM; n = 12) Waldenström macroglobulinaemia (WM). The overall response rate (ORR) was 76.2% (n = 16) in 21 evaluable patients with no patient achieving a complete response (CR). The median duration of treatment was 15.6 months, and after a median follow‐up time of 25.7 months, the median progression‐free survival (PFS) was 22.9 months. While the primary end‐point was not met (CR rate at any time) and 28.5% discontinued treatment due to toxicity, ibrutinib plus ixazomib led to a clinically meaningful ORR and PFS. Combined Bruton's tyrosine kinase (BTK) and proteasome inhibition merits further evaluation in WM.

Plasma cell disorders are one of the most common hematologic malignancies. Monoclonal gammopathy of undetermined significance (MGUS) is defined by a serum monoclonal protein <3 g/dL, bone marrow plasma cell infiltration <10%, and most importantly absence of end-organ damage. The prevalence of MGUS in general population is estimated to be 1%–4% and its frequency increases with age with 3% among people above 50 y of age. The risk of progression to clinically significant plasma cell dyscrasia is estimated to be 1% per year. With aging population and increasing use of transplantation for the management of kidney disease in older adults, MGUS is being identified during the evaluation for kidney transplant candidacy or during the postkidney transplant follow-up. MGUS in patients with end-stage renal disease (ESRD) undergoing evaluation for kidney transplant can pose a complex management dilemma. In this article, we review the current state of knowledge about the prevalence of MGUS in ESRD population and the impact of kidney transplantation on the progression of MGUS to clinically significant plasma cell disorder. We make recommendations for the screening of ESRD patients undergoing kidney transplant evaluation and the management of MGUS after renal transplant.

Introduction: Treatment options for multiple myeloma (MM) are evolving rapidly with recent introduction of BCMA-targeting CAR-T (Ide-cel, Cilta-cel) and bispecific antibody (Bi-Ab; Teclistamab) alternatives. These are complex, logistically demanding therapies, and patient awareness/knowledge can affect treatment decisions. There are traditionally underserved patients in MM, and awareness among them must be investigated to uncover disparities which may impact their access to and choice of novel therapies, contributing to disparate outcome. Methods: The study involved an anonymous 25-question online English language survey covering basic demographics, understanding of available T-cell directed MM treatments (CAR-T, Bi-Ab), and preferences for these agents. MM patients within the Mayo Clinic database and members of International Myeloma Foundation's MM support groups were sent a link to the voluntary survey. The survey was active from March 30 until July 12, 2023. Descriptive statistics were calculated with R language (Bluesky Statistics, V7.40), and categorical variables among outcome demographic groups were compared using Pearson Chi-square test (p-value ≤0.05 considered statistically significant). Multiple model logistic regression was used for multivariate analysis amongst statistically significant outcomes. Results: The survey had 2370 respondents with median age 68 years (range: 30-95) and median age at MM diagnosis 62 years (range: 18-88). Time since diagnosis was &lt;5 years in 59.5%. Majority of the respondents (89.4%) were non-Hispanic Whites (NHW). Maximum education categories were high school (10.9%), some college but no degree (18.1%), associate/bachelor (39.7%), and master's/professional (32.3%). Geography and type of residence were reported as: West (24%), Midwest (46.2%), Northeast (3.3%), South (24.8%), outside U.S. (1.7%), and rural (26.7%), urban (21.4%), suburban (51.9%). The goals of MM treatment in order of reported importance were complete remission (66.1%), longer survival (55.3%) and low symptom burden (43.3%). Only 6.5% and 2.6% of respondents had received CAR-T and Bi-Ab, respectively, while 27.9% and 70.5% had never heard of CAR-T and Bi-Ab, respectively. A high proportion of respondents did not understand the risks/benefits of CAR-T (65.5%) or Bi-Ab (90.7%). Given a preference among CAR-T products, 5.4% would prefer Cilta-cel, 1.9% Ide-cel and 92.7% were not sure/no preference. Amongst only those who reported understanding the risks/benefits of CAR-T, the majority (73%) said they would prefer Cilta-cel. The majority (87.5%) were not sure of any differences between the two CAR-T products while some reported different targets (6.3%), response rate (5.9%), response duration (6.2%), side effects (4.9%), and manufacturing time (2.7%). The biggest concern for both CAR-T and Bi-Ab was side effects. Majority (89.4%) were not sure that Teclistamab Bi-Ab targeted BCMA, and nearly 70% felt that CAR-T was superior to Bi-Ab for treating MM. Reported sources of knowledge about MM treatment were healthcare team (82.6%), online resources (43.6%) and other patients/support groups (37.9%). Several demographic characteristics that significantly affected patient's responses to different questions in the survey. Selected questions and respondent categories with statistically significant results in multivariate analysis are shown in Table 1. Generally, higher education, living in northeast U.S., urban or suburban residency, and &gt;5 years since MM diagnosis were associated with better awareness/understanding of CAR-T and Bi-Ab. Respondents with &gt;70-year age were less likely to be aware of these agents or understand their risks/benefits. Race-ethnicity had no statistically significant associations in this cohort of predominantly NHW. Conclusions: This large cross-sectional study identifies lack of adequate awareness regarding CAR-T and Bi-Ab and provides a glimpse of current understanding of these complex therapies. There are disparate groups including rural, less educated, elderly and those with recent diagnosis of MM who have significantly lesser awareness. Some better-informed respondents had preferences among these treatments. Targeted awareness campaigns should be developed so that knowledge gaps can be bridged and patients across all sociodemographic groups are better equipped to take informed decisions about MM treatment.

While immunotherapies, such as CAR T therapy and bi-specific antibodies, have revolutionized the treatment of multiple myeloma (MM), patients with AL amyloidosis have been excluded from trials with these agents due to concerns of underlying autonomic, cardiac, and renal dysfunction, leading to potentially fatal toxicities from these therapies. In this communication, we described the outcomes of two patients with AL amyloidosis and concurrent MM with underlying cardiac and/or renal dysfunction who underwent anti-BCMA CAR T cell therapy with ide-cel or cilta-cel, received cytokine release syndrome prophylaxis, and tolerated therapy well with manageable toxicities and achieved a MRD-negative state. We described the preliminary efficacy and safety of CAR T in patients with AL amyloidosis and highlighted the importance of patient selection and medical optimization of cardiac and renal function prior to CAR T.

AbstractIntroductionHealth information technology (HIT) has the potential to improve healthcare delivery and engagement. Studying racial‐ethnic disparities in HIT engagement will help understand and overcome challenges to healthcare utilization.MethodsWe undertook a patient‐reported survey among patients with lymphoid malignancies at two campuses of Mayo Clinic, Florida to explore HIT‐related disparities. Variables between Whites and non‐Whites, and non‐Whites from the two campuses were compared.ResultsThe survey was completed by 1004 respondents, with 71% whites, 27% non‐Whites (race‐ethnicity not reported by 2%). Non‐Whites included 30% responders at the main campus and 64% at an inner‐city campus. Whites were significantly older and had higher education, while non‐Whites had lesser access to a computer. Only 51% of non‐Whites were registered to use electronic medical records (EMR) as compared to 72% Whites (p < 0.001) and significantly lesser number of non‐Whites even knew that EMR existed (81% vs. 92%, p < 0.001). Encouragingly, a higher number of non‐Whites wanted to engage in EMR. Non‐Whites from the main campus were older, more educated and had more access to a computer as compared to those from the inner‐city campus. Similar disparate factors were noted among minorities from the two campuses, suggesting impact of socioeconomic backgrounds on EMR usage among non‐Whites. Linguistic barriers were more striking among inner‐city campus non‐Whites.ConclusionsNon‐Whites continue to struggle with suboptimal utilization of the healthcare system and barriers related to integration in HIT, including disparities representing socioeconomic differences. Efforts need to be made at several levels to help racial‐ethnic minorities overcome awareness, access, and linguistic barriers to HIT utilization.

Abstract 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 &lt; .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.

AbstractBackgroundClinical trials are an essential part of advancing care for cancer patients. Historically, however, racial minorities and females have been underrepresented in these trials. Efforts like the National Institute of Health Revitalization Act attempted to mitigate these disparities, but despite these efforts, they continue to exist. These disparities can subsequently lead to minorities and females receiving suboptimal care.AimsThe purpose of our study was to understand the changing trends in reporting of participant race and sex as a demographic variable in phase III lung cancer clinical trials published over the last 35 years given these consequences of poor representation.Methods and resultsA total of 426 articles reporting the results of phase III lung cancer clinical trials published from 1984 to 2019 were identified in PubMed. From these articles, data on participant sex and race were collected from the demographic tables to construct the database for this study. This database was subsequently used to determine the rate of reporting of demographic factors like race and sex and the participation trends over the time of minority and female participation in lung cancer phase III clinical trials. The SciPy Stats package for Python was used to calculate descriptive statistics, 95% confidence intervals, two sample t‐test, one‐way analysis of variance test, and Pearson's correlation coefficients. The Matplotlib package for Python was used for figure generation. Only 137 (32.2%) of the 426 studies analyzed reported the race of participants. Among those studies, we found that the mean participation rate of White participants was significantly higher (82.65%; p < .001). We found a decrease in African American participants and an increase in Asian participants over time. When looking at sex, we found that although the rate of male participation (69.02%) was significantly higher than that of female participation (30.98%), female participation has improved with time at a rate of 0.65% per year.ConclusionWe found that the reporting and participation of minority races continue to lag that of other demographic factors like sex in phase III clinical trials in lung cancer. Based on our analysis, we note a decline in participation of African Americans in lung cancer phase III clinical trials despite the rising incidence of lung cancer.