Sher, Taimur

AbstractPatients 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].

Two Letters to Blood address the risks of COVID-19 in populations with precursors of hematological disease. In the first article, Miller and colleagues report on whether clonal hematopoiesis of intermediate potential (CHIP) is associated with adverse outcomes with COVID-19, finding no association between CHIP and 28-day mortality while providing data indirectly linking IL-6 signaling and patient outcomes. In the second article, Ho and colleagues investigate the outcomes of patients with monoclonal gammopathy of undetermined significance (MGUS) with COVID-19, reporting that one-fourth had a severe infection and that on multivariable analysis, adverse outcomes are more likely if immunoparesis is present.

Abstract Therapeutic strategies that target novel pathways are urgently needed for patients with relapsed/refractory multiple myeloma (RRMM). Ibrutinib is an oral covalent inhibitor of Bruton tyrosine kinase, which is overexpressed in MM cells. This phase 1 dose‐escalation study examined various doses of ibrutinib in combination with standard doses of lenalidomide (25 mg) and dexamethasone (40 mg) using a standard 3 + 3 design in RRMM patients. The primary objective was to determine the maximum tolerated dose (MTD) of ibrutinib in combination with lenalidomide and dexamethasone. Patients ( n = 15) had received a median of 4 prior regimens, 53% were triple‐class exposed, 33% were penta‐exposed, and 54% were lenalidomide‐refractory. The MTD of ibrutinib was 840 mg ( n = 6) and only 1 dose‐limiting toxicity; a grade 3 rash possibly related to ibrutinib was noted. The most common ≥ grade 3 adverse events were rash in 2 (13%), lymphopenia in 2 (13%), leukopenia, neutropenia, thrombocytopenia, and anemia all occurring in 3 (20%) patients each. One patient achieved a partial response for an overall response rate of 7%. The clinical benefit rate was 80%. The median time to progression was 3.8 months. Ibrutinib, lenalidomide and dexamethasone appears to be a safe and well‐tolerated regimen with reasonable efficacy in heavily pretreated RRMM patients.

AbstractPatients with relapsed follicular lymphoma who do not respond to CAR‐T have a poor outcome. We present a case of refractory follicular lymphoma who relapsed after two CAR‐T infusions and achieved a complete remission after treatment with obinutuzumab and lenalidomide. This represents a promising treatment option in the post‐CAR‐T setting.

AbstractWe retrospectively examined our experience with midostaurin therapy in 33 consecutive patients (median age 68 years; 58% females) with advanced systemic mastocytosis (adv‐SM): aggressive SM (ASM; n = 17), SM associated with another hematologic neoplasm (SM‐AHN; n = 14) and mast cell leukemia (MCL; n = 2). KITD816V mutation was detected in 84% of the patients and C findings in 91%. Eleven (33%) patients were previously treated with other cytoreductive drugs, including cladribine (n = 4) and imatinib (n = 3). Median time from diagnosis to initiation of midostaurin therapy was 2.2 months (range 0.3–41). Using modified valent criteria, overall response was 42% (53% ASM, 29% SM‐AHN, 50% MCL; p = .22), all classified as being major. Responses included ≥50% reduction in bone marrow mast cells in 40% and normalization of serum tryptase in 29%, of evaluated cases. After a median follow‐up of 14.6 months from initiation of midostaurin therapy, 7 (21%) deaths, 1 (3%) leukemic progression, and 18 (55%) treatment discontinuations were documented; median duration of midostaurin treatment was 7.9 months (range 0.5–123) and response duration 21.5 months (range 2.9–123). Most frequent side effect was gastrointestinal (51%) while grade 3/4 neutropenia or thrombocytopenia occurred in 12% of patients. Response to treatment was not predicted by KIT mutation (p = .67) or exposure to prior cytoreductive therapy (p = .44). Median survival was longer in midostaurin responders but not significantly (median 26.5 vs. 16 months; p = .15). Findings from the current study are broadly consistent with previously published clinical trial observations.

AbstractExtramedullary multiple myeloma is seen in advanced and aggressive disease and occurs due to plasma cell infiltration of sites other than the bone marrow. Myelomatous ascites or pleural effusion is seen in less than 1% of cases and can be differentiated from infectious etiologies based on fluid cytology.

Patients with relapsed follicular lymphoma who do not respond to CAR-T have a poor outcome. We present a case of refractory follicular lymphoma who relapsed after two CAR-T infusions and achieved a complete remission after treatment with obinutuzumab and lenalidomide. This represents a promising treatment option in the post-CAR-T setting.

Abstract Background: Concern exists that the clinical trial populations differ from respective cancer populations in terms of their age distribution affecting the generalizability of the results, especially the underrepresented minorities. We hypothesized that the clinical trials that do not report race are likely to suffer from a higher degree of age disparity as well and the issue should be addressed in conjunction with each other. Methods: Food and Drug Administration (FDA) drug approvals from 7/2007-6/2019 were reviewed to identify oncology approvals, and trials with age details were selected. The primary outcome was the weighted mean difference in age between the clinical trial population and realworld population for various cancers. The secondary outcomes were the prevalence of race reporting and association of age and race reporting with each other. Group comparisons for proportions were performed using the χ2 test while continuous variables were compared using multiple analysis of variance (MANOVA) test or students t-test as appropriate. P values < .05 were considered significant. Results: Of the 261 trials, the race was reported in 223 (85.4%) of the trials while 38 trials (14.6%) had no mention of race. Race reporting improved minimally over time – 29 (85.3%) in 2007-2010 vs. 49 (80.3%) in 2011-2014 vs. 145 (85.4%) during 2015-2019 (p-value=0.41). No significant association between type of cancer and race reporting was noted – 147 (86.5%) of solid cancer trials vs. 76 (83.5%) of hematological cancer trials reported race (p-value=0.52). Age discrepancy between the clinical trial population and the real-world population was present for several cancer types. The discrepancy was higher for studies that did not report race, mean difference - 8.8 years 4 (95% CI -12.6 to -5.0 years) vs. studies that did report the race, mean difference -5.1 years, (95% CI -6.4 to -3.7 years), p-value=0.04. Conclusion: The study demonstrates that a significant number of clinical trials leading to cancer drug approvals suffer from racial and age disparity when compared to real-world populations and that the two factors may be interrelated. We recommend continued efforts to recruit diverse populations. In the meantime, reporting these characteristics for these crucial trials should be mandated. Citation Format: Thejus Jayakrishnan, Sonikpreet Aulakh, Mizba Baksh, Kianna Nguyen, Meghna Ailawadhi, Ayesha Samreen, Ricardo Parrondo, Taimur Sher, Vivek Roy, Rami Manochakian, Aneel Paulus, Asher Chanan-Khan, Sikander Ailawadhi. Disparity in race and age reporting in landmark cancer clinical trials: Underrepresentation of the traditionally underserved U.S. population [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-104.