Absolute lymphocyte count after BCMA CAR-T therapy is a predictor of response and outcomes in relapsed multiple myeloma.

ABSTRACT: B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T cells (CAR-Ts) used in multiple myeloma (MM) are rapidly becoming a mainstay in the treatment of relapsed/refractory (R/R) disease, and CAR-T expansion after infusion has been shown to inform depth and duration of response (DoR), but measuring this process remains investigational. This multicenter study describes the kinetics and prognostic impact of absolute lymphocyte count (ALC) in the first 15 days after CAR-T infusion in 156 patients with relapsed MM treated with the BCMA-targeting agents ciltacabtagene autoleucel and idecabtagene vicleucel. Patients with higher maximum ALC (ALCmax) had better depth of response, progression-free survival (PFS), and DoR. Patients with ALCmax >1.0 × 103/µL had a superior PFS (30.5 months vs 6 months; P < .001) compared with those with ≤1.0 × 103/µL, whereas patients with ALCmax ≤0.5 × 103/µL represent a high-risk group with early disease progression and short PFS (hazard ratio, 3.4; 95% confidence interval, 2-5.8; P < .001). In multivariate analysis, ALCmax >1.0 × 103/µL and nonparaskeletal extramedullary disease were the only independent predictors of PFS and DoR after accounting for international staging systemic staging, age, CAR-T product, high-risk cytogenetics, and the number of previous lines. Moreover, our flow cytometry data suggest that ALC is a surrogate for BCMA CAR-T expansion and can be used as an accessible prognostic marker. We report, to our knowledge, for the first time the association of ALC after BCMA CAR-T infusion with clinical outcomes and its utility in predicting response in patients with R/R MM.

Prevalence and impact of diabetes on survival of patients with multiple myeloma in different racial groups.

ABSTRACT: Multiple myeloma (MM) is twice as common in Black individuals compared with in White individuals, and diabetes mellitus (DM) disproportionately affects Black patients. Although numerous studies have shown a correlation between DM and MM, this has not been studied in the context of race and in vivo mechanisms. We conducted a retrospective clinical study of 5383 patients with MM of which 15% had DM (White, 12% and Black, 25%). Multivariable Cox models showed reduced overall survival (OS) for patients with DM (hazard ratio, 1.27; 95% confidence interval, 1.11-1.47; P < .001). This appeared to be driven by a marked difference in OS between White patients with and without DM but not in Black patients. In contrast, obesity was associated with better OS in Black patients but not in White patients. To complement this analysis, we assessed MM growth in a genetically engineered immunocompromised nonobese diabetic (Rag1-/-/muscle creatinine kinase promoter expression of a human IGF1R [M] with a lysine [K] to arginine [R] point mutation) mouse model to evaluate the mechanisms linking DM and MM. MM.1S xenografts grew in more Rag1-/-/MKR mice and grew more rapidly in the Rag1-/-/MKR mice compared with in controls. Western blot analysis found that MM1.S xenografts from Rag1-/-/MKR mice had higher phosphorylated S6 ribosomal protein (Ser235/236) levels, indicating greater activation of the mammalian target of rapamycin pathway. Our study is, to our knowledge, the first to evaluate racial differences in DM prevalence and survival in MM, as well as the effect of DM on tumor growth in mouse models. Our results suggest that DM may contribute to the higher incidence of MM in Black patients; and to improve survival in MM, DM management cannot be ignored.

IVIg Use Associated with Ten-Fold Reduction of Serious Infections in Multiple Myeloma Patients Treated with Anti-BCMA Bispecific Antibodies.

BCMA-targeted bispecific antibodies (BiAb) are efficacious in relapsed/refractory multiple myeloma; however, serious infections have emerged as important toxicities. In this retrospective study, we characterized all infections and their risk factors, and evaluated the impact of infection prophylaxis in patients treated with BCMA-targeted BiAbs. Among 37 patients, 15 (41%) experienced a grade 3-5 infection, with two infection-related deaths during deep remissions. Most (84%) infections occurred during disease remissions. The cumulative probability of grade 3-5 infection increased over time with no plateau. Among responders (n = 26), profound hypogammaglobulinemia occurred in 100% and continued throughout the entire duration of treatment. During periods when patients were receiving intravenous immunoglobulin (IVIg), the rate of grade 3-5 infections was 90% lower than during observation (incidence rate ratio, 0.10; 95% confidence interval, 0.01-0.80; P = 0.0307). No other risk factors for infection were identified. This study demonstrates that profound hypogammaglobulinemia is universal with BCMA-targeted BiAbs, with intravenous immunoglobulin potentially abrogating most of the infection risk. SIGNIFICANCE: To the best of our knowledge, this is the first study to comprehensively analyze risk factors and mitigation strategies to prevent infections in myeloma patients receiving anti-BCMA bispecific antibodies. Profound and prolonged hypogammaglobulinemia was universal among responders, while immunoglobulin replacement was associated with 90% lower rates of grade 3-5 infections. See related commentary by Garfall and Stadtmauer, p. 427 . This article is featured in Selected Articles from This Issue, p. 419.

Sequencing T-cell redirection therapies leads to deep and durable responses in patients with relapsed/refractory myeloma.

T-cell redirection therapy using chimeric antigen receptor (CAR) T cells and bispecific antibodies (BiAbs) has shown promising efficacy in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), leading to the approval of 2 CAR T-cell products and numerous BiAb trials. Data on the outcomes after relapse following BiAbs are urgently required to develop strategies for sequencing salvage therapies. We identified 58 patients progressing after a BiAb trial at Mount Sinai Hospital. Progression-free survival (PFS) to the first salvage (PFS1), second salvage therapy (PFS2), and overall survival (OS) were estimated using the Kaplan-Meier method. The median age of the patients was 67 years, and 78% had high-risk cytogenetics. They had a median of 6 prior therapy lines, 89% were triple-class refractory, and 44% were penta-drug refractory. After the BiAb trial, patients were followed for a median of 30.5 months and received a median of 2 additional salvage therapies (range, 1-9). The most common first salvage was T-cell redirection in 19 patients (10 BiAb and 9 CAR T cells). Ten patients underwent T-cell redirection as a second salvage treatment. T-cell redirection therapy as first or second salvage was feasible and associated with a median PFS1 of 28.9 months, PFS2 of 30.9 months, and an OS of 62% at 2 years. The sequential use of different T-cell redirection therapies is possible and may lead to deep and durable responses following the relapse after BiAb therapy in RRMM.

Bridging advanced myeloma patients to subsequent treatments and clinical trials with classical chemotherapy and stem cell support.

Rapidly progressing relapsed/refractory multiple myeloma (RRMM) patients with compromised marrow have limited treatment options. Thus, non-myeloablative chemotherapy with a stem cell boost (SCB) may provide disease control and hematopoietic improvement as bridge to subsequent therapies. We identified 96 patients who received a SCB between January 2011 and December 2019 at the Mount Sinai Hospital. Patients had a median age of 64 years, received a median of 7 prior lines of therapy and 68 and 42% were triple-class and penta-drug refractory, respectively. Chemotherapy included melphalan (MEL) (n = 16), melphalan + carmustine (BCNU/MEL) (n = 52) or a variant of DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin) (n = 28). Median time to neutrophil recovery was 10 days and was significantly lower with DCEP (8 days) compared to MEL and BCNU/MEL (10-11 days) (p = 0.0047). Time to progression, progression-free survival and overall survival were 3.19, 2.7 and 8.38 months, respectively. The BCNU/MEL group had the highest response rate of 85% (p = 0.05), clinical benefit rate of 94% (p = 0.0014), progression-free survival of 3.3 months (p = 0.4) and overall survival of 8.7 months (p = 0.5). Sixty-six patients (69%) were bridged to new lines of therapy, including clinical trials. Non-myeloablative chemotherapy with SCB provides rapid disease control and marrow recovery with potential to receive further therapy.

Interventions and outcomes of patients with multiple myeloma receiving salvage therapy after BCMA-directed CAR T therapy.

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR T) therapy has demonstrated remarkable efficacy in patients with relapsed/refractory multiple myeloma, and now there are two US Food and Drug Administration-approved BCMA-directed CAR T products. However, despite high initial response rates, most patients eventually relapse. The outcomes of patients with disease recurrence after BCMA-directed CAR T have not been comprehensively studied, and such an analysis would help define optimal treatment strategies. We analyzed the salvage treatments and outcomes of 79 patients with multiple myeloma from two academic institutions, who had progression of disease after treatment with BCMA-directed CAR T. A total of 237 post-CAR T salvage treatment lines were used, and patients received a median of 2 (range, 1-10) treatment lines. The median overall survival from the date of relapse post-CAR T therapy was 17.9 months (95% confidence interval [CI], 14.0 non-estimable). The overall response rate to the first salvage regimen was 43.4%, with a median progression-free survival of 3.5 months (CI, 2.5-4.6). Thirty-five patients (44.3%) received a T-cell-engaging therapy (bispecific antibody or subsequent CAR T) as salvage treatment. The overall survival in patients who received subsequent T-cell-engaging therapy was not reached after a median follow up of 21.3 months. Patients with multiple myeloma who relapse after BCMA-directed CAR T have a limited prognosis but can be potentially treated with multiple lines of salvage therapy. T-cell-engaging therapies appear to maintain pronounced clinical activity in this setting.

POEMS Syndrome: Real World Experience in Diagnosis and Systemic Therapy - 108 Patients Multicenter Analysis.

POEMS syndrome, a rare plasma cell disorder, is challenging both in the diagnostic and therapeutic management. We present real word retrospective analysis of 108 cases analyzing clinical features and therapeutic modes. We compare our results with the available literature. This is the first description with such wide use of proteasome inhibitors in first line treatment. POEMS (Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) syndrome is a rare and challenging plasma cell disorder, both in the diagnostic and therapeutic management of the disease. Currently, the literature on POEMS is sparse with most evidence being case reports and small case studies. We present a retrospective real world experience of 108 patients with POEMS. We analyzed the clinical features and therapeutic interventions. Regarding clinical features, our findings demonstrated that skin lesions, thrombocythemia and polycythemia were present less frequently than reported previously. Regarding clinical interventions, this is one of the largest analyses of front line treatment in POEMS and the first one to include frequent utilization of proteasome inhibitors (37%). Bortezomib monotherapy was the most effective therapy achieving complete remission/very good partial remissions (CR/VGPR) in 69% of patients. Thirty percent of patients proceeded to planned autologous stem cell transplant (ASCT) as part of the front-line treatment resulting in statistically superior progression-free (PFS) and overall survival (OS) compared to non-ASCT treated patients (P= .003). In multivariate analysis, anemia, thrombocytopenia, and as age over 60 were associated with a negative impact on patient outcomes.

Anti-body building: The exercise of advancing immune based myeloma therapies.

The last decade has seen a marked improvement in the outcomes of patients with multiple myeloma. Much of this has been due to not only the advent of new therapies, but their inherent ability to be combined into 3 and 4 drug regimens without resulting in unacceptable toxicity. The general gestalt has been to combine agents of varied mechanisms of action. With the primary classes of agents such as proteasome inhibitors and immunomodulatory drugs as bases, the advent of antibody-based therapy in myeloma has allowed us to easily augment these therapies; much in the same way rituximab impacted the lymphoma world. With the approvals of daratumumab, elotuzumab and isatuximab; the myeloma world was ushered into the next wave of targeted agents. Here, we take a look at the current landscape of "off-the-shelf" antibody-based therapies in myeloma and peer into the next wave of multi-functional targeted agents.

Admission D-dimer levels, D-dimer trends, and outcomes in COVID-19.

Observational data suggest an acquired prothrombotic state may contribute to the pathophysiology of COVID-19. These data include elevated D-dimers observed among many COVID-19 patients. We present a retrospective analysis of admission D-dimer, and D-dimer trends, among 1065 adult hospitalized COVID-19 patients, across 6 New York Hospitals. The primary outcome was all-cause mortality. Secondary outcomes were intubation and venous thromboembolism (VTE). Three-hundred-thirteen patients (29.4%) died, 319 (30.0%) required intubation, and 30 (2.8%) had diagnosed VTE. Using Cox proportional-hazard modeling, each 1 µg/ml increase in admission D-dimer level was associated with a hazard ratio (HR) of 1.06 (95%CI 1.04-1.08, p < 0.0001) for death, 1.08 (95%CI 1.06-1.10, p < 0.0001) for intubation, and 1.08 (95%CI 1.03-1.13, p = 0.0087) for VTE. Time-dependent receiver-operator-curves for admission D-dimer as a predictor of death, intubation, and VTE yielded areas-under-the-curve of 0.694, 0.621, and 0.565 respectively. Joint-latent-class-modeling identified distinct groups of patients with respect to D-dimer trend. Patients with stable D-dimer trajectories had HRs of 0.29 (95%CI 0.17-0.49, p < 0.0001) and 0.22 (95%CI 0.10-0.45, p = 0.0001) relative to those with increasing D-dimer trajectories, for the outcomes death and intubation respectively. Patients with low-increasing D-dimer trajectories had a multivariable HR for VTE of 0.18 (95%CI 0.05-0.68, p = 0.0117) relative to those with high-decreasing D-dimer trajectories. Time-dependent receiver-operator-curves for D-dimer trend as a predictor of death, intubation, and VTE yielded areas-under-the-curve of 0.678, 0.699, and 0.722 respectively. Although admission D-dimer levels, and D-dimer trends, are associated with outcomes in COVID-19, they have limited performance characteristics as prognostic tests.

Ferritin levels in patients with COVID-19: A poor predictor of mortality and hemophagocytic lymphohistiocytosis.

INTRODUCTION: A hyperinflammatory environment has been a hallmark of COVID-19 infection and is thought to be a key mediator of morbidity. Elevated ferritin has been observed in many patients with COVID-19. Several retrospective studies have shown ferritin levels can be correlated and predictive of poor outcomes in COVID-19, though a rigorous analysis has been lacking. METHODS: A retrospective analysis of 942 adult COVID-19 patients admitted in March 2020 at a large New York City health system with available ferritin levels. RESULTS: The primary outcome, all-cause mortality, was observed in 265 (28.1%) patients. Patients who died had a significantly higher median admission and maximum ferritin levels than those who did not. However, death was poorly predicted by admission and maximum ferritin levels on receiver operator curve (ROC) analysis, with AUCs of 0.677 and 0.638, respectively. AUCs increased when the cohort was limited to progressively younger patients. Ferritin levels were minimally better at predicting our secondary outcomes. These included mechanical ventilation, observed in 280 (29.7%) patients with an ROC yielding an area under the curve (AUC) of 0.769, and new renal replacement therapy, observed in 80 (8.5%) of patients with an ROC yielding an AUC of 0.787. We also performed a subset analysis on 22 patients with ferritins >20 000 ng/mL. None of the patients met HLH-2004 diagnostic criteria. Fifteen (68.2%) of these patients had suspected or confirmed bacterial infections. CONCLUSIONS: Though many patients with COVID-19 present with hyperferritinemia, elevated ferritin levels are not accurate predictors of outcomes and do not appear to be indicative of hemophagocytic lymphohistiocytosis.

Therapeutic potential of isatuximab in the treatment of multiple myeloma: Evidence to date.

Management of multiple myeloma represents an ever changing paradigm with monoclonal antibodies adding the ability to treat patients with 3 and 4 drug regimens with acceptable toxicity profiles. In recent years, we have seen the FDA approve a number of regimens with both elotuzumab and daratumumab in combination with the standard approaches of immunomodulatory drugs, proteasome inhibitors, and steroids. Isatuximab is a naked, humanized IgG1 monoclonal antibody directed against CD38. With the recent FDA approval in March 2020, we seek to summarize the presented data to date and where this drug will fit into the future gestalt of myeloma therapy.

Association between neutrophil-lymphocyte ratio, socioeconomic status, and ethnic minority with treatment outcome in hepatocellular carcinoma.

BACKGROUND: Patients with lower socioeconomic status (SES), ethnic minorities and elevated neutrophil-lymphocyte ratio (NLR) have been suggested to have worse outcomes in hepatocellular carcinoma (HCC). However, how changes in NLR after intervention relate to survival has not been elucidated. OBJECTIVES: We evaluated the association of NLR with overall survival (OS) and progression-free survival (PFS) in a large institutional cohort of HCC. METHODS: We reviewed all patients diagnosed with HCC between 2005-2016. The association between elevated NLR (> 4) and survival was examined with univariable and multivariable Cox regression. RESULTS: We identified 991 patients diagnosed with HCC. Lower SES and Hispanic and non-Hispanic Black ethnicity were significantly associated with lower NLR (p = 0.015 and 0.019, respectively). Elevated NLR, but not SES or ethnicity, was an independent predictor of worse OS (HR = 1.66, p < 0.001) and PFS (HR = 1.25, p = 0.032). The median OS in patients with elevated NLR was 8 months, compared to 42 months in patients with normal NLR. Patients with elevated NLR unresponsive to treatment and those with NLR that became elevated after treatment had significantly worse 3-year OS (47% and 44%, respectively), compared to patients whose NLR remained normal or normalized after treatment (72% and 80%, respectively; p < 0.01). CONCLUSIONS: Our study showed that elevated NLR, but not SES or ethnicity, is an independent prognostic marker for OS and PFS in patients with HCC. NLR trends following intervention were highly predictive of outcome. NLR is easy to obtain and would provide valuable information to clinicians in evaluating prognosis and monitoring response after procedures.

HIV portends a poor prognosis in myelodysplastic syndromes.

Even though HIV is associated with worse prognosis in many malignancies, the clinical course of myelodysplastic syndrome (MDS) in HIV + patients has not been well studied. Determining the clinical presentation and outcomes of MDS in these patients would be important for future diagnostic strategies, as anemia and other cytopenias are commonly seen in HIV + patients. Unique data mining software was used to identify cases of MDS or AML in adult patients who were also HIV + at Albert Einstein/Montefiore Medical Center between 1 January 2003 and 1 January 2017. Using Chi-Square and Fisher's exact test, characteristics of the HIV + MDS patients were compared to 135 HIV - MDS patients from the same institution diagnosed between 1997 and 2011. Fourteen biopsy proven MDS patients were identified with concomitant HIV. HIV + MDS patients presented at a younger age (59 vs. 71 yrs, p = .001) had higher risk disease, faster progression to acute leukemia, and worse overall survival (median survival 11.2 vs. 69.1 mo, p < .001) compared to HIV - MDS controls. Additionally, there was a higher prevalence of clonal-hematopoiesis related mutations (ASXL1, DNMT3A) and a higher proportion of patients with high risk cytogenetics. Analysis of the largest single center cohort of HIV + MDS patients demonstrated that these individuals present at a significantly younger age and with higher risk disease than their HIV - counterparts.