Absolute Lymphocyte Count after BCMA CAR-T Therapy is a Predictor of Response and Outcomes in Relapsed Multiple Myeloma.

BCMA-targeting CAR-T cells used in multiple myeloma (MM) are rapidly becoming a mainstay in the treatment of relapsed/refractory (RR) disease, and CAR-T cell expansion post-infusion has been shown to inform depth and duration of response, 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 relapsed MM patients treated with the BCMA-targeting agents cilta-cel and ide-cel. Patients with higher maximum ALC (ALCmax) had better depth of response, progression-free survival (PFS), and duration of response (DoR). Patients with ALCmax >1.0 x103/uL had a superior PFS (30.5 versus 6 months, p <0.001) compared to those ≤1.0x103/uL, while patients with ALCmax ≤0.5 x103/uL represent a high-risk group with early disease progression and short PFS (HR 3.4, 95 CI: 2 -5.8, P <0.001). In multivariate analysis, ALCmax >1.0 x103/uL and non-paraskeletal extramedullary disease were the only independent predictors of PFS and DoR after accounting for ISS staging, age, CAR-T product, high-risk cytogenetics and number of previous lines. Moreover, our flow cytometry data suggests that ALC is a surrogate for BCMA CAR-T expansion and can be used as an accessible prognostic marker. We report for the first time the association of ALC after BCMA CAR-T infusion with clinical outcomes and its utility in predicting response in RRMM patients.

Real-world multiple myeloma front-line treatment and outcomes by transplant in the United States.

Stem cell transplantation (SCT) has been an integral treatment modality for multiple myeloma (MM) for decades. However, as standard-of-care therapies have improved, the benefit of SCT has been repeatedly called into question. This retrospective study evaluated the association between SCT in the first line of therapy (LOT) and outcomes for patients with newly diagnosed multiple myeloma (NDMM) in the United States. We included patients from a de-identified electronic health record-derived database who initiated front-line MM therapy between January 1, 2016, and January 31, 2022. Overall, 18.8% (1127 of 5996 patients) received SCT in the first LOT. Multivariable-adjusted Cox proportional hazards models, in which SCT was modeled as time varying, revealed longer real-world progression-free survival (rwPFS; hazard ratio [HR] 0.49; 95% confidence interval [CI] 0.43-0.57) and real-world overall survival (rwOS; HR 0.47; 95% CI 0.39-0.56) for patients who received SCT in the first LOT. The degree of rwPFS and rwOS benefit imparted by SCT was consistent across all subgroups examined, including patients aged ≥75 years, women, non-Hispanic Black/African American patients, those with renal impairment, and those with high-risk cytogenetics. Findings from this analysis of real-world patients with NDMM suggest that SCT remains an important standard of care in the era of novel therapies.

Teclistamab for Multiple Myeloma: Clinical Insights and Practical Considerations for a First-in-Class Bispecific Antibody.

Teclistamab is a BCMAxCD3 bispecific antibody, the first approved for the treatment of relapsed or refractory multiple myeloma. Given its impressive efficacy in heavily pretreated patients and better accessibility compared to BCMA-directed CAR T cells, teclistamab is sure to become a staple of relapsed/refractory multiple myeloma therapy. Teclistamab carries a set of notable adverse effects including cytokine release syndrome (CRS), infections, and neurotoxicity for which providers must take unique precautions and prophylactic measures. Here, we review the preclinical and clinical data, which led to teclistamab's approval, important patient selection considerations, strategies for managing CRS and other side effects, and finally the future of bispecific antibody therapy in multiple myeloma.

Outcomes with panobinostat in heavily pretreated multiple myeloma patients.

Panobinostat is an oral pan histone-deacetylase inhibitor used in the treatment of relapsed and refractory multiple myeloma. Previously published studies of panobinostat demonstrated synergy with bortezomib but included few patients exposed to newer agent combinations (ie, panobinostat plus daratumumab or carfilzomib). Here, we report outcomes of panobinostat-based combinations at an academic medical center among patients whose disease had been heavily pretreated with modern agents. We retrospectively analyzed 105 patients with myeloma treated with panobinostat at The Mount Sinai Hospital in New York City between October 2012 and October 2021. These patients had a median age of 65 (range 37-87) and had received a median of 6 prior lines of therapy while in 53% the disease was classified as triple class refractory and in 54% the disease had high-risk cytogenetics. Panobinostat was most commonly utilized at 20 mg (64.8%) as part of a triplet (61.0%) or quadruplet (30.5%). Aside from steroids, panobinostat was most commonly administered in combination with lenalidomide, pomalidomide, carfilzomib, and daratumumab in descending order of frequency. Among the 101 response-evaluable patients, the overall response rate was 24.8%, clinical benefit rate (≥minimal response) was 36.6%, and median progression-free survival was 3.4 months. Median overall survival was 19.1 months. The most common toxicities ≥grade 3 were hematologic, primarily neutropenia (34.3%), thrombocytopenia (27.6%), and anemia (19.1%). Panobinostat-based combinations produced modest response rates in patients with heavily pretreated multiple myeloma, over half of whom had triple-class refractory disease. Panobinostat warrants continued investigation as a tolerable oral option for recapturing responses in patients whose disease has progressed after receipt of standard-of-care therapies.

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.

Filanesib plus bortezomib and dexamethasone in relapsed/refractory t(11;14) and 1q21 gain multiple myeloma.

Filanesib is a first-in-class kinesin spindle protein inhibitor which demonstrated safety and encouraging activity in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma in a preliminary analysis of dose-escalation phase results. This multicenter study included first a dose-escalation phase to determine maximum tolerated dose of two schedules of filanesib, bortezomib, and dexamethasone and a subsequent dose-expansion phase using the maximum tolerated doses. In the dose-expansion phase, 28 patients were evaluable for safety and efficacy. The most common grade ≥3 adverse events were neutropenia (21%) and anemia (18%), which were noncumulative and reversible, and hypertension (18%). The overall response rate was 43% with median duration of response not yet reached (range, 2.8-23.7+ months) with median follow-up of 6.3 months. A post hoc analysis incorporated 29 dose-escalation phase patients who received therapeutic filanesib doses, with an overall response rate of 39% and median duration of response of 18.0 months among the 57 total patients with median progression-free survival of 8.5 months. Notably, the PFS of high risk patients was comparable at 8.5 months, driven by the patients with 1q21 gain, characterized by increased MCL-1 expression, with a PFS of 9.1 months versus 3.5 months for the remainder of high risk patients. Patients with t(11;14) also had an encouraging PFS of 15.0 months. The combination of filanesib, bortezomib, and dexamethasone continues to show safety and encouraging activity in relapsed/refractory multiple myeloma, particularly in those patients with 1q21 gain and t(11;14).

Evaluating Race and Time to Transplantation in Multiple Myeloma: The Mount Sinai Hospital Experience.

BACKGROUND: Previous studies have found that Black patients with multiple myeloma undergo autologous stem-cell transplantation (ASCT) less frequently than their white counterparts, although the factors leading to decreased access and utilization have not been fully elucidated. PATIENTS AND METHODS: To identify whether racial differences in transplantation timing played a role in these disparities, we retrospectively analyzed 410 Black and white patients who received their first transplant at The Mount Sinai Hospital between 2011 and 2016 (260 white and 150 Black patients). We compared the time from initial diagnosis to stem-cell collection and the time from collection to transplantation between the 2 races while controlling for age, socioeconomic status, and functional status. RESULTS: Between Blacks and whites, time from diagnosis to collection was higher in Black patients (median 238, vs. 195 days, respectively, P = .051). Functional status, socioeconomic status, and age were also significantly associated with time to collection, and after controlling for these covariates, the effect of race was not significant (P = .0625). Conversely, time from collection to transplantation was increased in white patients compared to Black. CONCLUSION: Increased time from diagnosis to stem-cell collection for Black patients was driven in part by socioeconomic status and baseline functional status.

Where We Stand With Precision Therapeutics in Myeloma: Prosperity, Promises, and Pipedreams.

Multiple myeloma remains an incurable disease despite numerous novel agents being approved in the last decade. Furthermore, disease behavior and susceptibility to current treatments often vary drastically from patient to patient. To date there are no approved therapies in myeloma that are targeted to specific patient populations based on genomic or immunologic findings. Precision medicine, using biomarkers descriptive of a specific tumor's biology and predictive of response to appropriate agents, may continue to push the field forward by expanding our treatment arsenal while refining our ability to expose patients to only those treatments likely to be efficacious. Extensive research efforts have been carried out in this endeavor including the use of agents targeting Bcl2 and the RAS/MAPK and PI3K/AKT/mTOR pathways. Thus far, clinical trials have yielded occasional successes intermixed with disappointments, reflecting significant hurdles which still remain including the complex crosstalk between oncogenic pathways and the nonlinear genetic development of myeloma, prone to cultivating sub-clones with distinctive mutations. In this review, we explore the landscape of precision therapeutics in multiple myeloma and underscore the degree to which research efforts have produced tangible clinical results.

Clinical developments in epigenetic-directed therapies in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a highly heterogeneous disease arising from acquired genetic and epigenetic aberrations which stifle normal development and differentiation of hematopoietic precursors. Despite the complex and varied biological underpinnings, induction therapy for AML has remained fairly uniform over 4 decades and outcomes remain poor for most patients. Recently, enhanced understanding of the leukemic epigenome has resulted in the translational investigation of a number of epigenetic modifying agents currently in various stages of clinical development. These novel therapies are based on mechanistic rationale and offer the potential to improve AML patient outcomes. In light of many recent advances in this field, we provide an updated, clinically oriented review of the evolving landscape of epigenetic modifying agents for the treatment of AML.

Increased Incidence of Nocardial Infections in an Era of Atovaquone Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

Nocardial infections have been rare after allogeneic hematopoietic stem cell transplantation (HSCT). We report 10 recent cases of late-onset nocardiosis (median time of onset of 508 days after transplantation) primarily in patients on high doses of corticosteroids for graft-versus-host disease. All 10 patients had pulmonary infection caused by Nocardia species susceptible to trimethoprim-sulfamethoxazole (TMP-SMX). At time of diagnosis 8 of 10 patients were not receiving TMP-SMX for prophylaxis of Pneumocystis jiroveci pneumonia (PJP; 7 on atovaquone, 1 on i.v. pentamidine). After the initiation of atovaquone prophylaxis for PJP in place of TMP-SMX for many UCLA allogeneic HSCT patients in 2012, 9 cases of nocardiosis occurred in 411 patients (2.2%) over the next 6 years (2012 to 2017) compared with only 1 case in 575 patients (0.17%) during the previous 12 years (2000 to 2011). Although there were no deaths directly related to nocardial infection treated primarily with TMP-SMX, overall mortality in this group of patients was 40%. Based on this experience, the use of atovaquone for PJP prophylaxis in place of TMP-SMX may be associated with an increased risk for previously rare nocardial infections after allogeneic HSCT.