Stockerl-Goldstein, Keith

PURPOSE In immunoglobulin light chain (AL) amyloidosis, amyloid fibrils cause organ dysfunction. Anselamimab, a monoclonal antibody, selectively binds to amyloid fibrils, accelerating their clearance. METHODS Newly diagnosed patients with European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis were randomly assigned to receive anselamimab or placebo with cyclophosphamide, bortezomib, and dexamethasone (with or without daratumumab). The primary end point was a hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVHs), analyzed using the Finkelstein-Schoenfeld test and win ratio estimation. RESULTS Among 406 randomly assigned patients, the primary end point win ratio for anselamimab versus placebo was 1.11 (95% CI, 0.83, 1.50; P = .332) and the hazard ratio (HR) for ACM was 0.80 (95% CI, 0.57, 1.13; P = .290). CVH rates in the anselamimab and placebo groups were 0.59 (95% CI, 0.42, 0.83) and 0.89 (95% CI, 0.55, 1.43), respectively ( P = .145). Among patients with kappa isotype (n = 72), the win ratio was 2.06 (95% CI, 0.98, 4.31; P = .100) and anselamimab reduced ACM by 62% versus placebo (HR, 0.38; 95% CI, 0.17 to 0.86; nominal P = .012), and CVH by 71% (IRR, 0.29; 95% CI, 0.10 to 0.87; nominal P = .028) with improvements in Kansas City Cardiomyopathy Questionnaire-Overall Score. There was no clinical benefit observed in the lambda population. Anselamimab was generally well-tolerated; safety data were comparable between treatment arms overall. CONCLUSION Treatment with anselamimab, an antifibril antibody used alongside antiplasma cell dyscrasia therapy, while not meeting the primary end point in the overall population, significantly improved ACM and CVH in patients with kappa AL, potentially offering a new therapeutic option for this isotype.

Abstract Background: The t(11;14) translocation occurs in 50-60% patients with systemic AL amyloidosis. Venetoclax, an oral BCL2 inhibitor, has shown promising efficacy across t(11;14)-positive plasma cell disorders. However, till date, there are no prospective data in patients with previously treated AL amyloidosis, including those with prior exposure to anti-CD38 monoclonal antibodies (mAbs). Methods: We conducted an investigator-initiated phase 1/2 multicenter open-label trial of venetoclax (± dexamethasone) in patients with relapsed/refractory AL amyloidosis. Key inclusion criteria were central-laboratory confirmed t(11;14) by FISH analysis in ≥5% of CD-138-selected cells on bone marrow aspirate, measurable hematologic disease (dFLC≥2 mg/dL and/or M-spike ≥0.5 g/dL), prior exposure to anti-CD38 mAb, and ≥1 prior line of therapy. Key exclusion criteria were NT-proBNP>8500 pg/mL, NYHA class IIIb/IV, and ECOG>2. Phase 1 dose escalation utilized Bayesian Optimal Interval Network (BOIN) design to determine maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) across four levels: DL1 (venetoclax 200mg), DL2 (400mg), DL3 (400mg + dexamethasone 10mg weekly), and DL4 (400mg + dexamethasone 20mg weekly). A maximum of 6 cycles of therapy on the protocol were planned, with dose limiting toxicities (DLTs) being evaluated in cycle 1. The design accommodated 12-15 patients with ~67% probability of selecting the dose closest to the 25% target toxicity rate. Here, we present the results of the Phase 1 portion of the study, which has completed enrollment. Accrual in Phase 2 portion is currently ongoing. Results: Of 16 patients screened, 12 were enrolled and evaluable for safety and efficacy. Screen failures were attributed to second malignancy (n=2), t(11;14) positivity in <5% CD-138-selected cells (n=1), and t(11;14) negativity (n=1). Enrolled patients had a median age of 64 years, with 25% female, and 17% Black representation. At screening, the median percentage of CD-138-selected cells with t(11;14)-positivity on FISH was 65%. All patients had prior anti-CD38 mAb-exposure by protocol design, with 11/12 patients also exposed to bortezomib. The median number of prior lines of therapy was 1 (range, 1-5). Disease markers at treatment initiation included median dFLC of 14.35 mg/dL (range, 2.13-186.28), median NT-proBNP of 712.5 pg/mL (range, 54-8831), and the median serum creatinine of 0.99 mg/dL (range, 0.69-3.01). Regarding safety, there were no DLTs encountered during the specified timeframe. One patient each received DLs 1, 2, and 3, with all remaining patients receiving DL 4 (400mg + dexamethasone 20mg weekly), which is the RP2D in this trial. There was only one patient that developed grade 3 infection (lung infection; COVID-19). No tumor-lysis syndrome, grade 3 or higher cytopenia, or treatment-emergent deaths occurred. Hematologic overall response (PR or better) was achieved in 11/12 patients (91.7%), with 9/12 (75%) attaining ≥VGPR [4/12 (33.3%) heme-CR, with the remaining being VGPR]. The median time from treatment initiation to best response was 29 days. Among 7 patients that were evaluable for cardiac response, one underwent heart transplant after 3 cycles of study treatment (while in heme-CR), hence was no longer evaluable for cardiac organ response. Of the remaining 6 patients, 2 have achieved cardiac response till date. Renal organ response was observed in 4/7 evaluable patients. At a median follow-up of 8.8 months, 4 out of 12 patients have completed 6 treatment cycles, with 2 receiving ongoing therapy. Six patients discontinued treatment early due to hematologic progression (n=1), suboptimal hematologic response (n=2), patient preference (n=2), and heart transplant (n=1). Patient-reported outcomes (assessed by PROMIS-29) showed no significant changes in Physical Functioning and Fatigue domains among 5 patients with paired baseline and end-of-treatment assessments. Updated follow-up data will be presented at the meeting. Conclusions: To our knowledge, this represents the first prospective evaluation of venetoclax-dexamethasone in relapsed/refractory t(11;14) AL amyloidosis. The combination demonstrated substantial hematologic efficacy (75% ≥VGPR rate) and a favorable safety profile without dose-limiting toxicities. Our results support investigation of venetoclax-based combinations in the frontline treatment of newly diagnosed t(11;14) AL amyloidosis.

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS–CoV‐2) has given rise to a pandemic of unprecedented proportions in the modern era because of its highly contagious nature and impact on human health and society: coronavirus disease 2019 (COVID‐19). Patients with cardiovascular (CV) risk factors and established CV disease (CVD) are among those initially identified at the highest risk for serious complications, including death. Subsequent studies have pointed out that patients with cancer are also at high risk for a critical disease course. Therefore, the most vulnerable patients are seemingly those with both cancer and CVD, and a careful, unified approach in the evaluation and management of this patient population is especially needed in times of the COVID‐19 pandemic. This review provides an overview of the unique implications of the viral outbreak for the field of cardio‐oncology and outlines key modifications in the approach to this ever‐increasing patient population. These modifications include a shift toward greater utilization of cardiac biomarkers and a more focused CV imaging approach in the broader context of modifications to typical practice pathways. The goal of this strategic adjustment is to minimize the risk of SARS–CoV‐2 infection (or other future viral outbreaks) while not becoming negligent of CVD and its important impact on the overall outcomes of patients who are being treated for cancer.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, workup, treatment, follow-up, and supportive care for patients with monoclonal gammopathy of renal significance, solitary plasmacytoma, smoldering myeloma, and multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates and changes in the 1.2020 version of the NCCN Guidelines for Multiple Myeloma.

Abstract HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy–based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor–based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival (P = .15), leukemia-free survival (P = .50), nonrelapse mortality (P = .16), relapse (P = .90), or grade II-IV acute GVHD (P = .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; P < .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease–donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy–based Haplo-HCT vs MSD using calcineurin inhibitor–based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients.

BACKGROUND/OBJECTIVES The incidence of myeloma in older adults is increasing, yet little is known about geriatric impairments in these patients. We aimed to examine the prevalence of geriatric impairments in older adults with myeloma and the association between geriatric assessment and autologous stem cell transplant eligibility. DESIGN Prospective cohort study. SETTING Two academic medical centers. PARTICIPANTS A total of 40 adults 65 years and older with newly diagnosed myeloma were enrolled. MEASUREMENT Participants completed a primarily self‐administered geriatric assessment, including measures of functional status, comorbidities, polypharmacy, psychosocial status, social support, quality of life, cognition, and physical performance. Outcomes were autologous stem cell transplant eligibility and receipt. RESULTS Forty patients enrolled; their mean age was 71 years. Geriatric impairments were common: 62% reported dependence in one or more instrumental activities of daily living (IADL), 76.9% had polypharmacy (four or more medications), and 47.5% had one or more comorbidities. Median time on the Timed Up and Go was 13.3 ± 4.9 seconds. Those considered candidates for autologous stem cell transplant (N = 26) were younger, with fewer comorbidities, better performance status, and faster performance on the Timed Up and Go test. Factors independently associated with receiving autologous stem cell transplant (N = 21) included age and IADL dependence. CONCLUSION Impairments in geriatric domains are common in this population, even among those considered to have a good performance status. Geriatric assessment domains are associated with both transplant eligibility and receipt. J Am Geriatr Soc 67:987–991, 2019.

Objective Assess the effects of linezolid on hematologic outcomes in newly diagnosed patients with acute myeloid leukemia ( AML ) following induction chemotherapy. Design Single‐center, retrospective, observational, cohort study. Setting Large, tertiary care academic medical center. Patients A total of 225 patients ≥ 18 years admitted between December 2010 and 2013 with newly diagnosed AML were assessed for inclusion. Patients were identified through the use of ICD ‐9 codes and chemotherapy ordered via the computerized physician order entry system. Sixty‐eight patients met inclusion criteria and were grouped into two arms based on antimicrobial treatment: LZD group (linezolid plus gram‐negative antimicrobial, n=21) or control group (vancomycin or daptomycin plus gram‐negative antimicrobial, n=47). Interventions The LZD group received linezolid ≥ 72 hours. The control group received vancomycin or daptomycin ≥ 72 hours. If patients switched extended gram‐positive therapy, they were included in the LZD group as long as they had received ≥ 72 hours of linezolid. Measurements/Results The primary end point of time to neutrophil recovery was not statistically different (28 days for LZD group vs 26 days for control group; p=0.675). The preplanned subgroup analysis of patients who received ≥ 14 days of linezolid demonstrated statistically similar median times to neutrophil recovery (29 days for LZD group vs 26 days for control group; p=0.487). Total duration of extended gram‐positive antimicrobial therapy was significantly longer in the LZD group (27 days vs 16 days; p<0.001). Secondary end points not found to be statistically significant included platelet count at time of neutrophil recovery, duration of neutropenia, and length of hospital stay. Conclusions There were no significant differences in hematologic outcomes in newly diagnosed AML patients who received linezolid for extended gram‐positive antimicrobial coverage following induction chemotherapy. This study provides new insight with a primary focus on the effects of hematologic outcomes when using linezolid in a well‐defined acute leukemia population. Further study is warranted with larger populations to assess the potential adverse effects linezolid may have in patients with acute leukemia.

Bendamustine is a multifunctional alkylating agent with single agent activity in myeloma. We designed the current phase 1/2 trial to determine the maximum tolerated doses (MTD) of bendamustine that can be safely combined with lenalidomide and dexamethasone and to assess the safety and efficacy of the combination. Patients with relapsed MM following at least 1 prior therapy, but no more than four lines of prior therapy and with measurable disease were enrolled. Bendamustine 75 mg/m2 given on days 1 and 2, lenalidomide 25 mg given days 1–21 and dexamethasone 40 mg on days 1, 8, 15, and 22, was the recommended Phase 2 dose. Seventy‐one patients were accrued: 21 on Phase 1 and 50 on Phase 2. The median age was 62.3 years; patients had a median of three prior lines of therapy (range 1–4), with over 70% of the patients having received prior lenalidomide, bortezomib, and/or peripheral blood stem cell transplant. Thirty‐four of 70 (49%) patients had a confirmed partial response or better, including 20 patients (29%) with a very good partial response or better. An additional 4 patients had a minor response, translating to an overall 55% clinical benefit rate. Grade 3 or higher toxicity was seen in 96% of patients, with ≥grade 3 hematologic in 94% and nonhematologic in 50%. The median progression free survival was 11.8 months and the median duration of response was 23 months. The combination of bendamustine, lenalidomide, and dexamethasone is very effective in relapsed multiple myeloma with high response rates and durable responses Am. J. Hematol. 90:1106–1110, 2015. © 2015 Wiley Periodicals, Inc.