Impact of Second Primary Malignancy Post–Autologous Transplantation on Outcomes of Multiple Myeloma: A CIBMTR Analysis

The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P \u3c .001 and HR 5.01, P \u3c .001, respectively) and OS (HR 3.85, P \u3c .001 and HR 8.13, P \u3c .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT

RNASeq Analysis for Accurate Identification of Fusion Partners in Tumor Specific Translocations Detected by Standard FISH Probes in Hematologic Malignancies

Background: Fluorescence labeled DNA probes and in situ hybridization methods had shorter turn round time for results revolutionized their clinical application. Signals obtained from these probes are highly specific, yet they can produce fusion signals not necessarily representing fusion of actual genes due to other genes included in the probe design. In this study we evaluated discordance between cytogenetic, FISH and RNAseq results in 3 different patients with hematologic malignancies and illustrated the need to perform next generation sequencing (NGS) or RNASeq to accurately interpret FISH results. Methods: Bone marrow or peripheral blood karyotypes and FISH were performed to detect recurring translocations associated with hematologic malignancies in clinical samples routinely referred to our clinical cytogenetics laboratory. When required, NGS was performed on DNA and RNA libraries to detect somatic alterations and gene fusions in some of these specimens. Discordance in results between these methods is further evaluated. Results: For a patient with plasma cell leukemia standard FGFR3 / IGH dual fusion FISH assay detected fusion that was interpreted as FGFR3 -positive leukemia, whereas NGS/RNASeq detected NSD2::IGH . For a pediatric acute lymphoblastic leukemia patient, a genetic diagnosis of PDGFRB -positive ALL was rendered because the PDGFRB break-apart probe detected clonal rearrangement, whereas NGS detected MEF2D::CSF1R . A MYC -positive B-prolymphocytic leukemia was rendered for another patient with a cytogenetically identified t(8;14) and MYC::IGH by FISH, whereas NGS detected a novel PVT1::RCOR1 not previously reported. Conclusions: These are 3 cases in a series of several other concordant results, nevertheless, elucidate limitations when interpreting FISH results in clinical applications, particularly when other genes are included in probe design. In addition, when the observed FISH signals are atypical, this study illustrates the necessity to perform complementary laboratory assays, such as NGS and/or RNASeq, to accurately identify fusion genes in tumorigenic translocations

Global Longitudinal Strain Is Associated with Mortality in Patients with Multiple Myeloma

Patients with multiple myeloma (MM) are at a high risk for developing cardiovascular complications. Global longitudinal strain (GLS) can detect early functional impairment before structural abnormalities develop. It remains unknown if reduced GLS is associated with reduced survival in patients with MM. We conducted a retrospective cohort analysis of patients diagnosed with MM between 1 January 2000 and 31 December 2017 at our institution. Patients with a 2D transthoracic echocardiogram completed within 1 year of MM diagnosis, left ventricular ejection fraction (LVEF) greater than 40%, and no history of myocardial infarction prior to MM diagnosis were included. GLS was measured using an artificial-intelligence-powered software (EchoGo Core), with reduced GLS defined as an absolute value of 9.6, LVEF/GLS > 4.1, higher LV mass index, and low-voltage ECG. A Total of 126 (52.1%) deaths occurred during follow-up. Overall survival was lower among patients with reduced GLS (adjusted HR: 1.81, CI: 1.07–3.05)

Real-world experience of patients with multiple myeloma receiving ide-cel after a prior BCMA-targeted therapy

Abstract Most patients with multiple myeloma experience disease relapse after treatment with a B-cell maturation antigen-targeted therapy (BCMA-TT), and data describing outcomes for patients treated with sequential BCMA-TT are limited. We analyzed clinical outcomes for patients infused with standard-of-care idecabtagene vicleucel, an anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, at 11 US medical centers. A total of 50 patients with prior BCMA-TT exposure (38 antibody-drug conjugate, 7 bispecific, 5 CAR T) and 153 patients with no prior BCMA-TT were infused with ide-cel, with a median follow-up duration of 4.5 and 6.0 months, respectively. Safety outcomes between cohorts were comparable. The prior BCMA-TT cohort had a lower overall response rate (74% versus 88%; p = 0.021), median duration of response (7.4 versus 9.6 months; p = 0.03), and median progression-free survival (3.2 months versus 9.0 months; p = 0.0002) compared to the cohort without prior BCMA-TT. All five patients who received a prior anti-BCMA CAR T responded to ide-cel, and survival outcomes were best for this subgroup. In conclusion, treatment with ide-cel yielded meaningful clinical responses in real-world patients exposed to a prior BCMA-TT, though response rates and durability were suboptimal compared to those not treated with a prior BCMA-TT

Impact of Second Primary Malignancy Post-Autologous Transplantation on Outcomes of Multiple Myeloma: A CIBMTR Analysis

The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials employing auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in MM patients following auto-HSCT using CIBMTR registry data. Adult MM patients who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n=3,948). At a median follow up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (HR 2.62, P<.001 and HR 5.01, P<.001, respectively) and OS (HR 3.85, P<.001 and HR 8.13, P<.001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% versus 30% and 53% versus 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in MM patients and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT