Alessandro Laganà

• PhD
• Professor (Assistant) at Icahn School of Medicine at Mount Sinai

Background Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of malignant plasma cells within the bone marrow. The disease’s complexity is underpinned by a variety of genetic and molecular abnormalities that drive its progression. Methods This review was conducted through a state-of-The-art literature se...

Introduction: Multiple myeloma (MM) has a highly heterogeneous genomic landscape, challenging patient stratification and clinical management. By combining bulk tumor profiling with single-cell data of the tumor microenvironment (TME), we aimed to create a comprehensive multi-omics network model to dissect inter-tumor heterogeneity, which enabled us...

Introduction: Our research has shown that ~10% of multiple myeloma (MM) patients harbor pathogenic or likely-pathogenic germline variants (PGVs) in cancer predisposition genes, with a significant enrichment observed in BRCA1/2 genes (Thibaud et al, Blood Cancer Discovery, 2024). PGVs were notably more common in younger MM patients and those with a...

Background Anti-BCMA CAR-T therapy is an effective therapy with high response rates in refractory patients and got recent approvals for earlier lines of therapy in myeloma. However, disease relapses can occur after CAR-T and loss of target antigen (BCMA) only occurs in minority of CAR-T therapy failures; implicating the immunosuppressive environmen...

Introduction: In the past 15 years, survival in multiple myeloma (MM) has greatly improved due to new treatments, including immunomodulatory drugs (IMiDs) and T cell therapies (CAR-T and BiTEs). Recent studies suggest the MM microenvironment (TME) plays a key role in disease and treatment outcomes. Understanding the MM-TME in high-risk cases is cru...

Multiple Myeloma (MM) is a genomically heterogeneous cancer of malignant plasma cells (PC) residing in the bone marrow. Despite recent therapeutic advances, it is incompletely understood why some patient populations remain largely therapy-refractory or relapse, even with targeted immunotherapies. Whilst MM classification based on genomic features a...

Background: In the recent phase I/II MonumenTAL-1 trial (NCT03399799, NCT04634552), the CD3xGPRC5D bispecific antibody (BiAb) Talquetamab (Tal) showed ≥70% response rate at the recommended phase 2 doses (RP2D) in heavily pretreated multiple myeloma (MM) patients (Chari A et al., NEJM 2022). However, there is still a need to identify tumor intrinsic...

First-degree relatives of patients with multiple myeloma are at increased risk for the disease, but the contribution of pathogenic germline variants (PGV) in hereditary cancer genes to multiple myeloma risk and outcomes is not well characterized. To address this, we analyzed germline exomes in two independent cohorts of 895 and 786 patients with mu...

Multiple Myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We established a harmonized consortium to generate an Immune Atlas of MM aimed at inf...

Iberdomide is a potent cereblon E3 ligase modulator (CELMoD agent) with promising efficacy and safety as a monotherapy or in combination with other therapies in patients with relapsed/refractory multiple myeloma (RRMM). Using a custom mass cytometry panel designed for large-scale immunophenotyping of the bone marrow tumor microenvironment (TME), we...

During the past decade, significant technological and computational advances have provided unprecedented opportunities for gaining a better understanding of cancer biology and translating this knowledge into meaningful and concrete clinical benefits. Research has made considerable progress in identifying genes and molecular changes that promote can...

Introduction Newly-diagnosed multiple myeloma (MM) patients often share tumor genetic abnormalities associated with a high risk of progression and poor survival. We hypothesized that single-cell transcriptomic characterization of the tumor immune microenvironment (TIME) may be combined with tumor-based risk stratification to uncover novel disease b...

Background: Talquetamab (Tal) is a CD3xGPRC5D bispecific antibody (BiAb) that redirects endogenous T cells to mediate killing of GPRC5D-expressing multiple myeloma (MM) cells. In the recent phase I/II MonumenTAL-1 trial (NCT03399799), Tal showed ≥ 70% response rate when given at the recommended phase 2 doses (RP2D) in heavily pretreated MM patients...

Introduction: We previously showed that ~10% of patients with multiple myeloma (MM) carry pathogenic or likely-pathogenic (P/LP) germline variants (PGVs) in known cancer predisposition genes, and that moderate/high-penetrance PGVs in DNA repair genes may be associated with MM risk and favorable response to alkylating chemotherapy. Increasingly appl...

Genetic clonal heterogeneity is common in multiple myeloma (MM). However, the specific drivers of subclonal evolution associated with disease progression under therapeutic selection has not been fully characterized with the resource of sequential samples to accurately observe changes in relation to drug exposures. To address this gap, we generated...

Introduction Multimodal single cell technologies allow us to dissect the mechanisms of therapeutic resistance by integrating transcriptomics and proteomics through the combination of antibody labeling and next-generation sequencing. Using CITE-seq, mass cytometry (CyTOF) and quantitative multiplexed proteomics (Olink), we sought to understand the d...

Background The effect of immunomodulatory drugs (IMiDs) and novel cereblon E3 ligase modulators (CELMoDs) on the tumour microenviroment (TME) of multiple myeloma (MM) patients remains poorly understood. A recent multi-center phase 1/2 trial (CC-92480-MM-001) of CELMoD Mezigdomide (MEZI) demonstrated clinical response in triple-class refractory, hea...

Introduction: Multiple myeloma (MM) is the second most prevalent hematological malignancy, characterized by the abnormal proliferation of plasma cells in the bone marrow. Approximately 20% of MM patients present with high-risk (HR) clinical and genetic features that are associated with aggressive disease course and poor prognosis. Novel immune ther...

Epitranscriptomic studies of miRNAs have added a new layer of complexity to the cancer field. Although there is fast-growing interest in adenosine-to-inosine (A-to-I) miRNA editing and alternative cleavage that shifts miRNA isoforms, simultaneous evaluation of both modifications in cancer is still missing. Here, we concurrently profiled multiple mi...

T-cell redirection therapy with chimeric antigen receptor (CAR)-T cells and bispecific antibodies (BiAbs) has shown promising efficacy in heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients, leading to the approval of two CAR-T cell products and numerous BiAb trials. Data regarding outcomes after relapse following BiAbs are urge...

Background Multiple Myeloma (MM) is a progressive plasma cell neoplasm characterized by heterogeneous clonal expansion. Despite promising response rates achieved with anti-BCMA CAR-T cell therapy, patients may still relapse and there are currently no clear therapeutic options in post-CAR-T settings. In this report, we present a case of a post-BCMA...

PURPOSE Selinexor is the first selective inhibitor of nuclear export to be approved for the treatment of relapsed or refractory multiple myeloma (MM). Currently, there are no known genomic biomarkers or assays to help select MM patients at higher likelihood of response to selinexor. Here, we aimed to characterize the transcriptomic correlates of re...

Single-cell sequencing technologies are revolutionizing cancer research and are poised to become the standard for translational cancer studies. Rapidly decreasing costs and increasing throughput and resolution are paving the way for the adoption of single-cell technologies in clinical settings for personalized medicine applications. In this chapter...

Precision oncology is a novel research field and approach to cancer care which leverages high-throughput sequencing technologies and bioinformatics pipelines to determine diagnosis, prognosis, and treatment of patients in a personalized manner. This chapter provides an overview of a typical precision oncology software platform, from raw data to pat...

Precision oncology mainly relies on genetic and molecular patient profiling from high-throughput sequencing data. The necessity to process and analyze large volumes of data has led to the development of robust computational tools and methods. The most challenging aspect in the implementation of a precision oncology workflow involves proper handling...

While the clonal model of cancer evolution was first proposed over 40 years ago, only recently next-generation sequencing has allowed a more precise and quantitative assessment of tumor clonal and subclonal landscape. Consequently, a plethora of computational approaches and tools have been developed to analyze this data with the goal of inferring t...

All solid tumors and many hematological malignancies grow and proliferate in a tumor microenvironment (TME), a spectrum of continuous and highly dynamic interactions with different immune and stromal cells. This ecosystem contributes to the extensive heterogeneity that exists between and within cancer patients. Understanding the characteristics of...

Precision oncology is an innovative approach to cancer care in which diagnosis, prognosis, and treatment are informed by the individual patient's genetic and molecular profile. The rapid development of novel high-throughput omics technologies in recent years has led to the generation of massive amount of complex patient data, which in turn has prom...

Selinexor is the first selective inhibitor of nuclear export (SINE) to be approved for treatment of relapsed or refractory multiple myeloma (MM). There are currently no known genomic biomarkers or assays to help select MM patients at higher likelihood of response to selinexor. Here, we aim to characterize transcriptomic correlates of response to se...

B-cell maturation antigen (BCMA) is a prominent tumor-associated target for chimeric antigen receptor (CAR)-T cell therapy in multiple myeloma (MM). Here, we describe the case of a patient with MM who was enrolled in the CARTITUDE-1 trial (NCT03548207) and who developed a progressive movement disorder with features of parkinsonism approximately 3 m...

The remarkable genetic heterogeneity of multiple myeloma poses a substantial challenge for proper prognostication and clinical management of patients. Here, we introduce MM-PSN, the first multiomics patient similarity network of myeloma. MM-PSN enabled accurate dissection of the genetic and molecular landscape of the disease and determined 12 disti...

Background: Iberdomide (IBER) is a potent cereblon E3 ligase modulator (CELMoD agent) with direct anti-tumor and immunomodulatory activities in multiple myeloma (MM). An ongoing phase 1b/2a multicenter, open-label, dose-escalation study has reported favorable efficacy and safety of IBER plus low-dose dexamethasone (DEX) in heavily pretreated patien...

Background Racial disparities exist in the prevalence of multiple myeloma (MM) and monoclonal gammopathy of unknown significance (MGUS), with significantly higher prevalence in African American/ black (AA) compared to non-AA individuals. AA patients are also younger than non-AA at the time of diagnosis. We aimed to determine if differences in syste...

Background: Novel treatment approaches including chimeric antigen receptor (CAR) T therapy and bispecific antibodies (Abs) have shown remarkable efficacy in highly pretreated multiple myeloma (MM) patients. With recent approval of BCMA-targeted CAR T in MM, and other agents in development, CAR T is poised to become more widely used in relapsed/refr...

Selinexor acts by inhibiting the nuclear export protein XPO1; however, its mRNA expression does not correlate with response, and the biological mechanisms underlying treatment response for different patients remain unclear. There is a critically unmet need for validated genomic biomarkers to help guide treatment recommendations to selinexor based t...

BACKGROUND: There is growing evidence supporting inherited predisposition to multiple myeloma (MM). Epidemiologic studies have shown that 1st-degree relatives of MM patients (pts) have a 2-4 fold increase in risk of developing MGUS or MM. Genome-wide association studies (GWAS) have identified common SNPs as well as rare high-penetrance variants tha...

Background: BCMA CAR-T cell therapy has shown great promise in relapsed/refractory multiple myeloma (RRMM) patients, even though there is unpredictable variability in the duration and depth of response. The mechanisms behind these divergent outcomes and relapse are not well understood and heterogeneity of MM patients at the level of both tumor geno...

Background Despite a growing arsenal of treatment choices, patient relapse post-BCMA-targeted CART therapy remains a challenge and the therapeutic path is still undefined. Among the most frequently observed actionable mutations, BRAF V600E, is present in ~7% of multiple myeloma (MM) patients. The availability of selective inhibitors of BRAF V600E m...

Background Racial disparities exist in the prevalence of multiple myeloma (MM) and monoclonal gammopathy of unknown significance (MGUS), with significantly higher prevalence in African American/ black (AA) compared to non-AA individuals. AA patients are also younger than non-AA at the time of diagnosis. We aimed to determine if differences in syste...

Background Anti-BCMA chimeric antigen receptor (CAR) T have shown remarkable efficacy in highly pretreated multiple myeloma (MM) patients. With recent FDA approval of BCMA-targeted CAR T in MM and other agents in late stages of development, CAR T is poised to become more widely used. However, the outcomes of MM patients after relapse on CAR T are l...

Background GWAS have identified common SNPs & rare high-penetrance variants that explain ~16% of the estimated heritability of multiple myeloma (MM)(PMID 30213928). Pathogenic/likely-pathogenic germline variants (PGV) in hereditary cancer genes (HCG) are common in adult cancer pts (~8%), but prevalence in MM is not known. The aim of our study is to...

MicroRNAs (miRNAs) are regulatory small non-coding RNAs that function as translational repressors. MiRNAs are involved in most cellular processes, and their expression and function are presided by several factors. Amongst, miRNA editing is an epitranscriptional modification that alters the original nucleotide sequence of selected miRNAs, possibly i...

Background: Epidemiologic studies have shown familial aggregations of multiple myeloma (MM) and other hematologic malignancies, but little is known about heritable genetic susceptibilities in these patients. The purpose of this study is to investigate the prevalence of known germline cancer-predisposing mutations (CPM) in patients with multiple mye...

Background : Supportive care improves outcomes in many cancers. In the pivotal STORM study selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, and low-dose dexamethasone proved to be an effective treatment for patients with triple-class refractory myeloma. We conducted a post-hoc analysis to test the hypothesis that increased...

Purpose: Mantle Cell Lymphoma (MCL) is a fatal subtype of Non-Hodgkin's Lymphoma. SOX11 transcription factor is overexpressed in the majority of nodal MCL. We have previously reported that B-cell specific overexpression of SOX11 promotes MCL pathogenesis via critically increasing BCR signaling in vivo. SOX11 is an attractive target for MCL therapy...

MiRNA Epitranscriptomics has placed a new layer of complexity in the cancer field. Despite miRNA editing and shifted miRNA isoforms are gaining attention due to recent improvements in next-generation sequencing, a simultaneous study of both modifications in cancer is still missing. Here, we concurrently profiled multiple miRNA modifications, such a...

e20035 Background: Multiple myeloma (MM) is heterogeneous from symptoms, mechanisms of tumorigenesis and progression, to the treatment outcome. Besides age and tumor stage, prognostic models based on the genomic or transcriptomic profiles were developed to stratify patients into risk groups at diagnosis. Even though mutation burden at diagnosis is...

T cell–based therapies have induced cancer remissions, though most tumors ultimately progress, reflecting inherent or acquired resistance including antigen escape. Better understanding of how T cells eliminate tumors will help decipher resistance mechanisms. We used a CRISPR/Cas9 screen and identified a necessary role for Fas–FasL in antigen-specif...

Mantle Cell Lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation. This hallmark oncogenic event transposes CCND1 (11q13) under the control of the immunoglobin heavy chain (IGH) locus (14q32) resulting in constitutive cyclin D1 expression. Although Cyclin D1 (CCND1) overexpression is a key hallmark of MCL, CCND1 overexpressing muri...

The remarkable genetic heterogeneity of Multiple Myeloma poses a significant challenge for proper prognostication and clinical management of patients. Here, we introduce MM-PSN, the first multi-omics Patient Similarity Network of Myeloma. MM-PSN enabled accurate dissection of the genetic and molecular landscape of the disease and determined twelve...

MicroRNAs (miRNAs) are a class of regulatory small non-coding RNAs that modulate gene expression. As such, miRNAs are indirectly involved in most cellular mechanisms, including cell differentiation, proliferation, survival, and homeostasis. Several different mechanisms finely regulate miRNA expression levels and functions. Among these, miRNA editin...

Relapsed/refractory multiple myeloma patients treated with pomalidomide and dexamethasone have an overall response rate (ORR) of ∼30% and median progression-free survival (PFS) of 4–5 months. Previous studies explored addition of weekly cyclophosphamide, but we hypothesized that daily dosing allows for better synergy. We report the open-label, sing...

Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) and myeloid sarcoma (MS) are two extremely rare and aggressive hematological diseases. Both malignancies most commonly arise with skin lesions with or without extramedullary organ involvement before leukemic dissemination. Given its rarity and less known biology, in some cases with def...

MicroRNAs (miRs), a class of regulatory single-stranded small non-coding RNAs, are frequently deregulated in cancer and have been proposed as diagnostic and prognostic biomarkers in this fatal disease. Recent improvements in high-throughput sequencing (HTS) technologies have allowed the discovery of post-transcriptional modification phenomena invol...

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) and myeloid sarcoma (MS) are two rare and aggressive hematological neoplasms with rather similar clinico‐pathologic features. Here, we show that the two tumours have a quite similar microRNA expression profile. However, BPDCN and MS display a set of deregulated miRNAs predicted to modulate key bi...

The remarkable genetic heterogeneity of Multiple Myeloma (MM) poses a significant challenge for proper prognostication and clinical management of patients. Accurate dissection of the genetic and molecular landscape of the disease and the robust identification of homogeneous classes of patients are essential steps to reliable risk stratification and...

The type I Melanoma Antigen Gene (MAGE) A3 is a functional target associated with survival and proliferation in multiple myeloma (MM). To investigate the mechanisms of these oncogenic functions, we performed gene expression profiling (GEP) of p53 wild-type human myeloma cell lines (HMCL) after MAGE-A knockdown, which identified a set of 201 differe...

RNA editing is an epitranscriptomic modification of emerging relevance to disease development and manifestations. ADAR1, which resides on human chromosome 1q21, is an RNA editor whose over-expression, either by interferon (IFN) induction or through gene amplification, is associated with increased editing and poor outcomes in Multiple Myeloma (MM)....

The enhancer of zeste homolog 2 (EZH2) is the main enzymatic subunit of the PRC2 complex, which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to promote transcriptional silencing. EZH2 is overexpressed in multiple types of cancer including triple-negative breast cancer (TNBC), and high expression levels correlate with poor prognosis....

Purpose: Somatic mutations in cancer cells can give rise to novel protein sequences that can be presented by antigen-presenting cells as neoantigens to the host immune system. Tumor neoantigens represent excellent targets for immunotherapy, due to their specific expression in cancer tissue. Despite the widespread use of immunomodulatory drugs and i...

Selinexor is the first FDA-approved drug for penta-refractory multiple myeloma (MM) patients, i.e. patients refractory to at least two proteasome inhibitors, two immunomodulatory drugs, and an anti-CD38 monoclonal antibody. Selinexor is an oral selective inhibitor of nuclear export (SINE), which specifically targets XPO1 (Exportin 1)-mediated nucle...

Background: Iberdomide (IBER), a novel cereblon (CRBN) E3 ligase modulatory compound (CELMoD), is being evaluated in a phase 1/2 clinical trial for treatment (tx) of RRMM, as a monotherapy, in combination with low-dose dexamethasone (DEX), or in combination with DEX and daratumumab, bortezomib, or carfilzomib (CC-220-MM-001; NCT02773030). IBER modu...

RNA editing is an epitranscriptomic modification of emerging relevance to disease development and manifestations. Here we identify a novel role of the RNA editing enzyme ADAR1 in multiple myeloma (MM) progression as inducer of cognate DNA mutations. We have previously demonstrated (Lagana et al, ASH 2017) that ADAR1, which resides on human chromoso...

Multiple myeloma (MM) is the second most prevalent hematological cancer. MM is a complex and heterogeneous disease, and thus, it is essential to leverage omics data from large MM cohorts to understand the molecular mechanisms underlying MM tumorigenesis, progression, and drug responses, which may aid in the development of better treatments. In this...

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare and aggressive hematological disease, deriving from the malignant transformation of plasmacytoid, alpha-interferon producing dendritic cells (pDCs) Recent studies shed new light on BPDCN genomic and trascriptomic alterations, but the microRNA (miRNA) profile is st...

This detailed book provides a comprehensive state-of-the-art presentation of all aspects of miRNA target identification, from the prediction of miRNA binding sites on their target molecules to their experimental validation and downstream functional analysis. It also explores methodologies and tools for target prediction and related analysis, as wel...

Immunotherapeutic agents are quickly becoming a routine aspect of treatment paradigms. However, despite clinical successes, cancer immunotherapy faces major challenges. One such challenge is that efficacy in most patients is unpredictable. Many immunotherapy treatments have demonstrated efficacy in only select cancer types. Variability in patient r...

HLA-E is a non-classical major histocompatibility complex (MHC) class I molecule characterized by limited polymorphism in contrast to its class I counterparts HLA-A, -B, and -C. HLA-E elicits an inhibitory signal via its interactions with NKG2A on NK cells (and subsets of T cells) and is considered the most dominant inhibitory signal for an NK cell...

Selinexor (KPT-330) is a selective inhibitor of nuclear export (SINE) which specifically targets XPO1 (Exportin 1)-mediated nuclear export, leading to increased nuclear retention of major tumor suppressor proteins and inducing selective apoptosis in cancer cells. Several phase I and II clinical trials demonstrate evidence of anti-cancer activity of...

The type I Melanoma Antigen Gene (MAGE) A3 is a promising functional target in multiple myeloma (MM). MAGE-A3 expression in primary MM specimens is associated with proliferation and progression of disease. Previous laboratory studies showed that MAGE-A3 inhibits p53-dependent and independent apoptosis and cell cycle regulation in human myeloma cell...

Purpose: Multiple myeloma (MM) is a malignancy of plasma cells, with a median survival of 6 years. Despite recent therapeutic advancements, relapse remains mostly inevitable, and the disease is fatal in the majority of patients. A major challenge in the treatment of patients with relapsed MM is the timely identification of treatment options in a p...

Oncogenic KRAS induces tumor onset and development by modulating gene expression via different molecular mechanisms. MicroRNAs (miRNAs) are small non-coding RNAs that have been established as main players in tumorigenesis. By overexpressing wild type or mutant KRAS (KRASG12D) and using inducible human and mouse cell lines, we analyzed KRAS-regulate...

The domestic cat is an important human companion animal that can also serve as a relevant model for ∼250 genetic diseases, many metabolic and degenerative conditions, and forms of cancer that are analogous to human disorders. MicroRNAs (miRNAs) play a crucial role in many biological processes and their dysregulation has a significant impact on impo...

In NSCLC alterations in PDGF receptors are markers of worst prognosis and efficient targeting of these receptors is yet to be achieved. In this study, we explored PDGFR-regulated microRNAs demonstrating that miR-23b cluster and miR-125a-5p are downregulated by increased expression of PDGFR-α or PDGFR-β in NSCLC cells. Mechanistically, the expressio...

Micro-RNAs (miRNAs) regulate gene expression of target genes and act as key players of pathophysiology pathways of various diseases. Over the last decade, miRNAs were used as therapeutic agents and has shown great promise in altering tumor progression, immune responses, and heart failure. Oligonucleotides based anti-miR have shown therapeutic effic...

miRandola (http://mirandola.iit.cnr.it/) is a database of extracellular non-coding RNAs (ncRNAs) that was initially published in 2012, foreseeing the relevance of ncRNAs as non-invasive biomarkers. An increasing amount of experimental evidence shows that ncRNAs are frequently dysregulated in diseases. Further, ncRNAs have been discovered in differe...