Nikhil C. Munshi's research while affiliated with Harvard Medical School and other places
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Publications (750)
Therapeutic targeting of CDK7 has proven beneficial in pre-clinical studies, yet the off-target effects of currently available CDK7 inhibitors make it difficult to pinpoint the exact mechanisms behind MM cell death mediated by CDK7 inhibition. Here, we show that CDK7 expression positively correlates with E2F and MYC transcriptional programs in mult...
PSMD4/Rpn10 is a subunit of the 19S proteasome unit that is involved with feeding target proteins into the catalytic machinery of the 26S proteasome. Since proteasome inhibition is a common therapeutic strategy in multiple myeloma (MM), we investigated Rpn10 and found that it is highly expressed in MM cells versus normal plasma cells. Rpn10 levels...
High Dose Melphalan (HDM) improves progression free survival (PFS) in multiple myeloma (MM), yet melphalan is a DNA damaging alkylating agent, so we assessed its mutational effect on surviving myeloma cells by analyzing paired MM samples collected at diagnosis and relapse from the IFM 2009 study. We performed deep whole genome sequencing on 68 pati...
Background:
We aimed to evaluate and compare the performance of multiple myeloma (MM) selection algorithms for use in Veterans Affairs (VA) research.
Methods:
Using the VA Corporate Data Warehouse (CDW), the VA Cancer Registry (VACR), and VA pharmacy data, we randomly selected 500 patients from 01/01/1999 to 06/01/2021 who had (1) either one MM...
With growing knowledge of multiple myeloma (MM) pathobiology and the introduction of novel therapies, risk stratification continues to evolve. Myeloid-derived suppressor cells and tumor-associated macrophages, derived from peripheral blood monocytes, support malignant plasma cell proliferation in the bone marrow. Since peripheral blood absolute mon...
Context:
Cilta-cel, a CAR-T cell therapy with 2 BCMA-targeting single-domain antibodies, led to early, deep, and durable responses in heavily pretreated patients with RRMM in the phase 1b/2 CARTITUDE-1 study (NCT03548207).
Objective:
To report updated results from CARTITUDE-1. Data 2-years post LPI (~30-month median follow-up [MFU]) will be pres...
Long noncoding RNAs (lncRNA) can drive tumorigenesis and are susceptible to therapeutic intervention. Here, we used a large-scale CRISPR interference viability screen to interrogate cell growth dependency to lncRNA genes in multiple myeloma (MM), and identified a prominent role for the miR-17-92 cluster host gene (MIR17HG). We show that a MIR17HG-d...
Although translocation events between chromosome 4 (NSD2 gene) and chromosome 14 (IgH locus) (t(4;14)) is considered high-risk in newly diagnosed multiple myeloma (NDMM), only ~30-40% of t(4;14) patients are clinically high-risk. We generated and compared a large whole genome sequencing (WGS) and transcriptome (RNA-sequencing) from 258 t(4;14) (N=1...
Although caregivers of patients with MM play a critical role in supporting their loved ones throughout the illness course, studies examining caregiver quality of life (QOL), psychological distress, and prognostic awareness are lacking. We conducted a cross-sectional, multisite study of patients undergoing treatment with MM and their caregivers. Eli...
Objective
To understand the experience of patients with relapsed and refractory multiple myeloma (RRMM) receiving idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor T cell therapy, in the pivotal, phase 2 KarMMa trial.
Methods
Optional semi-structured interviews before leukapheresis (pre-treatment) cap...
LBA4
Background: Optimal use of triplet/quadruplet induction, ASCT, and R-based maintenance in patients (pts) with NDMM who are eligible for transplant continues to evolve. The IFM 2009 trial, which used R maintenance for 1 year (y), showed progression-free survival (PFS; median, 35.0 vs. 47.3 months [mos]) but no overall survival benefit (OS; 60 v...
Background:
In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown.
Methods:
In this phase 3 trial, adults (18 to 65 years of age)...
PURPOSE
CARTITUDE-1, a phase Ib/II study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel) in heavily pretreated patients with relapsed/refractory multiple myeloma, yielded early, deep, and durable responses at 12 months. Here, we present updated results 2 years after last patient in (median follow-up [MFU] approximately 2...
8028
Background: Ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen (BCMA)–targeting single-domain antibodies, led to early, deep, and durable responses in the phase 1b/2 CARTITUDE-1 study (NCT03548207) in heavily pretreated patients (pts) with relapsed/refractory multiple myel...
2542
Background: A strategy for reversal of T cell exhaustion is reprograming of antigen-specific CTL to early lineage memory T cells with selective anti-tumor activities. To accomplish this goal, we epigenetically reprogrammed BCMA-specific CD8 ⁺ CTL to a pluripotent state through key defined transcription factors, established “induced Pluripotent...
Genomic instability contributes to cancer progression and is at least partly due to dysregulated homologous recombination. Here, we show that an elevated level of ABL1 kinase overactivates the HR pathway and causes genomic instability in multiple myeloma (MM) cells. Inhibiting ABL1 with either shRNA or a pharmacological inhibitor (nilotinib) inhibi...
Genomic instability fuels genomic alterations that befit cancer cells with necessary adaptations to keep proliferating and overcome the impact of host anti-tumor immunity and cytotoxic therapy. Since DNA breaks are required for genomic rearrangements to take place, we hypothesized that dysregulated nuclease activity mediates genomic instability in...
Infection remains the leading cause of morbidity and mortality in patients with multiple myeloma because of the cumulative effect of disease, treatment, and host-related factors. Given that infectious risk is cumulative through the course of the disease, preventing infections is paramount. Optimal preventive strategies include vaccination against c...
Background:
Multiple myeloma (MM) is an incurable hematologic malignancy requiring long-term, continuous therapy. Despite its chronic and unrelenting course, studies examining quality of life (QOL), psychological distress, and perceptions of prognosis by line of therapy are lacking.
Methods:
The authors conducted a cross-sectional, multisite stu...
Immune profiling in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM) provides the framework for developing novel immunotherapeutic strategies. Here, we demonstrate decreased CD4⁺ Th cells, increased Treg and G-type MDSC, and upregulation of immune checkpoints on ef...
Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy, showed deep, durable responses in patients with triple-class exposed (TCE) relapsed and refractory multiple myeloma (RRMM) in the phase 2 KarMMa trial. We assessed health-related quality of life (HRQoL) among KarMMa patients...
Long noncoding RNAs (lncRNA) can drive the tumorigenesis and be susceptible to therapeutic intervention. To define the landscape of therapeutically actionable lncRNA dependencies in multiple myeloma (MM), we coupled our extensive lncRNA transcriptomic profile with lncRNA targeted CRISPR interference viability screen and identified RNA Regulator of...
Importance
Patients with cancer are at increased risk for severe COVID-19, but it is unknown whether SARS-CoV-2 vaccination is effective for them.
Objective
To determine the association between SARS-CoV-2 vaccination and SARS-CoV-2 infections among a population of Veterans Affairs (VA) patients with cancer.
Design, Setting, and Participants
Retro...
Introduction
Outcomes for patients with relapsed and refractory multiple myeloma (RRMM) and previous exposure to immunomodulatory agents, proteasome inhibitors (PIs), and anti-CD38 antibodies are poor. Ide-cel is a B-cell maturation antigen (BCMA)-directed CAR T cell therapy. In the pivotal phase 2 KarMMa trial (NCT03361748), ide-cel demonstrated f...
Introduction
Outcomes for patients (pts) with relapsed/refractory multiple myeloma (RRMM) previously treated with immunomodulatory agents, proteasome inhibitors (PIs), and anti-CD38 antibodies are poor; novel treatments that prolong survival in pts with RMMM are essential. Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen (BCMA)-directe...
Background: Multiple myeloma (MM) is an incurable hematologic malignancy requiring long-term, continuous therapy. Despite its chronic and unrelenting course, studies examining quality of life (QOL), psychological distress, and prognostic awareness by line of therapy are lacking.
Methods: We conducted a cross-sectional, multi-site study of patients...
New generation immunotherapies in Multiple Myeloma (MM) targeting BCMA, have shown remarkable clinical benefits. However relapse still occurs due to tumor intrinsic and extrisic resistance mechanisms including antigen loss related to mutation, deletion and splicing pattern changes. Two recent case reports including ours highlighted biallelic loss o...
Background: The acquisition of somatic clonal mutations in the blood of healthy individuals is referred to as clonal hematopoiesis (CH) and is associated with increased age, risk of hematologic malignancy, and non-malignant inflammatory outcomes. The presence of CH in patients with non-Hodgkin lymphoma (NHL) has been associated with adverse outcome...
Introduction:
Chimeric antigen receptor (CAR) T-cell therapy is a novel adoptive immunotherapy utilizing autologous T cells expressing synthetic fusion proteins that target specific antitumor antigens. Over recent years, novel CAR T-cell constructs have shown efficacy for the treatment of hematologic malignancies. The B-cell maturation antigen (BCM...
To identify therapeutically actionable genetic dependencies we have pursued various approaches to derive a deeper understanding of the oncogenic hallmarks of myelomagenesis. We have studied the long noncoding RNA (lncRNA) landscape in multiple myeloma (MM) and identified a large number of differentially expressed lncRNAs in MM versus normal plasma...
Multiple myeloma (MM) is marked by several genetic abnormalities, including chromosome translocation t(11;14). Overexpression of anti-apoptotic BCL-2 in t(11;14) MM promotes disease progression, prompting clinical use of the BH3 mimetic and BCL-2 inhibitor venetoclax in combination with proteasome inhibitor therapy. Despite high initial response ra...
Introduction: Ixazomib is an oral proteasome inhibitor (PI) that is currently approved to be administered once weekly in combination with lenalidomide (LEN) and dexamethasone in RRMM (Moreau et al N Eng J Med 2016; 374:1621-1634). As most patients are LEN refractory at the time of first relapse, pomalidomide-based regimens are commonly utilized due...
Integrated genomic analysis including whole genome and RNA sequencing in primary multiple myeloma (MM) cells have reported a universal loss of BCL7A gene in MM patients compared to normal plasma cells (PC). Our Genetic modulation in in-vitro and in-vivo MM models have also validated the loss of BCL7A as an oncogenic event responsible for acquisitio...
Introduction: Patients with heavily pretreated relapsed and refractory multiple myeloma (RRMM) have poor outcomes and poor health-related quality of life (HRQoL). The B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy ide-cel has shown frequent, deep, and durable responses in patients with RRMM who were triple-...
Introduction: Stromal cells in the bone marrow microenvironment maintain a complex bidirectional relationship with the malignant plasma cells and have been implicated in the growth and survival of multiple myeloma (MM) cells along with the development of drug resistance and disease progression. We hypothesized that the perpetual induction of gene e...
In multiple myeloma (MM), among the anomalies associated with shorter survival, it should be noted recurrent copy number variations (CNV), such as del(17p13), del(1p32), or 1q gains. These abnormalities are considered secondary, thus acquired during the course of the disease. Although they can be observed from diagnosis, they are only detected at t...
Multiple myeloma (MM) is a complex and heterogenous disease which is dependent on the surrounding microenvironment for growth and survival. In MM, dysregulation of transcriptional control is a major driver of tumor transformation and progression. To evaluate transcriptional programs activated in MM cells in the context of the bone marrow milieu, we...
Background
Focal amplifications and rearrangements drive tumor growth and evolution in cancer. Focally amplified regions often involve the juxtaposition of rearranged segments of DNA from distinct chromosomal loci into a single amplified region and nearly half of these regions can be explained by circular, extrachromosomal DNA (ecDNA) formation. Ca...
On an average, 1% of monoclonal gammopathy of undermined significance (MGUS) and 10% of smoldering Multiple Myeloma (SMM) progress to symptomatic MM every year within the first five years of diagnosis. The probability of progression significantly decreases for SMM patients after first 5 years. However, a distinct subset of SMM patients progress wit...
Background: Multiple myeloma (MM) is an incurable hematologic malignancy requiring long-term, continuous therapy. Although caregivers of MM patients play a critical role in supporting their loved ones throughout the illness course, studies examining caregiver quality of life (QOL), psychological distress, and prognostic awareness are lacking.
Metho...
Introduction : Multiple myeloma (MM) is a heterogeneous disease with diverse clinical outcomes. Although survival in MM has improved, high risk patients still experience early relapses and shorter survival. Current methods for risk stratification in MM are useful at diagnosis but need to be refined as our knowledge of disease pathobiology evolves....
Multiple myeloma (MM) cells are characterized by cell cycle dysregulation, epigenetic heterogeneity, and perturbation of the transcriptional landscape. We have previously shown that chemical and genetic perturbation of transcriptional regulator CDK7 significantly and selectively impacted MM cell growth and viability, supporting it as a pharmacologi...
T cell regenerative medicine represents an emerging immunotherapeutic approach using antigen-specific Induced Pluripotent Stem Cells (iPSC) to rejuvenate CD8 + cytotoxic T lymphocytes (CTL). Here we report on an iPSC-derived therapeutic strategy targeting B-Cell Maturation Antigen (BCMA) against multiple myeloma (MM) via establishment of antigen-sp...
Introduction: Idecabtagene vicleucel (ide-cel, bb2121) is the first chimeric antigen receptor (CAR) T cell therapy approved for the treatment of relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. bb21217 is a B-cell mat...
In a prior phase 2 study, personalized cancer vaccination with autologous dendritic cells (DCs) fused with primary MM tumor cells (DC/MM fusions) induced the expansion of circulating MM-reactive lymphocytes and was associated with conversion to complete response (CR) post-autoHCT in the absence of maintenance therapy. 1 We now present a multicenter...
Background: Chimeric antigen receptor (CAR)-T cells are highly effective in patients (pts) with multiple myeloma (MM), but duration of response can be limited, and pts with rapidly progressing disease require a fast and reliable CAR-T cell manufacturing process. Here, we report initial clinical data from a Phase I trial assessing PHE885 manufacture...
Introduction
Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, is particularly serious in patients with multiple myeloma (MM), with estimated mortality of over 30% in several studies. In the general population, SARS-CoV-2 vaccination has been demonstrated to be an effective approach to preventing infection. However, patients with...
Introduction: Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy, is approved by the US FDA for the treatment of adult patients (pts) with relapsed and refractory multiple myeloma (RRMM) after ≥ 4 prior lines of therapy, including an immunomodulatory agent, proteasome inhibit...
Introduction: Ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen (BCMA) targeting single-domain antibodies, demonstrated early, deep, and durable responses in the phase 1b/2 CARTITUDE-1 study in patients (pts) with relapsed/refractory multiple myeloma (RRMM) who had been heavil...
Background
Lenalidomide, bortezomib, and dexamethasone (RVD) is a standard front-line regimen for both transplant eligible and ineligible multiple myeloma (MM) patients. Based on original APEX study data, obtaining a complete blood count (CBC) before every administration of bortezomib has been recommended. Waiting for labs could add several hours t...
Identification of novel vulnerabilities in the context of therapeutic resistance is emerging as key challenge for cancer treatment. Recent studies have detected pervasive aberrant splicing in cancer cells, supporting its targeting for novel therapeutic strategies. Here, we evaluated the expression of several spliceosome machinery components in mult...
Background
With the deluge of available genomic data in recent years, it is becoming evident that MM cells are characterized by cell cycle dysregulation, epigenetic heterogeneity, and perturbation of the transcriptional landscape. We here elucidated the biological role of CDK7 and explored the functional consequence of its inhibition in MM using ch...
Background
This study reports on the reprogramming of B-Cell Maturation Antigen (BCMA)-specific CD8+ cytotoxic T lymphocytes (CTL) to induced pluripotent stem cells (iPSC) and their differentiation into rejuvenated antigen-specific CD8+ CTL as a potential therapeutic option to effectively treat cancer patients. Along with characterization of BCMA-s...
Background
Immunotherapies in MM targeting BCMA, have shown remarkable clinical benefits. However, two recent reports highlighted that biallelic loss of BCMA cause resistance to anti-BCMA therapy. In both studies BCMA locus was deleted bringing in focus importance of del16p. We have evaluated 2883 MM patients at diagnosis and relapse to understand...
Introduction
Long noncoding RNAs (lncRNAs) are profoundly dysregulated in multiple myeloma (MM), yet their tumor-promoting features remain to be defined. Here, we have coupled extensive transcriptomic profiling of patient samples (n=360) with a genome-wide CRISPR interference (CRISPRi) viability screen (4 cell lines) to generate a map of lncRNA “de...
Background
Patients (pts) with RRMM who were exposed to immunomodulatory agents, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs) have poor outcomes with subsequent treatments. Ide-cel, a BCMA-directed CAR T-cell therapy, has shown frequent, deep, and durable responses in triple-class exposed pts with RRMM in the pivotal KarM...
Background
Multiple myeloma (MM) is an incurable hematologic malignancy requiring long-term, continuous therapy. Although caregivers of MM patients play a critical role in supporting their loved ones throughout the illness course, studies examining caregiver quality of life (QOL), psychological distress, and prognostic awareness are lacking.
Metho...