Publications by authors named "Nikhil C Munshi"

313 Publications

Association of COVID-19 Vaccination With SARS-CoV-2 Infection in Patients With Cancer: A US Nationwide Veterans Affairs Study.

JAMA Oncol 2021 Dec 2. Epub 2021 Dec 2.

VA Cooperative Studies Program, VA Boston Healthcare System, Boston, Massachusetts.

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: Retrospective, multicenter, nationwide cohort study of SARS-CoV-2 vaccination and infection among patients in the VA health care system from December 15, 2020, to May 4, 2021. All adults with solid tumors or hematologic cancer who received systemic cancer-directed therapy from August 15, 2010, to May 4, 2021, and were alive and without a documented SARS-CoV-2 positive result as of December 15, 2020, were eligible for inclusion. Each day between December 15, 2020, and May 4, 2021, newly vaccinated patients were matched 1:1 with unvaccinated or not yet vaccinated controls based on age, race and ethnicity, VA facility, rurality of home address, cancer type, and treatment type/timing.

Exposures: Receipt of a SARS-CoV-2 vaccine.

Main Outcomes And Measures: The primary outcome was documented SARS-CoV-2 infection. A proxy for vaccine effectiveness was defined as 1 minus the risk ratio of SARS-CoV-2 infection for vaccinated individuals compared with unvaccinated controls.

Results: A total of 184 485 patients met eligibility criteria, and 113 796 were vaccinated. Of these, 29 152 vaccinated patients (median [IQR] age, 74.1 [70.2-79.3] years; 95% were men; 71% were non-Hispanic White individuals) were matched 1:1 to unvaccinated or not yet vaccinated controls. As of a median 47 days of follow-up, 436 SARS-CoV-2 infections were detected in the matched cohort (161 infections in vaccinated patients vs 275 in unvaccinated patients). There were 17 COVID-19-related deaths in the vaccinated group vs 27 COVID-19-related deaths in the unvaccinated group. Overall vaccine effectiveness in the matched cohort was 58% (95% CI, 39% to 72%) starting 14 days after the second dose. Patients who received chemotherapy within 3 months prior to the first vaccination dose were estimated to have a vaccine effectiveness of 57% (95% CI, -23% to 90%) starting 14 days after the second dose vs 76% (95% CI, 50% to 91%) for those receiving endocrine therapy and 85% (95% CI, 29% to 100%) for those who had not received systemic therapy for at least 6 months prior.

Conclusions And Relevance: In this cohort study, COVID-19 vaccination was associated with lower SARS-CoV-2 infection rates in patients with cancer. Some immunosuppressed subgroups may remain at early risk for COVID-19 despite vaccination, and consideration should be given to additional risk reduction strategies, such as serologic testing for vaccine response and a third vaccine dose to optimize outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2021.5771DOI Listing
December 2021

CCL20 induces colorectal cancer neoplastic epithelial cell proliferation, migration, and further CCL20 production through autocrine HGF-c-Met and MSP-MSPR signaling pathways.

Oncotarget 2021 Nov 23;12(24):2323-2337. Epub 2021 Nov 23.

Research Service, VA Boston Healthcare System, West Roxbury, MA, USA.

CCL20-CCR6 interactions promote colorectal cancer through direct effects on neoplastic epithelial cells and through modulating the tumor microenvironment. The mechanism of these effects on neoplastic epithelial cells is poorly understood. This study demonstrates that CCL20 induces secretion of hepatocyte growth factor (HGF) and phosphorylation of HGF's cognate receptor c-Met in HT29 and HCT116 colorectal cancer cell lines both in concentration- and time-dependent manners. Similar to CCL20, HGF induces migration, autofeedback CCL20 secretion, and ERK1/2 phosphorylation in the colon cancer cells. CCL20-dependent ERK1/2 phosphorylation is blocked by HGF inhibition, and CCL20-dependent migration and CCL20 secretion are blocked by inhibition of HGF or ERK. Interestingly, unlike CCL20, HGF does not induce proliferation of colon cancer cells, and CCL20-dependent cell proliferation is not blocked by direct HGF inhibition. CCL20-dependent proliferation, however, is blocked by the multi-tyrosine kinase inhibitor crizotinib. Exploring this effect, it was found that CCL20 also induces production of MSP and phosphorylation of MSP's receptor MSPR by the colorectal cancer cells. CCL20-dependent cell proliferation is inhibited by directly blocking MSP-MSPR interactions. Thus, CCL20-mediated migration and CCL20 secretion are regulated through a pathway involving HGF, c-Met, and ERK, while CCL20-mediated proliferation is instead regulated through MSP and its receptor MSPR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.28131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629403PMC
November 2021

IgM-MM is predominantly a pre-germinal center disorder and has a distinct genomic and transcriptomic signature from WM.

Blood 2021 Nov;138(20):1980-1985

Department of Data Science, Dana-Farber Cancer Institute, Boston, MA.

Immunoglobulin M (IgM) multiple myeloma (MM) is a rare disease subgroup. Its differentiation from other IgM-producing gammopathies such as Waldenström macroglobulinemia (WM) has not been well characterized but is essential for proper risk assessment and treatment. In this study, we investigated genomic and transcriptomic characteristics of IgM-MM samples using whole-genome and transcriptome sequencing to identify differentiating characteristics from non-IgM-MM and WM. Our results suggest that IgM-MM shares most of its defining structural variants and gene-expression profiling with MM, but has some key characteristics, including t(11;14) translocation, chromosome 6 and 13 deletion as well as distinct molecular and transcription-factor signatures. Furthermore, IgM-MM translocations were predominantly characterized by VHDHJH recombination-induced breakpoints, as opposed to the usual class-switching region breakpoints; coupled with its lack of class switching, these data favor a pre-germinal center origin. Finally, we found elevated expression of clinically relevant targets, including CD20 and Bruton tyrosine kinase, as well as high BCL2/BCL2L1 ratio in IgM-MM, providing potential for targeted therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2021011452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602933PMC
November 2021

Apoptosis reprogramming triggered by splicing inhibitors sensitizes multiple myeloma cells to Venetoclax treatment.

Haematologica 2021 Oct 21. Epub 2021 Oct 21.

Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Clinic of Haematology, Genoa, Italy.

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 multiple myeloma (MM) cells and the impact of splicing modulation on tumor cell growth and viability. A comprehensive gene expression analysis confirmed the reported deregulation of spliceosome machinery components in MM cells, compared to normal plasma cells (PCs) from healthy donors, with its pharmacological and genetic modulation resulting in impaired growth and survival of MM cell lines and patient-derived malignant PCs. Consistent with this, transcriptomic analysis revealed deregulation of BCL2 family members, including decrease of antiapoptotic long form of myeloid cell leukemia-1 (MCL1) expression, as crucial for "priming" MM cells for Venetoclax activity in vitro and in vivo, irrespective of t(11;14) status. Overall, our data provide a rationale for supporting the clinical use of splicing modulators as a strategy to reprogram apoptotic dependencies and make all MM patients more vulnerable to BCL2 inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2021.279276DOI Listing
October 2021

Don't Compromise Myeloma Care Due to COVID-19 Pandemic!

Blood Cancer Discov 2020 Nov 13;1(3):218-220. Epub 2020 Oct 13.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Patients with active myeloma, especially with earlier stages of the disease, are susceptible to COVID-19 infection and can have adverse outcomes, even in those on first-line treatment. Importantly, myeloma therapy can be safely administered, and optimal control of myeloma is associated with improved outcome. https://vimeo.com/486246183/559a80cfae .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2643-3230.BCD-20-0151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504755PMC
November 2020

Clonal phylogeny and evolution of critical cytogenetic aberrations in multiple myeloma at single cell level by QM-FISH.

Blood Adv 2021 Oct 15. Epub 2021 Oct 15.

Institute oh hematology and blood disease hospital, Tianjin, China.

Single-cell analysis is of significant importance in delineate the exact phylogeny of subclonal population and in discovering subtle diversification. So far studies of intratumor heterogeneity and clonal evolution in multiple myeloma (MM) were largely focused at the bulk tumor population level. Here, we performed quantitative multi-gene fluorescence in situ hybridization (QM-FISH) in 129 longitudinal samples of 57 MM patients. All the patients had newly-diagnosed and relapsed paired samples. An expanded cohort of 188 MM patients underwent conventional FISH (cFISH) to validate the cytogenetic evolution in bulk tumor level. 43 of 57 patients (75.4%) harbored three or four cytogenetic clones at diagnosis. We delineated the phylogeny of subclonal tumor population and derived the evolutionary architecture in each patient. Patients with clonal stabilization had a significantly improved OS than those with other evolutionary patterns (median OS, 71.2 vs. 39.7 vs. 35.2 vs. 25.5 months, for stable, differential, branching and linear patterns, respectively, p=0.001). Besides, a high degree of consistency and complementarity across QM-FISH and cFISH was observed in evaluation of cytogenetic evolution pattern in MM. Survival after relapse were greater influenced by the presence of high-risk aberrations at relapse (hazard ratio =2.07) rather than present at diagnosis (hazard ratio=1.55). This study shows that QM-FISH is a valuable tool to elucidate the clonal architecture at single cell level. Clonal evolution pattern is of prognostic significance, highlighting the need for repeated cytogenetic evaluation in relapsed MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004992DOI Listing
October 2021

Dysregulated APOBEC3G causes DNA damage and promotes genomic instability in multiple myeloma.

Blood Cancer J 2021 Oct 8;11(10):166. Epub 2021 Oct 8.

Dana Farber Cancer Institute, Boston, MA, 02115, USA.

Multiple myeloma (MM) is a heterogeneous disease characterized by significant genomic instability. Recently, a causal role for the AID/APOBEC deaminases in inducing somatic mutations in myeloma has been reported. We have identified APOBEC/AID as a prominent mutational signature at diagnosis with further increase at relapse in MM. In this study, we identified upregulation of several members of APOBEC3 family (A3A, A3B, A3C, and A3G) with A3G, as one of the most expressed APOBECs. We investigated the role of APOBEC3G in MM and observed that A3G expression and APOBEC deaminase activity is elevated in myeloma cell lines and patient samples. Loss-of and gain-of function studies demonstrated that APOBEC3G significantly contributes to increase in DNA damage (abasic sites and DNA breaks) in MM cells. Evaluation of the impact on genome stability, using SNP arrays and whole genome sequencing, indicated that elevated APOBEC3G contributes to ongoing acquisition of both the copy number and mutational changes in MM cells over time. Elevated APOBEC3G also contributed to increased homologous recombination activity, a mechanism that can utilize increased DNA breaks to mediate genomic rearrangements in cancer cells. These data identify APOBEC3G as a novel gene impacting genomic evolution and underlying mechanisms in MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41408-021-00554-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501035PMC
October 2021

Bortezomib induces anti-multiple myeloma immune response mediated by cGAS/STING pathway activation.

Blood Cancer Discov 2021 Sep 23;2(5):468-483. Epub 2021 Apr 23.

Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA.

Proteasome inhibitor bortezomib induces apoptosis in multiple myeloma (MM) cells, and has transformed patient outcome. Using as well as immunodeficient and immunocompetent murine MM models, we here show that bortezomib also triggers immunogenic cell death (ICD) characterized by exposure of calreticulin on dying MM cells, phagocytosis of tumor cells by dendritic cells, and induction of MM specific immunity. We identify a bortezomib-triggered specific ICD-gene signature associated with better outcome in two independent MM patient cohorts. Importantly, bortezomib stimulates MM cells immunogenicity activation of cGAS/STING pathway and production of type-I interferons; and STING agonists significantly potentiate bortezomib-induced ICD. Our studies therefore delineate mechanisms whereby bortezomib exerts immunotherapeutic activity, and provide the framework for clinical trials of STING agonists with bortezomib to induce potent tumor-specific immunity and improve patient outcome in MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2643-3230.bcd-21-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462183PMC
September 2021

Indatuximab ravtansine plus dexamethasone with lenalidomide or pomalidomide in relapsed or refractory multiple myeloma: a multicentre, phase 1/2a study.

Lancet Haematol 2021 Nov 13;8(11):e794-e807. Epub 2021 Sep 13.

Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Background: Indatuximab ravtansine (BT062) is an antibody-drug conjugate that binds to CD138 and synergistically enhances the antitumor activity of lenalidomide in preclinical models of multiple myeloma. This phase 1/2a study was done to determine the safety, activity, and pharmacokinetics of indatuximab ravtansine in combination with immunomodulatory drugs in patients with relapsed or refractory multiple myeloma.

Methods: This open-label, phase 1/2a study took place at nine hospital sites in the USA. Eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma, and ECOG performance status or Zubrod score of 2 or below. Patients who received indatuximab ravtansine with lenalidomide and dexamethasone (indatuximab ravtansine plus lenalidomide) had failure of at least one previous therapy. Patients treated with indatuximab ravtansine with pomalidomide and dexamethasone (indatuximab ravtansine plus pomalidomide) had failure of at least two previous therapies (including lenalidomide and bortezomib) and had progressive disease on or within 60 days of completion of their last treatment. In phase 1, patients received indatuximab ravtansine intravenously on days 1, 8, and 15 of each 28-day cycle in escalating dose levels of 80 mg/m, 100 mg/m, and 120 mg/m, with lenalidomide (25 mg; days 1 to 21 every 28 days orally) and dexamethasone (20-40 mg; days 1, 8, 15, and 22 every 28 days). In phase 2, the recommended phase 2 dose of indatuximab ravtansine was given to an expanded cohort of patients in combination with lenalidomide and dexamethasone. The protocol was amended to allow additional patients to be treated with indatuximab ravtansine plus pomalidomide (4 mg; days 1 to 21 every 28 days orally) and dexamethasone, in a more heavily pretreated patient population than in the indatuximab ravtansine plus lenalidomide group. The phase 1 primary endpoint was to determine the dose-limiting toxicities and the maximum tolerated dose (recommended phase 2 dose) of indatuximab ravtansine, and the phase 2 primary endpoint was to describe the objective response rate (ORR; partial response or better) and clinical benefit response (ORR plus minor response). All patients were analysed for safety and all patients with post-treatment response assessments were analysed for activity. This study is registered with ClinicalTrials.gov, number NCT01638936, and is complete.

Findings: 64 (86%) of 74 screened patients were enrolled between July 3, 2012, and June 30, 2015. 47 (73%) patients received indatuximab ravtansine plus lenalidomide (median follow-up 24·2 months [IQR 19·9-45·4]) and 17 (27%) received indatuximab ravtansine plus pomalidomide (24·1 months [17·7-36·7]). The maximum tolerated dose of indatuximab ravtansine plus lenalidomide was 100 mg/m, and defined as the recommended phase 2 dose for indatuximab ravtansine plus pomalidomide. An objective response for indatuximab ravtansine plus lenalidomide was observed in 33 (71·7%) of 46 patients and in 12 (70·6%) of 17 patients in the indatuximab ravtansine plus pomalidomide group. The clinical benefit response for indatuximab ravtansine plus lenalidomide was 85% (39 of 46 patients) and for indatuximab ravtansine plus pomalidomide it was 88% (15 of 17 patients). The most common grade 3-4 adverse events in both groups were neutropenia (14 [22%] of 64 patients), anaemia (10 [16%]), and thrombocytopenia (seven [11%]). Treatment-emergent adverse events (TEAEs) that led to discontinuation occurred in 35 (55%) of the 64 patients. Five (8%) patients with a TEAE had a fatal outcome; none was reported as related to indatuximab ravtansine.

Interpretation: Indatuximab ravtansine in combination with immunomodulatory drugs shows preliminary antitumor activity, is tolerated, and could be further evaluated in patients with relapsed or refractory multiple myeloma.

Funding: Biotest AG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-3026(21)00208-8DOI Listing
November 2021

Lack of differential impact of del17p on survival in African Americans compared with White patients with multiple myeloma: a VA study.

Blood Adv 2021 09;5(18):3511-3514

VA Boston Healthcare System, Boston, MA.

Multiple myeloma (MM) is a heterogeneous disease that has an increased incidence in African Americans (AAs). We previously observed that, with equal access to health care, younger AA patients (age < 65 years) have superior overall survival (OS) compared with younger White patients. Because MM prognosis is influenced by 17p deletion (del17p), we investigated racial differences in its occurrence and impact in a large cohort of MM patients from the Veterans Affairs (VA) system. Among 2243 VA patients with MM for whom del17p data were available, del17p was present in 8.83% of all patients, with a significantly lower prevalence in AAs (5.56%) compared with Whites (10.52%; P < .001). The difference was even more pronounced among younger AAs (<65 years) vs younger Whites (4.34% vs 9.8%, respectively; P = .004). However, we did not observe any significant difference in survival between AA and White patients with del17p, regardless of age category, suggesting that del17p carries a poor prognosis across race and age. Interestingly, among patients without del17p, we still noted a significantly superior OS in younger AAs compared with younger Whites (7.75 vs 5.10 years; P = .042). Our study shows a lower incidence of del17p in AAs but suggests that the survival advantage for younger AAs is primarily due to factors other than del17p.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020004001DOI Listing
September 2021

The DNA methylation landscape of multiple myeloma shows extensive inter- and intrapatient heterogeneity that fuels transcriptomic variability.

Genome Med 2021 08 9;13(1):127. Epub 2021 Aug 9.

Université de Nantes, CNRS, INSERM, CRCINA, Nantes, F-44000, France.

Background: Cancer evolution depends on epigenetic and genetic diversity. Historically, in multiple myeloma (MM), subclonal diversity and tumor evolution have been investigated mostly from a genetic perspective.

Methods: Here, we performed an analysis of 42 MM samples from 21 patients by using enhanced reduced representation bisulfite sequencing (eRRBS). We combined several metrics of epigenetic heterogeneity to analyze DNA methylation heterogeneity in MM patients.

Results: We show that MM is characterized by the continuous accumulation of stochastic methylation at the promoters of development-related genes. High combinatorial entropy change is associated with poor outcomes in our pilot study and depends predominantly on partially methylated domains (PMDs). These PMDs, which represent the major source of inter- and intrapatient DNA methylation heterogeneity in MM, are linked to other key epigenetic aberrations, such as CpG island (CGI)/transcription start site (TSS) hypermethylation and H3K27me3 redistribution as well as 3D organization alterations. In addition, transcriptome analysis revealed that intratumor methylation heterogeneity was associated with low-level expression and high variability.

Conclusions: We propose that disrupted DNA methylation in MM is responsible for high epigenetic and transcriptomic instability allowing tumor cells to adapt to environmental changes by tapping into a pool of evolutionary trajectories.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-021-00938-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351364PMC
August 2021

Clonal hematopoiesis in patients receiving chimeric antigen receptor T-cell therapy.

Blood Adv 2021 08;5(15):2982-2986

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Chimeric antigen receptor (CAR) T-cells have emerged as an efficacious modality in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). Clonal hematopoiesis of indeterminate potential (CHIP), a state in which mutations in hematopoietic cells give rise to a clonal population of cells, is more common in patients exposed to cytotoxic therapies, has been shown to influence inflammatory immune programs, and is associated with an adverse prognosis in patients with NHL and MM receiving autologous transplantation. We therefore hypothesized that CHIP could influence clinical outcomes in patients receiving CAR T-cell therapy. In a cohort of 154 patients with NHL or MM receiving CAR T-cells, we found that CHIP was present in 48% of patients and associated with increased rates of complete response and cytokine release syndrome severity, but only in patients younger than age 60 years. Despite these differences, CHIP was not associated with a difference in progression-free or overall survival, regardless of age. Our data suggest that CHIP can influence CAR T-cell biology and clinical outcomes, but, in contrast to autologous transplantation, CHIP was not associated with worse survival and should not be a reason to exclude individuals from receiving this potentially life-prolonging treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361461PMC
August 2021

Minimal Residual Disease in Myeloma: Application for Clinical Care and New Drug Registration.

Clin Cancer Res 2021 Jul 28. Epub 2021 Jul 28.

Departamento de Hematologia, Hospital Universitario de Salamanca.

The development of novel agents has transformed the treatment paradigm for multiple myeloma (MM), with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow-based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in MM patients. Complementary liquid biopsy-based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid-based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory MM, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in MM is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-21-1059DOI Listing
July 2021

Targeting LAG3/GAL-3 to overcome immunosuppression and enhance anti-tumor immune responses in multiple myeloma.

Leukemia 2021 Jul 21. Epub 2021 Jul 21.

Dana-Farber Cancer Institute, Boston, MA, USA.

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 effector/regulatory and CD138 cells in MM patients, compared MGUS/SMM patients or healthy individuals. Among the checkpoints profiled, LAG3 was most highly expressed on proliferating CD4 Th and CD8 Tc cells in MM patients BMMC and PBMC. Treatment with antibody targeting LAG3 significantly enhanced T cells proliferation and activities against MM. XBP1/CD138/CS1-specific CTL generated in vitro displayed anti-MM activity, which was further enhanced following anti-LAG3 treatment, within the antigen-specific memory T cells. Treg and G-type MDSC weakly express LAG3 and were minimally impacted by anti-LAG3. CD138 MM cells express GAL-3, a ligand for LAG3, and anti-GAL-3 treatment increased MM-specific responses, as observed for anti-LAG3. Finally, we demonstrate checkpoint inhibitor treatment evokes non-targeted checkpoints as a cause of resistance and propose combination therapeutic strategies to overcome this resistance. These studies identify and validate blockade of LAG3/GAL-3, alone or in combination with immune strategies including XBP1/CD138/CS1 multipeptide vaccination, to enhance anti-tumor responses and improve patient outcome in MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-021-01301-6DOI Listing
July 2021

Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, MAIA.

Blood 2021 Jul 21. Epub 2021 Jul 21.

Dana-Farber Cancer Institute, Boston, Massachusetts, United States.

We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible newly diagnosed multiple myeloma (TIE NDMM) using data from four phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD-negativity rates and reduced the risk of disease progression or death by approximately half versus standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response (CR) or better with MRD-negative status, and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10‒5 threshold). Patient-level data were pooled from all four studies, and for patients with TIE NDMM plus patients with RRMM who received ≤2 prior lines of therapy (≤2PL). PFS was evaluated by response and MRD status. Median follow-up (months) was: POLLUX, 54.8; CASTOR, 50.2; ALCYONE, 40.1; and MAIA, 36.4. Patients who achieved ≥CR and MRD negativity had improved PFS versus those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM ≤2PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.ClinicalTrials.gov: NCT02076009/NCT02136134/NCT02195479/NCT02252172.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2021011101DOI Listing
July 2021

Lysine Demethylase 5A is Required for MYC Driven Transcription in Multiple Myeloma.

Blood Cancer Discov 2021 07 10;2(4):370-387. Epub 2021 Apr 10.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02215.

Lysine demethylase 5A (KDM5A) is a negative regulator of histone H3K4 trimethylation, a histone mark associated with activate gene transcription. We identify that KDM5A interacts with the P-TEFb complex and cooperates with MYC to control MYC targeted genes in multiple myeloma (MM) cells. We develop a cell-permeable and selective KDM5 inhibitor, JQKD82, that increases histone H3K4me3 but paradoxically inhibits downstream MYC-driven transcriptional output and . Using genetic ablation together with our inhibitor, we establish that KDM5A supports MYC target gene transcription independent of MYC itself, by supporting TFIIH (CDK7)- and P-TEFb (CDK9)-mediated phosphorylation of RNAPII. These data identify KDM5A as a unique vulnerability in MM functioning through regulation of MYC-target gene transcription, and establish JQKD82 as a tool compound to block KDM5A function as a potential therapeutic strategy for MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2643-3230.BCD-20-0108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265280PMC
July 2021

CD44 v5 domain inhibition represses the polarization of Th2 cells by interfering with the IL-4/IL-4R signaling pathway.

Immunol Cell Biol 2021 Jul 5. Epub 2021 Jul 5.

Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.

The balance between Th1 and Th2 cells is critical for both innate and acquired immune reactions. But the precise mechanisms of T helper cells differentiations are still unclear. As an important T cell activation molecular, CD44 participates in the Th1 and Th2 differentiation. We demonstrated that CD44 variant exon-v5 is highly expressed by induced human Th2 cells. In order to investigate the role of CD44v5 domain in Th2 cell differentiation, we treated human CD4 T cells with CD44v5 antibody and observed that the levels of pSTAT6 and GATA3 and the secretion of IL-4 were significantly decreased after the treatment. We also further found that the inhibition of Th2 differentiation was caused by the IL-4Rα degradation, CD44v5 domain co-localized with IL-4Rα on cell surface, the degradation of IL-4Rα increased after CD44v5 blocking or ablating. Our results indicated that CD44v5 antibody treatment interrupted the interaction between CD44v5 and IL-4Rα, but the CD44v5 domain blockage would not spoil the co-localization between IL4R expression and TCR and the immunological synapse formation, similar results were also found in CD44v5 deficient CD4 T cells. In conclusion, we revealed the function of CD44v5 domain in Th2 cell differentiation, blocking or ablating CD44v5 domain could accelerate IL-4Rα degradation and then induce the Th2 cell inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imcb.12491DOI Listing
July 2021

Contemporary Analysis of Electronic Frailty Measurement in Older Adults with Multiple Myeloma Treated in the National US Veterans Affairs Healthcare System.

Cancers (Basel) 2021 Jun 18;13(12). Epub 2021 Jun 18.

New England Geriatrics Research, Education and Clinical Center, VA Boston Healthcare System, Boston, MA 02130, USA.

Electronic frailty indices based on data from administrative claims and electronic health records can be used to estimate frailty in large populations of older adults with cancer where direct frailty measures are lacking. The objective of this study was to use the electronic Veterans Affairs Frailty Index (VA-FI-10)-developed and validated to measure frailty in the national United States (US) VA Healthcare System-to estimate the prevalence and impact of frailty in older US veterans newly treated for multiple myeloma (MM) with contemporary therapies. We designed a retrospective cohort study of 4924 transplant-ineligible veterans aged ≥ 65 years initiating MM therapy within VA from 2004 to 2017. Initial MM therapy was measured using inpatient and outpatient treatment codes from pharmacy data in the VA Corporate Data Warehouse. In total, 3477 veterans (70.6%) were classified as frail (VA-FI-10 > 0.2), with 1510 (30.7%) mildly frail (VA-FI-10 > 0.2-0.3), 1105 (22.4%) moderately frail (VA-FI-10 > 0.3-0.4), and 862 (17.5%) severely frail (VA-FI-10 > 0.4). Survival and time to hospitalization decreased with increasing VA-FI-10 severity (log-rank -value < 0.001); the VA-FI-10 predicted mortality and hospitalizations independently of age, sociodemographic variables, and measures of disease risk. Varying data sources and assessment periods reclassified frailty severity for a substantial portion of veterans but did not substantially affect VA-FI-10's association with mortality. Our study supports use of the VA-FI-10 in future research involving older veterans with MM and provides insights into its potential use in identifying frailty in clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13123053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233717PMC
June 2021

Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study.

Lancet 2021 07 24;398(10297):314-324. Epub 2021 Jun 24.

Legend Biotech USA, Piscataway, NJ, USA.

Background: CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis.

Methods: This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 10 CAR-positive viable T cells per kg) was administered 5-7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207.

Findings: Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 10 CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6-15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2-99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9-1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9-not estimable), neither was progression-free survival (16·8-not estimable). The 12-month progression-free rate was 77% (95% CI 66·0-84·3) and overall survival rate was 89% (80·2-93·5). Haematological adverse events were common; grade 3-4 haematological adverse events were neutropenia (92 [95%] of 97 patients), anaemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5-8) and median duration of 4·0 days (IQR 3-6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events.

Interpretation: A single cilta-cel infusion at the target dose of 0·75 × 10 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions.

Funding: Janssen Research & Development and Legend Biotech.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(21)00933-8DOI Listing
July 2021

CRISPR Interference (CRISPRi) and CRISPR Activation (CRISPRa) to Explore the Oncogenic lncRNA Network.

Methods Mol Biol 2021 ;2348:189-204

Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

The human genome contains thousands of long noncoding RNAs (lncRNAs), even outnumbering protein-coding genes. These molecules can play a pivotal role in the development and progression of human disease, including cancer, and are susceptible to therapeutic intervention. Evidence of biologic function, however, is still missing for the vast majority of them. Both loss-of-function (LOF) and gain-of-function (GOF) studies are therefore necessary to advance our understanding of lncRNA networks and programs driving tumorigenesis. Here, we describe a protocol to perform lncRNA's LOF or GOF studies in multiple myeloma (MM) cells, using CRISPR interference (CRISPRi) or CRISPR activation (CRISPRa) technologies, respectively. These approaches have many advantages, including applicability to large-scale genetic screens in mammalian cells and possible reversibility of modulating effects; moreover, CRISPRa offers the unique opportunity to enhance lncRNA expression at the site of transcription, with relevant biologic implications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-0716-1581-2_13DOI Listing
September 2021

In Vitro Silencing of lncRNAs Using LNA GapmeRs.

Methods Mol Biol 2021 ;2348:157-166

Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy.

Despite substantial advancements have been achieved in the identification of long noncoding RNA (lncRNA) molecules, many challenges still remain into their functional characterization. Loss-of-function approaches are needed to study oncogenic lncRNAs, which appear more difficult to knock down by RNA interference as compared to mRNAs. In this chapter, we present a protocol based on the use of a novel class of antisense oligonucleotides, named locked nucleic acid (LNA) GapmeRs, to inhibit the oncogenic lncRNA NEAT1 in multiple myeloma cells. Overall, this approach holds many advantages, including its possible independence from delivery reagents as well as the capability to knock down lncRNAs even in hard-to-transfect suspension cells, like hematopoietic cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-0716-1581-2_10DOI Listing
September 2021

Idecabtagene Vicleucel in Relapsed Myeloma. Reply.

N Engl J Med 2021 06;384(24):2357-2358

Clínica Universidad de Navarra, Pamplona, Spain.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMc2105069DOI Listing
June 2021

The HCK/BTK inhibitor KIN-8194 is active in MYD88-driven lymphomas and overcomes mutated BTKCys481 ibrutinib resistance.

Blood 2021 Nov;138(20):1966-1979

Bing Center for Waldenstrom's Macroglobulinemia.

Activating mutations in MYD88 promote malignant cell growth and survival through hematopoietic cell kinase (HCK)-mediated activation of Bruton tyrosine kinase (BTK). Ibrutinib binds to BTKCys481 and is active in B-cell malignancies driven by mutated MYD88. Mutations in BTKCys481, particularly BTKCys481Ser, are common in patients with acquired ibrutinib resistance. We therefore performed an extensive medicinal chemistry campaign and identified KIN-8194 as a novel dual inhibitor of HCK and BTK. KIN-8194 showed potent and selective in vitro killing of MYD88-mutated lymphoma cells, including ibrutinib-resistant BTKCys481Ser-expressing cells. KIN-8194 demonstrated excellent bioavailability and pharmacokinetic parameters, with good tolerance in rodent models at pharmacologically achievable and active doses. Pharmacodynamic studies showed sustained inhibition of HCK and BTK for 24 hours after single oral administration of KIN-8194 in an MYD88-mutated TMD-8 activated B-cell diffuse large B-cell lymphoma (ABC DLBCL) and BCWM.1 Waldenström macroglobulinemia (WM) xenografted mice with wild-type BTK (BTKWT)- or BTKCys481Ser-expressing tumors. KIN-8194 showed superior survival benefit over ibrutinib in both BTKWT- and BTKCys481Ser-expressing TMD-8 DLBCL xenografted mice, including sustained complete responses of >12 weeks off treatment in mice with BTKWT-expressing TMD-8 tumors. The BCL_2 inhibitor venetoclax enhanced the antitumor activity of KIN-8194 in BTKWT- and BTKCys481Ser-expressing MYD88-mutated lymphoma cells and markedly reduced tumor growth and prolonged survival in mice with BTKCys481Ser-expressing TMD-8 tumors treated with both drugs. The findings highlight the feasibility of targeting HCK, a key driver of mutated MYD88 pro-survival signaling, and provide a framework for the advancement of KIN-8194 for human studies in B-cell malignancies driven by HCK and BTK.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2021011405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602936PMC
November 2021

Integrated genomics and comprehensive validation reveal drivers of genomic evolution in esophageal adenocarcinoma.

Commun Biol 2021 05 24;4(1):617. Epub 2021 May 24.

Dana Farber Cancer Institute, Boston, MA, USA.

Esophageal adenocarcinoma (EAC) is associated with a marked genomic instability, which underlies disease progression and development of resistance to treatment. In this study, we used an integrated genomics approach to identify a genomic instability signature. Here we show that elevated expression of this signature correlates with poor survival in EAC as well as three other cancers. Knockout and overexpression screens establish the relevance of these genes to genomic instability. Indepth evaluation of three genes (TTK, TPX2 and RAD54B) confirms their role in genomic instability and tumor growth. Mutational signatures identified by whole genome sequencing and functional studies demonstrate that DNA damage and homologous recombination are common mechanisms of genomic instability induced by these genes. Our data suggest that the inhibitors of TTK and possibly other genes identified in this study have potential to inhibit/reduce growth and spontaneous as well as chemotherapy-induced genomic instability in EAC and possibly other cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-021-02125-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144613PMC
May 2021

Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group.

Lancet Oncol 2021 03;22(3):e105-e118

Rigshospitalet, Copenhagen University, Copenhagen, Denmark.

This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(20)30756-7DOI Listing
March 2021

Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma.

N Engl J Med 2021 02;384(8):705-716

From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute (N.C.M.), the Veterans Affairs Boston Healthcare System, Harvard Medical School (N.C.M.), and Massachusetts General Hospital (N.R.), Boston, and bluebird bio, Cambridge (F.P., M.M.) - all in Massachusetts; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas (L.D.A.); the University of California, San Francisco, San Francisco (N.S.); Icahn School of Medicine at Mount Sinai, New York (D.M.); Sarah Cannon Research Institute and Tennessee Oncology, Nashville (J.B.); Emory School of Medicine, Atlanta (S.L.); Mayo Clinic, Rochester, MN (Y.L.); Hackensack University Medical Center, Hackensack (D.S.), and Bristol-Myers Squibb, Princeton (J.N.C., S.K., P.P., L.H., T.B.C., K.H.) - both in New Jersey; Institut Josep Carreras and Institut Catala d'Oncologia, Hospital Germans Trias i Pujol, Badalona (A.O.), and Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Centro de Investigación Biomédica en Red de Cáncer, Pamplona (J.S.-M.) - both in Spain; Centre Hospitalier Universitaire (CHU) de Nantes, Nantes (P.M.), and CHU de Lille, University of Lille, INSERM Unité 1286, Institute for Translational Research in Inflammation, Lille (I.Y.-A.) - both in France; University Hospital Leuven, Leuven, Belgium (M.D.); "Seràgnoli" Institute of Hematology, Bologna University School of Medicine, Bologna (M.C.), the Department of Oncology and Hematology, University of Milan, Milan (A.R.), and Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy; University Hospital of Würzburg, Würzburg (H.E.), University Hospital Heidelberg (H.G.) and the National Center for Tumor Diseases (H.G.), Heidelberg, the University Medical Center Hamburg-Eppendorf, Hamburg (K.W.), and Universitätsklinikum Tübingen, Tübingen (K.W.) - all in Germany; and Princess Margaret Cancer Centre, Toronto (D.R.).

Background: Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma.

Methods: In this phase 2 study, we sought to confirm the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma. Patients with disease after at least three previous regimens including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody were enrolled. Patients received ide-cel target doses of 150 × 10 to 450 × 10 CAR-positive (CAR+) T cells. The primary end point was an overall response (partial response or better); a key secondary end point was a complete response or better (comprising complete and stringent complete responses).

Results: Of 140 patients enrolled, 128 received ide-cel. At a median follow-up of 13.3 months, 94 of 128 patients (73%) had a response, and 42 of 128 (33%) had a complete response or better. Minimal residual disease (MRD)-negative status (<10 nucleated cells) was confirmed in 33 patients, representing 26% of all 128 patients who were treated and 79% of the 42 patients who had a complete response or better. The median progression-free survival was 8.8 months (95% confidence interval, 5.6 to 11.6). Common toxic effects among the 128 treated patients included neutropenia in 117 patients (91%), anemia in 89 (70%), and thrombocytopenia in 81 (63%). Cytokine release syndrome was reported in 107 patients (84%), including 7 (5%) who had events of grade 3 or higher. Neurotoxic effects developed in 23 patients (18%) and were of grade 3 in 4 patients (3%); no neurotoxic effects higher than grade 3 occurred. Cellular kinetic analysis confirmed CAR+ T cells in 29 of 49 patients (59%) at 6 months and 4 of 11 patients (36%) at 12 months after infusion.

Conclusions: Ide-cel induced responses in a majority of heavily pretreated patients with refractory and relapsed myeloma; MRD-negative status was achieved in 26% of treated patients. Almost all patients had grade 3 or 4 toxic effects, most commonly hematologic toxic effects and cytokine release syndrome. (Funded by bluebird bio and Celgene, a Bristol-Myers Squibb company; KarMMa ClinicalTrials.gov number, NCT03361748.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2024850DOI Listing
February 2021

Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma.

Nat Commun 2021 02 8;12(1):868. Epub 2021 Feb 8.

Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-21177-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870932PMC
February 2021

Defining Multimorbidity and Its Impact in Older United States Veterans Newly Treated for Multiple Myeloma.

J Natl Cancer Inst 2021 Aug;113(8):1084-1093

Harvard Medical School, Boston, MA, USA.

Background:  Traditional count-based measures of comorbidity are unlikely to capture the complexity of multiple chronic conditions (multimorbidity) in older adults with cancer. We aimed to define patterns of multimorbidity and their impact in older United States veterans with multiple myeloma (MM).

Methods:  We measured 66 chronic conditions in 5076 veterans aged 65 years and older newly treated for MM in the national Veterans Affairs health-care system from 2004 to 2017. Latent class analysis was used to identify patterns of multimorbidity among these conditions. These patterns were then assessed for their association with overall survival, our primary outcome. Secondary outcomes included emergency department visits and hospitalizations.

Results: Five patterns of multimorbidity emerged from the latent class analysis, and survival varied across these patterns (log-rank 2-sided P < .001). Older veterans with cardiovascular and metabolic disease (30.9%, hazard ratio [HR] = 1.33, 95% confidence interval [CI] = 1.21 to 1.45), psychiatric and substance use disorders (9.7%, HR = 1.58, 95% CI = 1.39 to 1.79), chronic lung disease (15.9%, HR = 1.69, 95% CI = 1.53 to 1.87), and multisystem impairment (13.8%, HR = 2.25, 95% CI = 2.03 to 2.50) had higher mortality compared with veterans with minimal comorbidity (29.7%, reference). Associations with mortality were maintained after adjustment for sociodemographic variables, measures of disease risk, and the count-based Charlson Comorbidity Index. Multimorbidity patterns were also associated with emergency department visits and hospitalizations.

Conclusions: Our findings demonstrate the need to move beyond count-based measures of comorbidity and consider cancer in the context of multiple chronic conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djab007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328982PMC
August 2021

Revealing the impact of structural variants in multiple myeloma.

Blood Cancer Discov 2020 Nov 15;1(3):258-273. Epub 2020 Sep 15.

Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The landscape of structural variants (SVs) in multiple myeloma remains poorly understood. Here, we performed comprehensive analysis of SVs in a large cohort of 752 multiple myeloma patients by low coverage long-insert whole genome sequencing. We identified 68 SV hotspots involving 17 new candidate driver genes, including the therapeutic targets BCMA (), and Catastrophic complex rearrangements termed chromothripsis were present in 24% of patients and independently associated with poor clinical outcomes. Templated insertions were the second most frequent complex event (19%), mostly involved in super-enhancer hijacking and activation of oncogenes such as and . Importantly, in 31% of patients two or more seemingly independent putative driver events were caused by a single structural event, demonstrating that the complex genomic landscape of multiple myeloma can be acquired through few key events during tumor evolutionary history. Overall, this study reveals the critical role of SVs in multiple myeloma pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2643-3230.bcd-20-0132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774871PMC
November 2020

Clinical features associated with COVID-19 outcome in multiple myeloma: first results from the International Myeloma Society data set.

Blood 2020 12;136(26):3033-3040

Intergroupe Francophone du Myélome (IFM), Paris, France.

The primary cause of morbidity and mortality in patients with multiple myeloma (MM) is an infection. Therefore, there is great concern about susceptibility to the outcome of COVID-19-infected patients with MM. This retrospective study describes the baseline characteristics and outcome data of COVID-19 infection in 650 patients with plasma cell disorders, collected by the International Myeloma Society to understand the initial challenges faced by myeloma patients during the COVID-19 pandemic. Analyses were performed for hospitalized MM patients. Among hospitalized patients, the median age was 69 years, and nearly all patients (96%) had MM. Approximately 36% were recently diagnosed (2019-2020), and 54% of patients were receiving first-line therapy. Thirty-three percent of patients have died, with significant geographic variability, ranging from 27% to 57% of hospitalized patients. Univariate analysis identified age, International Staging System stage 3 (ISS3), high-risk disease, renal disease, suboptimal myeloma control (active or progressive disease), and 1 or more comorbidities as risk factors for higher rates of death. Neither history of transplant, including within a year of COVID-19 diagnosis, nor other anti-MM treatments were associated with outcomes. Multivariate analysis found that only age, high-risk MM, renal disease, and suboptimal MM control remained independent predictors of adverse outcome with COVID-19 infection. The management of MM in the era of COVID-19 requires careful consideration of patient- and disease-related factors to decrease the risk of acquiring COVID-19 infection, while not compromising disease control through appropriate MM treatment. This study provides initial data to develop recommendations for the management of MM patients with COVID-19 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020008150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759145PMC
December 2020
-->