Publications by authors named "Irene M Ghobrial"

257 Publications

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

Phase I study of Ibrutinib and the CXCR4 antagonist Ulocuplumab in CXCR4 mutated Waldenstrom Macroglobulinemia.

Blood 2021 07 21. Epub 2021 Jul 21.

Harvard Medical School, United States.

MYD88 and CXCR4 mutations are common in Waldenström Macroglobulinemia (WM). Mutated CXCR4 (CXCR4Mut) impacts BTK-inhibitor response. We conducted a Phase I trial of the CXCR4-antagonist ulocuplumab with ibrutinib in this first-ever study to target CXCR4Mut in WM. Ibrutinib was initiated at 420 mg/day with Cycle 1 and continued until intolerance or progression; ulocuplumab was given cycles 1-6, with a 3+3 dose-escalation design. Each cycle was 4 weeks. Thirteen symptomatic patients, nine treatment-naive were enrolled. Twelve were evaluable for response. At best response, their median serum IgM declined from 5,574 to 1,114 mg/dL; bone marrow disease decreased from 65% to 10%; and hemoglobin increased from 10.1 to 14.2 g/dL (p<0.001). The major and VGPR response rates were 100% and 33%, respectively, with VGPRs observed at lower ulocuplumab dose cohorts. Median times to minor and major responses were 0.9 and 1.2 months, respectively. With a median follow-up of 22.4 months, the estimated 2-year PFS was 90%. The most frequent recurring Grade ≥2 adverse events included reversible thrombocytopenia, rash, and skin infections. Ulocuplumab dose-escalation did not impact adverse events. The study demonstrates the feasibility of combining a CXCR4-antagonist with ibrutinib, and provides support for the development of CXCR4-antagonists for CXCR4Mut WM. www.clinicaltrials.gov (NCT03225716).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2021012953DOI Listing
July 2021

ROBO1 Promotes Homing, Dissemination, and Survival of Multiple Myeloma within the Bone Marrow Microenvironment.

Blood Cancer Discov 2021 Jul;2(4):338-353

Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA.

The bone marrow (BM) microenvironment actively promotes multiple myeloma (MM) pathogenesis and therapies targeting both cancer cells and the niche are highly effective. We were interested in identifying novel signaling pathways supporting MM-BM crosstalk. Mutations in the transmembrane receptor Roundabout 1 (ROBO1) were recently identified in MM patients, however their functional consequences are uncertain. Through protein structure-function studies, we discovered that ROBO1 is necessary for MM adhesion to BM stromal and endothelial cells and ROBO1 knock out (KO) compromises BM homing and engraftment in a disseminated mouse model. ROBO1 KO significantly decreases MM proliferation in vitro and intra- and extramedullary tumor growth, in vivo. Mechanistically, ROBO1 C-terminus is cleaved in a ligand-independent fashion and is sufficient to promote MM proliferation. Viceversa, mutants lacking the cytoplasmic domain, including the human-derived G674* truncation, act dominantly negative. Interactomic and RNA sequencing studies suggest ROBO1 may be involved in RNA processing, supporting further studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2643-3230.bcd-20-0164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265993PMC
July 2021

The 2020 BMT CTN Myeloma Intergroup Workshop on Immune Profiling and Minimal Residual Disease Testing in Multiple Myeloma.

Transplant Cell Ther 2021 10 6;27(10):807-816. Epub 2021 Jun 6.

Roswell Park Comprehensive Cancer Center, Buffalo, New York.

The fifth annual Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup Workshop on Immune Profiling and Minimal Residual Disease Testing in Multiple Myeloma was conducted as one of the American Society of Hematology Annual Meeting Scientific Workshops on Thursday December 3, 2020. This workshop focused on four main topics: (1) integrating minimal residual disease into clinical trial design and practice; (2) the molecular and immunobiology of disease evolution and progression in myeloma; (3) adaptation of next-generation sequencing, next-generation flow cytometry, and cytometry by time of flight techniques; and (4) chimeric antigen receptor T-cell and other cellular therapies for myeloma. In this report, we provide a summary of the workshop presentations and discuss future directions in the field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.05.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478786PMC
October 2021

Inflammatory stromal cells in the myeloma microenvironment.

Nat Immunol 2021 06;22(6):677-678

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41590-021-00947-9DOI Listing
June 2021

Pro-organic radical contrast agents ("pro-ORCAs") for real-time MRI of pro-drug activation in biological systems.

Polym Chem 2020 Aug 26;11(29):4768-4779. Epub 2020 Jun 26.

Department of Chemistry, Massachusetts Institute of Technology (MIT).

Nitroxide-based organic-radical contrast agents (ORCAs) are promising as safe, next-generation magnetic resonance imaging (MRI) tools. Nevertheless, stimuli-responsive ORCAs that enable MRI monitoring of prodrug activation have not been reported; such systems could open new avenues for prodrug validation and image-guided drug delivery. Here, we introduce a novel "pro-ORCA" concept that addresses this challenge. By covalent conjugation of nitroxides and drug molecules (doxorubicin, DOX) to the same brush-arm star polymer (BASP) through chemically identical cleavable linkers, we demonstrate that pro-ORCA and prodrug activation, , ORCA and DOX release, leads to significant changes in MRI contrast that correlate with cytotoxicity. This approach is shown to be general for a range of commonly used linker cleavage mechanisms (, photolysis and hydrolysis) and release rates. Pro-ORCAs could find applications as research tools or clinically viable "reporter theranostics" for and MRI-correlated prodrug activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0py00558dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009311PMC
August 2020

Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma.

Nat Cancer 2020 May 27;1(5):493-506. Epub 2020 Apr 27.

Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, 02215, USA.

Precursor states of Multiple Myeloma (MM) and its native tumor microenvironment need in-depth molecular characterization to better stratify and treat patients at risk. Using single-cell RNA sequencing of bone marrow cells from precursor stages, MGUS and smoldering myeloma (SMM), to full-blown MM alongside healthy donors, we demonstrate early immune changes during patient progression. We find NK cell abundance is frequently increased in early stages, and associated with altered chemokine receptor expression. As early as SMM, we show loss of GrK memory cytotoxic T-cells, and show their critical role in MM immunosurveillance in mouse models. Finally, we report MHC class II dysregulation in CD14 monocytes, which results in T cell suppression . These results provide a comprehensive map of immune changes at play over the evolution of pre-malignant MM, which will help develop strategies for immune-based patient stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s43018-020-0053-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785110PMC
May 2020

Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development.

Cell 2020 12 3;183(6):1714-1731.e10. Epub 2020 Dec 3.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Targeted protein degradation (TPD) refers to the use of small molecules to induce ubiquitin-dependent degradation of proteins. TPD is of interest in drug development, as it can address previously inaccessible targets. However, degrader discovery and optimization remains an inefficient process due to a lack of understanding of the relative importance of the key molecular events required to induce target degradation. Here, we use chemo-proteomics to annotate the degradable kinome. Our expansive dataset provides chemical leads for ∼200 kinases and demonstrates that the current practice of starting from the highest potency binder is an ineffective method for discovering active compounds. We develop multitargeted degraders to answer fundamental questions about the ubiquitin proteasome system, uncovering that kinase degradation is p97 dependent. This work will not only fuel kinase degrader discovery, but also provides a blueprint for evaluating targeted degradation across entire gene families to accelerate understanding of TPD beyond the kinome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2020.10.038DOI Listing
December 2020

Progression signature underlies clonal evolution and dissemination of multiple myeloma.

Blood 2021 Apr;137(17):2360-2372

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

Clonal evolution drives tumor progression, dissemination, and relapse in multiple myeloma (MM), with most patients dying of relapsed disease. This multistage process requires tumor cells to enter the circulation, extravasate, and colonize distant bone marrow (BM) sites. Here, we developed a fluorescent or DNA-barcode clone-tracking system on MM PrEDiCT (progression through evolution and dissemination of clonal tumor cells) xenograft mouse model to study clonal behavior within the BM microenvironment. We showed that only the few clones that successfully adapt to the BM microenvironment can enter the circulation and colonize distant BM sites. RNA sequencing of primary and distant-site MM tumor cells revealed a progression signature sequentially activated along human MM progression and significantly associated with overall survival when evaluated against patient data sets. A total of 28 genes were then computationally predicted to be master regulators (MRs) of MM progression. HMGA1 and PA2G4 were validated in vivo using CRISPR-Cas9 in the PrEDiCT model and were shown to be significantly depleted in distant BM sites, indicating their role in MM progression and dissemination. Loss of HMGA1 and PA2G4 also compromised the proliferation, migration, and adhesion abilities of MM cells in vitro. Overall, our model successfully recapitulates key characteristics of human MM disease progression and identified potential new therapeutic targets for MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020005885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085483PMC
April 2021

Pregnancy outcomes, risk factors, and cell count trends in pregnant women with essential thrombocythemia.

Leuk Res 2020 11 29;98:106459. Epub 2020 Sep 29.

Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA. Electronic address:

Pregnancy in essential thrombocythemia (ET) is associated with increased risk of obstetric complications. We retrospectively evaluated risk factors in 121 pregnancies in 52 ET women seen at 3 affiliate hospitals. Univariable and multivariable analyses were performed at the α = 0.10 level. Cell counts were characterized throughout pregnancy and correlated with outcomes using logistic modeling. The overall live birth rate was 69 %. 48.7 % of all women experienced a pregnancy complication, the most common being spontaneous abortion, which occurred in 26 % of all pregnancies. Maternal thrombosis and hemorrhage rates were 2.5 % and 5.8 %. On multivariable analysis, aspirin use (OR 0.29, p = 0.014, 90 % CI 0.118-0.658) and history of prior pregnancy loss (OR 3.86, p = 0.011, CI 1.49-9.15) were associated with decreased and increased pregnancy complications, respectively. A Markov model was used to analyze the probability of a future pregnancy complication based on initial pregnancy outcome. An ET woman who suffers a pregnancy complication has a 0.594 probability of a subsequent pregnancy complication, compared to a 0.367 probability if she didn't suffer a complication. However, despite this elevated risk, overall prognosis is good, with a >50 % probability of a successful pregnancy by the third attempt. Platelet counts decreased by 43 % in ET during pregnancy, with nadir at delivery and prompt recovery in the postpartum period. Women with larger declines in gestational platelet counts were less likely to suffer complications (p = 0.083). Our study provides important guidance to physicians treating ET women during pregnancy, including counseling information regarding risk assessment and expected trajectory of platelet levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.leukres.2020.106459DOI Listing
November 2020

Long-Term Follow-Up of Ibrutinib Monotherapy in Symptomatic, Previously Treated Patients With Waldenström Macroglobulinemia.

J Clin Oncol 2021 02 15;39(6):565-575. Epub 2020 Sep 15.

Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA.

Purpose: We report the long-term findings and final analysis of a pivotal multicenter trial of ibrutinib monotherapy in previously treated patients with Waldenström macroglobulinemia (WM).

Patients And Methods: Sixty-three symptomatic patients with median prior therapies of two (range, one to nine therapies), of whom 40% were refractory to their previous therapy, received ibrutinib at 420 mg/d. Dose reduction was permitted for toxicity.

Results: The median follow-up was 59 months, and overall and major response rates were 90.5% and 79.4%, respectively. At best response, median serum immunoglobulin M declined from 3,520 to 821 mg/dL, bone marrow disease involvement declined from 60% to 20%, and hemoglobin rose from 10.3 to 14.2 g/dL ( < .001 for all comparisons). Responses were impacted by mutated (Mut) and status. Patients with , wild-type (WT) showed higher major (97.2% 68.2%; < .0001) and very good partial (47.2% 9.1%; < .01) response rates and a shorter time to major response (1.8 4.7 months; = .02) versus patients with . Conversely, four patients who had disease showed no major responses. The median 5-year progression-free survival (PFS) rate for all patients was not reached, and was 70% and 38% for those with and WM, respectively ( = .02). In patients with , the median PFS was 0.4 years ( < .01 for three-way comparisons). The 5-year overall survival rate for all patients was 87%. Grade ≥ 3 adverse events in more than one patient at least possibly related included neutropenia (15.9%), thrombocytopenia (11.1%), and pneumonia (3.2%). Eight patients (12.7%) experienced atrial arrhythmia, and seven of the eight continued therapy with medical management.

Conclusion: Ibrutinib is highly active and produces long-term disease control in previously treated patients with WM. Treatment is tolerable. Response depth, time to major response, and PFS are impacted by and mutation status.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.00555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078354PMC
February 2021

Genome instability in multiple myeloma.

Leukemia 2020 11 10;34(11):2887-2897. Epub 2020 Jul 10.

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

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by clonal proliferation of plasma cells and a heterogenous genomic landscape. Copy number and structural changes due to chromosomal instability (CIN) are common features of MM. In this review, we describe how primary and secondary genetic events caused by CIN can contribute to increased instability across the genome of malignant plasma cells; with a focus on specific driver genomic events, and how they interfere with cell-cycle checkpoints, to prompt accelerated proliferation. We also provide insight into other forms of CIN, such as chromothripsis and chromoplexy. We evaluate how the tumor microenvironment can contribute to a further increase in chromosomal instability in myeloma cells. Lastly, we highlight the role of certain mutational signatures in leading to high mutation rate and genome instability in certain MM patients. We suggest that assessing CIN in MM and its precursors states may help improve predicting the risk of progression to symptomatic disease and relapse and identifying future therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-020-0921-yDOI Listing
November 2020

Monoclonal Gammopathy of Undetermined Significance (MGUS)-Not So Asymptomatic after All.

Cancers (Basel) 2020 Jun 12;12(6). Epub 2020 Jun 12.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Monoclonal Gammopathy of Undetermined Significance (MGUS) is considered to be a benign precursor condition that may progress to a lymphoproliferative disease or multiple myeloma. Most patients do not progress to an overt condition, but nevertheless, MGUS is associated with a shortened life expectancy and, in a minority of cases, a number of co-morbid conditions that include an increased fracture risk, renal impairment, peripheral neuropathy, secondary immunodeficiency, and cardiovascular disease. This review aims to consolidate current evidence for the significance of these co-morbidities before considering how best to approach these symptoms and signs, which are often encountered in primary care or within a number of specialties in secondary care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12061554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352603PMC
June 2020

Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant.

Nat Commun 2020 06 12;11(1):2996. Epub 2020 Jun 12.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.

Multiple myeloma (MM) is a plasma-cell neoplasm that is treated with high-dose chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. The presence of somatic mutations in the peripheral blood is termed clonal hematopoiesis of indeterminate potential (CHIP) and is associated with adverse outcomes. Targeted sequencing of the stem cell product from 629 MM patients treated by ASCT at the Dana-Farber Cancer Institute (2003-2011) detects CHIP in 136/629 patients (21.6%). The most commonly mutated genes are DNMT3A, TET2, TP53, ASXL1 and PPM1D. Twenty-one from fifty-six patients (3.3%) receiving first-line IMiD maintenance develop a therapy-related myeloid neoplasm (TMN). However, regardless of CHIP status, the use of IMiD maintenance associates with improved PFS and OS. In those not receiving IMiD maintenance, CHIP is associated with decreased overall survival (OS) (HR:1.34, p = 0.02) and progression free survival (PFS) (HR:1.45, p < 0.001) due to an increase in MM progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-16805-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293239PMC
June 2020

Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression.

J Clin Oncol 2020 07 22;38(21):2380-2389. Epub 2020 May 22.

Broad Institute of MIT and Harvard, Cambridge, MA.

Purpose: Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models.

Methods: We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors.

Results: We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway ( and single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, , and SNVs), and (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort.

Conclusion: SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.00437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367550PMC
July 2020

The COronavirus Pandemic Epidemiology (COPE) Consortium: A Call to Action.

Cancer Epidemiol Biomarkers Prev 2020 07 5;29(7):1283-1289. Epub 2020 May 5.

Social & Scientific Systems, Durham, North Carolina.

The rapid pace of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) pandemic presents challenges to the real-time collection of population-scale data to inform near-term public health needs as well as future investigations. We established the COronavirus Pandemic Epidemiology (COPE) consortium to address this unprecedented crisis on behalf of the epidemiology research community. As a central component of this initiative, we have developed a COVID Symptom Study (previously known as the COVID Symptom Tracker) mobile application as a common data collection tool for epidemiologic cohort studies with active study participants. This mobile application collects information on risk factors, daily symptoms, and outcomes through a user-friendly interface that minimizes participant burden. Combined with our efforts within the general population, data collected from nearly 3 million participants in the United States and United Kingdom are being used to address critical needs in the emergency response, including identifying potential hot spots of disease and clinically actionable risk factors. The linkage of symptom data collected in the app with information and biospecimens already collected in epidemiology cohorts will position us to address key questions related to diet, lifestyle, environmental, and socioeconomic factors on susceptibility to COVID-19, clinical outcomes related to infection, and long-term physical, mental health, and financial sequalae. We call upon additional epidemiology cohorts to join this collective effort to strengthen our impact on the current health crisis and generate a new model for a collaborative and nimble research infrastructure that will lead to more rapid translation of our work for the betterment of public health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-20-0606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357669PMC
July 2020

Intensification and consolidation therapy in multiple myeloma in the current era.

Lancet Haematol 2020 06 30;7(6):e427-e429. Epub 2020 Apr 30.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-3026(20)30110-1DOI Listing
June 2020

Clinical Controversies in the Management of Smoldering Multiple Myeloma.

Am Soc Clin Oncol Educ Book 2020 Mar;40:1-6

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

Forty years ago this year, smoldering multiple myeloma was defined as a clinical entity that identifies a group of patients with a substantial burden of disease but with a relatively indolent natural history compared with symptomatic disease. Since then, there has been a revolution in the therapeutic options for multiple myeloma. The aim of this article is to describe recent advances in the identification of those patients who are at the highest risk of progression and whether they may benefit from therapy. Treatment of smoldering myeloma is an area of active debate and we present contrasting interpretations of the available trial data. We conclude by identifying the priorities for research that will help to clarify the management of this condition, which can be challenging for physicians and patients alike.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/EDBK_278911DOI Listing
March 2020

Bone marrow niches in haematological malignancies.

Nat Rev Cancer 2020 05 28;20(5):285-298. Epub 2020 Feb 28.

Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Medicine, Frankfurt, Germany.

Haematological malignancies were previously thought to be driven solely by genetic or epigenetic lesions within haematopoietic cells. However, the niches that maintain and regulate daily production of blood and immune cells are now increasingly being recognized as having an important role in the pathogenesis and chemoresistance of haematological malignancies. Within haematopoietic cells, the accumulation of a small number of recurrent mutations initiates malignancy. Concomitantly, specific alterations of the niches, which support haematopoietic stem cells and their progeny, can act as predisposition events, facilitating mutant haematopoietic cell survival and expansion as well as contributing to malignancy progression and providing protection of malignant cells from chemotherapy, ultimately leading to relapse. In this Perspective, we summarize our current understanding of the composition and function of the specialized haematopoietic niches of the bone marrow during health and disease. We discuss disease mechanisms (rather than malignancy subtypes) to provide a comprehensive description of key niche-associated pathways that are shared across multiple haematological malignancies. These mechanisms include primary driver mutations in bone marrow niche cells, changes associated with increased hypoxia, angiogenesis and inflammation as well as metabolic reprogramming by stromal niche cells. Consequently, remodelling of bone marrow niches can facilitate immune evasion and activation of survival pathways favouring malignant haematopoietic cell maintenance, defence against excessive reactive oxygen species and protection from chemotherapy. Lastly, we suggest guidelines for the handling and biobanking of patient samples and analysis of the niche to ensure that basic research identifying therapeutic targets can be more efficiently translated to the clinic. The hope is that integrating knowledge of how bone marrow niches contribute to haematological disease predisposition, initiation, progression and response to therapy into future clinical practice will likely improve the treatment of these disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41568-020-0245-2DOI Listing
May 2020

Genomic Landscape of Waldenström Macroglobulinemia and Its Impact on Treatment Strategies.

J Clin Oncol 2020 04 21;38(11):1198-1208. Epub 2020 Feb 21.

Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA.

Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM), including (95%-97%), (30%-40%), (17%), and (8%-15%). Deletions involving chromosome 6q are common in patients with mutated and include genes that modulate NFKB, BCL2, Bruton tyrosine kinase (BTK), and apoptosis. Patients with wild-type WM show an increased risk of transformation and death and exhibit many mutations found in diffuse large B-cell lymphoma. The discovery of and mutations in WM has facilitated rational drug development, including the development of BTK and CXCR4 inhibitors. Responses to many agents commonly used to treat WM, including the BTK inhibitor ibrutinib, are affected by and/or mutation status. The mutation status of both and can be used for a precision-guided treatment approach to WM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.02314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351339PMC
April 2020

Prediagnosis dietary pattern and survival in patients with multiple myeloma.

Int J Cancer 2020 10 28;147(7):1823-1830. Epub 2020 Feb 28.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Inflammation and endogenous growth factors are important in multiple myeloma (MM) pathogenesis. Although diets that modulate these biologic pathways may influence MM patient survival, studies have not examined the association of dietary patterns with MM survival. We conducted pooled prospective survival analyses of 423 MM patients from the Nurses' Health Study (1986-2016) and the Health Professionals Follow-up Study (1988-2016) using Cox regression models. We used data from repeated food frequency questionnaires (FFQ) to compute dietary patterns as of the last prediagnosis FFQ, including the Alternate Healthy Eating Index (AHEI)-2010, alternate Mediterranean Diet, Dietary Approaches to Stop Hypertension, Prudent, Western and empirical dietary inflammatory patterns and empirical dietary indices for insulin resistance and hyperinsulinemia. During follow-up, we documented 295 MM-related deaths among 345 total deaths. MM-specific mortality was 15-24% lower per one standard deviation (SD) increase (e.g., toward healthier habits) in favorable dietary pattern scores. For example, the multivariable-adjusted hazard ratio [HR] and 95% confidence interval [CI] per 1-SD increase in AHEI-2010 score were 0.76, 0.67-0.87 (p < 0.001). In contrast, MM-specific mortality was 16-24% higher per 1-SD increase (e.g., toward less healthy habits) in "unhealthy" diet scores; for example, the multivariable-adjusted HR, 95% CI per 1-SD increase in Western pattern score were 1.24, 1.07-1.44 (p = 0.005). Associations were similar for all-cause mortality. In conclusion, our consistent findings for multiple dietary patterns provide the first evidence that MM patients with healthier prediagnosis dietary habits may have longer survival than those with less healthy diets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.32928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423719PMC
October 2020

Dissecting racial disparities in multiple myeloma.

Blood Cancer J 2020 02 17;10(2):19. Epub 2020 Feb 17.

Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.

Multiple myeloma (MM) is a fatal plasma cell dyscrasia with a median overall survival of 5 to 10 years. MM progresses from the more common but often subclinical precursor states of monoclonal gammopathy of undetermined significance (MGUS), and smoldering multiple myeloma (SMM) to overt MM. There are large racial disparities in all stages of the disease. Compared with Whites, Blacks have an increased MGUS and MM risk and higher mortality rate, and have not experienced the same survival gains over time. The roots of this disparity are likely multifactorial in nature. Comparisons of Black and White MGUS and MM patients suggest that differences in risk factors, biology, and clinical characteristics exist by race or ancestry, which may explain some of the observed disparity in MM. However, poor accrual of Black MGUS and MM patients in clinical and epidemiological studies has limited our understanding of this disparity and hindered its elimination. Disparities in MM survival also exist but appear to stem from inferior treatment utilization and access rather than underlying pathogenesis. Innovative and multidisciplinary approaches are urgently needed to enhance our understanding of disparities that exist at each stage of the MM disease continuum and facilitate their elimination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41408-020-0284-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026439PMC
February 2020

miR-15a/16-1 deletion in activated B cells promotes plasma cell and mature B-cell neoplasms.

Blood 2021 04;137(14):1905-1919

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

Chromosome 13q deletion [del(13q)], harboring the miR-15a/16-1 cluster, is one of the most common genetic alterations in mature B-cell malignancies, which originate from germinal center (GC) and post-GC B cells. Moreover, miR-15a/16 expression is frequently reduced in lymphoma and multiple myeloma (MM) cells without del(13q), suggesting important tumor-suppressor activity. However, the role of miR-15a/16-1 in B-cell activation and initiation of mature B-cell neoplasms remains to be determined. We show that conditional deletion of the miR-15a/16-1 cluster in murine GC B cells induces moderate but widespread molecular and functional changes including an increased number of GC B cells, percentage of dark zone B cells, and maturation into plasma cells. With time, this leads to development of mature B-cell neoplasms resembling human extramedullary plasmacytoma (EP) as well as follicular and diffuse large B-cell lymphomas. The indolent nature and lack of bone marrow involvement of EP in our murine model resembles human primary EP rather than MM that has progressed to extramedullary disease. We corroborate human primary EP having low levels of miR-15a/16 expression, with del(13q) being the most common genetic loss. Additionally, we show that, although the mutational profile of human EP is similar to MM, there are some exceptions such as the low frequency of hyperdiploidy in EP, which could account for different disease presentation. Taken together, our studies highlight the significant role of the miR-15a/16-1 cluster in the regulation of the GC reaction and its fundamental context-dependent tumor-suppression function in plasma cell and B-cell malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020009088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033455PMC
April 2021

The microenvironment in myeloma.

Curr Opin Oncol 2020 03;32(2):170-175

Dana-Farber Cancer Institute, Boston.

Purpose Of Review: The aim of the review is to describe recent advances in our understanding of how multiple myeloma interacts with its cellular and molecular neighbours in the bone marrow microenvironment, and how this may provide targets for prognostication and prevention.

Recent Findings: The bone marrow microenvironment in myeloma is beginning to yield targets that are amenable to therapy. A number of trials demonstrate some clinical efficacy in heavily pretreated disease. The challenge remains for how and when these therapeutic interventions are of particular benefit early in disease progression.

Summary: Multiple myeloma is rarely curable and its interactions with the bone marrow microenvironment are evident. However, separating cause from effect remains a challenge. We propose that targeting specific niches within the bone marrow will yield therapies that have the potential for significant benefit in myeloma and may facilitate earlier intervention to disrupt an environment that is permissive for myeloma progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCO.0000000000000615DOI Listing
March 2020

A Phase Ib/II Trial of the First-in-Class Anti-CXCR4 Antibody Ulocuplumab in Combination with Lenalidomide or Bortezomib Plus Dexamethasone in Relapsed Multiple Myeloma.

Clin Cancer Res 2020 01 31;26(2):344-353. Epub 2019 Oct 31.

University of Washington, Seattle, Washington.

Purpose: Ulocuplumab (BMS-936564) is a first-in-class fully human IgG4 monoclonal anti-CXCR4 antibody that inhibits the binding of CXCR4 to CXCL12.

Patients And Methods: This phase Ib/II study aimed to determine the safety and tolerability of ulocuplumab alone and in combination with lenalidomide and dexamethasone (Arm A), or bortezomib and dexamethasone (Arm B), in patients with relapsed/refractory multiple myeloma.

Results: Forty-six patients were evaluated (median age, 60 years; range, 53-67). The median number of prior therapies was 3 (range, 1-11), with 70% of subjects having received ≥3. This trial had a dose-escalation and a dose-expansion part. Using a 3+3 design on both arms of the trial, ulocuplumab's dose was escalated to a maximum of 10 mg/kg without reaching MTD. The most common treatment-related adverse events (AE) were neutropenia (13 patients, 43.3%) in Arm A and thrombocytopenia (6 patients, 37.5%) in Arm B. No deaths related to study drugs occurred. The combination of ulocuplumab with lenalidomide and dexamethasone showed a high response rate (PR or better) of 55.2% and a clinical benefit rate of 72.4%, even in patients who had been previously treated with immunomodulatory agents (IMiD).

Conclusions: This study showed that blockade of the CXCR4-CXCL12 axis by ulocuplumab is safe with acceptable AEs and leads to a high response rate in combination with lenalidomide and dexamethasone in patients with relapsed/refractory myeloma, making CXCR4 inhibitors a promising class of antimyeloma drugs that should be further explored in clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-0647DOI Listing
January 2020

Antibody-targeting of ultra-small nanoparticles enhances imaging sensitivity and enables longitudinal tracking of multiple myeloma.

Nanoscale 2019 Nov 25;11(43):20485-20496. Epub 2019 Oct 25.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. and Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

Monitoring malignant progression and disease recurrence post-therapy are central challenges to improving the outcomes of patients with multiple myeloma (MM). Whereas current detection methods that rely upon bone marrow examination allow for precise monitoring of minimal residual disease and can help to elucidate clonal evolution, they do not take into account the spatial heterogeneity of the tumor microenvironment. As such, they are uninformative as to the localization of malignant plasma cells and may lead to false negative results. With respect to the latter challenge, clinically-available imaging agents are neither sufficiently sensitive nor specific enough to detect minute plasma cell populations. Here, we sought to explore methods by which to improve detection of MM cells within their natural bone marrow environment, using whole-animal magnetic resonance imaging to longitudinally monitor early-stage disease as well as to enhance tumor detection after systemic therapy. We conducted a proof-of-concept study to demonstrate that ultra-small (<5 nm) gadolinium-containing nanoparticles bound to full-length antibodies against the B-cell maturation antigen (BCMA) exhibit rapid tumor uptake followed by renal clearance, improving the signal-to-noise ratio for MM detection beyond levels that are currently afforded by other FDA-approved clinical imaging modalities. We anticipate that when combined with bone marrow or blood biopsy, such imaging constructs could help to augment the effective management of patients with MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c9nr06512aDOI Listing
November 2019

Phase I/II trial of the CXCR4 inhibitor plerixafor in combination with bortezomib as a chemosensitization strategy in relapsed/refractory multiple myeloma.

Am J Hematol 2019 11 4;94(11):1244-1253. Epub 2019 Oct 4.

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

We tested the hypothesis that using CXCR4 inhibition to target the interaction between the tumor cells and the microenvironment leads to sensitization of the tumor cells to apoptosis. Eligibility criteria included multiple myeloma (MM) patients with 1-5 prior lines of therapy. The purposes of the phase I study were to evaluate the safety and maximal-tolerated dose (MTD) of the combination. The treatment-related adverse events and response rate of the combination were assessed in the phase II study. A total of 58 patients were enrolled in the study. The median age of the patients was 63 years (range, 43-85), and 78% of them received prior bortezomib. In the phase I study, the MTD was plerixafor 0.32 mg/kg, and bortezomib 1.3 mg/m . The overall response rate for the phase II study was 48.5%, and the clinical benefit rate 60.6%. The median disease-free survival was 12.6 months. The CyTOF analysis demonstrated significant mobilization of plasma cells, CD34+ stem cells, and immune T cells in response to plerixafor. This is an unprecedented study that examines therapeutic targeting of the bone marrow microenvironment and its interaction with the tumor clone to overcome resistance to therapy. Our results indicate that this novel combination is safe and that the objective response rate is high even in patients with relapsed/refractory MM. ClinicalTrials.gov, NCT00903968.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.25627DOI Listing
November 2019

Immunotherapy for hematological malignancies.

J Life Sci (Westlake Village) 2019 Jun;1(1):46-52

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA Harvard Institute of Medicine Room 237, 4 Blackfan Circle, Boston MA 02115.

Tumor immune tolerance remains a major barrier for effective anti-cancer therapy. A growing number of pathways whereby solid tumors escape immune surveillance have been characterized (1). This progress led us to revisit the "hallmarks of cancer" and brought forward many promising immunotherapies. Every growing bodies of research have brought forward many exciting treatment strategies for hematological cancers like chimeric antigen receptor T cells (CAR-T cells) and immune checkpoint inhibitors. Given the distinct characteristics of the different cancers, some benefited profoundly from such therapies while some remain challenging for scientists and physicians. Here, we discuss the unique aspect of hematological malignancies, and briefly review the history, existing and future of immunotherapies for this group of cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709701PMC
June 2019

Reply to F.D. Leonard.

J Clin Oncol 2019 10 19;37(29):2701-2702. Epub 2019 Aug 19.

Mark Bustoros, MD; Romanos Sklavenitis-Pistofidis, MD; Jorge J. Castillo, MD; Steven P. Treon, MD, PhD; and Irene M. Ghobrial, MD, Dana-Farber Cancer Institute, Boston, MA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.01708DOI Listing
October 2019
-->