Chromothripsis as a pathogenic driver of multiple myeloma.

Analysis of the genetic basis for multiple myeloma (MM) has informed many of our current concepts of the biology that underlies disease initiation and progression. Studying these events in further detail is predicted to deliver important insights into its pathogenesis, prognosis and treatment. Information from whole genome sequencing of structural variation is revealing the role of these events as drivers of MM. In particular, we discuss how the insights we have gained from studying chromothripsis suggest that it can be used to provide information on disease initiation and that, as a consequence, it can be used for the clinical classification of myeloma precursor diseases allowing for early intervention and prognostic determination. For newly diagnosed MM, the integration of information on the presence of chromothripsis has the potential to significantly enhance current risk prediction strategies and to better characterize patients with high-risk disease biology. In this article we summarize the genetic basis for MM and the role played by chromothripsis as a critical pathogenic factor active at early disease phases.

Considerations for the Management of Oncology Patients During the COVID-19 Pandemic.

Worldwide incidence and mortality due to the coronavirus disease 2019 (COVID-19) pandemic is greatest in the United States, with the initial epicenter in New York. In Nassau County, New York, where we practice, our institution has had more than 2500 cases and has discharged from the hospital more than 1000 patients. As many academic and private institutions have swiftly shifted their clinical and research priorities to address the pandemic, data are emerging regarding both the impact of malignancy on COVID-19 outcomes as well as the challenges faced in assuring that cancer care remains unimpeded. Of concern, recent studies of cancer patients primarily in China and Italy have suggested that advanced malignancy is associated with increased susceptibility to severe COVID-19 infection. At present, more than 500 clinical trials are underway investigating the pathogenesis and treatment of COVID-19, including expanded use of oncology drugs, such as small molecular inhibitors of cytokine pathways. Here, we begin by reviewing the latest understanding of COVID-19 pathophysiology and then focus our attention on the impact of this virus on hematologic and oncologic practice. Finally, we highlight ongoing investigational treatment approaches that are so relevant to the care of oncology patients during this extraordinary pandemic.

Management of Newly Diagnosed Elderly Multiple Myeloma Patients.

PURPOSE OF REVIEW: Given the median age at diagnosis of 69, multiple myeloma (MM) is commonly identified among elderly individuals. Over-treatment of the frail may lead to unnecessary morbidity, while under-treatment of fit elderly patients may prevent improvement in organ function; both instances reducing quality of life. Here, we summarize assessments of frailty and include considerations in managing newly diagnosed elderly MM patients. RECENT FINDINGS: Eligibility criteria for studies of anti-myeloma agents have traditionally relied on performance status and comorbidities; however, geriatric and myeloma-specific frailty assessments are beginning to be incorporated for more accurate stratification of patients for treatment. The IMWG and R-MCI scores are validated metrics that predict survival in elderly MM patients. In addition, dose-attenuated induction regimens and conditioning before autologous transplant may decrease morbidity in elderly MM patients. Although MM remains incurable, multi-drug regimens have the ability to prolong survival of both untreated and relapsed elderly patients. Older patients require a highly individualized approach since they may have preexisting organ dysfunction, worse frailty scores, and variable goals of care.

Association between climate factors, pollen counts, and childhood hay fever prevalence in the United States.

BACKGROUND: Climate factors and pollen counts may play a role in hay fever. OBJECTIVE: We sought to determine the impact of specific climate factors and pollen counts on the US prevalence of hay fever and statewide variation in prevalence. METHODS: We used a merged analysis of the 2007 National Survey of Children's Health from a representative sample of 91,642 children aged 0 to 17 years and the 2006-2007 National Climate Data Center and Weather Service measurements of relative humidity (%), indoor heating degree days, precipitation, Palmer Hydrological Drought Index, clear sky and issued ultraviolet indices, stratospheric ozone levels, and outdoor air temperature and National Allergy Bureau total pollen counts. Multivariate survey logistic regression models controlled for sex, race/ethnicity, age, household income, and birthplace. RESULTS: The US prevalence of hay fever in childhood was 18.0% (95% CI, 17.7% to 18.2%), with the highest prevalence in southeastern and southern states. Hay fever prevalence was significantly lower with second and third quartile mean annual relative humidity (logistic regression, P ≤ .01 for both), fourth quartile mean annual Palmer Hydrological Drought Index (P = .02), third and fourth quartile mean annual heating degree days (P < .0001 for both), and third and fourth quartile mean annual stratospheric ozone levels but increased with second, third, and fourth quartile mean annual temperature (P ≤ .02 for both), fourth quartile mean annual precipitation (P = .0007), mean total pollen counts (P = .01), and second, third, and fourth quartile issued ultraviolet index (P ≤ .0001 for all). Principal-component analysis was also used to determine the combined effects of correlated climate variables and pollen counts. CONCLUSIONS: This study provides evidence of the influence of climate on the US prevalence of childhood hay fever.

Overcoming Barriers to Autologous Stem Cell Transplantation in Multiple Myeloma: Recommendations from a Multidisciplinary Roundtable Discussion.

Autologous stem cell transplantation (ASCT) is a standard of care treatment for patients with multiple myeloma (MM). However, only 20% to 30% of patients with MM for whom the procedure is indicated undergo ASCT. Barriers to ASCT may be informational, financial, logistic, or cultural and may affect patients and treating oncologists. Available and accessible accurate ASCT-related information is essential to overcome these barriers. Such resources can be created by blood and marrow transplantation societies and patient advocacy groups, ideally in collaboration with MM specialists at transplant centers. An umbrella office at the society level is also recommended to connect oncologists, advocacy groups, and transplantation specialists; provide informational resources to patients; and conduct research into region- and population-specific barriers to ASCT.

Multiomic Mapping of Acquired Chromosome 1 Copy-Number and Structural Variants to Identify Therapeutic Vulnerabilities in Multiple Myeloma.

PURPOSE: Chromosome 1 (chr1) copy-number abnormalities (CNA) and structural variants (SV) are frequent in newly diagnosed multiple myeloma (NDMM) and are associated with a heterogeneous impact on outcomes, the drivers of which are largely unknown. EXPERIMENTAL DESIGN: A multiomic approach comprising CRISPR, gene mapping of CNAs and SVs, methylation, expression, and mutational analysis was used to document the extent of chr1 molecular variants and their impact on pathway utilization. RESULTS: We identified two distinct groups of gain(1q): focal gains associated with limited gene-expression changes and a neutral prognosis, and whole-arm gains, which are associated with substantial gene-expression changes, complex genetics, and an adverse prognosis. CRISPR identified a number of dependencies on chr1 but only limited variants associated with acquired CNAs. We identified seven regions of deletion, nine of gain, three of chromothripsis (CT), and two of templated insertion (TI), which contain a number of potential drivers. An additional mechanism involving hypomethylation of genes at 1q may contribute to the aberrant gene expression of a number of genes. Expression changes associated with whole-arm gains were substantial and gene set enrichment analysis identified metabolic processes, apoptotic resistance, signaling via the MAPK pathway, and upregulation of transcription factors as being key drivers of the adverse prognosis associated with these variants. CONCLUSIONS: Multiple layers of genetic complexity impact the phenotype associated with CNAs on chr1 to generate its associated clinical phenotype. Whole-arm gains of 1q are the critically important prognostic group that deregulate multiple pathways, which may offer therapeutic vulnerabilities.

Characterization of Second Primary Malignancies in Mucosa-Associated Lymphoid Tissue Lymphomas: A SEER Database Interrogation.

INTRODUCTION: Second primary malignancies (SPMs) are long-term complications in cancer survivors. Mucosa-associated lymphoid tissue (MALT) lymphomas are indolent extra-nodal marginal zone lymphomas, the majority of which typically have long-term survival. In this study, we investigated the incidence and pattern of SPMs in adult patients diagnosed with MALT lymphomas between January 2000 and December 2016. METHODS: Using the SEER-18 database and multiple primary standardized incidence ratio (MP-SIR) session of SEER stat software for statistical analysis, we assessed SPMs in MALT lymphomas. RESULTS: During this time, a total of 12,500 cases of MALT lymphomas were diagnosed, of which 1466 patients developed 1626 SPMs (O/E ratio: 1.48, 95% CI:1.41-1.55, P<.001). The median latency period for development of SPMs was 54 months (range 6-201 months). Secondary non-Hodgkin lymphomas, as defined by SEER as distinct from the primary lymphoma, was the most common SPM with 299 cases, followed by lung cancer (O/E ratio: 6.15, 95% CI:5.47-6.89, P<.0001). There were 898 SPMs that developed between 6- 59 months (O/E ratio: 1.47, 95% CI:1.37-1.57, P<.0001) and 728 after 60 months latency (O/E ratio: 1.5, 95% CI:1.39-1.61, P<.0001) after diagnosis of the primary MALT lymphomas. An increased incidence of both solid and hematologic cancers occurred in patients as early as 6 months after diagnosis of MALT lymphoma. CONCLUSION: These findings indicate that despite the indolent nature of most MALT lymphomas, there is an increased risk for SPMs warranting long-term follow up.

Outcomes of Patients With Hematologic Malignancies Who Received Inpatient Palliative Care Consultation.

PURPOSE: Palliative care (PC) plays an established role in improving outcomes in patients with solid tumors, yet these services are underutilized in hematologic malignancies (HMs). We reviewed records of hospitalized patients with active HM to determine associations between PC consultation and length of stay, intensive care unit stay, 30-day readmission, and 6-month mortality compared with those who were not seen by PC. METHODS: We reviewed all oncology admissions at our institution between 2013 and 2019 and included patients with HM actively on treatment, stratified by those seen by PC to controls not seen by PC. Groups were compared using Wilcoxon rank-sum, chi-square, and Fisher's exact tests on the basis of the type and distribution of data. Multiple logistic regression models with stepwise variable selection methods were used to find predictors of outcomes. RESULTS: Three thousand six hundred fifty-four admissions were reviewed, among which 370 unique patients with HM were included. Among these, 102 (28%) patients saw PC, whereas the remaining 268 were controls with similar comorbidities. When compared with controls, PC consultation was associated with a statistically significant reduction in 30-day readmissions (16% v 27%; P = .024), increased length of stay (11.5 v 6 days; P < .001), increased intensive care unit admission (28% v 9%; P < .001), and increased 6-month mortality (67% v 15%; P < .001). These data were confirmed in multivariable models. CONCLUSION: In this retrospective study, more than two thirds of patients with HM did not receive PC consultation despite having similar comorbidities, suggesting that inpatient PC consultation is underutilized in patients with HM, despite the potential for decreased readmission rates.

Hemoglobin Alpha Chain Variant Zara Associated With Familial Asymptomatic Hypoxemia.

Numerous hemoglobin (Hb) gene mutations have been identified, leading to a spectrum of phenotypes ranging from asymptomatic carrier states to complicated hemolytic anemias. We report a rare case of asymptomatic hypoxemia in a father and his teenage daughter both of whom were found to be carriers of Hb gene variant Zara. Workup for alternative cardiovascular causes of hypoxemia was unremarkable. Further sequencing of the alpha globin locus showed both individuals to be heterozygous for the Hb Zara c.274C>A (p.Leu92Ile) variant of unknown significance in the alpha2-globin gene. This is the first documented association of this Hb variant with familial asymptomatic hypoxemia, highlighting the importance of evaluating for hemoglobinopathies in patients with reduced oxygen saturation.

Inflammation and infection in plasma cell disorders: how pathogens shape the fate of patients.

The role of infection and chronic inflammation in plasma cell disorders (PCD) has been well-described. Despite not being a diagnostic criterion, infection is a common complication of most PCD and represents a significant cause of morbidity and mortality in this population. As immune-based therapeutic agents are being increasingly used in multiple myeloma, it is important to recognize their impact on the epidemiology of infections and to identify preventive measures to improve outcomes. This review outlines the multiple factors attributed to the high infectious risk in PCD (e.g. the underlying disease status, patient age and comorbidities, and myeloma-directed treatment), with the aim of highlighting future prophylactic and preventive strategies that could be implemented in the clinic. Beyond this, infection and pathogens as an entity are believed to also influence disease biology from initiation to response to treatment and progression through a complex interplay involving pathogen exposure, chronic inflammation, and immune response. This review will outline both the direct and indirect role played by oncogenic pathogens in PCD, highlight the requirement for large-scale studies to decipher the precise implication of the microbiome and direct pathogens in the natural history of myeloma and its precursor disease states, and understand how, in turn, pathogens shape plasma cell biology.

Structural variants shape the genomic landscape and clinical outcome of multiple myeloma.

Deciphering genomic architecture is key to identifying novel disease drivers and understanding the mechanisms underlying myeloma initiation and progression. In this work, using the CoMMpass dataset, we show that structural variants (SV) occur in a nonrandom fashion throughout the genome with an increased frequency in the t(4;14), RB1, or TP53 mutated cases and reduced frequency in t(11;14) cases. By mapping sites of chromosomal rearrangements to topologically associated domains and identifying significantly upregulated genes by RNAseq we identify both predicted and novel putative driver genes. These data highlight the heterogeneity of transcriptional dysregulation occurring as a consequence of both the canonical and novel structural variants. Further, it shows that the complex rearrangements chromoplexy, chromothripsis and templated insertions are common in MM with each variant having its own distinct frequency and impact on clinical outcome. Chromothripsis is associated with a significant independent negative impact on clinical outcome in newly diagnosed cases consistent with its use alongside other clinical and genetic risk factors to identify prognosis.

A new decade: novel immunotherapies on the horizon for relapsed/refractory multiple myeloma.

INTRODUCTION: Survival in multiple myeloma (MM) has improved due to the ongoing revolution of therapeutic approaches. Nevertheless, many patients relapse, and additional novel approaches are required to prolong remissions and prevent disease progression. AREAS COVERED: Considering the success of monoclonal antibodies (mAbs) against CD38 and SLAMF7 in relapsed/refractory MM (R/R MM), additional antigens expressed on malignant plasma cells are being investigated as treatment targets. Among these, many trials are focusing on B cell maturation antigen (BCMA), using either antibody-drug conjugates (ADCs), bispecific T cell engagers (TCE), or chimeric antigen receptor T cells (CAR-T). Other potential targets include the myeloma markers CD138, GPRC5D, FcRH5, the plasma cell differentiating factors APRIL, TACI and BAFF, and the immune checkpoint proteins CD47 and TIGIT. Additionally, novel immunomodulatory Cereblon E3 Ligase Modulators (CELMoDs) offer the potential to overcome resistance to conventional immunomodulatory agents. Based upon PubMed and abstract searches primarily from the past 4 years, here we review the data supporting novel immunotherapies for R/R MM. EXPERT OPINION: Overcoming disease resistance remains a challenge in R/R MM. Novel therapeutic approaches targeting MM antigens and/or enhancing immune cell function offer the potential to prolong survival and are actively being investigated in clinical trials.

Management of atypical chronic lymphocytic leukemia presenting with extreme leukocytosis.

Atypical chronic lymphocytic lymphoma (CLL) with CCND1 translocation is poorly described, particularly in the era of modern inhibitors of the B-cell receptor pathway. We present a patient with atypical CLL who had a significant response to ibrutinib, highlighting the effectiveness of this agent in higher risk CLL subgroups.

Plasma Cell Myeloma Presenting With Amyloid-Laden Crystal-Negative Histiocytosis.

OBJECTIVES: Crystal-storing histiocytosis (CSH) is rare in plasma cell dyscrasias, with only 3 cases reported in the setting of amyloid. No cases of crystal-negative histiocytosis coincident with multiple myeloma and amyloidosis have been reported previously. METHODS: A 58-year-old woman presented with pain due to destructive bone lesions and was found to have plasma cell myeloma (PCM) and marrow amyloid deposition associated with crystal-negative histiocytosis. Differential diagnoses included Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai Dorfman disease. BRAF mutations were negative, and there was no evidence of paraprotein crystals, arguing against typical CSH. RESULTS: The patient was treated with bortezomib, cyclophosphamide, and dexamethasone, and she subsequently underwent autologous stem cell transplant and ixazomib maintenance. She achieved complete remission with improvement of her symptoms and preserved remission after following up at 60 months. CONCLUSIONS: We describe a case of crystal-negative histiocytosis associated with PCM. CSH is a rare disorder associated with paraprotein-producing conditions in which immunoglobulins aggregate as intracellular crystals in the lysosomes of organ-specific phagocytic macrophages. Light chain tropism in PCM can also lead to the development of amyloid deposition in organs and, in rare cases, is associated with light chain aggregation as intracellular crystals in macrophages.

COVID-19 infections and outcomes in patients with multiple myeloma in New York City: a cohort study from five academic centers.

Importance: New York City is a global epicenter for the SARS-CoV-2 outbreak with a significant number of individuals infected by the virus. Patients with multiple myeloma have a compromised immune system, due to both the disease and anti-myeloma therapies, and may therefore be particularly susceptible to coronavirus disease 2019 (COVID-19); however, there is limited information to guide clinical management. Objective: To assess risk factors and outcomes of COVID-19 in patients with multiple myeloma. Design: Case-series. Setting: Five large academic centers in New York City. Participants: Patients with multiple myeloma and related plasma cell disorders who were diagnosed with COVID-19 between March 10th, 2020 and April 30th, 2020. Exposures: Clinical features and risk factors were analyzed in relation to severity of COVID-19. Main Outcomes and Measures: Descriptive statistics as well as logistic regression were used to estimate disease severity reflected in hospital admissions, intensive care unit (ICU) admission, need for mechanical ventilation, or death. Results: Of 100 multiple myeloma patients (male 58%; median age 68, range 41-91) diagnosed with COVID-19, 74 (74%) were admitted; of these 13 (18%) patients were placed on mechanical ventilation, and 18 patients (24%) expired. None of the studied risk factors were significantly associated (P>0.05) with adverse outcomes (ICU-admission, mechanical ventilation, or death): hypertension (N=56) odds ratio (OR) 2.3 (95% confidence interval [CI] 0.9-5.9); diabetes (N=18) OR 1.1 (95% CI 0.3-3.2); age >65 years (N=63) OR 2.0 (95% CI 0.8-5.3); high dose melphalan with autologous stem cell transplant <12 months (N=7) OR 1.2 (95% CI 0.2-7.4), IgG<650 mg/dL (N=42) OR=1.2 (95% CI 0.4-3.1). In the entire series of 127 patients with plasma cell disorders, hypertension was significantly associated with the combined end-point (OR 3.4, 95% CI 1.5-8.1). Conclusions and Relevance: Although multiple myeloma patients have a compromised immune system due to both the disease and therapy; in this largest disease specific cohort to date of patients with multiple myeloma and COVID-19, compared to the general population, we found risk factors for adverse outcome to be shared and mortality rates to be within the higher range of officially reported mortality rates.

COVID-19 Infections and Clinical Outcomes in Patients with Multiple Myeloma in New York City: A Cohort Study from Five Academic Centers.

Patients with multiple myeloma have a compromised immune system, due to both the disease and antimyeloma therapies, and may therefore be particularly susceptible to COVID-19. Here, we report outcomes and risk factors for serious disease in patients with multiple myeloma treated at five large academic centers in New York City in the spring of 2020, during which it was a global epicenter of the SARS-CoV-2 pandemic. Of 100 patients with multiple myeloma (male 58%; median age 68) diagnosed with COVID-19, 75 were admitted; of these, 13 patients (17%) were placed on invasive mechanical ventilation, and 22 patients (29%) expired. Of the 25 nonadmitted patients, 4 were asymptomatic. There was a higher risk of adverse outcome (intensive care unit admission, mechanical ventilation, or death) in Hispanics/Latinos (n = 21), OR = 4.7 (95% confidence interval, 1.3-16.7), and African American Blacks (n = 33), OR = 3.5 (1.1-11.5), as compared with White patients (n = 36). Patients who met the adverse combined endpoint had overall higher levels of inflammatory markers and cytokine activation. None of the other studied risk factors were significantly associated (P > 0.05) with adverse outcome: hypertension (n = 56), OR = 2.2 (0.9-5.4); diabetes (n = 18), OR = 0.9 (0.3-2.9); age >65 years (n = 63), OR = 1.8 (0.7-4.6); high-dose melphalan with autologous stem cell transplant <12 months (n = 7), OR = 0.9 (0.2-5.4); and immunoglobulin G <650 mg/dL (n = 42), OR = 0.9 (0.3-2.2). In this largest cohort to date of patients with multiple myeloma and COVID-19, we found the case fatality rate to be 29% among hospitalized patients and that race/ethnicity was the most significant risk factor for adverse outcome. Significance: Patients with multiple myeloma are immunocompromised, raising the question whether they are at higher risk of severe COVID-19 disease. In this large case series on COVID-19 in patients with multiple myeloma, we report 29% mortality rates among hospitalized patients and identify race/ethnicity as the most significant risk factor for severe outcome.See related commentary by Munshi and Anderson, p. 218. This article is highlighted in the In This Issue feature, p. 215.

Correction: COVID-19 Infections and Outcomes in Patients with Multiple Myeloma in New York City: A Cohort Study from Five Academic Centers.

[This corrects the article DOI: 10.1158/2643-3230.BCD-20-0102.].

Targeting Toll-Like Receptors for Cancer Therapy.

The immune system encompasses a broad array of defense mechanisms against foreign threats, including invading pathogens and transformed neoplastic cells. Toll-like receptors (TLRs) are critically involved in innate immunity, serving as pattern recognition receptors whose stimulation leads to additional innate and adaptive immune responses. Malignant cells exploit the natural immunomodulatory functions of TLRs, expressed mainly by infiltrating immune cells but also aberrantly by tumor cells, to foster their survival, invasion, and evasion of anti-tumor immune responses. An extensive body of research has demonstrated context-specific roles for TLR activation in different malignancies, promoting disease progression in certain instances while limiting cancer growth in others. Despite these conflicting roles, TLR agonists have established therapeutic benefits as anti-cancer agents that activate immune cells in the tumor microenvironment and facilitate the expression of cytokines that allow for infiltration of anti-tumor lymphocytes and the suppression of oncogenic signaling pathways. This review focuses on the clinical application of TLR agonists for cancer treatment. We also highlight agents that are undergoing development in clinical trials, including investigations of TLR agonists in combination with other immunotherapies.