Bone marrow stromal cells induce chromatin remodeling in multiple myeloma cells leading to transcriptional changes.

The natural history of multiple myeloma is characterized by its localization to the bone marrow and its interaction with bone marrow stromal cells. The bone marrow stromal cells provide growth and survival signals, thereby promoting the development of drug resistance. Here, we show that the interaction between bone marrow stromal cells and myeloma cells (using human cell lines) induces chromatin remodeling of cis-regulatory elements and is associated with changes in the expression of genes involved in the cell migration and cytokine signaling. The expression of genes involved in these stromal interactions are observed in extramedullary disease in patients with myeloma and provides the rationale for survival of myeloma cells outside of the bone marrow microenvironment. Expression of these stromal interaction genes is also observed in a subset of patients with newly diagnosed myeloma and are akin to the transcriptional program of extramedullary disease. The presence of such adverse stromal interactions in newly diagnosed myeloma is associated with accelerated disease dissemination, predicts the early development of therapeutic resistance, and is of independent prognostic significance. These stromal cell induced transcriptomic and epigenomic changes both predict long-term outcomes and identify therapeutic targets in the tumor microenvironment for the development of novel therapeutic approaches.

Predictors of hematologic response and survival with stem cell transplantation in AL amyloidosis: A 25-year longitudinal study.

High-dose melphalan and stem cell transplantation (HDM/SCT) is an effective treatment for selected patients with AL amyloidosis. We report the long-term outcomes of 648 patients with AL amyloidosis treated with HDM/SCT over 25 years. Hematologic CR was achieved by 39% of patients. The median duration of hematologic CR was 12.3 years, and 45% of patients with a hematologic CR had no evidence of a recurrent plasma cell dyscrasia at 15 years after HDM/SCT. With a median follow-up interval of 8 years, the median event-free survival (EFS) and overall survival (OS) were 3.3 and 7.6 years, respectively. Patients with a hematologic CR had a median OS of 15 years, and 30% of these patients survived >20 years. On multivariable analysis, dFLC >180 mg/L and BM plasma cells >10% were independently associated with shorter EFS, whereas BNP >81 pg/mL, troponin I > 0.1 ng/mL, and serum creatinine >2.0 mg/dL were independently associated with shorter OS. We developed a prognostic score for EFS, which incorporated dFLC >180 mg/L and BMPC% >10% as adverse risk factors. Patients with low-risk (0 factors), intermediate-risk (1 factor), and high-risk (2 factors) disease had median EFS estimates of 5.3, 2.8, and 1.0 years, respectively (p < .001). The 100-day treatment-related mortality rate was 3% in the latest treatment period (2012-2021), and the 25-year risk of t-MDS/AML was 3%. We conclude that HDM/SCT induces durable hematologic responses and prolonged survival with improved safety in selected patients with AL amyloidosis.

Predictive factors of outcomes in patients with AL amyloidosis treated with daratumumab.

Daratumumab as a single agent (sDARA) or in combination with chemotherapies (cDARA) leads to impressive hematologic and organ responses in AL amyloidosis. However, predictive factors associated with outcomes, and optimal duration of therapy remain unclear. We analyzed 107 patients with AL amyloidosis treated with daratumumab between 2017 and 2020. The median overall survival (OS) was not reached while the median major organ deterioration progression free survival (MOD-PFS) was 36 months in the sDARA cohort and not reached in the cDARA cohort, respectively. Hematologic response > VGPR was achieved in 81% of patients receiving sDARA and 86% of patients treated with cDARA. Several predictive factors were identified on a univariate analysis, including NTproBNP >8500 pg/mL but only achievement of at least VGPR and presence of 1q21 gain were independently associated with MOD-PFS and OS on a multivariate analysis. Finally, patients receiving > 12 cycles had significantly longer MOD-PFS (30 vs.13 months; (p = .0018) and OS (NR vs. 15 months; p < .0001). NTproBNP > 8500 pg/mL, presence of 1q21 gain and shorter duration of therapy (≤ 12 cycles) are strong negative predictive factors for outcomes with daratumumab therapy in AL amyloidosis.

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

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.

Prevalence and Outcome of COVID-19 Infection in Cancer Patients: A National Veterans Affairs Study.

BACKGROUND: Emerging data suggest variability in susceptibility and outcome to coronavirus disease 2019 (COVID-19) infection. Identifying risk factors associated with infection and outcomes in cancer patients is necessary to develop healthcare recommendations. METHODS: We analyzed electronic health records of the US Veterans Affairs Healthcare System and assessed the prevalence of COVID-19 infection in cancer patients. We evaluated the proportion of cancer patients tested for COVID-19 who were positive, as well as outcome attributable to COVID-19, and stratified by clinical characteristics including demographics, comorbidities, cancer treatment, and cancer type. All statistical tests are 2-sided. RESULTS: Of 22 914 cancer patients tested for COVID-19, 1794 (7.8%) were positive. The prevalence of COVID-19 was similar across age. Higher prevalence was observed in African American (15.0%) compared with White (5.5%; P < .001) and in patients with hematologic malignancy compared with those with solid tumors (10.9% vs 7.8%; P < .001). Conversely, prevalence was lower in current smokers and patients who recently received cancer therapy (<6 months). The COVID-19-attributable mortality was 10.9%. Higher attributable mortality rates were observed in older patients, those with higher Charlson comorbidity score, and in certain cancer types. Recent (<6 months) or past treatment did not influence attributable mortality. Importantly, African American patients had 3.5-fold higher COVID-19-attributable hospitalization; however, they had similar attributable mortality as White patients. CONCLUSION: Preexistence of cancer affects both susceptibility to COVID-19 infection and eventual outcome. The overall COVID-19-attributable mortality in cancer patients is affected by age, comorbidity, and specific cancer types; however, race or recent treatment including immunotherapy do not impact outcome.

Genomic Instability in Multiple Myeloma.

Genomic instability (GIN), an increased tendency to acquire genomic alterations, is a cancer hallmark. However, its frequency, underlying causes, and disease relevance vary across different cancers. Multiple myeloma (MM), a plasma cell malignancy, evolves through premalignant phases characterized by genomic abnormalities. Next-generation sequencing (NGS) methods are deconstructing the genomic landscape of MM across the continuum of its development, inextricably linking malignant transformation and disease progression with increasing acquisition of genomic alterations, and illuminating the mechanisms that generate these alterations. Although GIN drives disease evolution, it also creates vulnerabilities such as dependencies on 'superfluous' repair mechanisms and the induction of tumor-specific antigens that can be targeted. We review the mechanisms of GIN in MM, the associated vulnerabilities, and therapeutic targeting strategies.

Non-overlapping Control of Transcriptome by Promoter- and Super-Enhancer-Associated Dependencies in Multiple Myeloma.

The relationship between promoter proximal transcription factor-associated gene expression and super-enhancer-driven transcriptional programs are not well defined. However, their distinct genomic occupancy suggests a mechanism for specific and separable gene control. We explored the transcriptional and functional interrelationship between E2F transcription factors and BET transcriptional co-activators in multiple myeloma. We found that the transcription factor E2F1 and its heterodimerization partner DP1 represent a dependency in multiple myeloma cells. Global chromatin analysis reveals distinct regulatory axes for E2F and BETs, with E2F predominantly localized to active gene promoters of growth and/or proliferation genes and BETs disproportionately at enhancer-regulated tissue-specific genes. These two separate gene regulatory axes can be simultaneously targeted to impair the myeloma proliferative program, providing an important molecular mechanism for combination therapy. This study therefore suggests a sequestered cellular functional control that may be perturbed in cancer with potential for development of a promising therapeutic strategy.

A novel 3D mesenchymal stem cell model of the multiple myeloma bone marrow niche: biologic and clinical applications.

Specific niches within the tumor bone marrow (BM) microenvironment afford a sanctuary for multiple myeloma (MM) clones due to stromal cell-tumor cell interactions, which confer survival advantage and drug resistance. Defining the sequelae of tumor cell interactions within the MM niches on an individualized basis may provide the rationale for personalized therapies. To mimic the MM niche, we here describe a new 3D co-culture ex-vivo model in which primary MM patient BM cells are co-cultured with mesenchymal stem cells (MSC) in a hydrogel 3D system. In the 3D model, MSC with conserved phenotype (CD73+CD90+CD105+) formed compact clusters with active fibrous connections, and retained lineage differentiation capacity. Extracellular matrix molecules, integrins, and niche related molecules including N-cadherin and CXCL12 are expressed in 3D MSC model. Furthermore, activation of osteogenesis (MMP13, SPP1, ADAMTS4, and MGP genes) and osteoblastogenic differentiation was confirmed in 3D MSC model. Co-culture of patient-derived BM mononuclear cells with either autologous or allogeneic MSC in 3D model increased proliferation of MM cells, CXCR4 expression, and SP cells. We carried out immune profiling to show that distribution of immune cell subsets was similar in 3D and 2D MSC model systems. Importantly, resistance to novel agents (IMiDs, bortezomib, carfilzomib) and conventional agents (doxorubicin, dexamethasone, melphalan) was observed in 3D MSC system, reflective of clinical resistance. This 3D MSC model may therefore allow for studies of MM pathogenesis and drug resistance within the BM niche. Importantly, ongoing prospective trials are evaluating its utility to inform personalized targeted and immune therapy in MM.