Caspase 8 deletion causes infection/inflammation-induced bone marrow failure and MDS-like disease in mice.

Myelodysplastic syndromes (MDS) are a heterogeneous group of pre-leukemic hematopoietic disorders characterized by cytopenia in peripheral blood due to ineffective hematopoiesis and normo- or hypercellularity and morphologic dysplasia in bone marrow (BM). An inflammatory BM microenvironment and programmed cell death of hematopoietic stem/progenitor cells (HSPCs) are thought to be the major causes of ineffective hematopoiesis in MDS. Pyroptosis, apoptosis and necroptosis (collectively, PANoptosis) are observed in BM tissues of MDS patients, suggesting an important role of PANoptosis in MDS pathogenesis. Caspase 8 (Casp8) is a master regulator of PANoptosis, which is downregulated in HSPCs from most MDS patients and abnormally spliced in HSPCs from MDS patients with SRSF2 mutation. To study the role of PANoptosis in hematopoiesis, we generated inducible Casp8 knockout mice (Casp8-/-). Mx1-Cre-Casp8-/- mice died of BM failure within 10 days of polyI:C injections due to depletion of HSPCs. Rosa-ERT2Cre-Casp8-/- mice are healthy without significant changes in BM hematopoiesis within the first 1.5 months after Casp8 deletion. Such mice developed BM failure upon infection or low dose polyI:C/LPS injections due to the hypersensitivity of Casp8-/- HSPCs to infection or inflammation-induced necroptosis which can be prevented by Ripk3 deletion. However, impaired self-renewal capacity of Casp8-/- HSPCs cannot be rescued by Ripk3 deletion due to activation of Ripk1-Tbk1 signaling. Most importantly, mice transplanted with Casp8-/- BM cells developed MDS-like disease within 4 months of transplantation as demonstrated by anemia, thrombocytopenia and myelodysplasia. Our study suggests an essential role for a balance in Casp8, Ripk3-Mlkl and Ripk1-Tbk1 activities in the regulation of survival and self-renewal of HSPCs, the disruption of which induces inflammation and BM failure, resulting in MDS-like disease.

Busulfan, melphalan and carfilzomib high-dose chemotherapy and autologous haematopoietic stem cell transplantation in multiple myeloma.

The standard of care for fit, newly diagnosed multiple myeloma patients includes induction therapy followed by consolidative high-dose chemotherapy with melphalan and autologous stem cell transplant (AHSCT). Intensified preparative regimens, such as busulfan and melphalan (BuMel), have shown promise to lengthen progression-free survival (PFS). We previously reported that the addition of bortezomib to BuMel improved PFS compared to melphalan alone in CIBMTR-matched controls. We now integrate the second-generation protease inhibitor, carfilzomib, before and after BuMel (BuMelCar) in a phase I/II trial with carfilzomib. Patients with NDMM, relapsed/refractory MM (RRMM) and those failing prior AHSCT were eligible. Primary end-points were safety and tolerability. Secondary end-points included minimal residual disease negativity rates, PFS and OS. The study enrolled 19 patients. 73% were high risk either due to R-ISS III status, adverse genetics or relapsed after prior AHSCT. The maximum tolerated dose (MTD) of carfilzomib was determined to be 36 mg/m2. Noted grade 3 toxicities were febrile neutropenia (79%), mucositis (21%) and diarrhoea (16%). The 2-year PFS for the whole cohort and MTD was 89% and 100% respectively. 80% of all patients and 82% of patients in the MTD cohort achieved MRD negativity. Further studies regarding this regimen are planned.

Distinct roles of hematopoietic cytokines in the regulation of leukemia stem cells in murine MLL-AF9 leukemia.

Lymphoid-primed multipotent progenitor (LMPP)-like and granulocyte-monocyte progenitor (GMP)-like leukemia stem cells (LSCs) co-exist in the blood of most patients with acute myeloid leukemia (AML). Complete elimination of both types of LSCs is required to cure AML. Using an MLL-AF9-induced murine AML model, we studied the role of hematopoietic cytokines in the survival of LMPP- and GMP-like LSCs. We found that SCF or FLT3L promotes the survival of LMPP-like LSCs by stimulating Stat5-mediated Mcl1 expression, whereas interleukin-3 (IL-3) or IL-6 induces the survival of GMP-like LSCs by stimulating Stat3/nuclear factor κB (NF-κB)-mediated Bcl2 expression. Functional study demonstrated that, compared to AML cells cultured in IL-3 and IL-6 medium, AML cells in SCF- or Flt3L-only culture are highly clonogenic in in vitro culture and are highly leukemogenic in vivo. Our study suggests that co-inhibition of both STAT5-MCL1 and STAT3/NF-κB-BCL2 signaling might represent an improved treatment strategy against AML, specifically AML cases with a monocytic phenotype and/or FLT3 mutations.

Multicenter analysis of immunosuppressive medications on the risk of malignancy following adult solid organ transplantation.

Objective: This study aimed to assess the risk of maintenance immunosuppression on the post-transplant risk of malignancy across all solid organ transplant types. Methods: This is a retrospective cohort study from a multicenter hospital system in the United States. The electronic health record was queried from 2000 to 2021 for cases of solid organ transplant, immunosuppressive medications, and post-transplant malignancy. Results: A total of 5,591 patients, 6,142 transplanted organs, and 517 post-transplant malignancies were identified. Skin cancer was the most common type of malignancy at 52.8%, whereas liver cancer was the first malignancy to present at a median time of 351 days post-transplant. Heart and lung transplant recipients had the highest rate of malignancy, but this finding was not significant upon adjusting for immunosuppressive medications (heart HR 0.96, 95% CI 0.72 - 1.3, p = 0.88; lung HR 1.01, 95% CI 0.77 - 1.33, p = 0.94). Random forest variable importance calculations and time-dependent multivariate cox proportional hazard analysis identified an increased risk of cancer in patients receiving immunosuppressive therapy with sirolimus (HR 1.41, 95% CI 1.05 - 1.9, p = 0.04), azathioprine (HR 2.1, 95% CI 1.58 - 2.79, p < 0.001), and cyclosporine (HR 1.59, 95% CI 1.17 - 2.17, p = 0.007), while tacrolimus (HR 0.59, 95% CI 0.44 - 0.81, p < 0.001) was associated with low rates of post-transplant neoplasia. Conclusion: Our results show varying risks of immunosuppressive medications associated with the development of post-transplant malignancy, demonstrating the importance of cancer detection and surveillance strategies in solid organ transplant recipients.

Exploring health behaviors and the feasibility of a lifestyle intervention for patients with multiple myeloma.

PURPOSE: Multiple myeloma (MM) is the second most common hematologic malignancy in the USA, with higher rates observed in older adults and African Americans (AA). Survivors experience fatigue, bone pain, reduced functioning, and obesity, highlighting the value of developing lifestyle interventions for this diverse group. This study explores lifestyle behaviors and supportive care needs to inform future programs tailored to the MM community. METHODS: MM survivors, ≥ 100 days post autologous stem cell transplant (ASCT) with a BMI ≥ 20 kg/m2, were recruited from two university hospitals. Diet, physical activity, and quality of life (QOL) were measured using validated measures. Qualitative interviews gathered information on survivorship needs and interests related to supportive interventions. Quantitative data was analyzed using descriptive statistics; qualitative data were analyzed using deductive strategies. RESULTS: Seveny-two MM survivors participated (65% white, 35% black). Participants were 62.5 ± 15.8 years of age. Fifty percent were classified as obese and 65% were insufficiently active. Participants reported diets high in added sugars and saturated fats. QOL measures indicated clinically significant challenges in physical and sexual function. Most (87%) were interested in a lifestyle program. Predominant themes regarding survivors' desires for a lifestyle program included social support, guided exercise, meal preparation support, and disease management information. CONCLUSION: This study demonstrates the need for and interest in lifestyle change support among a racially diverse sample of MM survivors. Interventions that are group-based, target knowledge gaps, social connections, accountability, and provide structured framework with professional instruction will best address the needs of this survivor population.

Isolated leukemia cutis as extramedullary relapse of acute myeloid leukemia.

Acute myeloid leukemia (AML) arises from clonal expansion of malignant hematopoietic precursor cells in the bone marrow. In rare instances, AML can recur with prominent extramedullary manifestations (i.e., leukemia cutis or myeloid sarcoma), either simultaneously or preceding marrow involvement, or as a sole site of primary disease relapse.

The molecular mechanism and challenge of targeting XPO1 in treatment of relapsed and refractory myeloma.

Multiple myeloma (MM) treatment regimens have vastly improved since the introduction of immunomodulators, proteasome inhibitors, and anti-CD38 monoclonal antibodies; however, MM is considered an incurable disease due to inevitable relapse and acquired drug resistance. Understanding the molecular mechanism by which drug resistance is acquired will help create novel strategies to prevent relapse and help develop novel therapeutics to treat relapsed/refractory (RR)-MM patients. Currently, only homozygous deletion/mutation of TP53 gene due to "double-hits" on Chromosome 17p region is consistently associated with a poor prognosis. The exciting discovery of XPO1 overexpression and mislocalization of its cargos in the RR-MM cells has led to a novel treatment options. Clinical studies have demonstrated that the XPO1 inhibitor selinexor can restore sensitivity of RR-MM to PIs and dexamethasone. We will elaborate on the problems of MM treatment strategies and discuss the mechanism and challenges of using XPO1 inhibitors in RR-MM therapies while deliberating potential solutions.

Increasing genomic discovery in newly diagnosed multiple myeloma: defining disease biology and its correlation to risk.

Our understanding of MM genomics has expanded rapidly in the past 5-10 years as a consequence of cytogenetic analyses obtained in routine clinical practice as well as the ability to perform whole-exome/genome sequencing and gene expression profiling on large patient data sets. This knowledge has offered new insights into disease biology and is increasingly defining high-risk genomic patterns. In this manuscript, we present a thorough review of our current knowledge of MM genomics. The epidemiology and biology of chromosomal abnormalities including both copy number abnormalities and chromosomal translocation are described in full with a focus on those most clinically impactful such as 1q amplification and del(17p) as well as certain chromosome 14 translocations. A review of our ever-expanding knowledge of genetic mutations derived from recent whole-genome/exome data sets is then reviewed including those that drive disease pathogenesis from precursor states as well as those that may impact clinical outcomes. We then transition and attempt to elucidate how both chromosomal abnormalities and gene mutations are evolving our understanding of disease risk. We conclude by offering our perspectives moving forward as to how we might apply whole-genome/exome-level data in addition to routine cytogenetic analyses to improve patient outcomes as well as further knowledge gaps that must be addressed.

High-risk disease in newly diagnosed multiple myeloma: beyond the R-ISS and IMWG definitions.

Multiple myeloma (MM) is an acquired malignant plasma cell disorder that develops late in life. Although progression free and overall survival has improved across all age, race, and ethnic groups, a subset of patients have suboptimal outcomes and are labeled as having high risk disease. A uniform approach to risk in NDMM remains elusive despite several validated risk stratification systems in clinical use. While we attempt to capture risk at diagnosis, the reality is that many important prognostic characteristics remain ill-defined as some patients relapse early who were defined as low risk based on their genomic profile at diagnosis. It is critical to establish a definition of high risk disease in order to move towards risk-adapted treatment approaches. Defining risk at diagnosis is important to both effectively design future clinical trials and guide which clinical data is needed in routine practice. The goal of this review paper is to summarize and compare the various established risk stratification systems, go beyond the R-ISS and international myeloma working group risk stratifications to evaluate specific molecular and cytogenetic abnormalities and how they impact prognosis independently. In addition, we explore the wealth of new genomic information from recent whole genome/exome sequencing as well as gene expression data and review known clinical factors affecting outcome such as disease burden and early relapse as well as patient related factors such as race. Finally, we provide an outlook on developing a new high risk model system and how we might make sense of co-occurrences, oncogenic dependencies, and mutually exclusive mutations.

Maintenance therapy after second autologous hematopoietic cell transplantation for multiple myeloma. A CIBMTR analysis.

The role of maintenance therapy after high-dose chemotherapy and first autologous transplantation in multiple myeloma (MM) is well established. We explored the effect of maintenance therapy on outcomes after salvage second autologous hematopoietic cell transplant (AHCT2) using the Center for International Blood and Marrow Transplant Research registry. Outcomes of interest included non-relapse mortality (NRM), relapse/progression (REL), progression-free and overall survival (PFS, OS). Of 522 patients who underwent AHCT2 between 2010 and 2018, 342 received maintenance therapy and 180 did not. Maintenance regimens included lenalidomide (42%), pomalidomide (13%), and bortezomib (13%). Median follow up was 58 months in the maintenance group and 61.5 months in the no-maintenance group. Univariate analysis showed superior outcomes at 5 years in maintenance compared to the no-maintenance group: NRM 2 (0.7-3.9)% vs 9.9 (5.9-14.9)%, (p < 0.01), REL 70.2 (64.4-75.8)% vs 80.3 (73.6-86.3)% (p < 0.01), PFS 27.8 (22.4-33.5)% vs. 9.8 (5.5-15.2)% (p < 0.01), and OS 54 (47.5-60.5)% vs 30.9 (23.2-39.2)% (p < 0.01), respectively. Use of maintenance therapy retained its association with improved outcomes in multivariate analysis. There was no difference in second cancers in the two groups (p = 0.39). We conclude that maintenance after AHCT2 is associated with improved 5-year outcomes.

Busulfan, melphalan, and bortezomib compared to melphalan as a high dose regimen for autologous hematopoietic stem cell transplantation in multiple myeloma: long term follow up of a novel high dose regimen.

Melphalan at a dose of 200 mg/m2 (MEL200) remains the standard high dose therapy before autologous stem cell transplantation (ASCT) for multiple myeloma (MM). Intensifying the high dose regimen has shown promising results. We report here 7-year follow up of our novel high dose regimen of busulfan and melphalan followed by bortezomib (BuMelVel). Forty-three MM patients received BuMelVel high dose therapy with pharmacokinetic adjusted busulfan. Outcomes were compared to a matched control cohort from the CIBMTR database (n = 162) receiving MEL200. The primary endpoint was progression free survival. Five year PFS was 47% v 30% (95% CI; 32-62) in favor or the BuMelVel group (95% CI; 23-37) (p = 0.05). In multivariate analysis for PFS, BuMelVel (HR 0.65; 95% CI 0.44-0.97)(p = 0.036) was predictive. Similar to recent reports of double alkylator therapy, although depth of response was similar between the BuMelVel group and MEL200, the BUMELVEL group experienced an improved PFS.

The Role of Salvage Second Autologous Hematopoietic Cell Transplantation in Relapsed Multiple Myeloma.

Multiple myeloma (MM), a malignant disorder of plasma cells affecting primarily elderly patients, is the second most commonly diagnosed hematologic neoplasm. With the recent influx of effective new agents available, including proteasome inhibitors, immunomodulators, targeted monoclonal antibodies, and now chimeric antigen receptor T cell (CAR-T) therapy, the treatment landscape is evolving rapidly. Although the role of consolidative autologous stem cell transplantation (ASCT) in first remission is well established, in the relapsed setting after upfront ASCT, the role of a second ASCT (SAT) following reinduction is less clear and understudied. Practice patterns vary significantly across institutions, and most of the literature available to guide clinical decisions consists of single-institution experiences, with only 1 randomized study evaluating the role of SAT compared with a nontransplantation approach. SAT is likely underused, because it has not been included in clinical trials examining novel regimens for relapsed disease. Furthermore, outcomes likely can be improved with approaches to intensify the preparative regimen and the use of standard post-transplantation maintenance. In this review, we examine the role of SAT in the current MM treatment landscape in the context of recent data on the efficacy of CAR-T therapy in this disease. We caution the abandonment of SAT, given that CAR-T therapy is in its infancy in MM treatment, and that real-world data in the relapsed setting are consistently inferior to clinical trial outcomes.

Differential Diagnosis of Isolated Myeloid Sarcoma: A Case Report and Review of the Literature.

Myeloid sarcoma (MS) is a rare disease entity identified as a variety of manifestations defined by the occurrence of extramedullary myeloid cell masses with or without bone marrow involvement. This case describes an unusual presentation of isolated MS in a 60-year-old otherwise healthy male, who initially presented to his primary care physician with vague abdominal pain. After extensive workup including three omental biopsies, umbilical core biopsy, and inguinal lymph node biopsy, he was ultimately diagnosed with isolated MS with extensive extramedullary tumor burden. Despite advanced extramedullary disease, peripheral cell counts were normal and bilateral bone marrow biopsies unremarkable with normal cellular lineages, morphology, and cytogenetics. The patient underwent induction chemotherapy and is now greater than 100 days post myeloablative unrelated donor marrow transplantation with no evidence of disease recurrence and 100% donor status with full chimerism. This case demonstrates that making a prompt diagnosis with rapid initiation of treatment in myeloid sarcoma can be challenging due to its varied clinical presentation, cytomorphology, cytochemistry, and cytogenetic overlap with other lymphoid malignancies. Once a diagnosis of MS has been made, moving quickly to induction therapy is important. Several studies have shown that improved overall survival is attained when MS is treated as acute myeloid leukemia and increased survival is noted for patients undergoing bone marrow transplantation. Further prospective studies are needed to elucidate the many remaining questions in regards to the natural history, prognosis, and optimal treatment strategies for this deadly disease.