Outcomes after chimeric antigen receptor T-cell therapy across large B-cell lymphoma subtypes.

Not available.

A comparison of peripheral blood stem cell collection outcomes for multiple myeloma; mobilization matters in the era of IMiD induction.

Collection of peripheral blood stem cells (PBSCs) for autologous stem cell transplant (ASCT) requires mobilization from the bone marrow. There is variation in mobilization choice; during the COVID-19 pandemic BSBMT&CT guidelines recommended using granulocyte-colony stimulating factor (G-CSF) alone to minimize the use of chemotherapy. We report on the impact of mobilization regimen on stem cell collection, and whether IMiD-containing induction therapy impacts on mobilization and consequently transplant engraftment times for 83 patients undergoing ASCT at Leeds Teaching Hospitals. Cyclophosphamide plus G-CSF (cyclo-G) mobilization yielded more CD34+ cells (8.94 vs. 4.88 ×106/kg, p = < 0.0001) over fewer days (1.6 vs. 2.4 days, p = 0.007), and required fewer doses of salvage Plerixafor than G-CSF only (13.6% vs. 35%, p = 0.0407). IMiD-containing induction impaired all of these factors. CD34+ doses > 8×106/kg were more frequent with Cyclo-G (62% vs. 11%, p = 0.0001), including for those receiving IMiD 1st line induction (50% vs. 13.3%, p = 0.0381). Note that 92.6% of those receiving IMiD-free inductions were mobilized with Cyclo-G. The novel agents used in modern induction regimens (e.g Daratumumab) have been shown to impair yields, increasing the importance of optimizing mobilization regimens in the first instance. Furthermore, as cellular therapies become established in the management of multiple myeloma emerging data highlights the potential benefits of stem cell top up in the management of the haematological toxicities of these therapies. Our findings support re-adoption of Cyclo-G as the gold standard for mobilization to optimize PBSC harvesting and ensure sufficient cells for subsequent ASCTs.

Delayed diagnosis resulting in increased disease burden in multiple myeloma: the legacy of the COVID-19 pandemic.

The COVID-19 pandemic has had global healthcare impacts, including high mortality from SARS-CoV-2 infection in cancer patients; individuals with multiple myeloma (MM) are especially susceptible to poor outcomes. However, even for MM patients who avoided severe infection, the ramifications of the pandemic have been considerable. The consequences of necessary socio-geographical behavior adaptation, including prolonged shielding and interruptions in delivery of non-pandemic medical services are yet to be fully understood. Using a real-world dataset of 323 consecutive newly diagnosed MM patients in England, we investigated the impact of the COVID-19 pandemic on routes to myeloma diagnosis, disease stage at presentation and relevant clinical outcomes. We demonstrate increasing MM presentations via emergency services and increased rates of bony and extra-medullary disease. Differences were seen in choice of induction therapy and the proportion of eligible patients undertaking autologous stem cell transplantation. Whilst survival was statistically inferior for emergency presentations, significant survival differences have yet to be demonstrated for the entire cohort diagnosed during the pandemic, making extended follow-up critical in this group. This dataset highlights wide-ranging issues facing MM patients consequent of the COVID-19 pandemic, with full impacts for clinicians and policy-makers yet to be elucidated.

Immune senescence in multiple myeloma-a role for mitochondrial dysfunction?

Age-related immune dysfunction is primarily mediated by immunosenescence which results in ineffective clearance of infective pathogens, poor vaccine responses and increased susceptibility to multi-morbidities. Immunosenescence-related immunometabolic abnormalities are associated with accelerated aging, an inflammatory immune response (inflammaging) and ultimately frailty syndromes. In addition, several conditions can accelerate the development of immunosenescence, including cancer. This is a bi-directional interaction since inflammaging may create a permissive environment for tumour development. Multiple myeloma (MM) is a mature B-cell malignancy that presents in the older population. MM exemplifies the interaction of age- (Host Response Biology; HRB) and disease-related immunological dysfunction, contributing to the development of a frailty syndrome which impairs the therapeutic impact of recent advances in treatment strategies. Understanding the mechanisms by which accelerated immunological aging is induced and the ways in which a tumour such as MM influences this process is key to overcoming therapeutic barriers. A link between cellular mitochondrial dysfunction and the acquisition of an abnormal immune phenotype has recently been described and has widespread physiological consequence beyond the impact on the immune system. Here we outline our current understanding of normal immune aging, describe the mechanism of immunometabolic dysfunction in accelerating this process, and propose the role these processes are playing in the pathogenesis of MM.

NK cells CD56bright and CD56dim subset cytokine loss and exhaustion is associated with impaired survival in myeloma.

Natural killer (NK) cells are the key cells of the innate immune system that share many characteristics with T lymphocytes; their activation, however, is based on the integration of a range of activatory and inhibitory signals via receptors recognizing recurrent pathogen-associated molecular patterns. Two important populations of NK cells with differing functions are recognized: CD56bright and CD56dim. NK cells have the potential to recognize and kill malignant plasma cells, which offers therapeutic opportunities. We used mass cytometry to examine the phenotype and function of NK cell subsets from patients with newly diagnosed multiple myeloma (NDMM). We show that NK cells in NDMM are shifted toward a CD56bright but dysfunctional cytotoxic phenotype, which exhibits selective loss of cytokine production. The CD56dim subset has features of exhaustion with impaired proliferation, upregulation of programmed cell death protein 1, and loss of T-cell immunoglobulin and mucin domain 3 expression. Poor expression of NK cell activation markers is seen and is associated with inferior long-term survival. These results suggest that NK cell exhaustion is already present by the time of myeloma diagnosis and likely contributes to the loss of immunologic control of malignant plasma cells. Restoring NK cell function via immune-directed therapies offers a route to restoring immunologic control in multiple myeloma.