Issue Archive

It is established that in multiple myeloma, the depth of response to therapy predicts survival. However, the assessment of minimal residual disease (MRD) may be discordant with classical complete remission (CR) with patients having persistent M protein in the face of undetectable MRD. In this Blood Spotlight, Paiva et al review compelling evidence that survival is determined by MRD regardless of the presence or absence of CR.

Menu and Vanderkerken review the role of extracellular vesicles (EV), notably exosomes, in regulating intramedullary processes governing the growth of multiple myeloma (MM) cells and their response to therapy. Exosomes are small vesicles secreted by MM cells carrying protein and RNA that can be delivered to recipient cells. In MM, they have been implicated in immune suppression and drug resistance and contribute to angiogenesis and osteolysis. The authors suggest interventions to block exosome secretion as well as the potential of using EVs as drug delivery vehicles.

Multiple myeloma is associated with high rates of venous thromboembolism (VTE). A reliable prediction model would help guide decisions regarding prophylactic anticoagulation. Chakraborty and colleagues report on a new risk score for VTE prediction that includes disease biology as reflected in abnormal cytogenetics. The PRISM score, based on prior VTE, black race, immunomodulatory drug use, prior surgery, and abnormal metaphase cytogenetics, predicts low (2.7%), medium (10.8%), and high (36.5%) risk groups for a 12-month cumulative VTE incidence.

Cichocki et al report on a novel CAR-natural killer (CAR-NK) cell therapy for B-cell lymphoma that addresses antigen loss, tumor heterogeneity, and failed CAR-cell persistence. The authors engineered induced pluripotent stem cell (iPSC)-derived NK cells with anti-CD19 CAR and a noncleavable CD16 that augments toxicity in the presence of anti-CD20 therapy and added an IL-15/IL-15R fusion to promote cytokine-independent persistence. In vitro and xenograft models treated with the engineered NK cells plus rituximab had robust activity and may represent a promising “off the shelf” approach to targeting B-cell malignancies.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous clinical entity with a dismal prognosis, suggesting a need to better understand its pathophysiology. Vanden Bempt and colleagues identified MYCN as a newly identified recurrent driver of PTCL through cooperation between MYCN and its downstream target EZH2, which depends on phosphorylation by CDK1. MYCN-driven PTCL is sensitive to EZH2 degradation or CDK1 inhibition and shows synergy with histone deacetylase inhibitors.

Vallet et al report on a randomized phase 3 trial examining whether azithromycin could decrease pulmonary graft-versus-host disease. The results are sobering, demonstrating no improvement in bronchiolitis obliterans but an increase in disease relapse. This surprising result is linked to modulation of T-cell subsets toward immunomodulatory and exhausted profiles and raise caution about using azithromycin following stem cell transplantation for hematological malignancy.

Lawal et al report on a 45-fold increase in secondary hematologic malignancy in 120 patients following hematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD), comparable to what has been reported following gene therapy. Notably, the cohort is enriched for older patients and for haploidentical transplant recipients with mixed chimerism following HSCT. These data further support the idea that pre-existing premalignant myeloid clones undergo clonal selection in the setting of nonmyeloablative HSCT and contribute to secondary malignancy.