Drug development in MZL: caring for the forgotten child

Marginal zone lymphoma (MZL) comprises a biologically heterogenous group of indolent B-cell lymphomas that remain substantially underrepresented in clinical research. Despite recent and significant therapeutic advances in B-cell malignancies, trial design in MZL continues to face persistent challenges, including diagnostic heterogeneity, inconsistent control arms, suboptimal end points, and economic barriers. In this narrative review, we examine these key obstacles and discuss emerging strategies to overcome them, such as the standardization of diagnostic criteria, implementation of subtype-specific treatment approaches, validation of surrogate end points, and integration of novel response assessment modalities, such as metabolic imaging (positron emission tomography), minimal residual disease assessment using flow cytometry or single-cell molecular evaluation, and circulating tumor DNA measurement, but these need to be evaluated and harmonized for full appreciation. We argue that MZL should be understood as a methodologic paradigm rather than as a clinical exception. This may facilitate the refinement of trial design and ultimately accelerate therapeutic innovation across the broad spectrum of indolent lymphomas.