Multiple myeloma (MM) is a hematologic malignancy with a multistep evolutionary pattern, in which the pro-inflammatory and immunosuppressive microenvironment and genomic instability drive tumor evolution. MM microenvironment is rich in iron, released by pro-inflammatory cells from ferritin macromolecules, which contributes to ROS production and cellular damage. In this study, we showed that ferritin increases from indolent to active gammopathies and that patients with low serum ferritin had longer first line PFS (42.6 vs. 20.7 months and, p = 0.047, respectively) and OS (NR vs. 75.1 months and p = 0.029, respectively). Moreover, ferritin levels correlated with systemic inflammation markers and with the presence of a specific bone marrow cell microenvironment (including increased MM cell infiltration). Finally, we verified by bioinformatic approaches in large transcriptomic and single cell datasets that a gene expression signature associated with ferritin biosynthesis correlated with worse outcome, MM cell proliferation, and specific immune cell profiles. Overall, we provide evidence of the role of ferritin as a predictive/prognostic factor in MM, setting the stage for future translational studies investigating ferritin and iron chelation as new targets for improving MM patient outcome.

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by a multistep evolutionary pathway, with an initial phase called monoclonal gammopathy of undetermined significance (MGUS), potentially evolving into the symptomatic disease, often preceded by an intermediate phase called “smoldering” MM (sMM). From a biological point of view, genomic alterations (translocations/deletions/mutations) are already present at the MGUS phase, thus rendering their role in disease evolution questionable. On the other hand, we currently know that changes in the bone marrow microenvironment (TME) could play a key role in MM evolution through a progressive shift towards a pro-inflammatory and immunosuppressive shape, which may drive cancer progression as well as clonal plasma cells migration, proliferation, survival, and drug resistance. Along this line, the major advancement in MM patients’ survival has been achieved by the introduction of microenvironment-oriented drugs (including immunomodulatory drugs and monoclonal antibodies). In this review, we summarized the role of the different components of the TME in MM evolution from MGUS as well as potential novel therapeutic targets/opportunities.

• A higher GTL ratio improves daratumumab response and prolongs progression-free survival in patients with MM. • BM-derived granulocytes are involved in the therapeutic activity of daratumumab.

Multiple myeloma (MM) develops through asymptomatic precursor stages characterized by progressive remodeling of the bone marrow (BM) immune microenvironment and disruption of bone homeostasis. To delineate changes in natural killer (NK) cell states during disease evolution, we investigated coordinated immune-tumor remodeling by integrating NK cell functional states with plasma cell-intrinsic susceptibility programs derived from CRISPR-based screens across healthy donors (HD), monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and newly diagnosed MM patients. The integration of NK cell state-associated gene signatures with plasma cell transcriptional programs revealed stage-specific co-variation between immune and tumor compartments. Public single-cell RNA sequencing datasets were interrogated to resolve NK cell heterogeneity, identifying cytotoxic CD56^dim and regulatory CD56^bright subsets. NK cell dynamics displayed stage-dependent changes, with early expansion followed by the contraction of CD56^dim cells in BM, whereas CD56^bright cells showed predominantly compositional remodeling. Within the CD56^bright subset, transcriptional changes included an increased expression of KLRC1 (encoding NKG2A), subsequently validated by multiparametric flow cytometry. In parallel, plasma cell programs associated with NK sensitivity progressively decreased along disease stages, supporting tumor adaptation to immune pressure. The NKG2A ligand HLA-E displayed selective expression within CD16⁺ monocytes and followed a distinct variable pattern across disease stages, highlighting a microenvironmental contribution to NK cell regulation. Collectively, these findings indicate a coordinated process of immune-tumor co-evolution, characterized by dynamic remodeling of NK cell states and plasma cell susceptibility, with the NKG2A–HLA-E axis emerging as a central interface during MM progression.

Thrombosis is a common complication in multiple myeloma (MM) patients treated with immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide. When combined with anti-CD38 monoclonal antibodies, these agents are highly effective but may increase thrombotic events (TE), potentially delaying therapy. This exploratory, hypothesis-generating analysis, conducted within the MMVision mono-institutional prospective study, included 53 MM patients who initiated IMiD plus anti-CD38 therapy between May 2021 and December 2022 (median follow-up: 18 months). Treatment regimens comprised lenalidomide (n = 36) or thalidomide (n = 15) with daratumumab, and pomalidomide (n = 2) with isatuximab. Most patients (n = 38) received frontline therapy, and all were given thromboprophylaxis according to guidelines, mainly aspirin (73%). Five patients (9.4%) developed VTE after a median of 48 days, managed with short-term low-molecular-weight heparin (LMWH). Exploratory analysis of 27 clinical/laboratory parameters suggested possible associations between VTE and low levels of beta-2 microglobulin, ferritin, intact/free lambda light chains, and monocyte-to-lymphocyte ratio. Notably, four of the five VTEs occurred in patients without lytic bone disease, typically associated with bone-driven inflammation in MM. Although all patients received aspirin prophylaxis from treatment initiation, it remains unclear whether thrombosis would also have occurred among those with higher inflammatory burden. These preliminary observations may indicate that in patients with relatively lower inflammation, aspirin prophylaxis could be less effective, potentially favoring VTE onset. In two VTE cases, cytokine profiling showed decreased M-CSF, SCLF-β, and MIP-1α, with increased G-CSF, raising the hypothesis of distinct immune-inflammatory pathways contributing to TEs. Given the limited number of patients and thrombotic events, and the cytokine data available for only two VTE cases, these associations should be regarded as exploratory and interpreted with caution. Overall, these exploratory findings warrant validation in larger, independent cohorts and may help generate hypotheses on how inflammatory signatures influence thrombotic risk and prophylaxis efficacy in MM patients receiving IMiD/anti-CD38-based regimens.