IFN-α potentiates daratumumab response in multiple myeloma: A commpass study Free

Multiple myeloma (MM) is the most common plasma cell dyscrasia, the second most common blood cancer, and a source of tremendous comorbidity with dismal historical outcomes. The modern standard of care for MM comprises a triplet of an immunomodulator (lenalidomide or pomalidomide), a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib), and a glucocorticoid (dexamethasone). This triplet therapy (VRD) has transformed outcomes in MM. In fit patients, consolidation with autologous stem cell transplantation (ASCT) extends remission, and in recent trials, anti-CD38 antibodies (daratumumab) have improved outcomes across patients (60.7% vs 26.9% 1yr PFS; Sonneveld, NEJM 2023) without significant increases in side effects. Nevertheless, all myeloma patients eventually relapse, and the disease remains incurable.

CD38 is an ectoenzyme involved in NAD⁺ metabolism and calcium signaling, which is ubiquitous across various immune cell populations including B cells. We investigated the expression and presentation of CD38 in 858 patients from the Multiple Myeloma Research Foundation (MMRF) CoMMpass cohort, unexpectedly encountering large variability in CD38 expression at diagnosis independent of patient cytogenetics or demographics. While the mechanisms of response versus resistance to daratumumab are incompletely understood, the level of CD38 on the surface of MM cells directly correlates to daratumumab activity. Priming CD38_low patients prior to induction may therefore maximize daratumumab efficacy and lead to sustained remissions.

We decomposed RNA sequencing data from the MMRF CoMMpass cohort using non-negative matrix factorization (NMF) to assess differences in gene expression programs between patients with high or low CD38 at diagnosis. Specific NMF factors discriminated CD38_high from CD38_lowpatients, and gene set enrichment analysis of these factors implicated type I interferon and JAK/STAT signaling. We explored the relationship between type I IFNs and CD38 expression in MM cell lines with variable basal levels of CD38 and treated with type I IFNs. While IFN-β failed to produce a response, IFN-α robustly upregulated CD38 surface protein levels across all MM cell lines. CD38 regulation by type II interferon (IFN-γ) has been intensively studied, but there is limited research into the role of type I interferons. We thus assessed JAK/STAT pathway activity (the canonical signaling pathway for type I inducible genes) after IFN-α treatment. We observed significant upregulation of key members including the heterodimer receptor IFNAR1/2, the JAK kinases, STAT1/2, and the transcription factor IRF9. Our data suggest a IFN-α-mediated positive feedback loop for JAK/STAT pathway expression and activation resulting in CD38 expression on MM cells. To assess enhanced potential for daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC), we incubated IFN-α primed MM cells with donor effector immune cells. We observed a 39.8% decrease in viable MM cells treated with both IFN-α and daratumumab compared to daratumumab alone (50.7 vs 84.1 MM cells/μl). Interestingly, in support of the varied mechanisms of action for daratumumab, the combination treatment also increased direct apoptosis of MM cells in the absence of immune cells by 54.8% compared to daratumumab alone (83.3 vs 184.6 MM cells/μl).

The characteristically high rate of relapse and decreasing length of remission after subsequent relapses provides the rationale for exploring novel therapeutic options in MM. While daratumumab (+ VRD) remains the gold standard for frontline induction and an essential agent in maintenance therapy, CD38_low patients consistently respond at a lower rate. Here we demonstrate IFN-α may provide an established, FDA approved adjuvant for amplifying daratumumab efficacy. Our results warrant further investigation into the specific mechanisms of cytotoxicity induced by combination therapy as well as the optimal treatment window for IFN-α-dependent reprogramming of CD38_lowclones.