Ricerca di base nello sviluppo di isatuximab e il suo impiego per il trattamento dei pazienti con mieloma multiplo recidivato/refrattario

The CD38 molecule has become a target for antibody-mediated therapy of Multiple Myeloma (MM), providing favorable clinical results and manageable patient toxicity. There are currently two anti-CD38 antibodies available in Italy. This note is aimed at examining the characteristics of isatuximab (Isa), against the backdrop of accumulated evidence concerning the CD38 target. The results of pre-clinical studies are described and assessed in a translational perspective. Comparative analysis of these results is necessary because of the variety of functions attributed to CD38. The results obtained indicate that the molecule is an appropriate target, and that the antibody acts through the cooperation with effector leukocyte cells. The interaction with receptors for the Fc portion of the therapeutic molecule is then evaluated for increasing the half-life of Isa. CD38 is also an ectoenzyme, which metabolizes extracellular NAD+ and production of cADPR and ADPR. Isa was the only antibody inhibiting CD38 enzymatic activities. Evaluation of the antibody's mechanism of action leaves multiple unanswered questions. It is to be expected that the results from in vivo experience with Isa may shed light on some of them. Preclinical studies have shown that Isa activity is significantly enhanced when combined with immunomodulators, particularly pomalidomide (IsaPd). Indeed, the pomalidomide based combination can overcome lenalidomide (Len) resistance. Preclinical and clinical results supported the investigation of Isa as a monotherapy and in combination with IMiDs in clinical studies. Indeed, the clinical efficacy provided by the association of IsaPd hold the potential to challenge an unmet medical need represented by the Len previous exposure or refractoriness. Nowadays, if the patient is fit enough, a triplet-based approach seems more reasonable than a doublet one. Nevertheless, within the subgroup of Len exposed patients the mPFS is still unsatisfactory. Thus, given that frontline Len would represent a growing option the question regarding the relapse setting after those regimen warrants further improvements. ICARIA-MM is the first randomized phase 3 trial adding a CD38 antibody to Pd backbone. Remarkably, the patients' characteristics comprised subjects with renal insufficiency, approximately one third of the patients had three median lines of therapy, and most subjects was Len refractory. Benefit of anti-CD38 Isa addition was statistically and clinically significant, irrespectively from glomerular filtration rate, cytogenetic risk, Len refractoriness.