Antibody-drug conjugates: when chemotherapy meets immuno-oncology
Mené sur 64 patients atteints d'un myélome multiple réfractaire aux traitements ou récidivant (durée médiane de suivi : 24,2 mois), cet essai multicentrique de phase I/IIa détermine la dose maximale tolérée de l'indatuximab ravtansine en combinaison avec un traitement par dexaméthasone-lénalidomide ou dexaméthasone-promalidomide puis évalue la réponse objective et la toxicité associées à ces protocoles thérapeutiques
In multiple myeloma, immunomodulatory agents and proteasome inhibitors ignited the transition from conventional chemotherapy, mainly based on cytotoxic drugs interfering with DNA repair and cell proliferation, to targeted therapies specifically sabotaging plasma-cell functioning and eliciting the immune system against tumour cells. Another revolution in the therapeutic approach was the introduction of monoclonal antibodies that, being directed against cell-surface targets, increased on-target activity while sparing normal cells. Anti-CD38 monoclonal antibodies played a major role in this process and now represent, with proteasome inhibitors and immunomodulatory agents, the backbone of most anti-multiple myeloma regimens adopted at diagnosis or at relapse. However, given the high heterogeneity of multiple myeloma cell biology and the poor efficacy of current drugs in completely eradicating the disease, treatment-resistant clones will inevitably emerge, thus fostering the development of refractory disease. Resistance mechanisms to anti-CD38 monoclonal antibodies are not completely understood, and data on retreatment with different agents targeting the same surface antigen are scarce. Therefore, patients refractory to anti-CD38 therapies currently represent an unmet medical need, and the development of new compounds with different targets or mechanisms of action is warranted.