DRUGGABLE MM THERAPEUTICS: PATHOGENETIC PATHWAYS
In the current treatment scenario, after 1, 2 or at most 3 lines of therapy, most MM patients have exposed (or are refractory), to PIs, IMiDs and anti-CD38 MoAb. Novel alternatives are currently being developed, mostly using BCMA as a target, and some of them such as CAR-Ts or ADCs have already been approved although they are still not widely available, at least in Europe. But there is still an active search for novel therapeutic options based on the MM pathogenetic vulnerabilites. One such mechanism, although not novel, is DNA damage, and Melflufen, a Peptide-Drug conjugate (PDC) showed activity in heavily pretreated patients, what led to its initial FDA approval, although, significant concerns about long term toxicity have been raised in the phase III study. Selinexor inhibits XPO-1, a protein that exports different proteins from the nucleus of the tumor cell. In combination with dexamethasone, it has demonstrated activity in penta-refractory or triple-class refractory patients, with an ORR of 26% and a DOR of 4 months, that lead to its FDA and EMA approval. Another important target is the E3 ubiquitin ligase CRBN, and in fact, two CELMoDs (CRBN modulators), Iberdomide (CC-220) and CC-92480, have demonstrated activity (ORR 30-50%) and a favorable safety profile in heavily pretreated patients. MM cells are also largely dependent on the antiapoptotic molecule Bcl2, and venetoclax, an inhibitor of this protein, has demonstrated to be active particularly in patients carrying t(11;14). More recently, several Mcl-1 inhibitors are also being evaluated both preclinically and clinically. Another interesting target could be the RAS pathway as it is mutated in around 50% of MM patients and RAS/RAF/MEK inhibitors have demonstrated activity in selected patients populations. Other approaches are also attractive such as myc inhibition or additional ways of activating the immune system. In this last field, two novel mechanisms hold significant promise: inhibition of the do not eat me signal with anti-CD47 MoAb such as Magrolimab, or the use of Modakafusp a CD38 MoAb with two IFN attenuated molecules that induces a anti-tumoral One important field of investigation is the search for biomarkers predicting sensitivity or resistance to a given agents, such as venetoclax in t(11;14) patients, Mcl-1 inhibitors in patients with 1q+, or RAS/RAF/MEK inhibitors for patients with activation of this pathway.