The Present and Future Multiple Myeloma Landscape

The rapid pace of drug approvals in multiple myeloma (MM) shows no sign of abating. In the past two years, the U.S. Food and Drug Administration (FDA) approved the immune modulator pomalidomide and the proteasome inhibitor carfilzomib for the treatment of late-stage MM. These drugs now are being investigated in the early relapse and, for carfilzomib, frontline settings.

Earlier this year, panobinostat joined the ranks of FDA-approved drugs, the first of a new class of agents for MM patients – histone deaceytelases (HDAC) inhibitors. And the list of approved drugs is very likely to be expanded soon, with the anticipated approval of two monoclonal antibodies, elotzumumab and daratumumab.

This plenitude of new agents has already spawned a cottage industry of combination therapies, both with new drugs or in combination with the widely employed stalwarts bortezomib and lenalidomide. In one example, clinical trials evaluating panobinostat combined with carfilzomib have reported reduced toxicity, offering a new approach for the treatment of MM. These approaches offer hope of further extending and possibly curing patients with this disease.

Unfortunately, though, many patients with myeloma will inevitably relapse, exhausting the available drug options. There is still more work to be done – especially in the area of novel drug targets. For example, a new generation of drugs including venetoclax, which targets ABT-199, and selinexor, which targets nuclear transport, seem promising, as do trametinib, which targets KRAS mutations, and dinaciclib, which targets CDK5. More research with all of these agents is being undertaken.

However, with all of the innovative drugs in the pipeline, recent data seem to suggest that transplantation is still a very powerful option. We can expect an update from the French IMF trial on this subject at this year’s ASH annual meeting in December. For now, it seems that transplantation is here to stay.

In the future, I think we will start seeing more targeted agents for specific subsets of patients, and targeting MM translocations remains a promising route for the future. This can include FGFR3 inhibitors in the t(4;14) MM subtype, venetoclax for the t(11;14) subtype, and proteasome inhibitors in high-risk patients. There is also great hope in the immuno-
oncology space, with checkpoint inhibitors, chimeric antigen receptor T-cell therapy, bispecific T-cell engager antibodies, and monoclonal antibodies in development.