The frontline treatment of multiple myeloma has recently been revolutioned, thanks to the approval of a new backbone, daratumumab, anti-CD38 monoclonal antibody, in both transplant-eligibile and -not eligibile patients.

In transplant-eligible setting, daratumumab has been added, according to CASSIOPEIA trial, to the previous standard-of-care bortezomib-thalidomide-dexamethasone (Dara-VTD), followed by autologous-stem cell transplantation (ASCT), two cycles of consolidation, and oral lenalidomide maintenance until progression.

In transplant-ineligible setting, daratumumab is added, according to MAIA trial, to lenalidomide-dexamethasone (DRD) until progression, or, according to ALCYONE Trial, to bortezomib-melphalan-prednisone (Dara-VMP) x 9 cycles.

Results are incredible in both settings in terms of efficacy and tolerability, with the achievement of very good quality of life for patients, also thanks to the schedules and the subcutaneous administration of daratumumab.

Achieving the deepest response correlates with the best long term result, and that's why, in this scenario, the endpoint becomes not only the achievement of complete response/stringent complete response, but also MRD negativity. That's why the importance of testing accurately the results of the treatment, particularly evaluating MRD during the patient journey, also in real world, is becoming more and more important, not only in order to optimize the use of the drugs, also in maintenance setting, but also to balance correctly efficacy and toxicity.

Ongoing trials are also aiming to evaluate the role of new generation agents, in new quadriplets with potential deepest results but also risk of greater toxicities for which supportive care needs to be improved and standardized.

In next future, ongoing clinical trials aim to evaluate the role of new agents in induction regimens, and also anti-BCMA CAR-T in replacing ASCT, together with the role of bispecific antibodies in maintenance setting, and the idea of MRD-driven approach potentiating or reducing the treatment according to the response.

CAR-T have shown excellent results in heavily pretreated patients, with the limits of tolerability and feasibility, also for costs: the increasing opportunities for academic products could help to improve and optimize the use and also to better evaluate these agents in a less selected population.

Another interesting perspective is to anticipate the treatment, before the onset of symptoms, concentrating efforts on correctly diagnosing and treating high-risk Smoldering myeloma, strongly waiting for results coming from phase 3 trials aiming to compare IMIDs with the combination anti-CD38 antbody, IMIDs and dexamethasone, avoiding ASCT, and permitting to the patients to obtain deep response with a really good tolerability.

In conclusion, in frontline setting, considering the wonderful opportunities that we have in real world, and that are coming in next future, our endpoint, should be to achieve the deepest responses, aiming to MRD negativity, particularly in young and fit patients, balancing with tolerability and quality of life.

This should become the new endpoint of upcoming clinical trials, considering that its achievement could correlates with the best long-term response and could really help us and our patients to the cure of multiple myeloma.