“The first thing to say about multiple myeloma is that history is really changing and today we can finally give hope to our patients.” To speak is Claudio Circle, doctor and researcher of the Hematology Unit of the Romagnolo Institute for the Study of Tumors (IRST IRCCS) of Meldola, in Emilia Romagna, who has been dealing with this blood cancer for years. “Before 2015 – he continues – when a relapse occurred we had very few possibilities of cure, but for less than two years the landscape has drastically changed: we have smart drugs, without chemotherapy, which allow a life expectancy of many years, maintaining a good quality of life. And we’re conducting clinical trials on entirely new approaches. Multiple myeloma is no longer an incurable disease ”.
The new drugs in use
We are talking about a blood cancer in which B lymphocytes and other cells of the immune system (called plasma cells) proliferate uncontrollably and accumulate in the bone marrow. Although lagging behind other neoplasms, even for multiple myeloma we have now entered the era of precision oncology: there are many classes of drugs introduced in recent years, such as second generation proteasome inhibitors (carfilzomib, ixazomib) , immunomodulating drugs (thalidomide, lenalidomide and pomalidomide), monoclonal antibodies (daratumumab – which is confirmed, in combination with bortezomib and immunomodulators, the new standard first-line therapy in patients both eligible and not eligible for autologous stem cell transplantation – elotuzumab and isatuximab) and histone deacetylase inhibitors (panobinostat). “These new drugs – explains Cerchione – have shown a significant improvement in both progression-free survival and overall survival. In addition, they have excellent tolerability, which allows patients to do the therapies continuously ”. The goal is therefore to obtain a continuous control of the disease, making it chronic, and at the same time the aim is to improve the quality of life, to think about the person and not just about the tumor. Even after autologous stem cell transplantation – at the center of myeloma treatment in young patients – a long-term ‘maintenance therapy’ is now envisaged, always with an immunomodulating agent, lenalidomide.
Advanced therapies, the future is already among us
by Letizia Gabaglio
The therapies of tomorrow
We also have confirmation of the efficacy of immunotherapy with monoclonal antibodies from the first line of treatment, even in high-risk asymptomatic forms such as smoldering multiple myeloma, so far managed with a “wait and observe” strategy, in which satuximab, an antibody new generation anti-CD38 monoclonal. “Finally we can hope to talk, in the near future, not only about survival”, says the hematologist: “For the most difficult cases of myeloma to treat, however, in which all therapies have failed, innovative combinations of selinexor drugs belantamab mafodotin are showing increasingly encouraging results ”.
I’ll tell you about the CAR-T
Still, for those who do not respond to conventional treatments or lose the response previously obtained, frontier therapies that act on the immune system, such as bispecific antibodies and CAR-T, already approved for other blood cancers, are close at hand. Bispecific antibodies are drugs capable of latching on to two targets: on the one hand the T cells and on the other the tumor cells to be targeted; CAR-T – currently reserved for some selected patients – are therapies that are based on the removal of the patient’s own T lymphocytes: these cells are “armed” in the laboratory so that they can recognize and attack the tumor, and then reinfused into the patient . In both cases, studies are beginning to confirm very encouraging data of these innovative approaches for multiple myeloma as well.
Multiple myeloma: with Car T, survival exceeds two years
What it means to personalize care
At the same time, the understanding of the biology of this tumor also increases, which appears more and more as a heterogeneous pathology, and which does not only affect the elderly, as is often believed. “The challenge now is to outline the best therapeutic sequence and the correct combinations from the beginning, using the best weapon as soon as possible, in order to obtain the best result immediately, and at the same time personalizing the treatment”, underlines Cerchione. How? Thanks to patient profiling: “In IRST, for example, we perform the molecular characterization of all patients with multiple myeloma, who are also subjected to a new generation imaging exam, thanks to Whole Body magnetic resonance in addition to PET / CT , to improve staging. The aim is also to deepen the study of minimal residual disease and to determine new biomarkers of response. The therapy cannot be personalized if the patient is not monitored over time “.
A look to the future
Many of the ongoing clinical trials for relapsed / refractory multiple myeloma are evaluating precisely the combinations of multiple drugs that can work in the disease. Other phase 1 studies are testing new molecules, some of which do not even have a name yet, but are identified by abbreviations. Such as the bispecific antibody CC-93269, or the targeted drugs eftozanermin alfa and SAR439459, with innovative mechanisms of action that are already giving good results in patients who have failed conventional therapies. “For patients who have exhausted the therapeutic options, the possibility of entering a phase 1 trial means being subjected to a totally revolutionary treatment”, emphasizes Cerchione: “It is important to emphasize that this absolutely does not mean being ‘guinea pig’ , as many fear, but it represents an opportunity for treatment at the moment still at an early stage of study, but which could be approved to treat this pathology in the future and which otherwise could not be accessed outside the research protocol today ”.
Confirmations from real-world data
In addition to clinical studies, however, so-called real-world data, i.e. the data that come from daily clinical practice on unselected patient populations, are fundamental for research and for those who cannot access trials. At the last European Hematology Association (EHA) Congress 2021, which was held last week, the real-world data on the latest therapies for multiple myeloma were discussed: “In general – concludes Cerchione – to date the data confirm the good results obtained in controlled studies. And this is another excellent news for our patients: the road to treatment is no longer just a dream “.
.