Advancing the indication for CAR-T reduces the risk of myeloma progression by 74%
New data from a study presented at the American Society of Clinical Oncology (ASCO) annual meeting, in Chicago, support the use of the CAR-T therapy ciltacabtagen autoleucel (cilta-cel) in patients with multiple myeloma unresponsive to lenalidomide, from the first relapse. The trial, whose results are also published in The New England Journal of Medicine, proposes thus advancing the use of advanced therapy. The treatment is currently indicated in patients who have received at least three therapeutic lines, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.
Multiple myeloma mostly affects older people; According to data from the Spanish Society of Hematology and Hemotherapy (SEHH), it accounts for 10% of all cases of blood cancer.. Lenalidomide has become the basis of treatment for these patients, but its use has expanded so much that the number of patients where there is no response to the drug has also expanded.
In the range of treatments available for multiple myeloma, advanced CAR-T therapy has broken out in recent years, lymphocytes from the patient that are extracted to provide them with a CAR (chimeric antigen receptor, in English) and once modified, introduce them again in the patient in a way that they rocket to cells expressing BCMA, which is present primarily on the surface of multiple myeloma cells. In this way, the CAR-T lymphocytes identify and eliminate these tumor cells.
The results of an international study of 419 patients indicate that CAR-T cilta-cel therapy not only offers better results than current options in selected myeloma patients, but can also be used safely in earlier phases of treatment.
First recruiting country
Several of the principal investigators of this multicenter study are doctors from Spanish hospitals. Not surprisingly, Spain is the first country to recruit the trial, with more than 80 patients included. Jesús San Miguel, medical director and specialist in Hematology at the Clínica Universidad de Navarra, is the first signatory of the work at NEJM, where the hematologists Carlos Fernández de Larrea (Hospital Clínic de Barcelona) also participate; Joaquín Martínez-López (Hospital 12 de Octubre, Madrid); Albert Oriol (Catalan Institute of Oncology, Badalona), as well as María Victoria Mateos, from the Salamanca University Hospital.
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The hematologist María Victoria Mateos, president of the SEHH, highlights to this medium the repercussion of the study, “the first randomized in phase III that evaluates the role of a CAR-T versus BMCA, cilta-cel, in patients who have received between one and 3 previous lines of treatment, with the peculiarity that all the patients included are refractory to lenalidomide”. The fact is relevant, emphasizes Mateos, given that “after the first line of treatment, the vast majority of patients, I would say that 99%, will be refractory to lenalidomide.”
Two conventional treatments
In this population of patients, so similar to the one found today in consultations, the analysis compares the use of CAR-T against two standards of early treatment; specifically, in patients refractory to lenalidomide who have received one of the two pomalidomide-based treatments: bortezomib or daratumumab.
After analyzing the 419 randomized patients, “we saw that cilta-cel provides a very significant benefit in progression-free survival, with a risk ratio or hazard ratio of 0.26”, says the specialist. After a median follow-up of 16 months, the risk of progression was reduced by 74% compared with conventional treatments.
The objective response rates, or percentage of patients whose cancer responds to treatment, are established in the study at 84.6% in the CAR-T group versus 67.3% in those exposed to the standard combinations.
“73% of patients who received advanced therapy achieved at least a complete response. It's an unusual complete remission rate in relapsed myeloma, I'd even say it's unusual in front-line patients as well.”
Another element evaluated in the study is minimal residual disease, a factor that indicates the presence of some remaining tumor cells after receiving treatment.. It has been known for some time that having negative minimal residual disease is a very important marker of progression-free survival and overall survival, and this has been seen in 60.6% of those treated with cilta-cel compared to 15.6%. of the control branch.
The hematologist points out that in terms of safety, CAR-T therapy has a very different profile from that exhibited by conventional treatments. Cell therapy is associated with two characteristic side effects: cytokine release syndrome (usually caused by activation of immune cells and symptoms such as fever) and neurotoxicity.. “In up to 76% of patients treated with cilta-cel the syndrome was observed, and in up to 20% we found some neurotoxic event, although the vast majority were grade 1 or 2, and resolved with symptomatic treatment.”
Regarding adverse events comparable to treatment standards, haematological toxicity was observed in both arms of the study: more than 80% of the patients presented neutropenia in practically both treated groups.. “And there were no big differences in terms of infections; 25% of the patients presented them in grade 3 or 4.”
100% refractory
For this specialist, who has also headed the committee on plasmatic diseases of the American meeting, the great advantage pointed out by the study is that “one hundred percent of the patients included are refractory to lenalidomide. It is true that we are increasingly using monoclonal antibodies as part of the first line of treatment, and in the trial 22-23% of patients have received the monoclonal antibody daratumumab and are, in fact, refractory to the drug.. Although daratumumab is used first-line in clinical practice, as continuous treatment it is used only in older patients; in young patients, maintenance lenalidomide continues to be used, and patients will not initially receive daratumumab as part of maintenance, thus the patient population enrolled in the Cartitude-4 trial remains well represented,” argues.
At the moment, in Spain, CAR-T cells are still not accessible against BCMA (neither cilta-cel, nor the other approved construct, idecabtagene vicleucel or ide-cel).. However, María Victoria Mateos is optimistic about the possibility that the situation will change in the coming months “and we can count on advanced therapy for our patients; initially with the indication of advanced phases, that is, after having received three previous therapies, which may be the starting point to advance it to earlier lines”.