Minimal residual disease, which detects the number of malignant cells remaining in the marrow after treatment, is the most powerful criterion for predicting remission or relapse after treatment. A considerable saving of time and a better individualization of the treatment at the key.
Myeloma patients who obtain a negativity of a new criterion, “minimal residual disease”, with an ultrasensitive method (next generation genetic sequencing or NGS), obtain better therapeutic results, with a significant increase in overall survival and progression-free survival. Above all, this result is obtained regardless of the treatment followed, the existing risk factors (cytogenetics) and the stage of the disease.
With next-generation genetic sequencing, which defines minimal residual disease as the presence of less than one malignant cell in 1 million marrow cells (or 10-6) (Adaptive method), this criterion appears to be the most powerful prognostic factor among all the risk factors. These results come from the work of the Intergroupe Francophone du Myélome and are published in the journal Blood.
Multiple myeloma
Myeloma is a hitherto incurable blood cancer linked to the proliferation in the bone marrow of plasma cells, cells that traditionally secrete antibodies. This is the 2th most common form of blood cancer and predominates in men. The proliferation of malignant plasma cells is manifested by the suffocation of the bone marrow, with less production of all normal blood cells, and a risk of anemia, hemorrhages or infections. It is also the cause of an excess production of immunoglobulins, which damage the kidneys and other organs, and a weakening of the bone skeleton with a risk of fracture of almost all the bones and a rise in calcium in the blood (malignant hypercalcaemia).
Minimal residual disease
For a long time, progression under treatment of myeloma was measured by overall survival, then by progression-free survival, which is the time taken for the disease to relapse. This method had the main disadvantage of extending the time taken to evaluate treatments and the financial (long studies) and human (for patients in the least effective group) cost of clinical trials.
Minimal residual disease (MRD) is a new criterion which is now taken into account by the American (FDA) and European (EMEA) regulatory authorities as a clinical criterion, and it is hoped soon, as a substitute criterion, which will enable research on this disease to be transformed, by shortening evaluation times and individualising the treatment strategy.
There are 2 methods which evaluate this MRM on marrow samples: “multiparametric flow cytometry” which makes it possible to detect up to one malignant cell out of 10,000 to 100,000 marrow cells and “new generation genetic sequencing” (NGS) which makes it possible to detect one malignant cell in 100,000 or 1 million marrow cells. The sequencing performed in this study uses Adaptive technology which can detect one malignant cell out of 1 million marrow cells, which is extremely sensitive.
Significant increase in survival
Progression-free survival is significantly longer in patients who achieve or maintain a negative MRM at 10-6. The risk of myeloma progression is almost doubled between patients with an MRM level of 10-6 compared to those who are only 10-5. This risk of relapse is 3 times higher if the MRM is not reached at the end of the maintenance treatment.
Overall survival is also significantly prolonged in patients who have a negative MRM and survival 4 years after the start of maintenance treatment is 94% in negative patients against 79% in those who remain positive. Minimal residual disease negativity is significantly improved in patients who maintained or achieved negativity at the end of maintenance treatment. This last fact underlines the interest of re-measuring the MRM in the long term.
A paradigm shift
This study therefore confirms the prognostic value of minimal residual disease in myeloma: its importance is such that it erases the interest of all other techniques, including cytogenetic techniques.
The study also underlines the interest of having a very high sensitivity of the technique in order to get down to the detection of one malignant cell per million marrow cells. At this level of sensitivity, it is not only possible to obtain a very favorable level of remission, but it is also possible to follow the evolution of the disease and to adjust the treatment as well as possible.
It will now be possible (if the technique is available in France in clinical trials) to propose an intensification of the treatment or an extension of the maintenance treatment in the event of persistence of an MRM, to lighten the treatment in the event of Obtaining an MRM quickly and, why not, resuming the treatment as soon as the MRM becomes positive again.
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