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Answers to FAQs from our 4/5/23 webinar on Multiple Myeloma Precursor Conditions

What determines if patients with monoclonal gammopathy of undetermined significance (MGUS) will eventually advance to active multiple myeloma or something else like Waldenström’s macroglobulinemia and can anything be done to try and prevent this progression?

MGUS almost always occurs before a person develops myeloma or another malignant plasma cell disease (such as Waldenström’s macroglobulinemia or lymphoma). MGUS is associated with a risk of progression of approximately 1% per year. Therefore, the longer you have MGUS the higher the risk is that you will progress. For example, if a patient has had MGUS for 10 years there is a 10% risk and for 30 years the risk is 30%. Overall, the risk of progression is continuous and unfortunately, there are no data to definitively identify patients who have had MGUS for 10 to 15 years or longer that will never develop myeloma. The reason for this is that an MGUS cell clone might be stable during this time, but the longer one has this clone the more likely the clone will evolve to myeloma or another malignant plasma cell disease.

Immune regulation is thought to prevent the switch from MGUS to myeloma. Some data suggest that a patient’s immune system keeps the potentially malignant clone in check. For instance, MGUS that is diffuse (that is, spread out) in the bone marrow has a much lower risk of progression than clustered MGUS. Clustering excludes a patient’s immune cells from controlling the clone. Clusters of MGUS cells make it harder for the immune cells to get to the cells in the center of the cluster allowing the clone then to evolve and change and that is what we get into trouble with.

For now, doctors are unable to predict which MGUS patients will progress and as a result patients should be monitored continuously.

What does the hazard ratio mean when clinical trial data are reported?

The hazard ratio (HR) is a value calculated by statistical analysis that estimates survival endpoints such as overall survival or progression-free survival between two treatment groups over the entire duration of a randomized clinical trial (that is, a study that compares two different treatment groups: the experimental treatment versus the control treatment). The HR value (usually a number greater than or less than 1) indicates how much one treatment is better or worse than the other. For example, if the experimental treatment is better than the control treatment then the HR is less than 1 and if it is worse than the control treatment then the HR is greater than 1. A HR that is equal to 1 means equal efficacy between the two treatment groups.

What new data from myeloma precursor conditions should patients be aware of?

Several interventional trials are under way using newer immunotherapies in smoldering multiple myeloma patients who have the highest risk of developing myeloma within 1 to 2 years. The objective is to determine if immunotherapy has curative potential in these patients. Using immunotherapies earlier in the disease may be more beneficial than using them at relapse since a patient’s immune system is healthier at that stage. However, it is important to note that immunotherapy approaches come with a risk of infections. Infection risk for smoldering multiple myeloma patients may be quite significant considering they are asymptomatic to begin with. Also, it is not yet known whether targeting B-cell maturation antigen (BCMA) with a CAR T cell or bispecific antibody may wipe out the regulatory immune microenvironment that is necessary to control the malignant clone.