For myeloma patients, “cure” is a magical word. It’s like a coveted pot of gold at the end of the rainbow that disappears like a mirage in the desert as you get closer. This is why it’s very important to have a clear understanding of what “cure” really means and how close we are to achieving this much-desired goal of all myeloma patients.

The Basics

In order to achieve a cure, it’s a given that there should be no active myeloma and that the outcome or survival must be similar or equal to the survival of a matched individual where age, gender, and co-morbidities (i.e., other diseases or illnesses) are considered. Additionally, quality of life (QoL) is typically expected to be within the range of very good to excellent. 

Key Questions

When it comes to aspiring for a cure, there are some key questions that need to be addressed:
 

1. Is there zero residual myeloma?

Is myeloma present anywhere in the body with sophisticated testing? Patients found to have no minimal residual disease or are MRD-negative in the bone marrow and have no detectable disease elsewhere after blood testing and imaging (such as whole-body PET/CT) are most likely qualified to aspire for a cure.

2. Is myeloma permanently gone?

If no myeloma is found, is it gone permanently? This is a frequent and major uncertainty in 2024. We rely mostly on predictors of longer complete remissions such as younger age, early disease at the beginning of treatment, lack of poor prognosis, chromosome/genetic factors, and achievement of early deep response. There is a need for AI algorithms to provide better prediction. There is also the ability to predict likely long survival or not.

Reality Check


Studies on long-term survivors (20 years or longer) revealed that the bone marrow microenvironment remains abnormal. The source, which predisposed the early growth of myeloma, is still there. In addition, many patients even with very long survival are found to have tiny residual pockets of myeloma in areas where the myeloma first began—in areas of original, more bulky disease. In post-treatment MGUS, we can predict that patients will likely have these types of remaining pockets of residual disease.

Practical Definition: What is Functional Cure?

For the patient, there is no difference between MRD negative and the presence of a tiny amount of residual disease which is not active or growing. There is no impact on quality of life and comparatively, patients with true MRD negativity survive longer. This is, therefore, the ideal initial goal of therapy. However, not at the expense of major toxicities if the remaining disease is inactive.



Thus, functional cure (including patients with or without a tiny amount of inactive myeloma) is a reasonable goal and is currently being achieved for many patients. It is important to keep in mind that very late relapses can be managed with the very active and newer therapies that are currently available.
 
Additionally, functional cure can be a multi-step process, and dramatically effective relapse therapies can achieve deep responses and long-lasting benefits.

Functional Cure: By the Numbers

In an IMWG analysis of long survivors published in 2018, a cure fraction of 14.37 percent was noted.  (Usmani SZ, et.al. Clinical predictors of long-term survival in newly diagnosed transplant eligible multiple myeloma - an IMWG Research Project. Blood Cancer J. 2018 Nov 23;8(12):123. doi: 10.1038/s41408-018-0155-7. PMID: 30470751; PMCID: PMC6251924.)
 
This number indicated the fraction of patients still living at 20 years, while taking population comparisons into account. This serves as a baseline for assessments using more recent therapies, including novel and immune therapies.
 
In separate studies of patients included in these analyses, a mix of MRD negative and MRD positive patients was noted. Thus, these 20-year survivors have achieved functional cure—with or without documented residual disease. Predictors of longer survival included patients at a younger age, earlier disease, and non-IgA myeloma. 
 
More recent results indicate likely significant improvements from this 14.37 percent baseline. The GEM-CESAR Cure Trial achieved MRD negativity of ~40 percent at 6 years.
 
The corresponding ASCENT Cure Trial achieved an 84 percent MRD negative rate at 3 years. 
 
It is thus reasonable in 2024 and beyond to expect a significant improvement in the potential functional cure fraction at 20 years.

Similar results are now being seen with recent frontline therapies, such as the PERSEUS Trial; and the IsKia Trial in transplant-eligible patients with similar high early MRD negative rates.
 
From a patient standpoint, it is important to focus on the length of remission (progression-free survival or PFS) and overall survival (OS) potential. 
 
In 2024, an increasing number of patients are achieving first remissions of ~5 years or longer and overall survival of 10 years or longer, indicating early occurrence of functional cure. 
 
I would suggest a shift in focus to long survival, with excellent quality of life safe in the knowledge that many exciting new therapies can further extend survival and perhaps, result in achieving a cure, if not already. A long productive life is what is being sought!

The Bottom Line


When it comes to finding a cure for multiple myeloma, it seems that the “mirage in the desert” is now materializing and becoming a real oasis—with some riders and camels finding respite, as they continue their long journey to a seemingly elusive but nonetheless achievable goal.