IMS 2022: Moving Towards A Cure for Multiple Myeloma

What defines a myeloma cure? What does that mean? Can we cure every patient? What are the best strategies to cure multiple myeloma?

Myeloma specialists at the recent International Myeloma Society meeting in Los Angeles hosted a session to discuss these important questions.

Dr. Antje Hoering discussed the difference between a functional cure and an eradication cure. The term "functional cure" is used to describe myeloma cells that could be detectable but aren't causing relapse or myeloma progression. An eradication cure approach would be a patient who is MRD negative and the myeloma never returns. As you can imagine, a functional cure may be more realistic in today's myeloma world. 

Defining Functional Cure

The functional cure definition includes the idea of a "cure fraction" or a percentage of patients who are long-term myeloma survivors without experiencing myeloma progression or relapse.

Dr. Hoering mentioned the history of the University of Arkanasa's Total Therapy program which had cure as its goal. The idea of induction therapy, stem cell transplant (or two), consolidation therapy and maintenance therapy originated at UAMS with Dr. Bart Barlogie. That pattern for multi-step treatment is used commonly today.

In the UAMS example below, the data show an average of 16.4% cure rate for all patients who have ever participated in the Total Therapy protocol with an increasing percentage of patients growing as more recent therapies become available. Note the 31.3% of patients in the cure fraction treated between 2009-2013. 

Eradication Cure

Completely eradicating multiple myeloma requires more sensitive testing. Minimal Residual Disease (MRD) testing is an effort to find all remaining cells and the tests are becoming more sensitive. Many studies were mentioned that are now using MRD testing as part of the trial to determine what comes next or when to stop treatment.

One such example is the DRAMMATIC maintenance trial where daratumumab plus lenalidomide after stem cell transplant was used. Patients were randomized to either lenalidomide or dara/lenalidomide. After two years of maintenance, patients are tested for their MRD levels. MRD positive patients continue their therapy. MRD negative patients were then randomized to either discontinue treatment or continue maintenance. When that trial is completed, we will know if stopping therapy when a patient becomes MRD negative is the right choice.

Overall, using MRD testing to identify an eradication cure is a work in progress. 

Barriers to a Cure

Faith Davies, MD of NYU discussed current barriers to a cure. She noted that the American Cancer Society identified 34,470 new myeloma cases per year but still showed 12,640 deaths per year. She also noted that in older studies, the cure fraction was around 10-15% of patients and in more recent studies that percentage is in the 30% range, so things are improving but we aren't there yet. 

Top issues included: 

1. An incomplete understanding of myeloma biology
2. Late diagnoses when patients are more likely to have organ damage such as kidney issues, bone lesions, anemia or elevated calcium (CRAB criteria)
3. Early treatment of precursor conditions - should it be done or not? 
4. Waiting to see if earlier immunotherapy treatment will be helpful
5. An assessment of the tools we have - are there pieces missing?
6. The importance of personalizing management like treatment toxicity, patient factors, disease stage, etc.
7. Precision therapies that could impact specific disease biology/genetics or the micro-environment in the bone marrow

Dr. Davies noted that myeloma treatment is not a one-size-fits-all approach.

Using Immunotherapy to Achieve a Myeloma Cure

Simon Marrison, MD of the Royal Melbourne Hospital in Australia covered how immunotherapy could be used to achieve a cure. He noted that although stem cell transplant is very potent and helps get patients into stronger and longer remissions, 30% of the cure achieved through transplant with allo transplant is offset by graft vs. host disease. 

Dr. Marrison noted that the immune microenvironment fights back even with CAR T therapy approaches and myeloma can return. While some CAR T therapies have an impressive 100% overall response rate, CAR T remains a technologically and logistically complex treatment. Additional advances like donor (allo) CAR T therapies and bispecific therapies are coming and have advantages. Teclistamab is now approved in Europe and is anticipated to be approved soon in the US. Even newer approaches like CAR-NK cell therapy, CAR-macrophages and other NK cell therapy are now being looked at. 

Interestingly, CAR T excludes T cells from the micro-environment, so CAR T may not be helpful for patients with extramedullary disease (myeloma found outside the bone marrow). 

He discussed that a "Total Immunotherapy" approach could look something like:

1. T cell collection
2. Treatment that lowers/debulks the myeloma
3. Stem cell transplant
4. BCMA targeted CAR T therapy
5. Bispecific therapy perhaps targeting something different from BCMA

He noted that infection risk may be prevent such an approach from being feasible. Nevertheless, we have much to learn about a myeloma cure and there is significant development happening in the space.

We have much to be grateful for as myeloma patients in today's treatment landscape. Perhaps with better combinations, earlier immunotherapy use and different sequences and combinations of therapy, more patients may achieve that long-term cure.