The past 2 decades have seen so many advances in the treatment of multiple myeloma; in addition, median patient survival has grown from just 3 years in the late 1990s to between 8 and 10 years today,1 with some patients exceeding that prognosis by many years. Although still considered a stubbornly incurable cancer, higher rates of complete response achieved by targeted, immunomodulatory, and cellular therapies, as well as with conventional treatments such as autologous stem cell transplantation, are leading to the use of terms such as “functional cure” and “cure fraction or relative survival.” “Functional cure” is used to describe patients who have experienced an excellent response to therapy but still have low levels of residual tumor cells in their bone marrow; and “cure fraction or relative survival” describes when the survival of a patient with myeloma is the same as a peer without myeloma. However, because most patients with myeloma face persistent relapses despite remaining on continuous maintenance therapy, they do not meet the criterion for “cure,” argues S. Vincent Rajkumar, MD, Edward W. and Betty Knight Scripps Professor of Medicine at the Mayo Clinic, Rochester, Minnesota.
S. Vincent Rajkumar, MD
“People with lifelong diabetes can take insulin and die of something else. Do we call that a cure? No,” said Dr. Rajkumar. “The word ‘cure’ has a specific meaning as explained by Eric C. Easson and Marion H. Russell in their 1963 paper defining cure in Hodgkin disease. In cancer, they noted, ‘cure’ should ‘connote that in time—probably a decade or two after treatment—there remains a group of disease-free survivors whose annual death rate from all causes is similar to that of a normal population group of the same sex and age distribution.’2 Cure requires a fixed duration of therapy, and, in a subset of patients, the disease never comes back after stopping therapy. That happens in many cancers, and we know what it looks like. In some localized, resectable solid tumors, you remove the cancer, and patients are cured. In Hodgkin lymphoma, diffuse large B-cell lymphoma, and childhood acute lymphoblastic leukemia, you give chemotherapy for a finite period of time, and a subset of patients are cured and live out a normal life without recurrence. That is the real definition of ‘cure,’ and I don’t want to change that definition.
Dr. Rajkumar continued: “What we are actually doing in myeloma is turning it into a chronic disease that people can live with and have a normal life, but I don’t use the word ‘cure’ in that circumstance, because it is not true since patients need to be on continuous therapy and continue to face multiple relapses while on therapy.”
In 2018, Dr. Rajkumar and his colleagues published an article on defining cure in multiple myeloma in which they assessed overall and progression-free survival of patients with myeloma aged 50 and younger and compared outcomes with similarly aged patients diagnosed with follicular lymphoma, diffuse large B-cell lymphoma, and Hodgkin lymphoma. They found that nearly all patients with diffuse large B-cell lymphoma and Hodgkin lymphoma—but not follicular lymphoma or multiple myeloma—alive 3 years following their diagnosis were essentially cured of their cancer; they also found that their subsequent survival was similar to the matched background population, and that there was an unequivocal plateau in the overall survival and progression-free survival curves. The research found that patients with myeloma have a 20-fold excess mortality risk at the 3-year landmark compared with the general population. “Although young patients with multiple myeloma have a 10-year overall survival of nearly 50%, they are typically not being cured,” concluded the study authors.3
The ASCO Post talked with Dr. Rajkumar about his study’s results; what can be considered a “cure” in myeloma; and whether myeloma is curable if found early.
Determining Cure in Myeloma
In your study “Defining Cure in Multiple Myeloma,” you compared survival outcomes of young patients with myeloma with those of patients with other blood malignancies and concluded that myeloma remains an incurable cancer. Other studies show using a “total therapy” (TT) approach in which all myeloma-active drugs are used in the upfront setting to target drug-resistant subclones during initial treatment to prevent later relapse resulted in a “cure fraction” of almost 50% in patients receiving the TT3 maintenance protocol of dexamethasone, thalidomide, and bortezomib.4 Are these patients “cured” of myeloma?
You have to read our paper with a different frame of mind. It was not our intention to describe survival or progression-free survival or define cure in myeloma. We just wanted to give people a picture of what overall survival and progression-free survival curves of curable diseases, such as diffuse large B-cell lymphoma and Hodgkin lymphoma, look like and how different myeloma and follicular lymphoma look in comparison.
We wanted to make the point that we know what cure looks like and if we are really curing patients, we will know it because patients will stop relapsing, and the curve will become flat. To us, the survival curves in myeloma do not resemble the ones in curable diseases. Further, unlike diffuse large B-cell lymphoma and Hodgkin lymphoma, patients with multiple myeloma were likely receiving chronic therapy.
I am an investigator in the Black Swan Research Initiative, which is trying to achieve a true cure in patients with myeloma. I am also an investigator in the ASCENT trial, which is using a combination of carfilzomib, lenalidomide, dexamethasone, and daratumumab in patients with high-risk smoldering multiple myeloma. Our goal is to learn whether starting treatment early substantially improves outcomes, leads to deep response (including a higher proportion of minimal residual disease–negative disease), and may translate into sustained remissions and potential cure.
That’s our goal, to see patients live a normal lifespan without myeloma recurring following a fixed duration of therapy.
Understanding the Difference Between Curable and Cured
Some patients with myeloma live for decades after diagnosis. Are they cured of their cancer?
We need to distinguish between what it means when we say a disease is curable from what we mean when we say a patient is cured. There are always some patients who appear to be cured of a cancer we typically consider incurable. There are always some patients who do extraordinarily well and have no relapses even after 20 or 30 years. That happens in every disease.
The fact that some people are cured of their cancer is not in denial and that happens in myeloma as well. This was true before drugs such as thalidomide, lenalidomide, and bortezomib came on the market. Some patients lived 20 or 30 years after 1 year of melphalan and prednisone therapy and never had a myeloma recurrence. So, the fact that individual patients are cured or a small group of patients is cured is totally different from whether we consider a cancer curable, which is what we tried to say with our paper.
When you say a disease is curable, there are implications that go with that statement. Can I look a patient in the eye and say I’m going to give you some treatment for 6 months or a year and then after that you have a 50/50 chance of never having this cancer again? With myeloma, we are not able to look a patient in the eye and say that, particularly if the patient is young.
We are able to have that kind of dialogue with patients with Hodgkin lymphoma, diffuse large B-cell lymphoma, acute myeloid leukemia, and acute lymphoblastic leukemia, because that is the truth. Those diseases are then considered curable, and the chances of cure are known.
In those diseases, we do not have continuous, indefinite therapy. That’s what I would like in myeloma. That’s our goal; we are not there yet. Calling myeloma curable is very different from what we are able to achieve now, which is, with continuous therapy, a certain proportion of patients with myeloma are able to out a normal lifespan.
Can Early-Stage Myeloma Be Cured?
Is there a situation in which myeloma is a curable disease, for example, if found in the smoldering or monoclonal gammopathy of undetermined significance stage?
What we are doing with the Black Swan Research Initiative, the ASCENT trial, and the GEM-CESAR study for patients with high-risk smoldering multiple myeloma is to ask the fundamental question of whether myeloma is curable, and if so, what cure looks like. I’d like to cure myeloma. I just need to have a very clear vision of what cure means in this disease.
Why haven’t we been able to cure myeloma, and why haven’t we been able to do what our lymphoma colleagues have done for their patients? It’s a question I ask myself all the time. And I come back with two problems. One is, perhaps we are not curing patients because we don’t have the right drugs or the right tools yet, and once we have the right drugs and tools, we can cure myeloma. Or two, is the problem that we do have the right tools, but we are not using them correctly?
We have to keep finding new tools and will continue to do that. However, solving the second problem is more difficult to resolve or accept.
It is in this context that we had the hypothesis that perhaps we are using the tools we have too late. We are treating myeloma only after it is already symptomatic, rather than at the early, potentially curable stage. To test this hypothesis, we need to treat patients at the high-risk smoldering myeloma stage and determine whether we can cure the cancer. That is the goal we laid down when we launched the Black Swan Research Initiative and the ASCENT and GEM-CESAR studies to see whether we use the best possible treatments early, can we cure myeloma? Only time will tell.
DISCLOSURE: Dr. Rajkumar has received honoraria from Imedex, Research to Practice, SurvivorNet; holds intellectual property in UpToDate; and has held uncompensated relationships with United Health.
REFERENCES
1. Gulla A, Anderson KC: Haematologica 105:2358-2367, 2020.
2. Easson EC, Russell MH: Br Med J 1:1704-1707, 1963.
3. Ravi P, et al: Blood Cancer J 8:26, 2018.
4. Barlogie B, et al: Blood 124:3043-3051, 2014.
