As The Beacon previously reported, Spanish researchers recently presented clinical trial results showing that active treatment may be beneficial for some smoldering multiple myeloma patients.

Specifically, the results of the study showed that high-risk smoldering multiple myeloma patients who received Revlimid plus dexametha­sone followed by Revlimid maintenance had a longer time to disease progression and better overall survival than patients who did not receive treatment (see related Beacon ^[1] news).

To help Beacon readers put these results into perspective and better understand their implications, The Beacon asked myeloma specialist Dr. Ola Landgren for his feedback and thoughts on the study.

The resulting discussion was wide-ranging and touched on issues of interest to all multiple myeloma patients -- not just those with smoldering myeloma.

Dr. Ola Landgren, who was not involved with the Spanish study, is a Senior Investigator at the National Institutes of Health (NIH) and Chief of the Multiple Myeloma Section at the National Cancer Institute (NCI). He is regarded as an expert on monoclonal gammopathy of undetermined significance ^[6] (MGUS) and smoldering multiple myeloma ^[2], and he is involved in a number of important studies into potential new treatment regimens for multiple myeloma.

The Myeloma Beacon: How significant are the findings of the Spanish research team, led by Dr. María-Victoria Mateos?

Dr. Landgren:  I find the results by Mateos et al. of major importance. Their data show that treatment of high-risk smoldering multiple myeloma translates into both progression-free and overall survival benefits. These are novel insights. In my opinion, they set the stage for the development of new treatment studies for high-risk smoldering multiple myeloma, aiming to delay and/or prevent progression to multiple myeloma.

Are the findings sufficient to recommend any change in current practice in regard to the treatment of high-risk smoldering myeloma patients?

No, I don't think so. This study is based on approximately 60 treated and 60 non-treated high-risk smolder­ing multiple myeloma patients. The main reason why I don't think it is time to change clinical care is that I think we need to see the results replicated in other independent studies. This view is in full accord with that of the investigators of the Spanish study; they emphasize the need for validation.

Another reason is that, until we have better biological markers easily available to define an individual's risk of progression to symptomatic multiple myeloma, there is a risk of over- and under-treatment of patients diagnosed with smoldering multiple myeloma.

Let me also say that, based on our completed and ongoing research, I personally do not think that smol­dering myeloma truly exists as a disease entity.

I think there are patients in the so called “smoldering multiple myeloma” category that are more like patients with MGUS, while others are what I would call “early myeloma.”

This is not a perspective, however, that you will find in the textbooks (yet).

In our clinic at the NIH, we have assessed a large number of patients diagnosed as smoldering multiple myeloma, with a wide range of tools, including flow cytometry, biomarkers, microRNAs, genetic profiling, molecular / functional imaging, marrow vascularity, early bone changes, and so on.  And we have learned that there is tremendous heterogeneity in terms of biology and the risk of developing symptomatic multiple myeloma.

More importantly, what we have seen is that the biological markers in so-called “high-risk smoldering myeloma” patients are very similar to those seen in patients with symptomatic multiple myeloma. This is why I would rather call high-risk smoldering myeloma “early myeloma.”  The main difference is that the early myeloma patients have not (yet) developed kidney failure, bone fractures, or other symptoms.

[For more information about Dr. Landgren’s studies of precursor diseases and how they progress to active myeloma, see a related Beacon ^[7] opinion article.]

What caveats do you feel are important to mention in regard to the Spanish research?

In addition to the above mentioned need for validation of the results in other studies, I think a caveat is that the study focused mainly on clinical markers. For example, additional molecular markers and functional imaging would allow a much more detailed investigation into why and how the treatment works in some patients and not in others. That would be a translational / biological approach. I am in favor of translational / biological treatment studies to maximize the possibilities to advance the field.

Of course, I realize that it boils down to resources, and I know it is very expensive to do those types of things. Also it takes a lot of advanced infrastructure. Hopefully, future studies will provide more translational / biological insights.

If you believe the Spanish research argues in favor of early treatment of high-risk smoldering myeloma patients, do you feel that the treatment regimen used in the Spanish trial is the best treatment option, or is there evidence that treatment with other agents might be as effective – or even more effective?

The brief answer is: “nobody knows at this time”. We need to design and conduct clinical treatment studies designed to answer these questions. Until we have clear answers, we can only speculate based on available knowledge.

Here is my thinking: if you buy my arguments above about “early myeloma” – that is, that high-risk smol­dering myeloma is very much like symptomatic myeloma, just with less tumor burden – then you have to ask yourself: Would you treat a younger, newly diagnosed multiple myeloma patient with a Revlimid ^[8] (lena­lidomide) - dexa­metha­sone ^[9] (Decadron) combination followed by Revlimid maintenance only (that is, the treatment schedule used in the Spanish study)?

My standard answer would be “No.” So, why don't we do what we typically do for symptomatic multiple myeloma with these “early myeloma patients”?  Why don’t we use a three-drug combination like Revlimid, Velcade ^[10] (bortezomib), and dexamethasone (Decadron), or whatever combination we believe is better?

This is why I am so excited about our newest smoldering multiple myeloma study, which will open at the NIH during the spring of 2012. It will examine a treatment regimen involving eight cycles of carfilzomib ^[11] (Kyprolis ^[12]), Revlimid, and low-dose dexamethasone followed by Revlimid maintenance for a minimum of one year. We are using carfilzomib instead of Velcade in order to increase the efficacy and at the same time reduce the side effects, in particular peripheral neuropathy [a condition characterized by pain and tingling in the extremities due to nerve damage].

Let me stress again, however, the need for more studies before any of these ideas start to be considered “standard of care.”

But isn’t that quite a leap?  Essentially, you are advocating taking patients the medical profession today feels shouldn’t be actively treated, and treating them with one of the more aggressive drug regimens in use for active myeloma. 

Again, the brief answer is: “nobody knows at this time”. We need to design and conduct clinical treatment studies designed to answer these questions.

To me, the whole concept of 'watch and wait' for smoldering myeloma is a consequence of multiple factors, including the fact that, until recently, we have not had access to effective drugs with reasonable or low toxicity profiles.

Also the disease monitoring methods have been, and still are, quite limited in standard day-to-day practice.

With toxic and not very effective drugs, it was not justifiable to expose any person to therapy unless there was a compelling need – specifically, clinically active multiple myeloma.

With newer, effective, and less toxic drugs, that way of thinking has to be challenged scientifically, in my opinion. That is what we are doing as we speak.

Looking at other cancers such as early breast cancer and early prostate cancer, much more work has already been done along these lines, and improved survival outcomes have followed.

Even if we assume that high-risk smoldering myeloma is really “early” active myeloma, is it a form of active myeloma that should be treated with a three-drug regimen that includes two novel agents? 

Or, to put it another way, might this “early” myeloma best be considered a relatively “low risk” form of active myeloma.  And, if so, wouldn’t many myeloma specialists be more comfortable using a less aggressive approach for that kind of myeloma?

First of all, I want to stress the need for better terminology and criteria. When we talk about “high risk” in various settings, I think there is a lot of confusion and inconsistency.

For example, “high-risk multiple myeloma” is commonly used as a term for (active) myeloma patients with a poorer prognosis than the average myeloma patient.

However, just to be clear, “high-risk smoldering multiple myeloma” refers to patients at high risk of trans­formation from smoldering myeloma (or early myeloma) to symptomatic multiple myeloma.

As I mentioned before, I think that many high-risk smoldering myeloma patients are already myeloma (that is, “early myeloma”).

Likewise, I would like to be bold and say: High-risk multiple myeloma does not truly exist as one unique biological entity with a given outcome.

Let's do an intellectual experiment. Let’s say if all multiple myeloma patients were treated only with bisphosphonates ^[13] such as Zometa ^[14] (zoledronic acid) or Aredia ^[15] (pamidronate), then the outcome would be poor for everyone.

In such a scenario, one could call all forms of multiple myeloma “high risk.”

Instead, let's assume that a drug that cures all forms of myeloma was available. All multiple myeloma patients are treated with this drug, and all are being cured.

Now, all multiple myeloma patients are “low-risk.”

This example emphasizes the obvious.  “Risk” is an interaction between biology and intervention. And intervention is a variable that changes between clinicians and institutions, and it is constantly changing over time.

To me, it suggests that there is another way of looking at multiple myeloma patients currently called “high risk.” I prefer to think of these molecular subtypes of myeloma as “myelomas we have not yet figured out how to treat.”

Again, I don’t like the term “high-risk” myeloma. It think it is misleading in that it sounds like there is one subtype of myeloma that is inherently bad, and it does not respond to therapy.

That is not true. We know there are several molecular subtypes hidden in that group and they likely require different treatments for successful outcomes. We need to figure out the biological underpinnings, identify the treatment targets, and develop the right therapies for these subtypes soon!

Regarding your last question, where you assume that “early” myeloma best be considered a relatively “low risk” form of active myeloma. I don’t think there is any data to back that up; that is a theoretical assumption.

In fact, based on our ongoing research, there seem to be “early myeloma” patients with different disease biology. Consequently, as part of a clinical treatment study, I think it is reasonable to catch low disease burden and use powerful treatment strategies.

Just to be very clear; before we have these and other related answers sorted out in clinical treatment studies, in my opinion, we should not start treating early myeloma patients in standard, day-to-day practice.

Those are great points on terminology.  Can you explain a bit more, though, why you feel an aggressive approach with “early myeloma” (high-risk smoldering myeloma) may turn out to make the most sense?

If we think about “early myeloma” as a state of less tumor burden, it is theoretically possible that the less aggressive disease is curable, at least in some patients, with more effective therapy, while more aggressive disease will only be controlled (converted into chronic disease) using early therapy.

If we can cure a patient with early myeloma, that would be a huge thing for us. Of course, the pros and cons of treatment have to be balanced. We cannot accept side effects that are not in accord with the projected outcome.

In the coming years, I envision that some myeloma patients will be cured and others will have extended remission. Likely, many patients will have their disease controlled, which could be viewed as a “functional cure” -- similar, for example, to successfully treated hypertension.

Before we reach this point, a lot of work remains to be done. I think key future strategies will be (1) more rational therapies / drugs (precision medicine), (2) earlier start of therapy in many patients, and (3) better monitoring before, during, and after therapy.

Again, these are ideas and concepts based on our research. It is not meant to be implemented in any clinical standard-of-care setting at this time.

However, I am very optimistic about the future. We have many new clues and tools to advance the field. We will continue working hard for our patients. Our ultimate goal is to find a cure for myeloma. It is an exciting time to develop new strategies for myeloma and its precursor states!