In the last 10 years, we have witnessed dramatic changes in the treatment of multiple myeloma that have provided hope and optimism to myeloma patients worldwide.

We have a better understanding of the biology of the disease and an array of approved and investigational new drugs with excellent clinical activity.

Importantly, we have also come to the realization that myeloma is not one genetically distinct disease, but a clinical condition with many distinct molecular subtypes. Indeed, there are subtle differences in clinical presentation among the various subtypes.

More remarkable, however, are the dramatic differences in long-term outcome, even when all available new drugs are used aggressively early in the disease course as some academic centers have tried to do.

These differences in overall survival are the reason why understanding risk-stratification and risk-adapted therapy is so important for patients with multiple myeloma.

What do we know about risk factors in myeloma?

All things being equal (i.e., patients of similar age and functional status), there are some genetic abnormalities that appear to be associated with a shorter duration of response to therapy and shorter survival (high-risk myeloma). These include deletion of chromosome 17p- and translocations t(4;14), t(14;16), and t(14;20), all of which can be detected using a bone marrow test called "fluorescent in situ hybridization", or "FISH."

On the other hand, patients who have extra chromosomes ("hyperdiploidy"), translocation t(11;14), or translocation t(6;14) appear to have longer duration of response to therapy and better survival (standard-risk myeloma).

FISH is not the only way to assess risk status. Risk can also be assessed using other techniques like karyoptyping. Some centers use a full gene expression profile (GEP) to assess risk. Overall, approximately 75 percent to 80 percent of patients with myeloma have standard-risk disease.

What does risk stratification mean for patients? Can we overcome high-risk myeloma? Are these risk factors useful in the era of novel agents?

First of all, no one can predict outcome in a given patient. There are many high-risk myeloma patients I know, who have lived 10 to 15 years or longer.

Second, with recent advances I believe we are indeed starting to overcome some types of high-risk myeloma―at least to some degree. For example, studies at the Myeloma Institute for Research and Therapy (MIRT) at Little Rock, Arkansas, show that with modern therapy, patients with the t(4;14) translocation can on average expect almost similar outcomes as patients with standard-risk myeloma.

Third, although one can be tempted to dismiss risk stratification as an outdated concept or as an antiquated idea born prior to the arrival of new drugs, we must be careful not to throw the baby out with the bathwater. The “Total Therapy” studies at MIRT show clearly that certain cytogenetic groups still need help: t(14;16), t(14;20), and deletion 17p. More importantly, these studies show that not all patients need the same intensity of therapy. Whether such groups are best identified by FISH or GEP (or some futuristic technology) remains to be seen. But each method does identify a subset of patients that merit consideration of special treatment approaches and careful counseling.

How do we deal with this information about risk stratification? How has the myeloma field reacted?

There are two points of view that are being hotly debated. Both points of view come from well-meaning and thoughtful investigators.

One point of view is that all patients need to be given the best treatment options early in the disease course, and our goal should be to achieve a complete response (CR).

The opposing point of view is that it is time to abandon the “one size fits all” approach, and rather approach the treatment of a given patient based on the underlying risk stratification. I subscribe to the latter viewpoint, and I will give 3 reasons why:

First, in a perfect world, if we had treatments that have a good chance of curing myeloma, there is no question that most of us will encourage patients to put up with major (sometimes life-changing) side effects to pursue that possibility. But we don’t. Unfortunately, the treatments we have against myeloma, while incredibly effective in controlling the disease for a given time period, eventually fail. Moreover, all have side effects. The more drugs we administer, the more the toxicity. While patients with high-risk features may be willing to take on risks of increased side effects to achieve good disease control, patients with standard-risk myeloma who have an average expected survival in excess of 7 to 10 years may have little reason to take on the risks of serious side effects without proof that such treatments actually make them live longer.

Second, not everyone needs a CR. While many studies show that patients who achieve a CR live longer than patients who do not, these studies should not be construed as proof that CR is an important goal of therapy. Such logic has actually been shown to be flawed for decades in the cancer field, but rises periodically like the Phoenix. In fact, in any study, based on pure statistical considerations, patients who “respond” always look like they lived longer than patients who did not, even when the drug in question is useless. In my mind, CR is a bit like a mediocre prognostic factor for most patients with myeloma―not the specific goal of therapy.

In any case, CR in myeloma is seldom a true CR unlike say, large cell lymphoma. There are almost always residual myeloma cells even in CR patients. That is why almost all patients still relapse. The one thing trying to get a CR can however guarantee is more side effects. Now, this does not mean CR is not desirable―quite the contrary. Patients who achieve a CR should no doubt be pleased. But patients who fail to achieve a CR should by no means lose hope or feel disappointed either.

The best data today with current therapy shows that patients with standard-risk disease actually live the same length of time whether they achieve a CR or not. On the other hand, achieving a CR seems to be important for patients with high-risk features. Based on these considerations, I try and use available treatments in a sequential manner in standard risk patients with an emphasis on quality of life, while in high-risk patients I am more willing to pursue aggressive therapy.

Third, I am concerned about surrogate endpoints such as progression-free survival (PFS) and time to progression (TTP). These endpoints sound nice, and even have relevance when it comes to regulatory drug approval studies. However, in most clinical trials, trying to determine the timing of treatments or to define the optimal combinations, such endpoints are not as informative as overall survival. The optimistic results with these endpoints which tempt us to pursue a “one size fits all” approach can have unintended consequences. After all, how long a patient lives is not just dependent on efficacy, but on safety as well. If we use all the available drugs early on, what do we do at relapse? Further, for many patients, quality of life trumps longevity in terms of priority, and it helps to have an individualized, risk-adapted approach. For example, why take even a 5 percent risk of severe neuropathy in the first four months following the diagnosis of myeloma if one has a high probability of living longer than 10 years?

Before I close, I would like to be specific about what I mean by risk-adapted therapy. In standard-risk patients, I favor initial therapy with a regimen such as Revlimid ^[1] (lenalidomide) plus low-dose dexamethasone ^[2] (Decadron). If such patients are transplant candidates, I would collect stem cells early in the disease course, but leave the timing of transplantation open to many factors including patient preference. CR would be great, but not essential. In high-risk patients, I would favor initial therapy with a Velcade ^[3] (bortezomib)-containing regimen followed by autologous transplantation (if eligible) and then maintenance with a Velcade-based regimen. CR will be pursued as a specific treatment goal, and I will consider changing drugs if needed to achieve that goal.

Myeloma is a complex disease, and the above concepts are modified according to the individual situation and will evolve with time. I must emphasize that I prefer clinical trials over standard treatments whenever possible.

We have much work left to do. The strides made in the last decade are spectacular compared with most other cancers. I think in the near future we will have options that are safe and highly effective, which will make treatment approaches more uniform. My sense, though, is risk-adapted therapy is here to stay, but it will become more precise and more accurate in the next few years.

Dr. S. Vincent Rajkumar is a professor of medicine at the Mayo Clinic in Rochester, Minnesota. His research focuses on clinical, epidemiological, and laboratory research for myeloma and related disorders.