One of the most difficult questions in oncology is: “How long do I have to live?”

Patients often bring this up to their physicians following a diagnosis of cancer, and periodically during the course of their disease.

Of course, this is an impossible question to answer because we as physicians can seldom predict what the future holds for a particular patient. We can prob­a­bly estimate averages, but no patient is average; everyone is unique. Faced with this dilemma, each physician responds differently. Some provide the averages, some don’t.

Nevertheless, it is incredibly difficult for all.  Patients are entitled to have some idea of prognosis, but at the same time physicians feel unqualified to provide estimates that they themselves do not understand.

This already perplexing problem is made even worse in multiple myeloma ^[5] be­cause overall survival outcomes vary considerably based on so many dif­fer­ent variables referred to as prognostic factors. Understanding these fac­tors is crit­i­cal not just for physicians wanting to counsel patients and choose the right ther­a­py, but also for patients who often hear about these “risk fac­tors” or “high-risk markers” from other patients, the Internet, and so on.

First, it is important to recognize that overall survival for an individual patient with myeloma is determined not just by markers of aggressive disease biology (e.g., high-risk chromosomal abnormalities) but also by host factors (e.g., age and overall health) and the extent of myeloma (stage).

Second, each of these factors affects survival differently, and each needs to be tackled differently.

The strategy to overcome high-risk chromosomal abnormalities differs from strategies to overcome the problems posed by advanced age, other health problems, or kidney failure. Even within the overall group of high-risk chromosomal abnormalities, certain abnormalities may need to be tackled in a slightly different manner than others.

So there is no easy, uniform way to overcome “high risk.” It will depend on what exactly the high risk-factor is, and what can be done about that particular factor.

Third, things change over time. For example, response to therapy (good or bad) can have a dramatic effect on outcome and disrupt prior survival calculations. Similarly, patients may acquire new chromosomal abnormalities that change the dynamics of the disease and its treatment.

With the above understanding, we can now discuss what options are available to tackle each risk factor.

Host factors are typically approached by modifying treatment intensity.

Thus, in patients with advanced age, we avoid stem cell transplantation and often reduce the dose and intensity of chemotherapy to minimize toxic side effects and maximize control of the myeloma.

For patients with kidney failure, we try methods such as plasma exchange and chemotherapy with drugs that act rapidly to try and quickly reverse the kidney damage.

Disease stage is less important in myeloma than in other cancers for choosing therapy. However, treat­ments in myeloma can be modified in select situations based on disease stage.

For example, in patients with stage I multiple myeloma by the Durie-Salmon staging system who have a single bone lesion, radiation alone may be adequate, while systemic treatment is needed for more ad­vanced stages.

Disease biology is indeed one of the most important determinants of outcome. Among patients with similar age, overall health, and disease stage, survival can vary widely based on markers of aggressive disease biology.

At present, we consider deletion 17p, translocations t(14;16), t(14;20), a high-risk gene expression profiling signature, a high lactate dehydrogenase level, and plasma cell leukemia as high-risk factors.

Yet not all patients with these markers have high-risk myeloma.

For example, a recent study ^[6] led by my colleague Dr. Shaji Kumar shows that the presence of trisomies (an extra copy of one or more chromosomes) can neutralize the high-risk effects of certain high-risk factors (i.e., t(14;16), t(14;20), and 17p).

Similarly, translocation t(4;14) was previously considered to be a high-risk factor, but recent research ^[7] sug­gests that Velcade ^[8] (bortezomib)-based induction, stem cell transplantation, and Velcade-based consolidation/maintenance may be effective against this risk factor.

What are the treatment options for high-risk myeloma? There is intense research ongoing to improve sur­viv­al in this patient population.

Depending on the patient’s age and other health problems, treatment options vary – but many are available. Most researchers believe that the best strategy overall in high-risk myeloma is to try and achieve a complete response, or as close to one as possible, and then try to sustain it.

While it is important to provide some data to patients with high-risk myeloma to answer questions about prognosis, it is also important to note that no marker is perfect. We all have patients with 17p deletion who have done very well for many, many years and who defy textbook predictions.

Finally, while we make treatment plans based on the risk factor groups discussed above (host factors, stage, high-risk disease markers), they can change based on response to such therapy.

Progressive myeloma while on therapy is usually a sign that we need to change the treatment plans and regimens. However, response to therapy is complex and is affected by numerous factors.

Suffice it to say that while an excellent response to therapy is always desirable, we cannot get carried away with numbers alone. For example, there are patients who respond very slowly to therapy and never reach a complete response, but yet they achieve some of the best survival figures.

It is more important to recognize that the interplay between response and outcome is complex, and there is no need to grieve over failure to achieve a complete response.

I know this column probably raises more questions than it answers. My goal is to highlight that estimating and understanding prognosis is no easy task.

I believe that well-informed myeloma patients can work with their physicians to get a full picture of their own unique situation and to plan the most appropriate treatment strategy.

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.