Upfront Therapy for Myeloma; Impact on Choice at Relapse

Transcript:Shaji Kumar, MD: We have learned a lot about the biology of myeloma, and we certainly understand that it is not just one disease. Patients can have very different outcomes based on some of the initial characteristics that we see with this disease. This had led to the whole concept of risk stratification and risk adaptive therapy. And these concepts are not new to cancer, but I think we have the tools to apply that to myeloma now, more so than what we had in the past.

There have been a variety of different risk stratification systems that have been developed, but I think they all boil down to a few critical elements. The most important driver of outcome in myeloma is the genetic abnormalities that we see in this disease. So, by doing a FISH-based testing, we can identify that the majority of the patients with myeloma have some abnormalities, and about a quarter of these patients have abnormalities that we characterize as high-risk myeloma. They typically tend to be patients with deletion 17b, translocation 4;14, and translocation 14;16; patients with high levels of serum LDH; and also patients who fall on the high ISS staging system.

Now, these all have been compiled into a single staging system called the Revised International Staging System, which can be very beneficial in terms of trying to decide, or trying to explain to the patient, what outcome is anticipated with their particular myeloma. It also helps us decide what kind of treatments to give. In patients with particular abnormalities, especially the high-risk abnormalities like the 17p deletion and the t(4;14), a proteasome inhibitor-based approach certainly seems to improve their outcome. There are also data suggesting that we may be doing tandem autologous stem cell transplantation, which may be beneficial to those patients. So, the risk stratification systems we have now inform the patient about their prognosis, but also help the physicians choose therapy.

The frontline therapy for patients with myeloma depends a lot on the availability of the drugs. So, the choice may be different in the United States versus Europe versus some in the Asia Pacific regions. Let’s take the situation in the United States, for example. The most commonly used regimen in the newly diagnosed patient is currently bortezomib/lenalidomide/dexamethasone. A combination of a proteasome inhibitor and an immunomodulatory drug is the optimal combination, based on phase III data showing that there’s improved overall survival when you use the triplet combination compared with just using lenalidomide and dexamethasone.

How much further we can adapt the therapy depends on the particular characteristics that the patient has presented. Somebody who’s older, they may not be able to tolerate a triplet and you may decide to use just 2 drugs. We could also elect to use a triplet, but use it in lower doses in the older patient. Now, for patients who present with renal insufficiency, we would select drugs that are not affected by the renal failure. In such a patient, we might use the combination of bortezomib/cyclophosphamide/dexamethasone instead of bortezomib/lenalidomide/dexamethasone. Again, focusing on minimizing the toxicity, but at the same time, maximizing the efficacy.

Patients with myeloma live a lot longer than what they used to a decade ago. A lot of it is because we have a lot of different treatments and combinations available that keep the disease under control for longer periods of time. So, what we use for treatment of relapsed disease is becoming more and more important because we want to, and are able to, keep the disease under control for long periods of time.

Now, that also, in turn, will have an influence on what we select for the initial treatment. We want to be selecting medications or combinations that will have least impact on what the subsequent treatment will do for the patient, both in terms of efficacy and toxicity. We want to go with regimens in the beginning that will have the least likelihood of creating permanent toxicities that then might decrease the ability to use that particular class of drug in the subsequent lines of therapy. I think what we have today are patients who, in the first relapse, have better outcomes than what patients at the time of diagnosis had 10 years ago. So, it’s a very critical point in terms of what to use for the initial therapy.

It is also important how we manage the toxicity from the initial therapy. If somebody develops peripheral neuropathy that is irreversible, that can have an impact on what we may be able to use subsequently. Similarly, using treatments that could have a cumulative effect on the bone marrow and can lead to low blood counts can also impact what we may be able to use subsequently. So, these factors need to be taken into account, in terms of selection and in terms of adapting the doses as we go along with the treatment.

Transcript Edited for Clarity