Better predictions, better outcomes

Multiple myeloma is always preceded by a pre-cancerous condition. That’s what we do know.

But many of the plasma cell disorders linked to myeloma may never amount to cancer. So trying to determine who’s most at-risk of developing the disease – and whether or not to intervene early – is a challenge facing hematologists everywhere.

That’s where new UW Carbone Cancer Center member Timothy Schmidt, MD, comes in. In the clinic, Schmidt sees patients with multiple myeloma and other plasma cell disorders, but much of his research seeks to understand whether patients should be treated before symptomatic disease presents itself.

“We’re really asking ourselves if we can intervene upon patients with a high-risk disorder, prevent it from becoming myeloma, or at the very least, substantially delay the development of myeloma to a later point in time when we might have better treatments available,” Schmidt said.

It can be tricky, because a vast majority of patients with a plasma blood disorder won’t go on to develop cancer. Many of the patients Schmidt sees have a condition known as monoclonal gammopathy of undetermined significance, or MGUS. Only about one percent of these patients each year will go on to develop myeloma, so in most cases, early intervention isn’t practical or needed.

However, there’s another subset of patients that fall into an intermediate stage between MGUS and active myeloma. This condition, known as smoldering multiple myeloma, is riskier. About ten percent of these patients each year will go on to develop myeloma. While certain risk factors can be identified and monitored, Schmidt notes the risk of progression from smoldering myeloma to cancer is highly variable.

“Smoldering myeloma is a very hot topic in the field of plasma cell disorders,” Schmidt said. “You’ll find experts all over the country that say we should be treating most patients who are at particularly high risk of developing myeloma, and you’ll find experts who say we should be treating none of these patients.”

Along with Natalie Callander, MD, Schmidt recently published a review of current smoldering myeloma management and treatment practices. One approach involves treating high-risk smoldering myeloma patients with a drug called lenalidomide. The results of early clinical trials found that the drug effectively delayed the development of multiple myeloma symptoms, in comparison to patients who were not treated.

While lenalidomide is not considered a standard-of-care treatment for smoldering myeloma, it can be used and justified through an off-label prescription. However, Schmidt says there are still questions that need to be answered before prescribing lenalidomide routinely to more smoldering myeloma patients.

“We still don’t know yet for sure whether these patients are living longer, or if we’re changing anything about the disease biology when treating them,” Schmidt said. “The only way that we can really get to the bottom of this is by enrolling patients on clinical trials. That’s why we strongly recommend that these patients be referred here to us, or to any other places that are doing these studies.”

UW Carbone currently has one clinical trial, known as the DETER-SMM study, open for patients with high-risk smoldering myeloma. In this study, patients receive lenalidomide and dexamethasone – a common treatment regimen for myeloma. But some patients will also receive an additional drug: daratumumab. The goal is to find out if the treatment combination can delay or prevent myeloma development and help patients live longer, and also have increased quality of life.

Meanwhile, for patients that do develop myeloma, there are treatment options available at UW Carbone. Patients may receive a combination of targeted therapy, chemotherapy and a bone marrow/stem cell transplant. Some patients may also be eligible for participation in clinical trials that aim to further improve outcomes through new treatment options.

For instance, Schmidt is the lead investigator on a study known as the EQUATE trial, which is for patients with newly diagnosed myeloma. The phase III study is looking at whether the combination of four drugs – including bortezomib – helps patients who still have detectable myeloma live longer than those treated with a standard three-drug approach.

As the study progresses, investigators will test patients for what’s known as minimal residual disease negativity, or MRD negativity. Due to the development of more sensitive testing, study investigators can now track the response of a therapy, in real time, with great accuracy.

The testing can also provide investigators with key information about a patient’s risk of relapsing down the road, which in turn, could potentially determine future treatment decisions: ones that are more personalized to each patent.

“Right now, there’s still sort of a one-sized-fits-all approach to myeloma treatment,” Schmidt said. “But hopefully in the near future, we can really individualize and personalize treatment to reduce toxicity for those who don’t need extra therapy, and to escalate therapy if we need to get better control of things.”

In addition, Schmidt said the knowledge gained from these clinical trials is essential in better treating patients in the ‘maintenance’ phase, after the initial treatment is complete.

“We are starting to see patterns that are giving us the ability to predict who is going to have disease that’s easy to manage, and who might not,” Schmidt said. “Using tools like genomics and immunology, we can start to differentiate things and tailor treatment to individuals, so that we can be more aggressive when needed, less aggressive when it’s OK to take the foot off the brakes, and maybe allow for some patients to come off of their therapy.”