Differences in Multiple Myeloma are Key to Treatment Options

When diagnosing patients with multiple myeloma, it is important to identify the specific stage, mutations and risk level of the disease to determine the most effective treatment method, according to Jeffrey Wolf, M.D.

While many physicians in the oncology space have shortened the disease’s name by simply saying “myeloma”, Wolf — who is a clinical professor in the Department of Medicine and director of the Multiple Myeloma Program at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center – insists on using the full name because it is not one disease, but many.

“I decided it was time that we started calling it multiple myeloma again, the reason being that we are recognizing, more and more, that this disease does have many phenotypes,” Wolf said in an interview with OncLive, a sister publication of CURE. “Some patients present with bone lesions, some present with renal failure, and some just present with elevated proteins or light chains. [Additionally] some present with a lot of disease in their marrow and nothing in their bones, or a lot of disease in their bones and nothing in their bone marrow.”

He also noted this is not an identical population as subclones present different — meaning individual cells in patients with myeloma may actually be very different. Therefore, disease recurrence is often identified through drug resistance, which signifies that there may be a new subclone present.

Genetic profiling

Like other cancer types, genetic mutations have also played a part in multiple myeloma diagnosis and treatment. For example, Wolf said that clinicians need to look for 17p deletion — which is found in high-risk myeloma – in all patients when the first bone marrow biopsy is taken. As the disease mutates and the patient relapses, he also noted that it is a good idea to look for 17p deletion again, as new mutations will show up as others disappear. In addition, interphase fluorescence in situ hybridization (iFISH), which is used to identify this high-risk population, should be looked at in the initial bone marrow at diagnosis.

“We are discovering different mutations in each of these diseases, and it is becoming more and more important because we are finding drugs that are particularly good for those mutations,” he said. “We now know that not all [patients with multiple myeloma] are the same, and we recognize that we can use mutational analysis.”

Gene expression profiling is another way to identify high-risk patients. There are several signatures out there to do this, such as SKY92, which classifies patients who have standard-risk multiple myeloma from those who are high risk. While this expensive and not yet approved in the United States, Wolf noted that it may soon be used in conjunction with iFISH.

Targeted therapies

Targeted therapies like Venclexta (venetoclax) have been shown to be effective against mutations in myeloma.

In a trial designed to evaluate Venclexta monotherapy, researchers found that 21 percent of patients with relapsed or refractory multiple myeloma achieved objective responses to the targeted therapy at the time of data cutoff. In particular, patients with t(11;14) chromosomal translocation did particularly well with treatment.

An additional trial — designed to evaluate Venclexta in combination with Velcade (bortezomib) and dexamethasone in patients with relapsed or refractory multiple myeloma – showed an objective response rate of 68 percent among patients. Of note, the triplet regimen did not appear to add toxicity and was well tolerated.

“We are having particularly good responses with Venclexta and bortezomib these days,” said Wolf. “I believe that [Venclexta] is going to move forward, especially in patients who have t(11;14).”

He added that these results support ongoing phase 3 trial with this regimen in patients with relapsed/refractory disease, and advised that most relapses will occur from unknown subclones, and new drugs will need to be introduced into the treatment landscape.