Predicting the Most Effective Multiple Myeloma Drug for Patients
By Amy Gallagher
In 2020, there has been rapid advancement of FDA-approved multiple myeloma drugs that find oncologists with more questions than answers. As the pendulum swings from one extreme to the other, new approaches are needed to help doctors plan the best possible care for their patients.
To find the best treatment option for multiple myeloma patients, Daniel Sherbenou, MD, PhD, Assistant Professor of Hematology at the University of Colorado (CU) Cancer Center’s Blood Disorders and Cell Therapies Center, developed a tool to predict the most effective multiple myeloma drugs: the Myeloma Drug Sensitivity Testing (My-DST).
In April 2020, first author, Zachary Walker, MS, and colleagues from Sherbenou’s lab at the CU Cancer Center published on a new strategy of drug effect measurement to predict the specific classes of drugs that offer the greatest benefits for multiple myeloma patients (Blood Adv 2020;4(8):1628-1639).
“This retrospective study tested 55 patient samples using My-DST to identify the best drugs for killing the cancerous cells from each patient,” said Sherbenou. “In these samples, we could score which drugs worked best for actual patients from our clinic.”
They found they could predict the depth of responses patients achieved after receiving their treatment, which was very encouraging, he noted.
Finding the Best Drugs for Deeper Response
With a medical matrix of multiple myeloma drugs expanding rapidly, the new My-DST tool is designed to answer two of the most common questions posed by doctors treating multiple myeloma patients: What drug combination is best? and What is the best sequence for each individual situation? “New drugs are coming out in such abundance; three in the past year,” said Sherbenou.
Many of the choices are among similar agents, and patients end up receiving drugs multiple different times over the history of their treatment, he said.
“Ultimately, the new My-DST tool may identify the best drug combination for each patient each time they need a new therapy,” said Sherbenou.“Every patient deals with relapses; every physician deals with the frustration of sorting through the many drug options for each patient.”
The first remission is the period of time when the patient’s quality of life is best, and it can usually be kept at bay for long periods with oral medication if we achieve the best possible depth of response after diagnosis, Sherbenou explained.
“Another important objective is maximizing the treatment benefit to a multiple myeloma patient at relapse,” he said. “Our goal is to identify the best drug regimen at any point for which the patient needs to get back in remission. With My-DST, we hope to really move the needle toward optimizing our treatments.”
Currently oncologists use three or more agents combined together, which improves the chances of achieving a deep response, said Sherbenou.
“However, this creates problems knowing that the use of more drugs leads to increased side effects and increased costs,” he said. “These side effects can severely limit what can be done for older patients, the age group most commonly diagnosed.”
My-DST includes the testing of seven key drugs: lenalidomide, pomalidomide, bortezomib, carfilzomib, dexamethasone, cyclophosphamide and daratumumab.
Measuring Sensitivity & Specificity
For many years, the standard approach of most labs conducting multiple myeloma research has been to extract the myeloma cells away from the immune system and other cells, Sherbenou said.
“While this approach is great to study some aspects of myeloma biology, it is not ideal for measuring drugs effects,” said Sherbenou. “Our approach is to culture whole bone marrow aspirate, which is a liquid biopsy obtained to diagnose the disease. This liquid state is a huge advantage over solid biopsies, allowing us to culture the cells immediately with minimal perturbations.”
Sherbenou analyzed the testing in two key measures: sensitivity and specificity, and My-DST showed good performance characteristics.
“If our further studies validate our initial study, it may move us toward a new way to treat MM patients,” he noted.
Sherbenou said the assay is set up to test single drugs, but still performed well to determine the best drug combinations. “Our future research will aim to further improve test performance by adding new drugs as they become available, and by studying drug combinations to capture the synergism to account for their full benefits to patients.”
Testing Within Native Ecosystem
“Earlier studies conducted by other scientists purified myeloma cells away from the normal cells present in the bone marrow,” said Sherbenou. “However, those cells depend on the other cells in their environment, and if isolated away from them the survival of the diseased cells declines drastically, even without treatment.”
Knowing the cells will stay alive for only a few days in the lab, the point is to keep the cells viability as high as possible by treating the whole mixture of bone marrow when measuring the response to the different drugs, he explained.
“By deviating from the normal approach, My-DST also keeps the multiple myeloma cells with the patient’s normal immune cells, allowing us to include the immunotherapy daratumumab, which is extremely important among our current treatments.”
Diseased cells need to be tested in the closest possible way to their native environment within the ecosystem of the patient’s immune system and other cells, Sherbenou explained.
“Using the patient’s own immune system in the cultures allows us to account for the interactions that occur between a patient’s diseased and normal cells produce results most likely to represent what is happening in their body,” he said.
Promising Predictor for Clinical Trials
With the favorable results from his retrospective study, Sherbenou said the next step for the new My-DST tool will be conducting clinical trials which are currently in development with the goal to start enrolling in 2021.
“The first focus will be on using the My-DST prospectively in a clinical trial to see if we can improve upon the expected response rates and depth,” he said.
This will likely involve doing trials in both the newly diagnosed and relapsed settings. “Multiple myeloma doctors Peter Forsberg, MD, and Tomer Mark, MD, are designing these trials,” he said.
Sherbenou said his hope with the new My-DST tool is to help physicians and patients decide the best therapies by adding another layer of data to what we already have.
“At the same time, we also believe we can use the test to better guide the development of new drugs in the future,” he said.
Multiple myeloma is a relatively rare blood cancer that represents 2 percent of all cancers. “The number of people getting diagnosed, however, has increased steadily over the past several years and the overall number of people living with multiple myeloma has increased substantially as we have been successful in keeping patients alive much longer,” Sherbenou said. “Hopefully, My-DST can help build on this success by further optimizing their treatments.”