Researchers describe the case of an older patient who underwent myeloma drug sensitivity testing as part of an effort to identify the therapies most likely to produce a response in this difficult-to-treat population.
A recent report describes how researchers used a more precise bone marrow test in an effort to improve the outcome of a 72-year-old man with multiple myeloma (MM) by pinpointing the sensitivity of his myeloma cells to the most effective options.
Such tests could help oncologists determine more precise therapies for older, frail patients.
The authors note that while advances in drug development have improved outcomes for younger patients, older, frail patients have not seen similar benefit. Clinical trials in hematology and oncology tend to focus on younger subjects, leaving the applicability to older patients somewhat unknown.
Writing last month in Aging and Cancer, researchers from the University of Colorado Anschutz Medical Campus described a test they developed called Myeloma Drug Sensitivity (My-DST) that correlates well with clinical outcomes. My-DST is a rapid drug sensitivity test of plasma cells that can deliver results within a week.
The authors surmised that frail patients have not benefited from MM advances because younger patients can tolerate 3-drug combinations, while frail patients can often tolerate only 2 at a time.
Thus, they said, it is critical to do more to ensure that the 2 selected drugs have the best chance of success. Using personalized treatment could help move the needle in treating frail patients by avoiding undertreatment, limiting attrition of subsequent lines of therapy, reducing exposure to ineffective drugs, and streamlining the management of relapses. Older patients on average attempt subsequent lines of therapy less frequently, contributing to worsened survival outcomes.
Other cancers have seen progress with personalized medicine, the authors said. For example, inhibitors of epidermal growth factor receptor mutations have been shown to be tolerated even in patients 80 or older with non–small cell lung cancer.
However, no precision instruments have been available for MM, which comprises 10% of all malignant cancers, with a median age of onset of 70 years. MM is a more difficult disease for which to provide a rational targeted therapy design due to the genetic heterogeneity of the disease, the study said, with multiple causes and a lack of targetable abnormal gene products.
My-DST is a phenotype-targeted approach profiling primary tumor samples. Unlike other published platforms, the functional assay avoids CD138+ cell selection of bone marrow, optimizing the viability of plasma cells and maintaining their microenvironment, the study said. As a result, indirect drug effects that occur via other immune cell populations can be measured, such as monoclonal antibody responses via antibody-dependent cellular cytotoxins.
My-DST involves bone marrow aspirants that undergo mononuclear cell selection, followed by incubation for 48 hours with a panel of antimyeloma drugs and untreated controls. Each treatment condition is then assayed for plasma cell survival after treatment using multiparameter flow cytometry.
The panel of therapies includes proteasome inhibitors, immunomodulatory drugs, steroids, alkylator chemotherapies, and monoclonal antibodies. The percentage of cell death is measured with high-throughput multiparameter flow cytometry. Drugs that kill more than 20% of cells are predicted to be active agents, the authors said.
The man in the case was diagnosed with IgA‐lambda multiple myeloma after presenting with pain in his sacrum and had a Karnofsky Performance Score (KPS) of 60; an MRI showed multilevel metastatic disease and a bone marrow biopsy showed 10%–15% monoclonal plasma cells. Cytogenetic abnormalities included an atypical IGH rearrangement, monosomy 13, and loss of 1copy of 14q32. He was staged as low-risk as per the Revised International Staging System criteria.
The My‐DST showed sensitivity to proteasome inhibitors and dexamethasone, but relative resistance to the immunomodulatory drugs.
However, the treating physician was unaware of the testing results, and the patient began induction treatment with immunomodulatory drug‐based therapy lenalidomide and dexamethasone weekly. After finishing 2 cycles of therapy, he achieved only a minor response (< 25%) in reduction in monoclonal protein.
He was then switched to bortezomib and dexamethasone as the next line of therapy. As predicted by his My‐DST result, he rapidly achieved a very good partial response as determined by an M‐spike detectable only by immunofixation and a significant decline in the lambda free light chains to normal levels and his KPS improved to 100. He did well for the next 2 years, and died a year later of natural causes, prompting the authors to call the treatment a success.
Hematologic malignancies are more promising targets for personalized medicine because patients’ bone marrow samples are readily available and are amenable to culture for measuring drug effects, the researchers said.
The authors said even though advancing age is the greatest risk factor of cancer, clinicians can’t rely on chronological age as a way to predict drug tolerance or treatment outcomes in older patients.
“Thus, going forward, it is of utmost importance to include a universally accepted frailty scoring system in cancer clinical trial enrollment to quantify the bias toward younger patients and allow better subanalyses of broader findings in frail persons,” the authors wrote.
Reiman, LT, Walker, ZJ, Babcock, LR, et al. A case for improving frail patient outcomes in multiple myeloma with phenotype‐driven personalized medicine. Aging Cancer. Published online February 16, 2021. doi:10.1002/aac2.12022