Dr. Ashley Elizabeth Rosko speaks during the Education Session “Treating Myeloma in Older Patients."
“Myeloma is a disease of the aging adult,” said Ashley Rosko, MD, of The Ohio State University Wexner Medical Center. The median age at diagnosis is 69; there are approximately 13,000 U.S. adults age 65 and older with myeloma, and that number is expected to nearly double over the next 15 years.
Although recent years have yielded improvements in myeloma survival rates, only modest increases have been seen in older adults. Early mortality in particular is an issue in the elderly population; an analysis of data from the Surveillance, Epidemiology, and End Results (SEER) program showed a 26.9% absolute early mortality rate among patients older than age 65.
Among the major treatment decisions is whether to undergo stem cell transplant. This is particularly difficult for patients age 65 to 74, which represents the most common age of diagnosis; transplant is indicated in younger patients, and possibly contraindicated in patients older than age 74, but the evidence is unclear in this common range of ages. And, in fact, although the bulk of myeloma therapy in general is non-transplant based, older adults are far less likely than younger patients to undergo a transplant, by as much as 65%.
Determining treatment intensity, and whether to perform a transplant, involves consideration of age, comorbidities, fitness/frailty, and other factors. A frailty “phenotype,” which can be determined using geriatric assessment tools and used to assess fitness for treatment, includes slowness defined by a walking test, exhaustion, weight loss of 10 pounds or more in 1 year, low physical activity, and weakness based on a hand grip test. Frailty is common among patients with myeloma, Dr. Rosko said, noting that frail patients have substantially poorer survival and other outcomes than fit patients.
She added that a simple frailty score has been shown to be independently predictive of survival in multiple myeloma.
“Age alone is not reliable to determine treatment intensity,” Dr. Rosko said. “We can personalize medicine using frailty assessments in the same way we use bloodwork.”
Identifying Transplant Candidates
Dr. Sergio Giralt speaks during the Education Session “Treating Myeloma in Older Patients.”
Studies have shown that transplant can improve outcomes over high-dose medical therapy in patients with multiple myeloma, but the ages represented in those trials makes their conclusions problematic. “Most of the large clinical trials that have shown the benefit [of transplant] have limited themselves to patients younger than age 65,” Dr. Giralt said.
Evidence from a number of single-institution, retrospective trials indicates that age is not necessarily predictive of outcome with transplant. Dr. Giralt mentioned two studies that found that age—older or younger than 60 in one case, older than 70 compared with younger than 65 in the other—has no effect on outcome after autologous hematopoietic stem cell transplantation in patients deemed “suitable” for the procedure.
Despite those findings, and the arbitrary nature of the 65-year-old cutoff, most elderly patients are not even offered transplant as an option. Dr. Giralt said that white patients older than 65 undergo transplant less than 30% of the time; for black patients, the rate is under 15%.
“It is embarrassing,” he said. “It is not because these people are not fit; it is because people are not being referred for transplant.”
Dr. Giralt agreed with Dr. Rosko that a functional assessment is important in determining transplant eligibility. Certain factors can rule out transplant absolutely. These include frailty, poor performance status, active comorbidities, poor caregiver support, and of course, patient refusal. Other factors could be considered relative contraindications for transplant; these include the presence of low-risk disease with a major response to treatment, progressive disease, and age over 85.
He concluded by saying the evidence does not suggest age should be a contraindication for transplant. Notably, “patients should be encouraged to participate in clinical trials aimed to improve safety and efficacy of this procedure,” he said.
Aiming for Complete Responses
It is important to keep the goals of therapy in mind when treating older patients with myeloma, said Maria-Victoria Mateos, MD, PhD, of the University of Salamanca Hospital, Spain. These include prolonging survival, delaying disease progression, and ensuring a good quality of life. The question then arises as to whether the quality of response to treatment is a surrogate marker for progression-free survival (PFS) and overall survival (OS).
Dr. Maria-Victoria Mateos speaks during the Education Session “Treating Myeloma in Older Patients."
Taken together, Dr. Mateos said, “In elderly patients [who are] newly diagnosed with multiple myeloma, conventional complete response… is a surrogate marker predicting PFS, but not OS.” Given that, she suggested that the quality of the response could help better predict those outcomes.
One way to improve the assessment is with minimal residual disease (MRD). Studies suggest that MRD as assessed by flow cytometry, and more recently with next-generation sequencing, correlates with outcomes.
“How [do we] incorporate all this into daily activity of treatment?” Dr. Mateos asked. “Do we have to pursue MRD in all elderly patients?” Instead, she said that the depth of response would be extremely relevant in certain patients with high-risk features. “The achievement of high-quality, sustained CR [and] MRD negativity should be always balanced with acceptable toxicity and fitness/frailty status.”
Less Is More
Dr. Angela Dispenzieri speaks during the Education Session “Treating Myeloma in Older Patients."
“We’re talking about the elderly; we’re not talking about young folks,” she said, highlighting that toxicities associated with more extensive treatment regimens can lessen their efficacy.
Examples of the less-is-more concept are numerous. For instance, the MM-015 trial found improved PFS when lenalidomide was added to MP, but this did not translate into an OS advantage. Similar results have been seen in trials of proteasome inhibitors; for example, adding thalidomide to the VMP regimen failed to improve either PFS or OS in a trial of 260 patients. A meta-analysis of four trials showed that the simplest combination, MP, was the best tolerated compared with regimens with additional agents.
Dr. Dispenzieri did note that this is not entirely consistent, and that in some cases “more is more.” Still, keeping treatments simple may often be the best option, and the potential toxicity of the treatments again highlights the need for frailty assessments in elderly patients. “Further clinical trials will be required to optimize decision making in this complex patient population,” she said.