Redefining Fitness, Frailty, and Survivorship in Multiple Myeloma

Fueled by combination regimens, cellular therapies, and precision monitoring tools, survival for patients with multiple myeloma (MM) has improved dramatically over the past several decades.¹ From August 2023 to April 2024 alone, 5 novel therapies were given the greenlight from the FDA to expand the treatment armamentarium for patients with relapsed/refractory disease through accelerated, expanded, and traditional approvals: a bispecific antibody, a T-cell engager, a hematopoietic stem cell mobilizer, and 2 chimeric antigen receptor (CAR) T-cell therapies.² Monoclonal antibodies also have emerged within the past 20 years.³

The so-far uncurable hematologic cancer is considered rare, but patients with the disease can now live 10 years or more, depending on the stage and risk profile,⁴ and the average age at diagnosis is 69 years, according to recent estimates from the American Cancer Society.⁵ Therefore, even as the science advances, a central tension remains: the disease predominantly affects older adults who often experience several disease relapses, but much of the evidence guiding care comes from younger, fitter trial populations, forcing clinicians to shift their conversations from simply extending a patient’s life to redefining how that life is lived.

“I have worked in myeloma for 25 years or more, and it’s really only now that we’re starting to see this great benefit in older individuals,” explained Joseph Mikhael, MD, MEd, FRCPC, FACP, FASCO, chief medical officer, International Myeloma Foundation, and professor, Applied Cancer Research and Drug Discovery Division, Translational Genomics Research Institute, in an interview with The American Journal of Managed Care^® (AJMC^®). “It is absolutely the right time to talk about it.”

Targeting Smarter, Sparing More

“Survival in myeloma is clearly being prolonged,” says Mikhael. “Whereas historically, we saw a greater impact in younger individuals, we are seeing an impact in older individuals as well that is almost bringing them to the level of life expectancy.”

For example, in the completed phase 3 MAIA trial alone (NCT02252172), the treatment-naive patient population had an average age of 74 years⁶ and their median overall survival was 7.5 years.⁷ Further, in the ongoing phase 3 CEPHEUS trial (NCT03652064) among newly diagnosed patients with a median age of 70 years in whom hematopoietic stem cell transplant is not planned as initial therapy,⁸ median progression-free survival was not reached in the patients treated with daratumumab plus bortezomib (Velcade), lenalidomide (Revlimid) and dexamethasone (D-VRd).⁹

Autologous stem cell transplant has been the reigning standard of myeloma treatment, with patients who have undergone the procedure having meaningfully better outcomes. However, age, kidney function, and general overall health typically have prevented older and more frail patients from truly benefitting from prescribed treatments. The emergence of novel agents has upended this hierarchy. Monoclonal antibodies like daratumumab and, more recently, CAR T-cell therapies and bispecific antibodies, have shifted and expanded the landscape in ways that benefit older and frailer patients as a defining feature.

“The treatments that we’ve developed in myeloma are more on target and less off target,” Mikhael noted, “such that they are more easily delivered and more effective in older, more frail patients.” Patients in their 80s are receiving bispecifics, he added, and CAR T-cell therapy is no longer the exclusive domain of the young. “We’re not ageist, nor should we be,” he said. “We look at the whole of a patient and the whole of their existence, and not just their date of birth.”

Rethinking Frailty

Even as new therapies have broadened who can be treated, the field has had to grapple with a more fundamental question: how do you accurately assess whether a patient can tolerate treatment in the first place? The development of formal frailty scoring tools—most notably the International Myeloma Working Group (IMWG) Frailty Index, first introduced in 2015¹⁰—was an attempt to bring more nuance to a process that had long relied on age and a handful of laboratory values.

Hearn Jay Cho, MD, PhD, chief medical officer, Multiple Myeloma Research Foundation (MMRF), described 3 distinct changes now underway. Clinical trials, particularly in the relapsed/refractory setting, have begun to raise or eliminate upper age limits; larger company-sponsored trials also are increasingly including subcohorts specifically for frail patients, and a growing number of investigator-sponsored trials are designed exclusively for older and frailer populations. “Adoption of tools such as the Frailty Index is becoming more common both in preclinical trial assessments and in the general management of myeloma patients,” Cho said in an interview with AJMC. “It’s not universally implemented yet, but utilization is increasing.”

Mikhael is candid about where that work currently stands. “We understood when we started creating them that they were not fully sophisticated, not fully validated,” he said. The IMWG now has a subcommittee developing a revised index that is more rigorously validated and simpler to use. The stakes are practical: approximately 75% of patients with myeloma are treated in community oncology settings, not academic centers. A tool that only a specialist at a major cancer center can administer reliably will never reach most patients. “If we don’t have a tool that is not only validated but simple to use, it’ll never be adopted,” he said.

“I do not treat myeloma. I treat people.” — Joseph Mikhael, MD, MEd

Beyond the tools themselves, there is a deeper conceptual shift underway: frailty is not a fixed state. It is a dynamic one, and the field is beginning to account for that fully.

Treating the Person, Not the Disease

“I do not treat myeloma. I treat people,” is a phrase Mikhael returns to often, and it points toward what may be the most meaningful shift in myeloma medicine: the move from protocol-driven treatment to individualized care. For older adults, this shift has been especially consequential. Treatment decisions must account for functional status, comorbidities, patient preference, social support, and the practical realities of what a person’s life can accommodate, he explains. “There isn’t a simple algorithm or formula in myeloma. We incorporate the whole of the patient.”

Evidence supports the use of reduced-intensity regimens for older patients. Cho points to published results on combinations such as VRd and D-VRd using reduced doses, “recognizing that some of these treatments are harder to deliver on schedule in older patients because of adverse effects such as low blood counts.” That, he says, goes hand in hand with frailty assessment in that identifying the appropriate regimen requires first understanding the patient’s fitness to receive it.

A clear illustration of this principle is dexamethasone, a backbone of myeloma regimens for decades but also “often the one that causes the greatest harm,” according to Mikhael. Fluid retention, mood disturbance, blood sugar dysregulation, and infection risk are all likely adverse effects following treatment with the potent synthetic corticosteroid, he noted. He has argued in the past that the drug’s role has necessarily been reduced.¹¹ As combination regimens become more powerful, the opportunity, some might say the obligation, to de-escalate the most toxic elements grows. “We can de-escalate more quickly or more fully,” he says, “and focus specifically on some of those drugs that really do cause adverse effects, especially in older patients.”

As CAR T-cell therapies and bispecific antibodies have reshaped what’s possible for older patients, a different barrier has come into sharper focus. “The biggest barrier to the delivery of CAR T-cell [therapies] and bispecifics is not age or frailty. It is availability,” says Cho. “There’s a very limited number of centers that deliver CAR T cells, and a somewhat larger but still restricted number of sites that can deliver bispecific antibody treatments.”

The numbers are stark, he explains. Only about 15% to 20% of patients receive their care at academic medical centers or community practices with specialized expertise, which means roughly 80% of patients have restricted access to these newer treatments, regardless of their age or fitness. The MMRF’s Horizon One Adaptive Platform Trial, which includes bispecific antibody arms, has made a point of enrolling broadly, with substantial participation from patients older than 75 years—but the structural access problem extends well beyond any single trial.

Mikhael echoes the concern, noting that health equity gaps persist along geographic, racial, and socioeconomic lines. “That age and comorbidity and frailty gap has clearly been narrowed of late,” he says, “but it has not disappeared.”

Living Longer, Living Better

Mikhael says it used to be easy to identify who had myeloma and who was a caregiver just by looking at the room during patient meetings. “Now we go to these meetings and we don’t know. People look so much better than they ever did before,” he explains. This shift is as much about quantity of life as it is about quality of life. For older adults already navigating age-related conditions, this distinction carries particular weight.

Survivorship is not without its burdens, however. In the era of immune therapies, Cho identifies infection risk as the single biggest long-term concern. “We are very scrupulous about prophylactic medications, such as bacterial or viral prophylaxis, and we’re very diligent about adhering to vaccine schedules,” he says. Supportive care to enhance immune defenses, including intravenous immunoglobulin, is a central part of long-term management, he emphasizes. Rare but serious neurologic, gastrointestinal, and secondary malignancy risks also require ongoing vigilance.

Fatigue, peripheral neuropathy, and bone disease round also are common persistent quality-of-life challenges. “For patients who are long-term survivors in myeloma, those don’t necessarily go away,” Cho notes. He adds that these issues can be addressed through multidisciplinary care—palliative care, neurology, orthopedics, and physical therapy—with an explicit goal of minimizing dependence on pain medication over time.

Older patients also carry a higher baseline of comorbidities that require renewed attention as survival lengthens. “In the early days of myeloma, I was a little less concerned about someone’s blood pressure if they were only going to live a year,” Mikhael says. “Now, as patients are living longer, we want to make sure they have their routine screening for breast cancer and colon cancer, their regular checkups for blood pressure and blood sugar.”

Exercise is another area where evidence is accumulating.^12-14 “When I look at my practice and I see my older, historically even more frail patients who are thriving, these are the ones that are exercising on a regular basis,” Mikhael says. “The body was designed to move.”

Expanding Clinical Trial Access

For decades, eligibility criteria effectively excluded older and frailer patients through performance status requirements that many older patients could not meet or the assumption that trial participation was simply beyond them. That assumption, Mikhael says, is now “passé.”

The MMRF has worked to make this shift concrete. “When we talk about representative North American populations in our clinical trials, it’s not just race and ethnic demographics,” Cho says. “We actively recruit patients who are urban, suburban, rural, or older and younger. We need to have a broad, representative patient population in our clinical trials for them to be meaningful.”

The Horizon One (NCT06171685) and Horizon Two (NCT07053436) trials, sponsored through the Multiple Myeloma Research Consortium, rely on investigator judgment rather than strict age cutoffs to assess fitness for participation, Cho explained. Horizon One is being conducted among patients with relapsed/refractory disease,¹⁵ and Horizon Two will be conducted in the newly diagnosed setting.¹⁶ The MMRF has also partnered with Family Reach to provide financial support to patients and families, so that participation doesn’t come with an economic penalty.¹⁷

Barriers to participation are not just logistical but also historical, cultural, and relational. Addressing these types of barriers requires the same long-term investment as developing the therapies themselves. Mikhael recounted a patient at a large community event in Philadelphia, who described her reaction when her doctor first suggested a clinical trial. “She said, ‘Without even thinking about it, I covered my ears and I just said the word Tuskegee to the doctor.’” With time and trust and many conversations, she enrolled. “‘I was willing to listen to him speak to me,’ she said. “‘I’m still alive because of a clinical trial.’”

Building Next-Generation Treatment

Precision is the next frontier, Cho and Mikhael agree, and this entails understanding not just which patients can tolerate a given therapy, but which patients will respond best to which approach. The promise of personalized or precision medicine approaches still needs to be realized in the field, Cho adds.

“Clinicians have an array of really effective therapies,” he says. “Some already approved for frontline and some moving into frontline. There are characteristics of the disease and the disease environment, like the immune system, that are being very intensely investigated.” This means understanding which patients do better with immune therapies up front, which need more intensive regimens to keep their disease in check, and which older patients can be well served by lower-intensity approaches that prioritize sustained disease control over aggressive intervention.

On the horizon: in vivo or allo CAR T-cell therapies with comparable efficacy to their predecessors but with reduced-intensity adverse effects and next-generation bispecific and trispecific antibodies designed for monthly dosing and a limited duration, Mikhael explained. Cereblon E3 ligase modulatory drugs, or CELMoDs, make up a new class of oral agents that offer highly effective therapy patients can take at home.

“Social work is an intrinsic part of the multidisciplinary approach to myeloma care.” — Hearn Jay Cho, MD, PhD

“Their risks are potentially more manageable in older patients,” Cho says of the emerging immune therapy landscape. “As we move to the future where we can individualize therapy, I think there’s reason to hope that there will be immune therapy approaches and other approaches for older patients that will deliver just as good results as the more intensive regimens for younger patients.”

Supporting the Caregivers

A full account of survivorship in older patients with myeloma cannot fail to include the caregivers—the people who make that survivorship possible. In an aging patient population, caregivers are often aging, too. They are spouses and partners and other loved ones perhaps managing their own health challenges while coordinating complex treatment regimens, monitoring for adverse effects, and providing emotional support across a disease course that can last years. Caregivers are a critical part of the care team infrastructure.

The demands on caregivers have intensified as treatment has become more sophisticated. CAR T-cell therapy and bispecific antibodies both require active caregiver engagement, Mikhael underscores. But overall, patients need to be remotely monitored during the early weeks of treatment for such things are blood pressure, temperature, and neurological issues, and caregivers are indispensable in this regard. Therefore, when a caregiver lacks the capacity to participate, it can become a health equity issue in its own right.

“More than ever, our care partner is being called on,” Mikhael says. “And so more than ever, it is important for us to provide support for them, to have them understand the process, to be educated, and to be supported themselves.” Cho frames caregiver support as inseparable from patient care. “Social work is an intrinsic part of the multidisciplinary approach to myeloma care,” he says, encompassing not just direct patient support but financial assistance, mental health resources, and family leave—practical realities that determine whether a caregiver can sustain the role over time.

“Building communities around patients and their caregivers is critical to ensuring that everybody has the support they need,” Cho says. “It is emotionally taxing for patients and their families to deal with chronic illnesses and the persistent concern about whether the disease is going to recur. You can’t write a prescription for it.”

References

Looking Forward

There are limits to optimism. Health equity gaps in access to novel therapies have not disappeared. Geographic, racial, and socioeconomic disparities in who receives the most advanced treatments remain real and documented. Frailty assessment tools are still not standardized or widely adopted. The caregiving infrastructure that older patients depend on faces its own pressures. But the arc of the last 25 years in myeloma is unmistakably forward.

“I carry the same optimism for all patients with myeloma, but in particular older individuals,” Mikhael says. “Our standard has become very high, as we want patients to live better and longer with myeloma.” For a disease that once offered older patients little more than palliation, that standard represents a profound—and hard-won—change in expectation.

Cho concurs: “Having a patient-centered approach means having thoughtful strategies for all patients.”