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While high-dose chemotherapy and autologous hematopoietic cell transplantation (HCT) can deepen remissions and improve outcomes for multiple myeloma, these treatments come with significant risks, particularly for patients with comorbidities or advanced age. The assessment of fitness for transplant in multiple myeloma continues to evolve, guided by a blend of clinical judgment, patient-specific factors, and emerging data.

Age Not a Bar to Transplant

Assessing patient fitness involves more than evaluating chronological age, noted Brandon Blue, MD, of the Moffitt Cancer Center in Tampa. "Biologic age doesn't necessarily define you," he told 乌鸦传媒. Rather, he highlighted the need for a personalized approach. "There are patients who are 70 but look 50 and have taken great care of themselves, making them strong candidates for transplant."

While some healthcare systems may impose strict age cutoffs due to resource limitations, many centers, including those in the U.S., focus on a comprehensive assessment of overall health. This aligns with evidence that age alone is not a reliable indicator of transplant outcomes. In a at Moffitt Cancer Center, older patients undergoing HCT achieved survival rates comparable to their younger counterparts, suggesting that age should not automatically preclude stem cell transplant consideration.

Instead of relying on age cutoffs to determine fitness, Blue advocated an approach focused on biological fitness and comorbidities, while also underscoring the subjective nature of transplant assessment: "Our job as doctors is always to do no harm," said Blue. "We evaluate whether high-dose chemotherapy will benefit the patient or potentially harm them."

For patients who are biologically younger than their chronological age and don't have significant medical issues, transplant may offer substantial benefits. However, for others with extensive comorbidities or risk factors like poor cardiovascular health, the risks could outweigh the potential gains.

The final decision often rests on a personalized evaluation to ensure that the risks and benefits align with the patient's overall health and treatment goals. Nisha Joseph, MD, of Winship Cancer Institute at Emory University in Atlanta, emphasized that for standard-risk patients, particularly those at the borderline of age or fitness, the decision requires careful consideration. "Transplant can be very challenging, and if someone is 74 or 75 with a reasonable performance status but a few concerns, we might not push for transplant," Joseph explained.

Utilizing Frailty and Comorbidity Indices

While subjective clinical judgment plays a significant role, validated frailty and comorbidity indices are still used to determine patient fitness.

That takes a combination of frailty scores, clinical assessments, and patient consultations, said Ciara Freeman, MD, PhD, of Moffitt Cancer Center.

These evaluations often include basic tests such as the Timed Up and Go test, where patients stand, walk, and turn -- a simple yet powerful indicator of physical fitness and muscle strength. Standardized tools, such as the simplified frailty index and comorbidity indices, also aid in the evaluation of patient fitness. Such tests have been effective, said Freeman, pointing to indicating that objective measures of frailty correlate with higher risks of adverse outcomes.

One key aspect of assessing fitness for transplant is understanding how to optimize patients who may not initially meet fitness criteria. "We don't necessarily deny someone based on comorbidities," Freeman explained. "Instead, we focus on how we can optimize their condition." This might include improving dietary intake, managing medications, or addressing specific health concerns that could increase treatment risk.

Freeman noted that all patients over 65 at her center undergo assessments that may prompt further interventions.

"We ensure that every patient has a pharmacy consult before transplantation to optimize medication and reduce toxicity risk," Freeman explained. "If we find areas for improvement, such as polypharmacy or nutritional deficits, we address those before transplant."

The Potential Role of MRD

With advances in treatment leading to deep remissions, minimal residual disease (MRD) status may also influence transplant decisions. Current studies are investigating whether MRD-negative patients can bypass transplant and transition directly to maintenance therapy. "Patients who achieve MRD-negativity after a four-drug induction might not need a transplant, particularly if there are concerns about frailty and toxicity," Freeman said.

Although this strategy has not yet reached randomized clinical trials, Freeman said the research reflects a growing shift toward more personalized and evidence-based decision-making.

However, Freeman pointed to an important aspect of why transplantation has yet to be fully replaced by alternative therapies, even in patients who achieve MRD-negativity: the process of transplant essentially "resets" the immune system.

"Think of it like a bad neighborhood," Freeman analogized. "The neighborhood is filled with bad guys paying off corrupt police officers, preventing them from taking action. If you regenerate the neighborhood and bring in new, honest officers, they won't allow the bad guys to set up shop again." The transplant reset creates an immune environment less permissive to the return of multiple myeloma.

Nevertheless, said Freeman, "there are debates at every meeting" regarding the need for transplants in MRD-negative patients. "Some experts argue that the immune reset effect provided by a transplant offers benefits that cannot be achieved through standard therapies alone."

Future Directions and Evolving Practices

Despite these challenges, Joseph noted that the good news is the availability of strong non-transplant options. In an at a median follow-up of over 5 years, the addition of daratumumab (Darzalex) to lenalidomide (Revlimid) and dexamethasone continued to show significant progression-free survival (PFS) and overall survival benefits in transplant-ineligible patients with newly diagnosed multiple myeloma.

Emerging data also indicate that novel therapies like CAR T-cell treatments are highly effective, even for older patients, presenting alternative or complementary strategies to transplant. A showed that patients over 65 receiving anti-B-cell maturation antigen (BCMA) CAR T-cell therapy had comparable response rates to younger cohorts, despite slightly higher rates of neurotoxicity.

Despite advances in CAR T-cell therapy and other novel treatments, HCT remains a cornerstone in multiple myeloma care.

"If there's truly a concern about fitness, we have options," Joseph added. "However, I wouldn't want to oversimplify the situation by telling patients they can skip transplant entirely, as there is still a significant PFS benefit with transplant."

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