# The Evolving Treatment Landscape for the Elderly Multiple Myeloma Patient: From Quad Regimens to T-Cell Engagers and CAR-T

## TL;DR

This paper reviews how new immunotherapies like T-cell engagers and CAR-T are changing treatment for elderly multiple myeloma patients, despite challenges in adoption.

## Contribution

The paper provides a comprehensive review of the evolving treatment landscape for elderly multiple myeloma patients, focusing on novel immunotherapies and their unique challenges.

## Key findings

- Quadruplet regimens in elderly MM patients show improved progression-free survival but with increased toxicity.
- T-cell engagers and CAR-T therapies offer promising efficacy but face barriers like cost and logistical complexity.
- Elderly patients may benefit from non-chemotherapeutic immunotherapies due to their distinct toxicity profiles.

## Abstract

Elderly individuals account for approximately one-third of multiple myeloma (MM) diagnoses, yet they also represent a highly heterogeneous population due to medical comorbidities, frailty, and social factors. There have been dramatic therapeutic advances in MM—including the establishment of triplet and quadruplet regimens containing anti-CD38 monoclonal antibodies in newly diagnosed MM, bispecific T-cell engagers, and chimeric antigen receptor (CAR) T-cell therapies. Elderly and frail individuals were underrepresented in the pivotal clinical trials which defined these therapies as standard of care. Nonetheless, the distinct, non-chemotherapeutic toxicity profile of these agents makes them particularly well suited for elderly patients. As such, immunotherapies hold the potential to improve outcomes in this vulnerable group, but their adoption has been hampered by concerns about tolerability, access, logistical complexity, and cost. Herein, we review evidence on the safety, efficacy, and barriers to adopting these therapies in elderly MM patients.

Multiple myeloma (MM) is predominantly a disease of the elderly. In recent years, a surge of highly effective plasma cell therapies has revolutionized the care of elderly multiple myeloma (MM) patients, for whom frailty and age-related competing causes of mortality determine management. Traditionally, the treatment of newly diagnosed elderly patients has centered on doublet or triplet combinations composed of immunomodulators (IMIDs), proteasome inhibitors (PIs), anti-CD38 monoclonal antibodies (mAbs), and corticosteroids producing median progression-free survival (PFS) rates between 34 and 62 months. However, recently, a series of large phase III clinical trials examining quadruplet regimens of PIs, IMIDs, corticosteroids, and anti-CD38 mAbs have shown exceptional outcomes, with median PFS exceeding 60 months, albeit with higher rates of peripheral neuropathy (≥Grade 2: 27% vs. 10%) when PIs and IMIDs are combined, and infections (≥Grade 3: 40% vs. 29–41%) with the addition of anti-CD38mAbs. The development of T-cell redirecting therapies including T-cell engagers (TCEs) and CAR-T cells has further expanded the therapeutic arsenal. TCEs have shown exceptional activity in relapsed disease and are being explored in the newly diagnosed setting with promising early results. However, concerns remain regarding the logistical challenges of step-up dosing, which often necessitates inpatient admission, the infectious risks, and the financial burden associated with TCEs in elderly patients. CAR-T, the most potent commercially available therapy for MM, offers the potential of a ‘one and done’ approach. However, its application to elderly patients has been tempered by significant concerns of cytokine release syndrome, early and delayed neurological toxicity, and its overall tolerability in frail patients. Robust data in frail patients are still needed. How CAR-T and TCEs will be sequenced among the growing therapeutic armamentarium for elderly MM patients remains to be determined. This review explores the safety, efficacy, cost, and logistical barriers associated with the above treatments in elderly MM patients.