Management of Frail Older Adults with Newly Diagnosed Multiple Myeloma — Moving Toward a Personalized Approach

Case vignette

A 75-year-old male undergoes an evaluation for progressively worsening fatigue with associated shortness of breath. He also reports back pain worse at night, which does not resolve with acetaminophen. He is retired, but over the past 2 months he is unable to garden or perform household chores. Due to his pain and fatigue, he has limited his activity. He currently takes 9 prescription medications for chronic medical conditions, which include diabetes mellitus with neuropathy, hypertension, hyperlipidemia, and COPD. Initial evaluation reveals anemia (Hgb 9.0 g/dl last known normal was 2 years ago, Hgb 13.5 g/dl), renal impairment (serum creatinine 2.5 mg/dL), hypercalcemia (11.5 g/dl). Plain X-rays reveal compression fractures involving T3 and T4. Multiple myeloma is suspected, further labs confi rm the diagnosis of IgG kappa multiple myeloma. LDH is elevated, beta-2-microglobulin is elevated at 6.1 mg/L and albumin < 3.5 mg/dl. Bone marrow aspiration and biopsy reveal plasmacytosis of 55% and on fl uorescence in situ hybridization testing, del 17p/TP53 mutation in 85% of cells is detected. PET/CT confirms diffuse bone disease involving the axial and appendicular skeleton. His Karnofsky performance status (KPS) is 70%. He is widowed and lives alone but has 2 adult children who currently live out of state.

This abstract will discuss how assessments of fitness/frailty may be used to develop personalized care tailored to the unique needs of older frail adults with multiple myeloma.

Introduction

Multiple myeloma (MM) is a clonal plasma cell disorder, primarily affecting older adults, with nearly 70% of all new diagnoses occurring in adults aged ≥ 65 years.¹ Over the next 3 decades, the prevalence and incidence of MM is expected to rise in parallel with the projected rapid increase in the global number of adults aged ≥ 65 years.^2,3

Despite therapeutic advances leading to improved MM-related survival, those aged ≥ 75 years continue to account for the highest burden of death,⁴ while those aged ≥ 70 years remain at greatest risk for early mortality.⁵ The disparate MM-related survival is partially due to the presence of aging-related vulnerabilities such as comorbidities, functional disability, and frailty, which are more prevalent with advancing age. These vulnerabilities may impact biologic age, thus creating a heterogenous population of older adults with diverse clinical outcomes based on biologic and chronologic age.⁶ “Staging the aging” is an emerging concept that helps identify those more likely to experience significant treatment-related toxicities. Overall, “staging the aging”, and MM stage (“staging the cancer”) are necessary when developing personalized tailored care plans for the management of older adults with MM. Use of such personalized care plans allows tailoring of therapies to minimize toxicities while prioritizing patient preferences. Additionally, the personalized care model may reduce the risk of over-treating vulnerable frail older adults, while ensuring more robust patients receive therapies with maximal efficacy, thus minimizing potential under-treatment of this subset of patients.

Geriatric assessments and frailty scales available to assess vulnerabilities in an older adult with newly diagnosed multiple myeloma

The first step towards developing a personalized care plan involves performance of a geriatric assessment (GA). The GA is considered a multidomain assessment of areas such as function, physical health, and psychosocial issues, which collectively provide an estimate of an older adult’s overall fi tness. Though the comprehensive geriatric assessment (CGA) is considered the “gold standard” for a complete evaluation of an older adult’s health status, widespread use of the CGA is limited by time and resources required for its administration. Attempts have, therefore, been made to develop and validate simpler assessment tools capable of capturing the heterogeneity of aging. These tools commonly incorporate age with additional domains such as comorbidities, function, performance, and psychological status (Table 1).^7–13 The International Myeloma Working Group (IMWG) frailty scale and revised myeloma comorbidity index (R-MCI) are well-described validated tools capable of predicting toxicity and survival in adults with MM, according to three distinct fitness categories (fit, intermediate-frail, and frail).^7,8 These and other GA tools have evolved beyond evaluation of the predictive and prognostic effects associated with the identification of vulnerabilities to include the study of fitness/frailty-adapted approaches for the treatment of MM.¹⁴

Table 1.

Select predictive and prognostic indices for assessing frailty in adults with multiple myeloma.

Variables	IMWG	R-MCI	GAH	Mayo frailty index	Edmonton frailty scale	Facon et al. frailty scale	MRP
Age	X	X		X		X	X
Biomarker				X			X
Cognition			X		X
Comorbidities	X	X				X
Disease stage							X
Frailty		X
Functional status	X		X		X
Gait dysfunction					X
Nutrition			X		X
Performance status		X		X		X	X
Poly-pharmacy			X		X
Prior hospitalization					X
Psychological status			X		X
Self-rated health			X		X
Urinary incontinence					X

IMWG, International Myeloma Working Group; R-MCI, revised myeloma comorbidity index; GAH, Geriatric Assessment in Hematology scale; MRP, Myeloma Research Alliance Risk Profi le.

Prior studies have also addressed the barriers associated with GA implementation, demonstrating feasibility of conducting a GA in various clinical practice settings, including community-based hematology-oncology practices and myeloma-based practices.^15,16 Given the identified benefits of the GA, several large national oncology and geriatric societies have recently recommended the routine assessment of aging-related vulnerabilities for older adults with cancer.^17–19

Despite wide variations in the strategies used to assess fitness of an older adult, studies have consistently demonstrated worse outcomes with increasing levels of frailty.^7,20 It is important to note that frailty is dynamic, related to disease status, and exists on a continuum with fi tness.²¹ Therefore, reassessment of aging and disease-related factors may be required throughout a patient’s disease course, allowing dose escalation and de-escalation strategies in response to the older adult’s fitness/frailty status. This approach has been recommended by the European Myeloma Network consensus on practice in older adults with myeloma.¹⁸ Furthermore, dose-adjusted approaches guided by fitness highlight the importance of the key concept of “start low and go slow” in geriatric medicine, pertaining to the use of medications in older adults. This approach permits prompt therapy interruptions or modifications, while minimizing potentially harmful treatment-related toxicities, which may worsen the quality-of-life of older adults with MM. Further research in this and other areas evaluating the longitudinal changes in fitness/frailty status, and whether such changes alter disease-related outcomes such as progression-free and overall survival, are needed.

Overall, the care of older adults with MM remains complex and a framework which involves an assessment of a patient’s “fi tness” for therapy should be considered. The patient in the case vignette provides the background for important considerations in a frail older adult, with approach summarized in Figure 1. Other factors such as fi nancial costs, travel burden, and patient preferences may also need to be considered in the development of a personalized care plan tailored to each older adult’s unique needs.

Figure 1.

Approach to the frail older adult with newly diagnosed multiple myeloma.

Frontline therapy for frail older adults with newly diagnosed multiple myeloma

The frontline therapy options for older adults with MM have increased over the past decade following the introduction of novel combination therapies such as immunomodulatory agents, proteasome inhibitors, and immunotherapies. While high-dose chemotherapy followed by ASCT forms an important part of the care compendium for eligible patients, treatment of frail older adults with newly diagnosed MM remains limited to systemic therapy alone or in combination with supportive strategies.

Deciding which systemic therapy is appropriate for a frail older adult with MM requires a careful balance between tolerability and efficacy. It is important to recognize that a single optimal regimen for all frail older adults remains undefined. However, the treatment landscape has rapidly evolved since the initial recognition of the benefit of melphalan-based doublet regimens for older adults and recent guidelines emphasize the importance of triplet induction regimens when feasible.²⁶

For frail patients ineligible for triplet induction therapy, the randomized Frontline Investigation of Lenalidomide plus Dexamethasone versus Standard Thalidomide (FIRST) trial demonstrated superior efficacy of continuous lenalidomide and dexamethasone (Rd) for older adults ineligible for high-dose chemotherapy and remains an option for select frail older adults.²⁷ Importantly participants in this trial were enrolled based on age > 65 years or younger with comorbidities precluding ASCT eligibility, and Eastern Cooperative Oncology performance status ≥ 2 or KPS ≥ 60%, frailty/geriatric assessments were not used in the randomization schema.

Reports from a phase III trial evaluating a fitness-based approach (IMWG) suggested fixed-dose Rd administered in nine 28-day cycles, followed by lenalidomide monotherapy until disease progression may have similar efficacy and better tolerability than continuous Rd for intermediate-fi t patients (IMWG) with MM.²⁵ Though this study excluded frail (IMWG) patients, the results highlight potential challenges with continuous Rd in older less fit adults.

Additional therapeutic options for select frail older adults include bortezomib, lenalidomide, dexamethasone (VRd). Supporting data from the phase III Southwestern Oncology Group-S0777 trial comparing VRd to Rd, demonstrated improved progression-free survival (PFS) with VRd (43 months vs. 30 months) and median overall survival (75 months vs. 64 months).²⁸ While modifi ed lenalidomide (R ) bortezomib (V), dexamethasone (D) [RVD-lite] may provide an alternative for those intolerant to standard dose VRd.²⁹

The addition of daratumumab (Dara) to frontline therapies for older adults has led to further improvements in PFS for this population. Two recent randomized phase III trials, ALCYONE, evaluating Dara-VMP vs VMP (bortezomib (V), melphalan (M), prednisone (P),³⁰ and MAIA, evaluating Dara-Rd vs.Rd³¹ led to the approval of these two regimens for transplant-ineligible older adults with newly diagnosed MM. However, frailty/fitness-based approaches were not assessed in these trials; therefore, choice of frontline therapy in frail older adults requires a careful balance between safety and efficacy. Additional considerations such as travel burden associated with infusion and laboratory visits and clinical assessments should be weighed especially in older frail adults.

Future directions

The management of older adults with MM is rapidly evolving. The incorporation of geriatric and frailty tools in both the clinical and research settings are essential for creating a shift towards a personalized care model for older adults. Data from ongoing studies of unfit and frail older adults with newly diagnosed MM, such as HOVON 143 (EudraCT 2016–002600-90), evaluating the efficacy and tolerability of ixazomib in combination with daratumumab and dexamethasone could provide alternative treatment options for this population.³² Similarly, results from the planned phase III multicenter randomized trial: Myeloma XIV: Frailty-adjusted Therapy in Transplant Non-Eligible Patients With Newly Diagnosed Multiple Myeloma (FiTNEss) (NCT03720041), comparing standard therapy to frailty-adjusted therapy using the combination of ixazomib and Rd,¹⁴ will be critical to our understanding of how fitness/frailty may impact clinical outcomes of patients with MM.

Forging ahead, the approach to management of older adults with MM involves incorporating tools capable of assessing fitness/ frailty status. This involves understanding important geriatric principles, which can be integrated into the care of older adults with MM and other cancers. These principles should be guided by a strong-evidence base, and a care team capable of providing support/interventions for identified vulnerabilities. This approach is critical for the advancement of the field of geriatric oncology, whose overarching goal is the improvement of clinical outcomes for older adults with cancer.