Introduction

Multiple myeloma (MM) is an incurable malignancy of neoplastic plasma cells that primarily affects older adults, with a median age at diagnosis of 69 years [1]. The incidence of MM has increased over the years and this may be related to a number of different factors including the revised diagnostic criteria since 2014, improvement in diagnosis by providers, environmental and genetic influences [2, 3]. Additionally, the global population is aging with 15 million more people in the Unites States aged 65 or older in 2019 versus 2010 and is largely responsible for the increased incidence. Prevalence of MM is also increasing, with preliminary reports suggesting up to a 3 × increase, largely due to an increase in the aging population and prolonged survival [4]. Patients with MM, including the elderly, are living longer, largely related to clinical advances in the treatment of MM, the approval of novel therapies, and an increase in the rate of treatment for elderly [5, 6]. However, chronologic age is increasingly recognized as an inconsistent predictor of response, tolerability and toxicity to therapy. Indeed, the impact of novel agents on survival for the subset of older and more frail patients with MM is more limited and lags behind improvements for younger and more fit patients, resulting in the increasing recognition of frailty as an independent factor in patient outcomes [7].

The optimal approach for the treatment of older adults with MM has not been clearly defined, as this group is underrepresented in clinical trials due to stringent eligibility criteria and hesitancy of healthcare providers to enroll patients solely based on their age and/or comorbidities [8]. Given wide variations in their baseline fitness, the management of older patients with MM demands an individualized approach that is based on biologic rather than chronologic age.

In this article, we will review frailty scoring systems in MM, summarize data from clinical trials completed in the last 10 years which have included frailty-based outcomes, and discuss the general considerations for managing older and frail patients with newly diagnosed and relapsed/refractory (R/R) MM.

Frailty in Multiple Myeloma

Frailty is defined as a state of increased vulnerability to stressors resulting from a cumulative decline in multiple physiologic systems, which contributes to an increased risk of adverse health-related outcomes [9]. While increased frailty correlates with age, frailty is not synonymous with being elderly. Frailty has been associated with an increased risk of treatment toxicity, premature treatment discontinuation and decreased survival in MM, independent of disease stage and cytogenetic profile [10, 11]. Therefore, an assessment of frailty is needed to guide treatment decisions for older myeloma patients the clinical setting. Clinical judgement and physician-rated performance status have proven to be non-reliable in charaterizing frailty [11,12,13,14]. A comprehensive geriatric assessment (cGA) is considered the most sensitive means to assess frailty in cancer patients, providing a multidimensional evaluation of several health domains, including functional status, psychological state, cognition, social support, nutritional status, and comorbidities [15,16,17,18,19]. However, cGA has not been uniformly adopted in practice due to limited time and resources. Recognizing the impact of frailty on patient outcomes, there has been an increased use of frailty tools in clinical trials to evaluate outcomes based on frailty and/or to guide interventions adapted to fitness level. A recent systematic review reported 43 studies examining frailty in therapeutic MM trials, with the prevalence of frailty ranging from 17.2% to 73.6%, reflecting variability in the tools utilized to define frailty [20]. It is important to recognize that frailty is dynamic and the majority of patients will experience changes in their fitness level, manifesting in either improvement or deterioration during treatment (21). Thus, it is important to perform serial frailty assessments throughout treatment to guide treatment modifications.

Review of Frailty Tools in Multiple Myeloma

Several frailty scores have been developed in MM using select domains of the full cGA [10, 11, 22,23,24,25,26]. Among these, the 2015 International Myeloma Working Group (IMWG) score is the most widely used. This score categorizes patients into 3 fitness groups (fit, intermediate-fit, frail) based on age, functional status assessed by the Katz activities of daily living index and the Lawton instrumental activities of daily living scale, and comorbidities using the Charlston comorbidity index (CCI). This score was shown to be predictive of treatment toxicity and survival in older transplant-ineligible patients with newly-diagnosed MM [11]. A simplified frailty score was subsequently proposed by Facon et al., using the physician-assessed Eastern Cooperative Oncology Group (ECOG) performance status as a measure of functional status, along with age and the CCI, categorizing patients into frail and non-frail groups [26]. Several other frailty scores have been proposed, incorporating various combinations of chronological age, functional status, comorbidities, measures of renal and/or pulmonary function, laboratory parameters like NT-ProBNP and c-reactive protein, and disease stage [10, 21,22,23,24,25,26]. Table 1 provides a summary of the various frailty scores used in MM. Several of these scores, including the IMWG index, are based on data from clinical trials, which do not always provide an accurate representation of the real-world elderly population. In addition, these scores have mostly been developed using data from transplant-ineligible patients [11, 24, 26]. However, geriatric impairments have been shown to be prevalent in both transplant-ineligible and eligible patients, including those with good physician-rated performance status (PS) [27]. While the incorporation of ECOG PS and karnofsky performance status in several frailty scores offers convenience, physician-rated PS is subject to age-bias and is often inconsistent with the patient’s own assessment [13, 14]. Another limitation of most existing scores is the incorporation of chronological age. For instance, patients age > 80 years would be categorized as frail using the IMWG index based on age alone. In a study by Murillo et al., the IMWG index did not perform well when used in myeloma patients ≥ 75 years [28]. At this time, the major barriers to the incorporation of frailty assesments in the clinical setting are limited time and resources. Given wide variability in resources, it is difficult to standardize geriatric assessments across the various practice settings. In resource-limited settings, quick screening tools like the vulnerable Elders Survey-13 (VES-13) and the Geriatric 8 (G8) tools can be used to identify patients who would benefit from a cGA. Self-administered geriatric assessment tools are also available and can be utilized in this setting [29].

Table 1 Frailty Scoring Systems for Multiple Myeloma Patients
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Considerations in the Treatment of Older Patients with Multiple Myeloma

Goals of Therapy

The introduction of novel therapies has allowed deeper and more durable responses to be achieved with combination treatment. As in younger patients with MM, the achievement of complete responses translates into longer progression-free and overall survival in older transplant-ineligible (TI) patients, including those > 75 years [32, 33]. The introduction of novel therapies has allowed deeper and more durable responses to be achieved with combination treatment. As in younger patients with MM, the achievement of complete responses translates into longer progression-free and overall survival in older transplant-ineligible (TI) patients, including those > 75 years [34, 35]. However, this subset of patients is often at risk of undertreatment in real-world practice, where effective therapies may be withheld based on age alone [36]. Triplet combinations of novel agents should be offered to fit patients with the aim of achieving deep responses. On the other hand, it is important to balance efficacy and safety in patients who are intermediate-fit or frail given the negative impact of premature treatment discontinuation on outcomes [37]. It is also important to monitor closely for treatment tolerance and to perform serial frailty assessments to guide treatment modifications including adjusting the dose/schedule or adding a third agent if functional status and/or organ function improve.

Disease-Related Factors

Disease stage, cytogenetics, and aggressiveness should be taken into consideration when choosing treatment. Triplet therapies should be offered to patients with high-disease burden, with empiric dose adjustments based on fitness [38]. The relative impact of cytogenetics has been shown to decrease with age, while the prognostic impact of ISS and performance status are retained [39]. At this time, there is insufficient evidence for cytogenetic profile to guide treatment choices in transplant-ineligible patients. Supportive care should be provided in conjunction with plasma cell-directed therapy, including symptom control, infectious and thromboembolic prophylaxis, management of cytopenias, management of skeletal complications, fall prevention, and nutrition.

Patient-Related Factors

The choice of treatment regimen should take into account underlying comorbidities, baseline organ function, baseline symptoms including peripheral neuropathy, social support, adherence to oral medications, and travel burden. It is of utmost importance that patients are engaged in treatment decisions and that their values and preferences are prioritized while establishing treatment goals. It has been demonstrated that, when faced with decisions on cancer-directed therapy, a large proportion of older patients place higher value on maintaining cognitive ability and independence compared to survival [40]. Patient preferences for route of administration, dosing frequency, and infusion time should also be considered [41].

Treatment of Newly Diagnosed Multiple Myeloma in Frail Patients

The treatment of newly diagnosed MM usually involves a triplet or quadruplet regimen and depends largely on a patient’s functional status as well as disease risk stratification. Patients are first determined to be either eligible or ineligible for autologous stem cell transplant (ASCT). Transplant eligibility criteria vary between countries; while most European countries consider patients ≥ 65 years to be TI, there is no strict age cutoff for ASCT in the United States [42]. Older patients, including those ≥ 70 years, have been shown to benefit from ASCT, with outcomes comparable to younger patients [43, 44]. Thus, transplant eligibility is determined based on the assessment of PS, comorbidities, and baseline cardiac, pulmonary, and hepatic function. Renal dysfunction, including dialysis dependence, is not a strict contraindication to ASCT in MM [45]. The specific thresholds for PS and organ function vary between institutions; in general patients with PS > 2 are considered ineligible for ASCT. Some transplant centers rely on the Hematopoietic cell transplantation comorbidity index to estimate transplant risk [46]. The IMWG frailty index has also demonstrated utility in determining transplant eligibility among patients 70–75 years. There is also wide variability in transplant-eligibility criteria in the clinical trial setting, with a large number of trials using 65 years as a strict cutoff.

Currently, the standard of care treatment for patients that are considered to be transplant candidates generally entails four cycles of induction therapy with a quadruplet regimen followed by high dose chemotherapy with melphalan and an autologous stem cell transplant [47]. For patients that are deemed ineligible for transplant, the initial treatment consists of a doublet or triplet regimen for 8–9 cycles followed by maintenance until progression [48]. The EQUATE trial is a currently enrolling trial through the Eastern Cooperative Oncology Group that will assess the impact of a quadruplet regimen on transplant ineligible patients. The trial is limited to patients with an ECOG performance status of 0–2 and either R-ISS stage 1 or 2 disease, so the generalizability of this trial to a frail population remains to be seen.

The Southwest Oncology Group (SWOG) S0777 study investigated the addition of bortezomib to lenalidomide and dexamethasone in the transplant ineligible population and determined a significant improvement in median progression free survival (mPFS) (43 months vs 30 months, p = 0.0018) and median overall (mOS) (75 months vs 64 months, p = 0.025) with the triplet regimen [49]. Though designed as a transplant ineligible trial, the majority of enrolled patients were less than 65 years old and frailty status was not reported. Regardless, the benefit for triplet induction was retained in patients ≥ 75 years old. A subsequent retrospective cohort study of frail US veterans also demonstrated improved overall survival and decreased rates of hospitalization for the triplet combination [50]. Modifications to the triplet arm of S0777, including RVd lite, in older patients has also demonstrated efficacy in phase 2 studies [51].

The introduction of daratumumab in the frontline setting has led to more tolerable and effective combination therapies for newly diagnosed MM patients. This approach has reduced certain side effects from upfront use of proteasome inhibitors including neuropathy and cardiomyopathy, that this population may be particularly susceptible to developing. An updated analysis of the MAIA trial showed that the addition of daratumumab to lenalidomide and dexamethasone led to superior mPFS (61.9 months vs 34.4 months, p < 0.0001) and mOS (NR vs 65.5 months, p = 0.0003) compared to the doublet of lenalidomide and dexamethasone alone [52]. In a subgroup analysis of the MAIA study population by frailty status, the PFS benefit was maintained in frail patients (NR vs 30.4 months; HR, 0.62; p = 0.003) though non-frail patients had a longer PFS than frail patients [53]. Table 2 includes a summary of MM clinical trials that included frailty sub-analyses. The ALCYONE trial investigated the addition of daratumumab to VMP (bortezomib, melphalan, and prednisone), one of the preferred European regimens for transplant-ineligible patients [54]. The addition of daratumumab to this regimen resulted in superior 18-month PFS (71.6% vs 50.2%; HR 0.50; 95% CI, 0.38–0.65; p < 0.001). Minimal residual disease (MRD) lasting longer than 12 months was assessed in both trials and revealed improved sustained MRD rates in both groups receiving daratumumab (DRd 10.9% vs Rd 2.4%; D-VMP 14% vs VMP 2.8%)[55]. The S2209 Southwest Oncology Group trial is an ongoing phase III study comparing VRd-Lite, DRd-R, and DRd-DR in intermediate-fit or frail patients with newly diagnosed MM (NCT05561387).

While efficacy of a given induction regimen is important, health-related quality of life (HRQoL) is also of utmost importance in this especially vulnerable population, given their disproportionate susceptibility to therapy-related toxicity. Patient-reported outcomes were analyzed in the frail subgroup in the MAIA trial, and patients receiving DRd experienced greater improvements in their global health status and physical function from baseline, as well as greater reduction in pain scores [56]. These data, along with the efficacy analyses discussed above, support the use of a triplet whenever possible to achieve optimal disease control while balancing toxicity profiles.

There are select patients that may not be candidates for triplet therapy at the time of diagnosis and a doublet may need to be utilized. Historically, this has been the combination of lenalidomide and dexamethasone, which led to an improvement in PFS when compared to MPT (melphalan, prednisone, and thalidomide) (HR, 0.70; 95% CI 0.60–0.82; p < 0.001) [57]. With the incorporation of anti-CD38 antibodies into frontline MM treatment, this has increased the permutations for upfront doublet and triplet combinations in frail patients. The use of dexamethasone can sometimes be problematic in older and more frail patients due to the plethora of side effects that can result from chronic use, particularly in patients with greater medical comorbidities at the time of diagnosis. In a study of intermediate-fit elderly patients, lenalidomide maintenance after Rd for 9 cycles showed similar outcomes to Rd until progression (mPFS 20.2 vs 18.3 months, HR 0.78; 95% CI, 0.55–1.10; p = 0.16) 44. The IFM 2017–03 trial is a phase 3 randomized trial investigating a steroid-sparing approach of daratumumab and lenalidomide (DR) compared to lenalidomide and dexamethasone (Rd). Patients receiving DR had deeper and more durable responses with similar discontinuation rates for adverse events [58].

For extremely frail patients that are still deemed to be candidates for systemic therapy, single agent daratumumab may be utilized with dexamethasone for prevention of infusion related reactions [59]. This approach was initially studied in the heavily relapsed and refractory population but has been successfully utilized in the upfront setting for more frail patients [60]. Preliminary results of an ongoing study investigating a daratumumab based, response-adapted therapy for newly diagnosed frail patients with MM has shown 90% PFS at 1 year 61. Patients only receive the addition of lenalidomide or bortezomib if they achieved less than a partial response at 2 cycles and this approach appears to be efficacious with limited toxicity. This approach may also allow for the improvement of functional status with a calculated approach to escalation of therapy after achieving some degree of disease control.

For the majority of newly diagnosed multiple myeloma patients that are classified as frail, treatment in the context of a clinical trial would be the optimal approach. For those patients that do not have a clinical trial option available to them, utilization of a triplet would be preferred over a doublet regimen. If a patient is considered to be extremely frail and a doublet is being considered, then a daratumumab-containing regimen would be preferred.

Treatment of Frail Patients with Relapsed/Refractory Multiple Myeloma

The treatment of relapsed or refractory multiple myeloma in frail patients has become exceedingly complicated. There have been numerous drugs approved in the relapsed setting with variable tolerability profiles, broadening the landscape of MM treatment but adding to the complexity of determining optimal sequencing of drugs. In addition to factors guiding treatment in the frontline setting, treatment decisions in the R/R setting should take into consideration prior exposure history and refractoriness, tempo of progression, residual toxicities from prior treatments, thromboembolic risk, cardiac function, and bone marrow reserve. Patients who present with a slow biochemical relapse may be initially observed. For those who are on maintenance, an increase in the dose of the maintenance drug and/or addition of dexamethasone can be considered.

For patients that were not previously exposed to an anti-CD38 monoclonal antibody, the utilization of this therapeutic class can lead to deep and durable second remissions with a tolerable toxicity profile in frail patients. In the relapsed setting, the addition of anti-CD38 monoclonal antibodies (daratumumab and isatuximab) to immunomodulatory agents and proteasome inhibitors has yielded impressive response rates and durable remissions [61,62,63,64,65,66]. Of these studies, the APOLLO (DPd vs Pd) and ICARIA-MM (IsaPd vs Pd) trials enrolled the greatest number of patients aged ≥ 75 years with close to 20% of each arm on both studies being comprised of older patients [61, 62]. The addition of daratumumab to pomalidomide and dexamethasone appeared to benefit the older cohort (HR 0.55, 0.38–0.81) as did the addition of isatuximab to pomalidomide and dexamethasone (HR 0.48, 0.24–0.95). A frailty subgroup analysis of the ICARIA-MM trial also revealed that the addition of isatuximab to pomalidomide and dexamethasone led to favorable ORR (66.4 vs 52.1%) and treatment discontinuation rates (7.0 vs 8.3%) in non-frail vs frail patients (Table 2), respectively [67].

Table 2 Clinical Trials with Frailty Sub-analyses in NDMM and RRMM Patients
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When possible, these patients should be treated within the context of a clinical trial that includes enrollment of frail patients, or better yet, is specifically designed for this population. Otherwise, dose-reduced triplet or doublet regimens are preferred for frail patients. Frailty-adjusted doses should be based on published consensus guidelines, and may be increased by tolerance [38]. Carfilzomib should be avoided in patients with significant cardiac disease. There is no indication for adjusting the doses of CD38-targeting monoclonal antibodies based on fitness.

Role for Bispecifics and CAR T-cell therapies in older and frail patients:

The treatment landscape for R/R MM has undergone a recent transformation with the introduction of chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engagers, which have demonstrated unprecedented responses in this setting [70,71,72]. In contrast to CAR T-cells, which are generated by ex vivo engineering of autologous T-cells, bispecific antibodies redirect endogenous T cells towards plasma cells; one of their binding sites targets CD3 on the T-cell surface, while the other site targets an antigen that is selectively expressed on the plasma cell surface [72].

Guidance for selecting frail patients for therapeutic approaches such as the bispecific T-cell engagers (BiTES) or chimeric antigen receptor (CAR) T-cell therapy is very limited. There have been limited data for use of these agents in frail patients, but there is some data to suggest they might be appropriate options in select patients. A subgroup analysis of elranatamab, a BCMA-directed BiTE, in patients based on age and frailty status supported the safety and efficacy of this therapy in older and more frail patients 69. This was based on comparable overall response rates (63.1% vs 56.4%) and grade 3–4 adverse events (73.8% vs 64.1%) in non-frail vs frail patients, respectively.

CAR T-cell therapy targeting B-cell maturation antigen (BCMA) is the most promising new therapy approved for patients with relapsed and refractory multiple myeloma and has yielded more impressive response rates than any other therapy ever approved for treatment of multiple myeloma. The older patients included on the clinical trials leading to approval of these products were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, which selected for patients that were much less likely to be classified as frail [70, 73]. A meta-analysis of clinical trials investigating BCMA-directed CAR T-cell therapy in RRMM patients revealed that the pooled ORR in older adults was comparable to ORR in younger adults (93% vs 86%) and rates of grade 3 or higher cytokine release syndrome (CRS) were 21% and 20%, respectively, but the rate of ICANS (any grade) was higher in older patients (15% vs 6%)[74]. Without frailty assessment as a component of this analysis, it’s difficult to determine whether this would translate to efficacy and tolerability in patients characterized as frail regardless of chronological age.

Older patients being considered for CAR T-cell therapy should undergo functional, nutritional, cognitive, and psychosocial assessment in addition to physical performance testing, and evaluation of comorbidities and polypharmacy. Early referral for CAR T provides an opportunity for optimization of performance status through rehabilitation and of comorbidities through appropriate referrals. CAR T-cell therapy should be avoided in patients who have significant baseline neurological or cardiopulmonary disorders, as these patients are at increased risk of complications from CRS and/or neurotoxicity. In general, bispecific T cell engagers are preferred over CAR T-cell therapy in patients who are frail due to decreased risk of complications from CRS and neurotoxicity. These patients should be closely monitored, with consideration for inpatient administration of the initial step-up doses.

Conclusion

The management of older patients with MM should be guided by physiological rather than biological age. Several tools are available to define frailty with variability in the parameters and cutoffs used. Poor performance status that is not disease-related, and high comorbidity index, are both associated with an increased risk of treatment-related toxicity. When assessing performance status, patient-provided data is superior to the physician assessment. The treatment of frail patients with MM is a complex dilemma in the era of novel therapies with variable tolerability. In both the newly diagnosed and R/R setting, triplets are more efficacious than doublets. Utilizing a triplet therapy whenever possible is thought to be the optimal approach to patients that cannot tolerate a quadruplet regimen. In patients that are not thought to be candidates for triplet therapy, doublets may be considered with the intention to escalate if the patient’s performance status improves with the initiation of disease-directed therapy. The goal of treatment in frail patients should be achieving the greatest degree of disease-control possible while improving or maintaining quality of life.

Use of BiTES would be preferred over CAR T-cell therapy for patients who are considered to be frail because of the lower risk of complications from CRS and neurologic toxicity.

When possible, frail patients with MM should be treated in the context of a clinical trial so that clinical benefit may be optimized and data from their treatment may contribute to future decision-making in this population.