International Myeloma Working Group Frailty Research Articles

Patient-reported frailty phenotype (PRFP) vs. International Myeloma Working Group frailty index (IMWG FI) proxy: A comparison between two approaches to measuring frailty

IntroductionFrailty assessments may help to identify patients at highest risk for treatment-related toxicity, early treatment discontinuation due to toxicity, and death in Multiple Myeloma. We aimed to compare the patient-reported frailty phenotype (PRFP) and a modified version of the International Myeloma Working Group frailty index (IMWG FI) in terms of their strengths, limitations, and classification of frailty in a cohort of patients with relapsed/refractory multiple myeloma (RRMM). Materials and MethodsData were pooled from six RRMM Phase 3 randomized clinical trials submitted to the Food and Drug Administration for regulatory review between 2010 and 2021. Patients were classified as fit, intermediate fit/pre-frail, or frail using both PRFP and the IMWG FI proxy. Agreement between the two approaches in classification of patient frailty was assessed using weighted Cohen's kappa. A contingency table and Venn diagram were generated to analyze overlap in categorization of patient frailty across the different severity groups. Descriptive statistics were used to summarize and compare the clinical and demographic characteristics of patients categorized as frail by PRFP vs. IMWG FI proxy. ResultsOf the 2,750 patients included in this analysis, IMWG FI proxy classified 16.4% (452) patients as frail, 28.1% (772) as intermediate fit/pre-frail, and 55.5% (1,526) as fit. Meanwhile, PRFP classified 21.7% (597) of patients as frail, 24.5% (675) as intermediate fit/pre-frail, and 53.8% (1478) as fit. Fair agreement was observed between PRFP and IMWG FI proxy (weighted Cohen's Kappa = 0.34 [0.31–0.37]). On average, patients who were categorized as frail by IMWG FI proxy were older and had higher Charlson Comorbidity Index scores than patients classified as frail by PRFP. In contrast, patients who were classified as frail by PRFP had worse EORTC QLQ-C30 Physical Functioning subscale summary scores as compared to patients in the IMWG FI proxy frail group (median score of 40 vs. 47 out of 100). DiscussionOur analysis found fair concordance between IMWG FI proxy and PRFP. This demonstrates that while both frailty models measure the same underlying construct, the variables that constitute each approach may result in differing frailty categorizations for the same patient. Further prospective studies are needed to establish and compare the predictive and prognostic abilities of the different frailty indices in MM.

Carfilzomib-Lenalidomide-Dexamethasone (KRd) Vs. Lenalidomide-Dexamethasone (Rd) in Newly Diagnosed Fit or Intermediate-Fit Multiple Myeloma Patients Not Eligible for Autologous Stem-Cell Transplantation (Phase III EMN20 Trial): Analysis of Sustained Undetectable Minimal Residual Disease (MRD)

Background. Before the recent introduction of daratumumab (Dara) in the frontline setting, lenalidomide-dexamethasone (Rd) has represented a standard of care for transplant-ineligible (NTE), patients (pts) with newly diagnosed multiple myeloma (NDMM). Nonetheless, minimal residual disease negativity (MRD Neg) rate and median progression-free survival (PFS) with Rd were still relatively limited, as compared with 3/4-drug regimens, also including carfilzomib (K). The EMN20 trial (NCT04096066) is a randomized, multicenter study designed to compare weekly K in addition to Rd (KRd) with Rd in fit or intermediate-fit NTE NDMM pts, with the objective of attaining improved rates of PFS and 2-year MRD Neg through a triplet regimen. Methods. Fit or intermediate-fit NTE NDMM pts (according to the International Myeloma Working Group frailty score) were randomly assigned to receive KRd (28-day cycles, once-weekly K 56 mg/m² on days [dd] 1,8,15 for 12 cycles and on dd 1,15 from cycle 13 onwards for 5 years (yr), R 25 mg orally on dd 1-21 continuously and d 40 mg on dd 1,8,15,22 continuously) or continuous Rd (28-day cycles, R 25 mg on dd 1-21, d 40 mg on dd 1,8,15,22). Pts were stratified based on International Staging System (ISS) stage and fitness status, using a web-based procedure completely concealed from study participants. Patients in the KRd arm sustaining MRD Neg after 2 yr of treatment will discontinue carfilzomib early (at 2 yr) and continue Rd alone. The primary endpoints were MRD Neg after 2 yr of treatment and PFS. For MRD assessment, the clonoSEQ™ assay was used at the sensitivity of ≥10⁻⁵. The MRD Neg rate was the proportion of MRD-Neg pts (sensitivity ≥10⁻⁵) at 2 treatment yr. Key secondary endpoints included response rates, overall survival (OS) and safety. The protocol was prematurely stopped on Nov 23, 2021, after the introduction of frontline Dara-Rd. Results. A total of 101 pts were enrolled and 82 were randomized (KRd 42 vs Rd 40); 19 pts were not randomized due to screening failure (17) and withdrawal of consent (2). Pt characteristics were well balanced between the KRd and Rd arms: median age was 73 (IQR 70-76) and 74 yr (IQR 72-76), 60% vs 58% of pts were fit, 33% vs 30% had ISS III and 22% vs 22% had high-risk cytogenetics, respectively. In the KRd vs Rd arms, 33/42 (78.6%) vs 18/40 (45.0%) pts are still under treatment; reasons for discontinuation were medical decision (1 vs 4), death (2 vs 5), adverse events (AEs; 2 vs 1), progressive disease (3 vs 10), lost to follow-up (1 vs 0) and consent withdrawal (0 vs 2). After a median follow-up of 24.9 months (IQR 20-29), 79% of KRd pts and 50% of Rd pts were alive and progression-free. In the ITT population, MRD Neg rates (at 10⁻⁵) were observed in 21/42 (50%) KRd pts vs. 0 Rd pts at 1 yr of treatment (p<0.0001) and in 23/42 (55%) KRd pts and 0 Rd pts at 2 yr (p<0.0001). 16/42 (38%) KRd pts and 0 Rd pts sustained MRD Neg at 2 yr (p<0.0001; Figure panel a). At the time of abstract submission, the assessment of MRD at 2 yr of treatment was still pending for 6 KRd pts and 10 Rd pts. Median PFS was not reached with KRd vs 20.9 months with Rd (HR 0.29, 95% CI 0.13-0.64, p=0.002; Figure panel b). In multivariable analysis, no significant effect modification was observed in terms of ISS or frailty status. 2-yr OS was 89% with KRd vs 74% with Rd (HR 0.36, 95% CI 0.11-1.17, p=0.09). The most frequent grade 3-4 AEs with KRd were neutropenia (22%), thrombocytopenia (10%), cardiac AEs (7%), infection (7%) and hypertension (5%), while with Rd they were neutropenia (12%) and dermatologic AEs (10%). Second primary malignancy was observed in 1 pt (3%) in the Rd arm. Eighty-five percent of pts in the KRd and 70% in the Rd arms had ≥1 dose reductions of any drug. Conclusions. To our knowledge, these results demonstrate for the first time an unexpected high rate of MRD Neg in NTE NDMM pts. Half of pts treated with KRd achieved MRD Neg, improving over time with therapy (50% at 1 yr and 55% at 2 yr), and 38% of KRd patients sustained MRD Neg at 2 yr. This higher rate of MRD Neg was associated with prolonged PFS. Toxicities were predictable and manageable. Updated results will be presented at the meeting.

Dynamic Frailty Assessment in Transplant Non-Eligible Newly Diagnosed Myeloma Patients: Initial Data from UK Myeloma Research Alliance (UK-MRA) Myeloma XIV (FiTNEss): A Frailty-Adjusted Therapy Study

Background Multiple myeloma (MM) is a blood cancer that predominates in the older adult with significant morbidity and mortality. Frailty is increasingly recognized as a predictor for long- and short-term outcomes, with those who are frailer at risk of greater toxicity, treatment discontinuation and poorer survival. Identifying and tailoring treatment for frail older patients with MM remains an unmet need. The International Myeloma Working Group frailty score (IMWG FS) is a prognostic biomarker for survival, but no evidence exists for its predictive biomarker potential. In addition, defining frailty at a single timepoint (baseline) by the IMWG FS may mask disease overlay and the improvements seen with therapy delivery. Understanding both improvements and deteriorations in frailty during treatment may have important implications for dynamic treatment delivery. Study Design and Methods The UKMRA Myeloma XIV FiTNEss trial (NCT03720041) is a phase III, multi-centre, randomised controlled trial for newly diagnosed patients with MM ineligible for a stem cell transplant. The primary objectives of the study are 1) to compare early treatment cessation (within 60 days of randomisation) between patients randomised to standard (reactive) and frailty-adjusted (adaptive, based on IMWG FS) induction therapy delivery with the triplet ixazomib, lenalidomide and dexamethasone (IRd) and 2) to compare progression-free survival for maintenance lenalidomide (R) and lenalidomide plus ixazomib (IR). Baseline revised IMWG FS (considering only those scoring >=3 frail) and UKMRA Myeloma Risk Profile (MRP) were determined. Here we report the changes in IMWG FS for the patients recruited to the standard (toxicity-reactive) arm, including demographic data and the identification of an ultra-frail group. Results The FiTNEss trial opened on 04/08/2020 and at the time of data cut off (01/06/2023) recruitment is active at 84 sites, with 638 patients randomised. Baseline characteristics for the randomised patients are shown in Table 1. The median age of patients is 76 years (range 62, 93) with 34.8% aged 76-80 and 22.3% over 80. The IMWG FS at baseline for the full trial cohort was FIT 182/638 (28.5%), UNFIT 207/638 (32.4%) and FRAIL 249/638 (39.0%). Revised IMWG FS at baseline was Fit 28.5%, Unfit 56.0% and Frail 15.5% with MRP non-high risk (Fit or Unfit, nHR) in 64.3% and MRP HR (Frail) in 35.7% in patients with data available. For descriptive analysis of FS dynamism, we assessed the impact on FS of delivery of IRD in the control arm (n=319), calculating the FS at 2, 4, 6 and 12 months. The majority of changes were seen at 2 months across the frailty categories. For Fit patients, 20.9% demonstrated a deterioration in FS score at any timepoint. For Unfit patients, 26.7% demonstrated a deterioration in FS score whilst 16.2% demonstrated an improvement in FS at any timepoint. For Frail patients, 15.4% demonstrated an improvement in FS at any timepoint (Figure 1). Of those who demonstrated a deterioration in FS, 59.1% experienced a treatment related safety event. In those who demonstrated an improvement in FS, 26.3% experienced a treatment related safety event. Of the 250 whose FS remained constant 34% experienced a treatment related safety event. For frail patients, 119 could be stratified further and 57% were classified as Ultra-Frail (IMWG FS Frail and MRP HR). Conclusion The FiTNEss trial demonstrates the feasibility of recruiting older, less fit patients to clinical trials. The IMWG FS does demonstrate a dynamic biomarker potential both representing improved functionality in relation to disease response to therapy, as well as deterioration consequential to treatment-emergent toxicity. In addition, the concept of ultra-frail represents an exciting possibility to further stratify patients who may need additional support in order to improve their outcomes. Further work in these two areas is on-going as the trial dataset matures.

Dynamic Frailty Status Enables Better Prediction of Survival Probability - Results of the HOVON 143 Study

Introduction The clinical outcome of non-transplant eligible patients with newly diagnosed Multiple Myeloma (NDMM) is heterogeneous, largely depending on frailty level. Clinical scores such as the International Myeloma Working Group frailty index (IMWG-FI) classify patients in categories ‘fit’, ‘intermediate-fit’ or ‘frail’. As disease and treatment burden can change over time, frailty can improve but also deteriorate during treatment. However, data are scarce and the effects on clinical outcome are largely unknown. To address this, we prospectively investigated the dynamics of frailty scores and impact on clinical outcome of non-transplant eligible patients with NDMM (NTE-NDMM) included in the HOVON 143 study. Methods The HOVON 143 study included NTE-NDMM classified as intermediate-fit (score 1) or frail (score ≥2) by the IMWG-FI (score ranging from 0 to 5, fit being defined as 0). Patients were treated with nine 28 days-cycles of ixazomib (4mg on days 1, 4, 15), daratumumab (16mg/kg iv; cycles 1-2: days 1, 8, 15, 22; cycles 3-6: days 1, 15; cycles 7-9: day 1) and low dose dexamethasone (cycle 1-2: 20mg; subsequent cycles 10mg, co-administered with daratumumab). The IMWG-FI was calculated at baseline, after 3 and 9 cycles. A joint model was employed to model survival outcomes and longitudinal frailty score data. For this purpose, a cox model was used to model survival outcome and a mixed-effects model to model longitudinal frailty score data (R statistical program, package JM). Results Of the 130 included patients, 65 were intermediate-fit at baseline and 65 patients were frail (49% score 2, 28% score 3, 22 % score 4, 1% score 5). After nine cycles, 82 patients were still on protocol of whom frailty level over time was known in 74 patients (39 intermediate-fit, 35 frail). Six/35 frail patients could not improve in frailty score as well as category, as they were classified as ‘frail’ due to age >80 years without any impairments or comorbidities. Of the 29 frail patients that could improve, 14 (48%) improved in frailty score. Of those, 5 patients became intermediate-fit, 1 became fit and 8 remained frail because of still having a score of ≥2. Reasons for improvement were becoming less iADL dependent (11/14), less ADL dependent (10/14), or both (8/14). Improvement in Charlson Comorbidity Index (CCI) occurred in 4/14. Six out of 34 (18%) who could deteriorate in frailty score (excluding the patient with frailty score of 5), did so. Two frail patients became ADL dependent, 2 became iADL dependent and 2 deteriorated in score solely due to age (turning 81 years old during treatment). Out of the 39 intermediate-fit patients that could improve in frailty score, 6 (15%) improved and consequently became fit (frailty score from 1 to 0). Reasons for improvement were becoming less ADL dependent (3/6) and improved CCI (3/6). Five intermediate-fit patients (13%) deteriorated. One intermediate-fit patient became iADL dependent (1/5), 1 patient acquired a comorbidity (1/5) and 3 deteriorated in score solely due to age (turning 76 old during treatment). Median duration of follow up of all 130 patients was 46 months. Including frailty score as a time varying covariate in survival analysis by a joint model indicated that the frailty score improved over course of treatment, and that improvement of frailty score was associated with higher survival probabilities (HR 0.58 (95%CI 0.42 - 0.79), p<0.001) ( Figure 1). Conclusion This is the first study to report the dynamics in IMWG frailty assessment of non-transplant eligible patients with NDMM during a clinical trial. The frailty score improved in nearly half of frail patients and 15% of the intermediate fit patients during MM treatment. This led to reclassification to intermediate-fit or fit in a substantial number of patients. Improvement of the frailty score was associated with prolonged survival. Future studies are needed to investigate whether dynamic frailty status is a better predictor for clinical outcome than frailty status at baseline.

Retrospective Analysis of Four Frailty Assessment Tools in Elderly Patients with Multiple Myeloma

INRTODUCTION : The International Myeloma Working Group (IMWG) developed the frailty index (IMWG-FI) to predict the toxicity and mortality risk faced by elderly patients with multiple myeloma. However, due to the time-consuming nature and subjectivity of IMWG-FI, alternative frailty assessment tools have been developed to reduce subjectivity and enhance the ability to identify frailty. O BJECTIVE (S) To assess the consistency of various frailty assessment tools in elderly patients with multiple myeloma and their predictive efficacy for patients survival. M ETHOD (S) We systematically assessed 84 newly diagnosed multiple myeloma patients aged≥60 years old using various frailty assessment tools, including the IMWG frailty index (IMWG-FI), Mayo frailty score, simplified IMWG frailty index（IFM）, and British Myeloma Research Alliance Risk (MRP) score. We compared progression-free survival (PFS) and overall survival (OS) outcomes based on these different assessment tools. For the purpose of analysis, we combined patients categorized as Fit or Intermediate Fit into a single group called Non-Frail. RESULTS (S) The median age of the included patients was 68 years, ranging from 60 to 84 years. Among them, 59.5% were male. Additionally, 53.8% had an ECOG score of ≥2 and 26.9% had a CCI score of ≥2. Patients who chose the regimens based on ixazomib, bortezomib, and thalidomide were 11.2%, 70.7%, and 3.3%, respectively, while 7.8% of patients refused chemotherapy. The incidence of frailty in this cohort was as follows: 53.6% according to the IMWG-FI, 23.8% based on the Mayo frailty score, 46.4% using the MRP frailty score, and 67.85% according to the simplified IMWG frailty index. The consistency among the four frailty assessment tools was low, with a total of 64 patients (76.2%) identified as frail by at least one tool. Among them, 48 patients (75.0%) were identified as frail by at least two tools, while only 14 patients (21.9%) were classified as frail by all four tools. Among the cohort of 73 patients eligible for OS and PFS analysis, utilization of the IMWG-FI to evaluate frailty status revealed that the non-frail and frail groups exhibited median OS durations of undisclosed levels and 15.5 months, respectively ( P=0.01). In terms of PFS, the corresponding median durations were 42.5 months and 10.0 months, respectively ( P=0.011). When employing the Mayo frailty score, the non-frail and frail groups demonstrated median OS durations of 26.0 months and 7.0 months, respectively ( P=0.004), alongside median PFS durations of 42.5 months and 7.0 months, respectively ( P=0.024). Application of the MRP score to assess frailty resulted in non-frail and frail groups achieving undisclosed levels and a median OS of 15.0 months, respectively ( P<0.001). Their corresponding median PFS durations were 42.5 months and 9.0 months, respectively ( P<0.001). Additionally, the utilization of the simplified IMWG frailty index for frailty assessment rendered non-frail and frail groups achieving undisclosed levels and a median OS of 19.0 months, respectively ( P=0.225). Regarding the median PFS durations, they reached undisclosed levels and 15.0 months for the non-frail and frail groups, respectively ( P=0.495). CONCLUSION (S) The results of the four frailty assessment tools in this cohort vary significantly. The MRP score and IMWG frailty index demonstrate higher consistency and better prognostic stratification efficiency compared to the Mayo score and simplified IMWG frailty index. Therefore, combining the MRP score with the IMWG frailty index can effectively enhance the recognition ability for newly diagnosed elderly patients with frail multiple myeloma.

A prospective, multicenter, observational study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in Japan

Real-world studies permit inclusion of a more diverse patient population and provide more information on the effectiveness of treatments used in routine clinical practice. This prospective, multicenter, observational study investigated the effectiveness and safety of ixazomib plus lenalidomide and dexamethasone (IRd) in 295 patients with relapsed/refractory multiple myeloma (RRMM) in routine clinical practice in Japan. Patients had a median age of 74 years, 80.0% were aged ≥ 65 years, 42.0% had received ≥ 3 lines of prior treatment, and 28.5% were “frail” according to the International Myeloma Working Group frailty score. After a median follow-up of 25.0 months, median progression-free survival (PFS) was 15.3 (95% CI 12.4–19.5) months, while median overall survival was not reached. The overall response rate was 53.9%, and 31.5% of patients had a very good partial response or better. In the subgroup analysis, median PFS was better in patients with 1 versus 2 or ≥ 3 lines of prior treatment (29.0 vs 19.2 or 6.9 months) and paraprotein versus clinical relapse (16.0 vs 7.9 months), but median PFS was not notably affected by frailty score or age group. Dose adjustment was more frequent among patients aged > 75 years, especially early after IRd treatment initiation. Treatment-emergent adverse events (TEAEs) of any grade occurred in 84.4% of patients and 24.7% of patients discontinued treatment due to TEAEs; no new safety concerns were found. These findings suggest that oral IRd triplet regimen is an effective and tolerable treatment option for RRMM patients in real-world settings outside of clinical trials.ClinicalTrials.gov identifier: NCT03433001; Date of registration: 14 February 2018.

P-116 The simplified frailty index (S-FI) identifies a less vulnerable population of frail patients than patients who are defined frail using the International Myeloma working Group Frailty index (IMWG-FI)

P-116 The simplified frailty index (S-FI) identifies a less vulnerable population of frail patients than patients who are defined frail using the International Myeloma working Group Frailty index (IMWG-FI)

Safety and clinical activity of belantamab mafodotin plus lenalidomide and dexamethasone in transplant ineligible patients with newly diagnosed multiple myeloma: The phase 1/2, prospective, open-label, BelaRd study.

8050 Background: We present the updated safety and efficacy of upfront belantamab mafodotin (belamaf) plus lenalidomide and dexamethasone (Rd) in transplant ineligible (TI) pts with newly diagnosed multiple myeloma (NDMM). Methods: The ongoing, prospective, open-label, phase 1/2 BelaRd study (NCT04808037) aims to enroll 66 pts with TI NDMM, with ECOG PS < 2 and adequate organ function. In Part 1, 36 pts are randomized (1:1:1) to receive belamaf 2.5, 1.9, or 1.4 mg/kg Q8W plus Rd. Eye exams include Snellen best corrected visual acuity (BCVA) and corneal exam (slit lamp examination). Ocular adverse evets (OAEs) are classified by CTCAE v5.0. This descriptive analysis presents the updated safety and efficacy findings for all Part 1 pts (cutoff date 15/12/22). Results: The analysis included 36 pts [median age: 73 years (64–86); male: 19 (53%)], of whom 31 (86%) were still on treatment and 5 (14%) had discontinued [4 pts due to belamaf-unrelated adverse events (AEs); 1 pt withdrew consent]. At baseline, 32 (89%) pts were intermediate fit as per International Myeloma Working Group frailty score and 34 (94%) had ECOG PS≤1. Median follow up was 15 months (3–23); median belamaf administrations and number of cycles reached were 6 (2–10) and 15 (3–22). Thirty-four (94%) pts experienced ≥1 grade (Gr) ≥3 treatment-emergent AEs (TEAEs). Most common (≥ 10% of pts) non ocular Gr ≥3 TEAEs were fatigue (21 pts, 58%), rash (6 pts, 17%), diarrhoea (5 pts, 14%) and COVID-19 infection (4 pts, 11%); no Gr ≥3 thrombocytopenias and any Gr infusion-related reactions were reported. Regarding pts visual acuity, out of a total of 499 BCVA assessments, 164 (33%) were Gr 2 and 54 (11%) were Gr 3. Notably, a meaningful BCVA decline (worse than 20/50 in better seeing eye) was observed in 38 (8%) assessments, with a median time to resolution of 1 month. Regarding clinically relevant Gr≥2 ocular symptoms, blurred vision, dry eye and visual impairment were observed in 38 (8%), 96 (20%) and 98 (20%) assessments, with a median time to resolution of 2, 3 and 2 months. Slit lamp examinations by the ophthalmologist (N = 501) revealed a Gr 2 keratopathy in 55 (11%) assessments and Gr 4 keratopathy in 2 ( < 1%) assessments, with a median time to resolution of 4 months. Overall response rate [partial response (PR) or better] was 100.0% [36 pts; stringent complete response: 14% (5 pts); complete response: 19% (7 pts); very good partial response: 47% (17 pts); PR: 19% (7 pts)]. Median time to first response was 1 month. Conclusions: Part 1 of the BelaRd study showed that in TI pts with NDMM, the safety profile of belamaf plus Rd was manageable and a meaningful BCVA decline was noted in a minority ( < 10%) of assessments which resolved quickly (1 month). The combination induced rapid and deep responses, with all pts achieving ≥PR and first response observed at a median of 1 month. Clinical trial information: NCT04808037 .

Utilizing a two-step frailty assessment strategy in older adults with multiple myeloma (MM): A decision curve analysis.

8061 Background: The International Myeloma Working Group Frailty Index (IMWG-FI) has been shown to predict risk of toxicity and mortality in older adults with MM (Palumbo et al., Blood 2015). However, IMWG-FI requires a geriatric assessment (GA) that is not routinely done in clinical practice due to time constraints. A simplified frailty index (SFI; Facon et al., Leukemia 2020) has been proposed as an alternative using ECOG PS as a proxy to functional status. We previously reported a moderate concordance between these two frailty indices (Kappa statistic 0.50; Gahagan et al., ASH 2022). Here, we examined if SFI can be utilized as a screening tool to identify patients who would benefit from a formal GA and frailty assessment. We hypothesized that a two-step approach would minimize the need for unnecessary GAs, while saving time in clinical practice. Methods: For this analysis, we included patients ≥50yo with newly diagnosed (ND) or Relapsed/Refractory (RR)-MM at a single institution initiating a new treatment regimen (1st to 6th line) who are enrolled in a prospective registry (NCT05556928). All patients underwent a GA prior to a new line of therapy. ECOG PS and comorbidities were abstracted from medical records. We calculated IMWG-FI and SFI using published methods. Sensitivity, specificity along with their 95% CI were calculated for both SFI and IMWG-FI, using published SFI cutpoints. Lastly, we used decision curve analysis (DCA) as described by Vickers et al. to calculate the benefit of frailty screening using SFI for detection of non-frail patients and avoiding unnecessary GAs. We assumed that reasonable threshold probabilities were 0.25 and 0.33 respectively indicating that missing an unfit patient was 3 and 2 times worse than exposing a fit patient to an unnecessary GA (odds of 1:3 and 1:2 respectively). We quantified the net benefit (NB) of this two-step frailty assessment versus GA-for-all in terms of net reduction in unnecessary GAs. Results: A total of 146 adults with MM (49 ND-MM, 51 pre-transplant, and 46 RR-MM) starting a new line of therapy between 8/2020-1/2022 were included in this study. The median age was 62 (IQR 57-70) with 53% males and 36% blacks. The distribution by IWMG-FI was 43% fit, 32% intermediate-fit, and 25% frail. Using SFI, 32% of patients were frail. Using a cutpoint of ≥2, SFI as a screening tool had a sensitivity of 89.2% (95% CI 75-96%) and a specificity of 65% (95% CI 56% to 73%). DCA showed that selecting candidates for GA based on a two-step strategy (SFI followed by IMWG-FI) led to an absolute 40-45% reduction in the number of unnecessary GAs without missing any frail patients. Conclusions: Our results suggest that using a two-step frailty assessment strategy of SFI as a screening tool followed by confirmation with IMWG-FI reduces the need for unnecessary GAs by 40-45% and may be more suitable for integration in busy oncology practice.

Variable Frailty Categorization Among Real-World Patient with Multiple Myeloma: A Prospective Cohort Study (MFRAIL)

Introduction Multiple Myeloma (MM) is a non-curable cancer of older adults. Frailty has emerged as one important high-risk factor which confers a poor prognosis with reduced progression free survival, increased toxicity, higher rates of drug discontinuation and worse overall survival. Several tools have emerged for evaluation of frailty in MM in recent years. These include non-cancer specific geriatric assessment tools such as the Fried frailty index or more specific MM tools such as the International Myeloma Working Group (IMWG) frailty index, simplified frailty index or the Mayo frailty index. Uptake of these measures across clinical settings has been variable, leading to a gap in knowledge about the prevalence of geriatric impairments among MM patients as well as the proportion of patients classified as frail using these different scoring systems. The MFRAIL study is an ongoing prospective, multicentre study evaluating the association of different frailty assessment tools at baseline and longitudinally over time with clinical outcomes. In this abstract we present an interim analysis after at least 50% of patients have been enrolled. We describe baseline characteristics from the initial 57 patients enrolled into the study with the specific objective of 1) to report the prevalence of geriatric impairments among MM patients prior to therapy initiation 2) characterize the proportion of patients classified as frail using different frailty assessment tools. Methods The MFRAIL is an ongoing, prospective pilot cohort study being conducted at three sites within Ontario, Canada which was initiated in August 2021. Multiple myeloma patients aged >18 initiating a new line of therapy are enrolled in the preceding six weeks. Demographic and MM-specific factors are collected at baseline and at 12 months following treatment along with MM response criteria, toxicity and health care utilization. Additional collected measures include: comorbidities, physical performance measures (NIH 4 meter walk test and grip strength), cognition, patient reported outcome of quality of life and depression. Frailty assessment tools measured include the IMWG frailty index (Palumbo et al. Blood 2015), simplified frailty index (Facon et al. Leukemia 2020), Mayo frailty index (Milani et al. AJH 2016) and the Fried frailty index (modified from Fried et al. J Gerontol A Biol Sci Med Sci 2001). Results A total of 57 patients were enrolled in the study (data cut off June 1/2022) with baseline characteristics summarized in Table 1. The median age of the patients was 71 (range 47-93) with 61% males. A total of 26% and 35% of the patients had an ECOG and CCI status of 2 or higher, respectively. Polypharmacy was common with over 50% of the patients being prescribed five or more medications at baseline. Geriatric impairments were common with over 1/3 of the patients reporting at least one deficit in ADLs or IADLs. Additionally, cognitive impairment was present in 19.3% of the patients. With regards to treatment details, 61.4% of the enrolled patients received first line treatment (ASCT eligible 34.3%, ASCT ineligible 65.7%), 26.3% second line and the remainder third line and beyond. Immunomodulatory-based treatments were the most common with 57.8% of the patients utilizing these agents. Empiric dose reduction outside the product monograph was observed in 17.5% of the patients with the majority of dose reductions (80%) done for agents other than dexamethasone alone among those patients. The prevalence of frailty in our cohort ranged from 12.3% (Fried frailty index), 17.5% (Mayo frailty index), 38.6% (IMWG frailty index) to 52.6% (simplified frailty score). Similarly, the number of patients classified as fit/robust also varied ranging from 15.8% (Mayo frailty index), 25.3% (fried frailty index), 33.3% (IMWG frailty index) and 47.3% (simplified frailty score). Conclusion Impairments in geriatric domain are common among real-world patients with MM emphasizing the need to incorporate these assessments in routine clinical practise. Additionally, prevalence of patients classified as frail versus fit varies depending upon the assessment tool utilized with no uniform definition of frailty in routine clinical practise. Further work is needed in both evaluating and standardizing frailty assessment tools in different clinical settings and with different therapeutic modalities to further optimize outcomes in this high-risk patient subgroup. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Multicenter Prospective Study for Validation of the Korean Simple Geriatric Assessment Tool in Elderly Patients with Multiple Myeloma

Purpose Frailty is a multidimensional state of diminished reserve (energy, physical ability, cognition and health) which gives rise to vulnerability to cancer treatment. Geriatric assessment (GA) with management should be integrated into the clinical care of older patients with multiple myeloma (MM). with ageing-related conditions. The purpose of this study was to prospectively validate the Korean Cancer Study Group Geriatric Score (KG)-7, a simplified frailty assessment tool, in older patients with multiple myeloma (MM) planned to undergo first-line chemotherapy. Materials and Methods The study included 95 newly diagnosed MM patients aged 70 years or older. Participants answered the KG-7 questionnaire before undergoing International Myeloma Working Group (IMWG) frailty score and first-line bortezomib- and/or lenalidomide- based chemotherapy. KG-7 scores ranged from 0 to 7, and higher scores indicated better conditions. Results The median age was 77 years and 50.5% of patients were older than 75 years. Fifteen patients (15.8%) had an ADL score ≤ 4, 24 (25.3%) an IADL score ≤ 5, and 19 (20.0%) a CCI ≥ 2. Based on the < 5 cut-off value of KG-7 for frail group, frail group was shown in 29 (30.5%). There was the negative correlation between KG-7 and IMWG frailty score (Pearson correlation, 0.547; P < 0.001). The cumulative incidence of grade ≥ 3 non-hematologic adverse events was 27.3% in non-frail and 48.3% in frail patients (HR, 2.5; P = 0.046). There was no significant difference between the two groups of KG-7 with regard to grade ≥ 3 hematological toxicity and dose modification at cycle one. There was no significant difference between the two groups (frail versus non-frail) in PFS (hazard ratio [HR] = 1.37; 95% CI = 0.52-3.65; P = 0.525) and OS (HR = 1.85; 95% CI 0.52-6.58, P = 0.341), which was attributed to the short FU period of 11.6 months. Interpretation Despite the interim analysis, KG-7 appears to be an easy-to-define prediction model for defining the vulnerable patients with MM. Whether KG-7 is helpful in predicting survival outcome requires longer follow-up.

Evaluating Concordance between International Myeloma Working Group (IMWG) and Simplified Frailty Index (SFI) Among Older Adults with Multiple Myeloma (MM)

Introduction: Despite significant advances in therapeutics, older adults with MM are at increased risk of treatment related toxicity and mortality. Frailty is an aging-associated state of cumulative decline in many physiological systems, resulting in diminished resistance to stressors, including cancer therapy. In 2015, the International Myeloma Working Group (IMWG) developed a geriatric assessment (GA) based frailty index (IMWG-FI) using age, comorbidities, and physical function (instrumental activities of daily living, IADL; activities of daily living, ADL) to predict risk of toxicity and mortality among older adults with MM (Palumbo, et al., Blood 2015). However, GA is not routinely incorporated in clinical practice and a simplified frailty index (SFI; Facon et al Leukemia 2020) has been proposed as an alternative to using ECOG performance status (ECOG PS) as a proxy for physical function (IADL/ADL). However, the concordance between IMWG-FI and SFI remains relatively unknown, as well as their predictive ability in clinical practice, particularly among patients with relapsed, refractory multiple myeloma (RR-MM). Our goal was to describe the prevalence of frailty using IMWG-FI and SFI as well as evaluate their concordance among patients with newly-diagnosed (ND) and RR-MM. Methods: The Cancer and Aging Resilience Evaluation in Hematologic Malignancies (CARE-Heme) Registry is an ongoing prospective registry enrolling adults ≥50 years of age with a diagnosis of a hematologic malignancy undergoing treatment at a single institution. For this analysis, we included patients ≥50yo with ND- or RR-MM initiating a new treatment regimen (ranging from first to sixth line of treatment). All of the patients included in this study underwent a comprehensive GA prior to beginning a new line of therapy or stem cell transplant. We abstracted physician reported ECOG PS and comorbidities by reviewing medical records. We calculated IMWG frailty score as well as SFI using published methods. Each patient was categorized into frail/non-frail using the IMWG frailty score (fit, intermediate-fit, frail; collapsing fit/intermediate fit into the non-frail category) and the simplified frailty score (non-frail, frail) using published cutoffs. We measured the agreement between the total frailty scores using Spearman Correlation Coefficient and the frail/non-frail categorization using the Kappa statistic. Relevant treatment outcomes including progression-free survival, overall survival, and grade 2-5 toxicities (both hematologic and non-hematologic) were recorded until disease progression, death, or 6 cycles of treatment were completed. Results: A total of 146 adults with MM (49 ND-MM, 51 pre-transplant, and 46 RR-MM) starting a new line of therapy or ASCT between 8/2020 to 1/2022 were included in this study. The median age was 62 (IQR 57-70) with 53% males and 36% blacks. Most patients had IgG isotype (64%) with International Staging System (ISS) stage III disease (38%) whereas 30% patients had high risk cytogenetics. The distribution by IWMG Frailty category was as follows: 43% fit, 32% intermediate-fit, and 25% frail. Using SFI, 32% of patients were characterized as frail and 68% were characterized as non-frail (Figure 1). Although, the frailty scores were well correlated with each other (Spearman rho 0.67, p value <.001), the agreement between SFI and IMWG-FI in terms of frailty categorization was moderate (Kappa statistic 0.50); 79% of patients were classified in the same frailty group, however about 21% of patients were characterized in different frailty categories using the two scales (Table 1). SFI over-estimated frailty in about 14% of patients. There was very little agreement between a patient-reported vs physician rated ECOG-PS (Kappa statistic 0.13). The discordance between the two FI worsened if a patient reported version of ECOG PS (Kappa statistic 0.30) was used. Conclusions: Among older adults with MM, the prevalence of frailty ranged 25% by IMWG-FI to 32% by SFI. There was only a modest agreement between SFI and IMWG FI, which was worse when using patient reported version of ECOG PS. Studies comparing outcomes across the two frailty indices should take into account the potential for misclassification bias. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association of IMWG frailty score with health-related quality of life profile of patients with relapsed refractory multiple myeloma in Italy and the UK: a GIMEMA, multicentre, cross-sectional study

The clinical management of patients with relapsed or refractory multiple myeloma is challenging and there is a paucity of tools to help clinicians make more informed decisions for the most suitable treatment options. We aimed to investigate the clinical utility of the International Myeloma Working Group (IMWG) frailty score in the setting of relapsed or refractory multiple myeloma, by examining its ability to capture different patient-reported health-related quality of life profiles. We did a cross-sectional analysis of a prospective observational study of patients with relapsed or refractory multiple myeloma in Italy and the UK (30 hospitals across northern, central, and southern Italy, and one hospital in London, UK). Inclusion criteria were age 18 years or older and patients who had received at least one previous line of therapy and no more than five lines. Participants were excluded if they had a psychiatric disorder or major cognitive dysfunction, or any grade 3 or higher adverse event within 2 weeks before study entry. On study initiation, physicians had to assess frailty according to the IMWG criteria, which included the Charlson Comorbidity Index, the Katz Activity of Daily Living, and the Lawton Instrumental Activities of Daily Living. Patients were asked to complete patient-reported outcome measures, including the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core30 (EORTC QLQ-C30) and its validated multiple myeloma module (QLQ-MY20). A multivariable linear regression model was used to assess the mean differences in health-related quality of life scores between frailty groups to account for key potential confounding factors. Overall, between Nov 13, 2017, and Nov 15, 2021, 415 patients with relapsed or refractory multiple myeloma, with a median age of 69·8 years (IQR 62·8-75·2) were enrolled. The median time since diagnosis was 4·4 years (IQR 2·5-7·1) and most patients (351 [85%]) had received at least two previous lines of therapy. According to the IMWG frailty score, 200 (48%) were classified as fit, 112 (27%) were classified as intermediate-fit, and 103 (25%) patients were classified as frail. Each frailty group was associated with a distinct health-related quality of life profile, with most notable differences between fit and frail patients. The largest clinically meaningful adjusted differences between fit and frail patients by the EORTC QLQ-C30 questionnaire were observed for physical functioning (Δ=-19·0 [95% CI -25·6 to -12·5; p<0·0001), fatigue (Δ=16·7 [9·7 to 23·7]; p<0·0001), insomnia (Δ=13·4 [4·1 to 22·6]; p=0·0047), and dyspnoea (Δ=12·5 [4·6 to 20·4]; p=0·0021). The most prevalent clinically important symptom in the overall population was pain; however, its prevalence varied between IMWG frailty groups at 70·9% in frail patients, 55·9% in intermediate-fit patients, and 50·5% in fit patients. Our findings show the clinical utility of the IMWG frailty score in the setting of relapsed or refractory multiple myeloma, in helping to distinguish between groups of patients with distinct health-related quality of life profiles. Further research is needed to examine the value of patient-reported outcome data in improving assessment of frailty in the setting of relapsed or refractory multiple myeloma. Fondazione GIMEMA Franco Mandelli Onlus and Amgen.

Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma (FiTNEss (UK-MRA Myeloma XIV Trial)): a study protocol for a randomised phase III trial

IntroductionMultiple myeloma is a bone marrow cancer, which predominantly affects older people. The incidence is increasing in an ageing population.Over the last 10 years, patient outcomes have improved. However, this...

Fitness, a UK Myeloma Research Alliance (UK-MRA) Frailty-Adjusted Therapy Study, Supports the Feasibility of Recruiting Frail Newly Diagnosed Myeloma Patients to Large Clinical Trials

Fitness, a UK Myeloma Research Alliance (UK-MRA) Frailty-Adjusted Therapy Study, Supports the Feasibility of Recruiting Frail Newly Diagnosed Myeloma Patients to Large Clinical Trials

The Accuracy of the International Myeloma Working Group Frailty Score in Capturing Health-Related Quality of Life Profile of Patients with Relapsed Refractory Multiple Myeloma

The Accuracy of the International Myeloma Working Group Frailty Score in Capturing Health-Related Quality of Life Profile of Patients with Relapsed Refractory Multiple Myeloma

Frailty in relapsed/ refractory multiple myeloma registration trials.

e20017 Background: Multiple Myeloma (MM) is predominantly a disease of older adults with a median age of onset at 70 years. There is growing interest in using criterion other than chronological age, like frailty, to determine fitness for treatment and ultimately improve clinical outcomes in MM. Frailty is the accumulation of aging-associated diseases and disabilities, making patients more vulnerable to adverse outcomes when exposed to stressors like anti-cancer treatment. MM frailty measures have primarily been developed and tested in newly diagnosed patients. MM patients typically relapse, but there is limited knowledge regarding the prevalence of frailty in the relapsed/refractory (RRMM) setting. The aim of this research was to determine the prevalence of frailty in RRMM commercial clinical trials, at the time of trial enrollment, using the International Myeloma Working Group (IMWG) Frailty Index. Methods: We pooled baseline data from 6 RRMM clinical trials submitted for FDA regulatory review between 2010 and 2020. The IMWG Frailty Index was calculated for each patient based on 4 variables: age (≤75, 75–80, &gt;80 years, score 0, 1, 2, respectively), Charlson Comorbidity Index (CCI; ≤1 or ≥2, score 0 or 1), and (Instrumental) Activities Daily Living (ADL &gt;4 or ≤4, score 0 or 1; IADL &gt;5 or ≤5, score 0 or 1). As ADLs and IADLs are not routinely collected in clinical trials, we substituted this information with corresponding EQ-5D items on self-care and usual activities. Fit, Intermediate-fit, and Frail patients received IMWG scores of 0, 1, and ≥2 respectively. Descriptive statistics for frailty were summarized by age. Results: 2766 RRMM patients were aggregated from six clinical trials. 1502 (54%) patients were Fit, 780 (28%) were Intermediate-fit, and 484 (18%) were Frail. The median age of patients across trials was 65 [range 30-91]. The median CCI was 0 [range 0-7] out of 37. IMWG frailty scores have been presented by age category in Table. Prevalence of frailty at baseline by age in RRMM registration trials. Conclusions: Most patients in RRMM registration trials were classified as Fit at baseline, using the IMWG Frailty Index. This was expected due to stringent trial enrollment criteria which exclude patients with severe comorbidities, as reflected in the low average CCI. The IMWG index heavily weights patient age. As such, there were no Fit patients in the 75 – 80 year old cohort and only Frail patients in the 80+ year old cohort. This is despite the fact that these older patients met stringent trial enrollment criteria and had CCI scores &lt; 7. Chronologic age alone should not be used as an absolute exclusion for treatment, whether in the trial or real-world setting. Future research into frailty indices that do not heavily weight age is warranted.[Table: see text]

Diagnostic and Therapeutic Challenges in the Management of Intermediate and Frail Elderly Multiple Myeloma Patients.

Simple SummaryChoosing the optimal therapy for elderly patients with multiple myeloma (MM) poses a difficult challenge for clinicians. Older patients are an extremely heterogeneous population, they are underrepresented in clinical trials, and data on octogenarians have been mainly limited to real-life settings. Treatment options for intermediate and frail patients might include dose-adapted combinations and less toxic combinations based on novel agents. Moreover, the discriminative power of the International Myeloma Working Group (IMWG) frailty score in detecting frailty and vulnerability could be improved by combining together aging-related factors (performance status, comorbidities, functional status) with disease-related factors (International Staging System stage, cytogenetic risk). Objective parameters could improve the reproducibility of this score and limit the subjectivity determined by patient-reported questionnaires on functional evaluations. Efforts are ongoing to simplify the IMWG frailty score and expand its use in real-life clinical practice.Multiple myeloma (MM) mostly affects elderly patients, which represent a highly heterogeneous population. Indeed, comorbidities, frailty status and functional reserve may vary considerably among patients with similar chronological age. For this reason, the choice of treatment goals and intensity is particularly challenging in elderly patients, and it requires a multidimensional evaluation of the patients and the disease. In recent years, different tools to detect patient frailty have been developed, and the International Myeloma Working Group frailty score currently represents the gold standard. It identifies intermediate-fit and frail patients requiring gentler treatment approaches compared to fit patients, aiming to preserve quality of life and prevent toxicities. This subset of patients is underrepresented in clinical trials, and studies exploring frailty-adapted approaches are scarce, making the choice of therapy extremely challenging. Treatment options for intermediate-fit and frail patients might include dose-adapted combinations, doublets, and less toxic combinations based on novel agents. This review analyzes the available tools for the assessment of frailty and possible strategies to improve the discriminative power of the scores and expand their use in real-life and clinical trial settings. Moreover, it addresses the main therapeutic challenges in the management of intermediate-fit and frail MM patients at diagnosis and at relapse.

Social frailty predicts worse outcomes in patients with multiple myeloma: A novelty in an old approach.

Social frailty, defined as the loss of social roles and networks in the community, has never been evaluated in patients with multiple myeloma (MM). This study aimed to evaluate the usefulness of social frailty as a predictor of survival in MM. We retrospectively reviewed 237 consecutive patients with MM from 2009 to 2019. Activities of daily living (ADL), the instrumental ADL score, the Charlson Comorbidity Index, and factors to evaluate social relationships were routinely assessed at the time of initial diagnosis and first hospitalization at our center by hematological clinicians, nurses, and rehabilitation staff. Social frailty was evaluated using five social factors and was defined as a score of at least 2 points. Overall, 69 (30.0%) patients were defined as socially frail, with a median score of 0. Those who were socially frail showed significantly shorter progression‐free and overall survival than those who were not. Using the International Staging System, International Myeloma Working Group frailty score, and social frailty, we developed two staging systems, and these further demonstrated the importance of assessing frail patients with MM. Our findings have identified the usefulness for evaluating social frailty; however, to confirm our results, an independent study with larger patient numbers with an entirely prospective assessment is needed to confirm their results.

Caring for older adults with multiple myeloma during the COVID-19 Pandemic: Perspective from the International Forum for Optimizing Care of Older Adults with Myeloma

The novel coronavirus (SARS-CoV-2, COVID-19) was first identified in the province of Wuhan, China in December 2019 [1], following the emergence of new cases of pneumonia of unknown etiology. Since then, the manifestations of COVID-19 infections have ranged from asymptomatic to severe respiratory infections, with increased morbidity in older adults including those with co-morbidities and cancer [2,3]. Presently, global mortality is reported at 4.7%, but this varies widely by location, from 0.7% in Germany to 10.8% in Italy [4]. As of April 13, 2020, the number of infections continues to rise well beyond the 1.9 million cases, and approximately 120,000 COVID-19-related deaths that have already occurred globally [5]. Multiple myeloma (MM) is a malignant plasma cell dyscrasia which predominantly affects older and often frail adults. Although tremendous gains have been made for older adults with MM, infections, including respiratory infections, significantly impact the rate of early mortality in these patients [6,7]. Furthermore, older adults with MM have age-associated vulnerabilities leading to heterogeneity in outcomes [8]. The complexity of caring for older patients have increased substantially during this pandemic, due to concern about their risk of severe morbidity of COVID19 infection. Optimal strategies for these patients will involve staging the malignancy/aging, while simultaneously considering the local prevalence of COVID-19 infection. Herein, we discuss strategies for the risk reduction of COVID-19 transmission, treatment stratification of anti-myeloma therapy and discussion regarding goals of care for older adults with MM during the COVID-19 pandemic.