IMWG Frailty Score Research Articles

Quality of life gains in frail and intermediate-fit patients with multiple Myeloma: Findings from the prospective HOVON123 clinical trial

BackgroundFrailty in newly-diagnosed multiple myeloma (NDMM) patients is associated with treatment-related toxicity, which negatively affects health-related quality of life (HRQoL). Currently, data on changes in HRQoL of frail and intermediate-fit MM patients during active treatment and post-treatment follow-up are absent. MethodsThe HOVON123 study (NTR4244) was a phase II trial in which NDMM patients ≥ 75 years were treated with nine dose-adjusted cycles of Melphalan-Prednisone-Bortezomib (MPV). Two HRQoL instruments (EORTC QLQ-C30 and -MY20) were obtained before start of treatment, after 3 and 9 months of treatment and 6 and 12 months after treatment for patients who did not yet start second-line treatment. HRQoL changes and/or differences in frail and intermediate-fit patients (IMWG frailty score) were reported only when both statistically significant (p < 0.005) and clinically relevant (>MID). Results137 frail and 71 intermediate-fit patients were included in the analysis. Compliance was high and comparable in both groups. At baseline, frail patients reported lower global health status, lower physical functioning scores and more fatigue and pain compared to intermediate-fit patients. Both groups improved in global health status and future perspective; polyneuropathy complaints worsened over time. Frail patients improved over time in physical functioning, fatigue and pain. Improvement in global health status occurred earlier than in intermediate-fit patients. ConclusionHRQoL improved during anti-myeloma treatment in both intermediate-fit and frail MM patients. In frail patients, improvement occurred faster and, in more domains, which was retained during follow-up. This implies that physicians should not withhold safe and effective therapies from frail patients in fear of HRQoL deterioration.

Senescent Immune Signature in Frail and Vulnerable Newly Diagnosed Myeloma Patients: A Cohort Analysis from the UK-MRA Myeloma XIV Fitness Study

Introduction Physical frailty is a key factor driving treatment tolerability and outcome in multiple myeloma (MM). There is a close interplay between physiological aging, frailty and immune dysfunction, with the presence of a malignant disease overlay adding an additional dimension to the host response biology. The UKMRA Myeloma XIV FiTNEss study is the first phase 3 randomised clinical trial to explore the utilisation of frailty assessment as a tool to guide and optimise treatment decision making and deliverability. Here we report on the relationship between physical frailty and T cell dysfunction in a cohort of patients within this landmark study. Methods Multiparameter flow cytometry was used to assess the baseline T cell phenotype in the peripheral blood of 49 participants with NDMM receiving treatment within FiTNEss. Patients were assessed for frailty using the IMWG frailty score and additionally assessed for clinical vulnerability using the UKMRA MRP score (Cook et al, Lancet Haematol. 2019). The IMWG frailty score combines activities of daily living assessment and co-morbidity burden with age to generate a validated, prognostic frailty score. The UKMRA MRP is a risk profile which uses routinely collected clinical data including age, WHO performance status, ISS stage and CRP to define prognostic risk categories with the high-risk category encompassing frailer individuals. Normal T cell subsets were assessed based on CD45RA and CD28 phenotype while dysfunctional subsets (exhausted and senescent) were defined using CD28 and KLRG1. Results The median age of participants was 79 (range 68-90) and 55% were male. The distribution by IMWG was fit 18%, unfit 33%, frail 49% and by MRP was low risk 31%, intermediate risk 28%, high risk 38%. Absolute lymphocyte count (ALC) decreased with increasing frailty (p=0.02), with no patients classified as fit by IMWG or low risk by MRP criteria having a lymphocyte count below the lower limit of normal. No relationship was seen between ALC and age. The ratio remained stable across the IMWG cohorts, suggesting a global reduction in lymphocyte subsets. An accumulation of CD8 TEMRA cells was seen in the MRP high risk cohort (p=0.0085). No differences were seen between cohorts based on the IMWG frailty score. The accumulation of CD8 TEMRA cells indicates a loss of T cell differentiation plasticity and is associated with a cytotoxic and pro-inflammatory immune response. CD4 dysfunctional subsets were comparable across the cohorts. CD8 dysfunctional subsets were most marked in the frail and high-risk cohorts. The MRP high-risk cohort had a skewed ratio of exhausted to senescent cells (p=0.02), with a reduction in CD8 exhausted populations compared to the fit and unfit cohorts (p=0.0477) and a trend towards increased senescent cell burden (p=0.07). This was echoed within the IMWG frail cohort where elevated numbers of senescent CD8 cells were identified (p=0.02). No relationship was seen between CD8 senescent burden and age, CRP, ISS or WHO PS when each variable was assessed independently, suggesting that the presence of this immune population is not directly related to disease burden or physiological aging alone, but reflects a more complex interplay between host response biology and disease characteristics. Principal component analysis demonstrated a high degree of immunological heterogeneity within the MRP low and intermediate risks cohorts, while the high-risk cohort had a more uniform immunological profile (Figure 1A). Significant overlap between a proportion of the non-high-risk cohorts and high-risk cohorts was seen and requires further exploration. A multi-variable correlation analysis identified correlations between the CD4:8 ratio and CD8 cell senescent burden, MRP and ISS, highlighting the important interplay between immunological dysfunction, clinical vulnerability and disease burden (Figure 1B). Conclusion The T cell immunological landscape of the most vulnerable patient populations with newly diagnosed MM is characterised by an accumulation of senescent CD8 T cells which cannot be attributed to age or disease burden alone. Immune senescence is known to be associated with a chronic inflammatory state which may drive the acquisition of the physiological changes, such as sarcopenia, which characterise a frailty phenotype. This provides an opportunity for targeted intervention to address the biological drivers of disease related frailty.

IMWG /ECOG Frailty Score Was a Good Indicator for ASCT Candidate Selection for NDMM in China from a Hcmmd Retrospective Study

Background Autologous hematopoietic stem cell transplantation (ASCT) has always been considered as the standard choice for newly diagnosed multiple myeloma (NDMM) patients less than 65 years old, or even older. At present, how to define the patients who is suitable for transplantation is still controversial in clinic in China. Rate of utility of ASCT in front line was as low as 10%. The screening of transplant patients mainly depends on the evaluation of the general condition of patients, the wishes of patients and their families, and the evaluation of organ function by physical examination. In this way, it is particularly difficult for doctors in non-transplant medical units to recommend stem cell transplantation for patients. Based on “HemaTank” Chinese multiple myeloma database(HCMMD), a retrospective study of construction of special disease cohort and prognostic model for multiple myeloma were conducted to explore the posibilities of utility of IMWG/ECOG frailty score to select transplantation candidate, and the prognostic significance of frailty score in all MM patients. Methods In this study, 322 NDMM in the first affiliated Hospital of Soochow University from August 2018 to October 2022 were analyzed retrospectively. All patients were valuated with IMWG/ECOG frailty score before each cycle of treatment, which included age, the ECOG score, and the Charlson Comorbidity Index. Patients with IMWG frailty score≥2 were defined as frail, with score &amp;lt;2 were unfrail. Transplant patients received 4 courses of induction of VRd regimen followed by ASCT, and 2 courses of VRD consolidation after transplantation. Non-transplant patients received 8 courses of induction with VRD regimen. Standard risk patients received lenalidomide as maintenance therapy until PD. High risk patients received V+R as maintenance treatment until PD. Results The median age of 322 patients was 58(29-79). 178(55.3%) patients were male. 170 (52.8%) patients were unfrail at diagnosis, with a mean age of 56.72±7.11. 77.8% of the unfrail patients were less than 65 years old. 152 patients were frail at diagnosis, with a mean age of 59.47±8.28. 68% of the patients were less than 65 years old. There were statistical differences in age, DS stage, ISS stage and R-ISS stage between the two groups. (P &amp;lt; 0.05). After induction therapy, 246 patients (76%) rescored IMWG/ECOG frailty score before ASCT. 46 patients changed from frail state at first diagnosis to nonfrail before transplantation, mainly because of the improvement of ECOG score and renal function. There is no change from a nonfrail state at the first diagnosis to a frail state when entering the ASCT program. After logistics regression analysis of IMWG/ECOG score, age, renal function and CCI, unfrailty is the best indicator of selection patients as ASCT candidate, OR=0.37, 95%CI 0.21-0.63 (P &amp;lt; 0.001). At the time of ASCT, there was no significant difference in the ORR of induction therapy between frail and unfrail patients. But the granulocyte and platelet reconstruction during ASCT in the frail group was slower than that in the unfrail group, P&amp;lt;0.0001. The transplantation-related mortality was 0. In this cohort, the PFS and OS of the NDMM patients accepted VRD+transplantation was all better than those received VRD only. Most importantly, the OS of the frail patients scored at the time of ASCT was much poorer (P&amp;lt;0.05) than that of the unfrail group with no significant difference in PFS between two groups. But there were no significant differences in PFS and OS of the patients who changed from frail to unfrail after induction therapy compared with those remained unfrail at diagnosis and after induction therapy. Conclusion IMWG/ECOG frailty score can be used to select ASCT candidate for NDMM patients. In the study 144 patients (84.7%) remained unfrail at diagnosis and before transplantation accepted ASCT. and 46 frail patients (30.2%) at diagnosis transferred from frail to unfrail after induction and accepted transplantation. It was suggested that the IMWG/ECOG frailty score evaluated before transplantation is more instructive for long-term overall survival. The OS of unfrail patients was better than that of frail patients even with no significant difference in PFS.

The Effects of Second Primary Malignancies and Frailty on Overall Survival and Mortality in Geriatric Turkish Patients with Multiple Myeloma.

The study aims to investigate second primary malignancy (SPM) development and frailty in Turkish geriatric patients with multiple myeloma (MM) and to assess the relationship between overall survival (OS) and various characteristics including SPM and frailty. Seventy-two patients diagnosed with and treated for MM were enrolled in the study. Frailty was determined by the IMWG Frailty Score. Fifty-three participants (73.6%) were found to have clinically-relevant frailty. Seven patients (9.7%) had SPM. Median follow-up was 36.5 (22-48.5) months, and 17 patients died during the follow-up period. Overall (OS) was 49.40 (45.01-53.80) months. Shorter OS was found in patients with SPM (35.29 (19.66-50.91) months) compared to those without (51.05 (46.7-55.4) months) (Kaplan-Meier; p = 0.018). The multivariate cox proportional hazards model revealed that patients with SPM had 4.420-fold higher risk of death than those without (HR: 4.420, 95% CI: 1.371-14.246, p = 0.013). Higher ALT levels were also independently associated with mortality (p = 0.038). The prevalence of SPM and frailty was high in elderly patients with MM in our study. The development of SPM independently reduces survival in MM; however, frailty was not found to be independently associated with survival. Our results suggest the importance of individualized approaches in the management of patients with MM, particularly with regard to SPM development.

Daratumumab Based Response Adapted Therapy for Older Adults with Newly Diagnosed Multiple Myeloma: Interim Analysis of Phase II Study

Introduction The combination of daratumumab (DARA), lenalidomide (Len) and dexamethasone (Dex) is an FDA approved therapy for older adults with newly diagnosed multiple myeloma (NDMM) based on the MAIA study. A less intense bortezomib (Bort) lenalidomide dexamethasone combination (VRD lite) is also used. We thought to investigate a personalized daratumumab based response adapted therapy for older adults with NDMM. Methods Patients were required to have NDMM and were age over 65 and not deemed candidates for high dose chemotherapy and autologous stem cell transplant. Eligible patients received subcutaneous DARA and Dex (20 mg PO weekly) for 2 cycles: in the event of partial response or better, patient continued on DARA Dex per usual dose and schedule, in the event of less than a partial response, frailty adjusted dosing of Len or Bort was added to the usual DARA Dex regimen. The choice of Len or Bort was per the treating physician and informed by Ex Vivo drug sensitivity assay. Modified geriatric assessment (including IMWG frailty score, timed up and go) and bone marrow biopsy (for correlatives) were performed at screening as well as on C2D22. Capitalizing on this unique opportunity to examine the tumor and immune response to DARA Dex, additional correlative studies looking at single cell RNAseq and multi-parameter flow cytometry are included. The primary endpoint was best response per IMWG criteria. Secondary endpoints included PFS, ORR after 2 cycles of DARA Dex. Result: Between November 2019 and July 2022 (the data cutoff date), 25 patients were enrolled. The median age was 79 years (range 71-88) and 13 were males (52%). Frailty score per IMWG were 0 (fit), 1 (unfit), 2+(frail) in 16%, 32%, and 52% of patients respectively. Timed up and go was prolonged (>10s) in 7 (35%) patients. High risk FISH (t(4;14) and del17p) was noted in 3 (12%) with an additional 12 patients (48%) with gain 1q/Amp1q. RISS3 was noted in 16% of patients. After 2 cycles of DARA Dex, 23 patients are evaluable for response (2 patients have not yet completed 2 cycles of therapy); 8 patients (35%) had a partial response or better (no patients had progressive disease, 1 patient discontinued therapy after 1 dose of study therapy and a diagnosis of disseminated tuberculosis). Of the 14 patients (61%) with less than a PR, 9 patients had len added and 5 bort added. The overall best response (PR and better) was 95% for this response adapted strategy including CR/sCR, VGPR, PR in 3 (13%), 14 (61%), 5 (21%) respectively. After a median of 14.7 months of follow up on this response adapted therapy, 5 had progressive disease, the estimated PFS at 1 year was 90% (95%CI 65-97.4). Overall, no unexpected toxicity was noted. The most common grade 3+ AE at least possibly related to therapy included neutropenia, anemia, diarrhea, hyperglycemia, agitation and confusion and hypertension each occurring in 4% of patients. The most common possibly related any grade AE occurring in >25% of patients included hyperglycemia 80%, diarrhea 36%, neutropenia 28%, insomnia 28%, fatigue 28% Conclusions: Preliminary results of this DARA based response adapted therapy are encouraging in this mostly frail patient population with a high response rate and low rate of severe AE. Enrollment in this response adapted therapy for older adults with NDMM continues. With longer follow-up, we will integrate correlative studies evaluating the accuracy of ex vivo predictions in response to DARA and combinations in this unique population of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

SIOG2021-0145 - Discordance between simplified Frailty Score and the IMWG frailty score among newly diagnosed older adults with Multiple Myeloma: Findings from the CARE-HEME registry

SIOG2021-0145 - Discordance between simplified Frailty Score and the IMWG frailty score among newly diagnosed older adults with Multiple Myeloma: Findings from the CARE-HEME registry

Frailty Predicts Survival and Toxicity in Newly Diagnosed Multiple Myeloma Patients Ineligible for Autologous Stem Cell Transplantation; Report of the HOVON-87/Nmsg-18 Study Group

IntroductionWe previously reported the results of the phase III randomized HOVON-87/NMSG-18 study for Newly Diagnosed Multiple Myeloma patients not eligible for stem cell transplantation (nte-NDMM). The efficacy of melphalan, prednisolone and either thalidomide followed by thalidomide maintenance (MPT-T) versus lenalidomide followed by lenalidomide maintenance (MPR-R) was found to be comparable, being consistent across subgroups defined by age, cytogenetic risk and ISS [1]. As frailty is known to affect clinical outcome, we investigated the impact of frailty on outcome.MethodsFrailty was assessed by a modification of the IMWG frailty score based on age, the Charlson Comorbidity Index (retrospectively retrieved from the list of comorbidities that were present at entry) and the WHO performance as a proxy for (instrumental) Activities of Daily Living ((i)ADL). To assess the effect of frailty on progression free survival (PFS) and OS, the logrank test was used, while the chi-squared test was used to evaluate the association of frailty with discontinuation rate and toxicity.ResultsAll 637 eligible patients from the HOVON-87/NMSG-18 trial were included in the analysis. Median age was 73 years; 66% of patients were ≤ 75 years, 24% were 76-80 years and 10% were > 80 years. A CCI of 0, 1, 2 and ≥3 was found in 61, 20, 7 and 4% of patients respectively (8% unknown). The most common comorbidities were diabetes mellitus without end organ complications (12%) and myocardial infarction (6%). A WHO performance of 0, 1 and ≥ 2 was observed in 35, 47 and 16% respectively (3% unknown).Univariate analyses showed that older age (>80 years: HR 1.59 [95% CI 1.12-2.25]), a higher CCI (CCI ≥2: HR 1.41 [95% CI 1.01-1.95]); and a poor WHO performance (WHO ≥2: HR 2.05 [1.49-2.82]) were associated with an inferior OS. HR's were 1.07 [95% CI 0.82-1.40] and 1.27 [95% CI 0.98-1.65] for age 76-80 years and WHO performance respectively. For age and the CCI the IMWG frailty score classification was used. For the WHO, scores were assigned based on the HR: WHO 0; 0 points, WHO 1; 1 point and WHO ≥2; 2 points. Fit patients were defined as a proxy frailty score of 0, unfit as a score of 1 and frail as a score of ≥2, comparable to the IMWG frailty score.Using this modified IMWG frailty score, 135 patients were fit (21%), 199 were unfit (31%) and 259 were frail (41%) (7% unknown). The median OS was found to be significantly different in fit versus unfit versus frail patients; 58, 55 and 46 months respectively (p=0.004). In contrast no significant difference in median PFS was found; 26, 20 and 21 months respectively (p=0.30).The inferior OS for the frail might be partly explained by higher discontinuation rate of induction therapy; 50%, versus 43% in unfit, and 34% in fit patients (p=0.011), being mainly due to excessive toxicity (25, 23 and 16% respectively). The cumulative incidence of treatment discontinuation on protocol (induction plus maintenance), corrected for death and progressive disease which were considered as competing risks, is depicted in figure 1B. Discontinuation rate at 2 years for fit, unfit, and frail patients were 48%, 48%, and 59% respectively (p=0.06). There were significantly more grade ≥3 adverse events on protocol in frail and unfit patients (both 86%) as compared to fit patients (77%, p=0.039). Especially more grade ≥3 infections were found in frail (28% versus 18% in unfit and 13% in fit). In contrast, frailty was not associated with hematological toxicity.ConclusionWe here present a modified frailty score, using the WHO performance instead of the (i)ADL, combined with age and the CCI, that enables the identification of frail MM patients with an inferior OS, a higher discontinuation rate and a higher rate of grade ≥ 3 toxicity. This non-laborious modified frailty score can be easily implemented in clinical trials and allows to compare the outcome of frail patients in nte-NDMM trials, which will hopefully result in frailty-adapted therapy in clinical daily practice.Reference:1. Zweegman S, Holt vd B, Mellqvist U, et al. Blood 2016;127(9):1109-16 [Display omitted] DisclosuresMellqvist:Celgene: Honoraria; janssen: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Sandoz: Other: participation advisory board; Amgen: Honoraria, Other: participation advisory board. Abildgaard:Takeda: Research Funding. Plesner:Janssen: Research Funding; Janssen, Takeda: Consultancy; Janssen, Genmab: Membership on an entity's Board of Directors or advisory committees. Van De Donk:Janssen, Celgene, Bristol-Myers Squibb, Amgen: Research Funding. Sonneveld:Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding; Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy. Waage:Celgene, Takeda: Honoraria. Zweegman:Celgene: Other: advisory board participation, Research Funding; Janssen: Other: advisory board participation, Research Funding; Takeda: Other: advisory board participation, Research Funding; Amgen: Other: advisory board participation.

The Leeds Risk Profile Predicts Outcome for Older Myeloma Patients: A Prognostic Score Using Frailty Biomarkers Derived and Tested Using 2371 Clinical Trial Patients

Introduction:Multiple myeloma (MM) is molecularly heterogeneous but so too are the patients it affects. This heterogeneity becomes more significant in older, less fit patients in whom factors affecting their ability to withstand treatment may be more important than disease biology. Treatment tolerability does not deteriorate linearly with age and is better defined as ‘frailty’. Patient-reported activities of daily living and comorbidities have been combined with age to derive the IMWG Frailty Score (Palumbo A et al, Blood 2015), which can predict outcome. This requires completion of 3 patient questionnaires and may be open to bias.Several biochemical markers of frailty have been associated with adverse outcomes including inflammatory markers such as CRP, renal dysfunction and the ratio of lymphocytes to total white cells (L:W). Using biochemical surrogates to measure patient frailty is objective and avoids the need for potentially burdensome questionnaires. Here we describe a novel prognostic score (Leeds Risk Profile; LRP) that combines readily available laboratory measures of patient frailty with age and WHO performance status (PS) to predict outcomes in transplant non-eligible (TNE) MM patients.Methods:1852 TNE patients recruited to the NCRI Myeloma XI (MyXI) trial were used as a training set and 520 TNE patients recruited to the MRC Myeloma IX (MyIX) trial used as a validation set. MyXI compared IMiD-containing triplet combinations: cyclophosphamide and dexamethasone with thalidomide (CTD) or lenalidomide (CRD). Patients with a suboptimal response (<VGPR) were eligible for further induction with a PI-based triplet (cyclophosphamide, bortezomib and dexamethasone). There was a maintenance randomisation between lenalidomide and observation. MyIX compared induction with melphalan and prednisolone to CTD and maintenance thalidomide to observation.Baseline variables considered included PS, LDH, CRP, international staging score (ISS), age and L:W. The primary objective was overall survival (OS). Missing data in the training set (MyXI) for the variables was imputed via multiple imputation by chained equations. The model was built using a Cox model with LASSO penalty within each imputed dataset. The final model was derived by combining the coefficients and standard errors by Rubin's rules. The model was internally validated by bootstrap sampling and externally validated in the test set using the prognostic separation D-statistic.Results:Univariate Cox-regression analysis demonstrated a significant effect of PS, CRP, ISS, Age and L:W (all p<0.001) but not LDH (p=0.333) on OS within the training set.The final multivariable model (LRP) included PS, Age, ISS and CRP. The discrimination and calibration of the model were good, with calibration better closer to trial entry. The model was successfully internally validated by bootstrap re-sampling according to pre-defined criteria. The combined prognostic index was divided into tertiles to define 3 groups: Fit, Intermediate-fitness, Frail. All variables increased in severity across the three groups. The groups predicted outcomes as shown in Figure 1a (median OS: Fit 60 months [95%CI 55-NR], Intermediate-fitness 44 [39-48] and Frail 25 [22-30] (Log-rank p<0.0001)).External validation was successfully carried out using patients from MyIX. The test data was split into three separate risk groups using the same cut-offs derived and implemented within the training data. Significant differences in OS were again predicted (Figure 1b) (median OS: Fit 43 months [35-NR], Intermediate-fitness 34 [27-38] and Frail 20 [14-25] (Log-rank p<0.0001)).In exploratory analyses the risk groups derived for overall survival were applied to progression-free survival, early mortality and treatment delivery modifications and predicted outcome as expected. Predictive ability was maintained in those patients who were exposed to both IMiD and PI therapy.Conclusion:We have defined a novel score predictive of outcome in TNE MM patients (LRP). This score uses only factors already collected at baseline for MM patients using objective laboratory bloods tests combined with age and a simple WHO PS assessment. As such it would be easy and quick to use in the clinic and apply within clinical trials. The LRP will be prospectively validated, including a comparison to the IMWG Frailty Score, within the UK-MRA Myeloma XIV trial (FITNESS). [Display omitted] DisclosuresCook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Glycomimetcs: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pawlyn:Takeda: Honoraria, Other: Travel support; Janssen: Other: Travel support; Celgene: Honoraria, Other: Travel support. Gregory:Janssen: Honoraria; Celgene: Consultancy, Honoraria. Davies:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Morgan:Takeda: Consultancy, Honoraria; Bristol Myers: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Jackson:Chugai: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; J&J: Honoraria.

Efficacy and Safety of Ixazomib Induction and Maintenance in Newly Diagnosed Multiple Myeloma Patients According to the IMWG Frailty Score: A Post-Hoc Analysis of the EMN10-Unito Trial

Efficacy and Safety of Ixazomib Induction and Maintenance in Newly Diagnosed Multiple Myeloma Patients According to the IMWG Frailty Score: A Post-Hoc Analysis of the EMN10-Unito Trial

Risk of Early Severe Infections in Newly Diagnosed Multiple Myeloma Patients Treated with Novel Agents: A Pooled Analysis

Risk of Early Severe Infections in Newly Diagnosed Multiple Myeloma Patients Treated with Novel Agents: A Pooled Analysis

Real-Rd - Real Life Italian Experience with Lenalidomide and Low-Dose Dexamethasone (Rd) As First Line Treatment of Newly-Diagnosed Multiple Myeloma Patients Not Eligible to Stem Cell Transplantation: Outcomes and Tolerability

Real-Rd - Real Life Italian Experience with Lenalidomide and Low-Dose Dexamethasone (Rd) As First Line Treatment of Newly-Diagnosed Multiple Myeloma Patients Not Eligible to Stem Cell Transplantation: Outcomes and Tolerability

Efficacy and Safety of Ixazomib-Dexamethasone, Ixazomib-Cyclophosphamide-Dexamethasone, Ixazomib-Thalidomide-Dexamethasone and Ixazomib-Bendamustine-Dexamethasone for Elderly Newly Diagnosed Multiple Myeloma (NDMM) Patients: Analysis of the Phase II Randomized Unito-EMN10 Study

Efficacy and Safety of Ixazomib-Dexamethasone, Ixazomib-Cyclophosphamide-Dexamethasone, Ixazomib-Thalidomide-Dexamethasone and Ixazomib-Bendamustine-Dexamethasone for Elderly Newly Diagnosed Multiple Myeloma (NDMM) Patients: Analysis of the Phase II Randomized Unito-EMN10 Study

Selecting transplant in the elderly: validation of IMWG frailty score and Revised Myeloma Comorbidity Index compared to clinical judgment

Autologous stem cell transplantation (ASCT) has proven safe and effective in selected elderly patients (pts) with Multiple Myeloma (MM); several comorbidities scores have been proposed but specific criteria for evaluating ASCT eligibility in elderly MM pts still need to be established. We performed an external validation of the IMWG frailty score and the revised Myeloma Comorbidity Index (R-MCI) in unselected elderly pts considered for ASCT at our center and treated according to clinical judgment.

Impact of frailty, melphalan pharmacokinetics, and pharmacogenetics on outcomes post autologous hematopoietic cell transplantation for multiple myeloma.

Autologous hematopoietic cell transplantation (auto-HCT) using melphalan is the standard of care in the management of myeloma. Auto-HCT is a safe procedure with tolerable toxicity except in Asian-Indians. We hypothesized either one or a combination of factors: (1) frailty (assessed by IMWG frailty score), (2) generic melphalan pharmacokinetic area under the curve (AUC) assessed by high-performance liquid chromatography, and (3) pharmacogenetics of glutathione S-transferase (GSTP1) assessed by Sanger sequencing, to be associated with toxicity and survival outcomes post auto-HCT. Disease response was evaluated by IMWG response criteria at day +100 post auto-HCT. Gastrointestinal (GI) toxicity, infections, hospital stay, progression-free survival (PFS) were also recorded. A total of 35 patients were evaluated over 2 years (2016-2018). Frailty, not HCT-comorbidity index correlated with GI toxicity and infections. Overall there was an 11-fold variation in melphalan AUC with a median of 27.88 mg h/L (10.06-110.26). Patients with AUC more than the median had more GI toxicity and infections. Patients with wild-type GSTP1 polymorphism had more GI toxicity and infections. Frailty, AUC, or GSTP1 polymorphism did not impact hospitalization duration or PFS. A combination of the factors frailty, melphalan pharmacokinetics, and pharmacogenetics impacts GI toxicity and infections after auto-HCT in myeloma.

Geriatric Impairments and Low Muscle Mass Are Associated with Treatment Discontinuation and Overall Survival in Newly Diagnosed Non-Transplant Eligible Multiple Myeloma Patients (nte-NDMM) Treated with Dose-Adjusted Melphalan-Prednisone-Bortezomib (MPV) — Results of the Dutch HOVON 123 Study

Geriatric Impairments and Low Muscle Mass Are Associated with Treatment Discontinuation and Overall Survival in Newly Diagnosed Non-Transplant Eligible Multiple Myeloma Patients (nte-NDMM) Treated with Dose-Adjusted Melphalan-Prednisone-Bortezomib (MPV) — Results of the Dutch HOVON 123 Study

Efficacy and Feasibility of Dose/Schedule-Adjusted Rd-R Vs. Continuous Rd in Elderly and Intermediate-Fit Newly Diagnosed Multiple Myeloma (NDMM) Patients: RV-MM-PI-0752 Phase III Randomized Study

Efficacy and Feasibility of Dose/Schedule-Adjusted Rd-R Vs. Continuous Rd in Elderly and Intermediate-Fit Newly Diagnosed Multiple Myeloma (NDMM) Patients: RV-MM-PI-0752 Phase III Randomized Study

Once Weekly Versus Twice Weekly Carfilzomib in Combination with Cyclophosphamide and Dexamethasone in Newly Diagnosed Multiple Myeloma: A Pooled Analysis of Two Phase 1/2 Studies

Once Weekly Versus Twice Weekly Carfilzomib in Combination with Cyclophosphamide and Dexamethasone in Newly Diagnosed Multiple Myeloma: A Pooled Analysis of Two Phase 1/2 Studies

Feasibility and Efficacy of Dose Adjusted Melphalan - Prednisone - Bortezomib (MPV) in Elderly Patients ≥ 75 Years of Age with Newly Diagnosed Multiple Myeloma; the Non-Randomised Phase II HOVON 123 Study

BACKGROUNDThere is a high rate of toxicity-related discontinuation in elderly patients with NDMM, which in general is higher in patients ≥75 years. Therefore, we investigated the feasibility of a dose-adapted MPV scheme in patients ≥75 years and whether the International Myeloma Working Group frailty score (fit, unfit, and frail) predicts feasibility. Moreover, geriatric assessments, including functional assessments, were performed in order to design a model for more precise prediction of feasibility of treatment.METHODSPatients were treated with 9 cycles of MPV: Mel 6 mg/m2, day 1-4; Pred 30 mg/m2, day 1-4; and Bort 1.3 mg/m2 day 1,8,15 and 22 of a 35-day cycle. This first planned analysis on discontinuation rate was restricted to the first 100 eligible consecutive patients out of 240 planned patients. A preliminary analysis of grip strength and walking speed was performed, comparing tertiles.RESULTSOf the 96/100 evaluable patients, none were fit (because of age ≥75 years), 23/96 (24%) were unfit and 64/96 (67%) were frail (9/96 (9%) unknown). 28/64 (44%) frail patients were aged 75-80, and 8/64 (13%) patients were defined frail based on age >80 years only. Frail patients were found to have significantly less grip strength and lower walking speed as compared to unfit patients (see table 1), both for men and women. However, 19% (male) and 15% (female) of the patients with low grip strength were not frail, but unfit. For slow walking speed these percentages were 13% and 7% respectively, indicating these tools might be complementary to the IMWG frailty score in predicting outcome.The median follow up was 16 months. The discontinuation rate of MPV in the total population was 49%; 30% in unfit and 55% (including 7% discontinuation of bortezomib only) in frail patients (p=0.055). In patients >80 years (by definition frail) discontinuation rate was higher (69% (including 11% bortezomib only)) than in patients aged 75-80 years (37%; p=0.003). Reasons for early discontinuation in unfit versus frail were: progressive disease 1/7 vs 4/31, toxicity 3/7 vs 10/31, death 0/7 vs 4/31, non-compliance 1/7 vs 8/31, other 2/7 vs 5/31. In 72% 6 cycles of MPV were found to be feasible, both in unfit (78%) and frail (73%) patients.Response on protocol was ≥PR 69%, ≥VGPR 29% and ≥CR 7%, not significantly different in unfit versus frail patients. Median progression free survival (PFS) was 17 months: 22 for unfit and 17 months for frail patients (p=0.38). Overall survival (OS) at 18 months was 76%: 88% for unfit and 71% for frail (p=0.26) patients.ConclusionsTreatment of elderly NDMM patients ≥75 years with 9 cycles of dose-adjusted MPV results in a high discontinuation rate of 49%: 30% in unfit versus 55% in frail patients, indicating the need for further treatment adjustment and more precise selection of patients. Concerning the first; 6 cycles were found to be feasible in the majority of both unfit and frail patients. Concerning the latter; a preliminary analysis of functional geriatric assessments showed significantly lower performance in frail compared to unfit patients. Moreover, the results of functional geriatric assessments were found to add to the IMWG frailty score, hopefully leading to a better prediction of the feasibility of treatment in elderly NDMM patients.Functional assessments in unfit versus frail patients 1 p=0.18 2 p=0.012 3 p=0.0374 p=0.014Additional cognitive and nutritional geriatric assessments and biomarkers (sarcopenia and senescence markers) were performed in all patients.FISH analysis of isolated plasma cells will be available in the majority of patients.This trial was registered at www.trialregister.nl (NTR 4244), EudraCT 2013-000320-33, and supported by the Dutch Cancer Society (project number VU 2013-6411 ) and by an unrestricted grant from Janssen-Cilag. [Display omitted] DisclosuresZweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Ypma:Advisory Board Sanofi (Plerixafor): Membership on an entity's Board of Directors or advisory committees. Minnema:Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Jansen Cilag: Consultancy. van de Donk:BMS: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Amgen: Research Funding. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

N-terminal fragment of the type-B natriuretic peptide (NT-proBNP) contributes to a simple new frailty score in patients with newly diagnosed multiple myeloma.

Multiple myeloma (MM) patient frailty has been delineated primarily by age and ECOG performance score (PS) and recently by the IMWG frailty score based on functional status [Activity of Daily Living (ADL) and Instrumental‐ADL scores], comorbidities [Charlson‐comorbidity‐index (CCI)] and age. It was hypothesized that N‐terminal natriuretic peptide type B (NT‐proBNP) might be both a more convenient measure of frailty and a predictor of overall survival (OS). Three‐hundred and fifty‐one consecutive symptomatic MM patients who were seen at Mayo Clinic within 30 days of diagnosis and who had blood stored were eligible. Data from the first visit was abstracted and used to calculate an ADL, CCI, and measure the NT‐proBNP level. The best cutoff of NT‐proBNP predicting OS was 300 ng/L. Variables predictive for OS were ECOG‐PS, age, CCI, ADL, ISS, revised‐ISS, and NT‐proBNP. On multivariate analysis age ≥70, PS ≥2, and NT‐proBNP ≥300 were independent predictors of survival. Patients were assigned a score of 1 for each of these variables, creating stages I–IV with scores of 0–3 points, respectively. The median OS from diagnosis was not reached, 58, 28, and 18 months (P < 0.0001), respectively. This frailty risk schema was independent of initial therapy and the revised‐ISS. NT‐proBNP is a useful predictor of survival independent of age and PS. It is a widely available biomarker that could be added to the panel of laboratory tests of newly diagnosed MM patients and serve as a simple and objective tool of determining frailty in clinical practice. Am. J. Hematol. 91:1129–1134, 2016. © 2016 Wiley Periodicals, Inc.