Transplant-ineligible Multiple Myeloma Research Articles

A Prognostic Survival Model Incorporating Patient-Reported Outcomes for Transplant-Ineligible Patients With Multiple Myeloma.

Developing prognostic tools specifically for patients themselves represents an important step in empowering patients to engage in shared decision-making. Incorporating patient-reported outcomes may improve the accuracy of these prognostic tools. We conducted a retrospective population-based study of transplant-ineligible (TIE) patients with multiple myeloma (MM) diagnosed between January 2007 and December 2018. A multivariable Cox regression model was developed to predict the risk of death within 1-year period from the index date. We identified 2356 patients with TIE MM. The following factors were associated with an increased risk of death within 1 year: age > 80 (HR 1.11), history of heart failure (HR 1.52), "CRAB" at diagnosis (HR 1.61), distance to cancer center (HR 1.25), prior radiation (HR 1.48), no proteosome inhibitor/immunomodulatory therapy usage (HR 1.36), recent emergency department (HR 1.55) or hospitalization (HR 2.13), poor performance status (ECOG 3-4 HR 1.76), and increasing number of severe symptoms (HR 1.56). Model discrimination was high with C-statistic of 0.74, and calibration was very good. To our knowledge, this represents one of the first prognostic models developed in MM incorporating patient-reported outcomes. This survival prognostic tool may improve communication regarding prognosis and shared decision-making among older adults with MM and their health care providers.

CO24 Daratumumab in Combination with Lenalidomide and Dexamethasone Improves Survival in Newly Diagnosed Transplant-Ineligible Multiple Myeloma: A Parametric Network Meta-Analysis in a United Kingdom Setting

CO24 Daratumumab in Combination with Lenalidomide and Dexamethasone Improves Survival in Newly Diagnosed Transplant-Ineligible Multiple Myeloma: A Parametric Network Meta-Analysis in a United Kingdom Setting

A Prognostic Model Integrating Circulating Clonal Plasma Cells into R-ISS and PET-CT Based Tumor Burden in Transplant-Ineligible Multiple Myeloma

Introduction: Circulating clonal plasma cell (cCPC) is an easily obtained and non-invasive biomarker in multiple myeloma (MM), providing distinct prognostic information from the revised-international staging system (R-ISS). However, its prognostic relevance has been investigated primarily in transplant-eligible and clinical trial settings. Consequently, there is limited data on the impact of cCPC on outcomes and optimal cut-off values in transplant-ineligible (TIE) MM patients. Moreover, appropriate combinations to refine risk stratification, such as tumor burden measured by positron emission tomography-computed tomography (PET-CT), have yet to be fully explored. Methods: We performed a retrospective analysis on newly diagnosed TIE-MM patients with available peripheral blood (PB) flow cytometry (FCM) and PET-CT data from 2011 to 2021. Patients with primary plasma cell leukemia (n=8), defined as >5% monoclonal plasma cells in PB, were excluded from the study. Quantification of cCPC was performed using 6-color (2011-2016) or 8-color (2017-2021) FCM staining for CD19, CD56, CD38, CD138, cytoplasmic κ, and cytoplasmic λ to confirm monoclonality (Beckman Coulter, USA), which required at least 150000 mononuclear cell counts with the detectable limit at 0.01% (10 -4) based on previous reports (Gonsalves et al). Tumor burden was assessed by calculating total lesion glycolysis (TLG) using the following formula: the mean standardized uptake value (SUV) multiplied by the total tumor volume with an absolute SUV >2.5, using Metavol Software (Hokkaido University, Japan). Receiver operating curve analysis with the Youden index was employed to determine the optimal cutoff for predicting 2-year progression-free survival (PFS) and 5-year overall survival (OS). The predictive performance of R-ISS, cCPC, and TLG alone, along with their combinations, was compared using Harrell's concordance index (c-index). Results: 114 patients with TIE-MM were analyzed. The median age was 78 years (interquartile range [IQR] 73-83). The number of patients classified as R-ISS Ⅰ, Ⅱ, and Ⅲ was 12 (10.5%), 82 (71.9%), and 20 (17.5%), respectively. Most patients (85.1%) received proteasome inhibitor-based induction remission therapy. cCPCs were detectable in 90 patients (80.7%), with a median level of 6 ×10 -4 (IQR 1-22). Regarding tumor burden, 73 patients (64%) had at least one fluorodeoxyglucose avid lesion with a median TLG of 34.7 (IQR 0-268). cCPC levels were significantly correlated with CPC in bone marrow (R =0.24, P =0.01) but not with TLG (R =-0.01, P =0.88) and involved free light chain levels (R =0.07, P =0.41). The optimal cut-off values in predicting 2-year PFS and 5-year OS were 9 and 10 ×10 -4 for cCPC, and 325 and 343 for TLG, respectively. For simplicity, we classified >10 ×10 -4 for cCPC and >300 for TLG as high-risks. Notably, approximately two-thirds of the patients (62.3%) had at least one high-risk feature (Figure 1). Both high cCPC and TLG showed significant associations with worse OS and PFS (5-year OS rate: cCPC high vs. low, 40.2% vs. 69.3%; TLG high vs. low, 38% vs. 64.5%; 2-year PFS rate: cCPC high vs. low, 45.7% vs. 69.1%; TLG high vs. low, 46.4% vs. 64% all P < 0.05). These factors retained prognostic significance after adjustment for R-ISS on multivariate analysis. Finally, we constructed a novel predictive model integrating RISS, cCPC, and TLG. This model discriminated OS among patients with 0 (5-year OS rate, 80% [95% confidence interval 68.4%-93.6%]), 1 (50.5% [37.7%-67.7%]), and ≧2 factors (29% [13.3%-63.5%], P <0.001, Figure 2). The c-index was the highest (0.651) in this combined model compared to the single use of these risk factors (0.585, 0.594, and 0.569). Conclusions: We demonstrated the prognostic impact of cCPC, which is independently associated with R-ISS and TLG, on real-world TIE-MM patients. The new prediction model, integrated with these different clinical and biological features, may provide robust outcome discrimination.

Applying Artificial Intelligence Machine Learning to Discover Factors That Shorten Duration of Treatment in Patients with Multiple Myeloma Using Real-World Patient-Level Longitudinal Data from Medical Data Vision Database

Introduction: To maximize the benefit of treatment in multiple myeloma (MM), it is important to continue treatment for appropriate duration . Our recent real-world study using the Medical Data Vision (MDV) claim database showed that median duration of treatment (DoT) of 1 line (L), 2L and 3L treatment was rather short (range: 6.7 to 8.6 months) in Japanese non-transplant patients with MM (Handa H, et al. Plos one. 2023). However, the broad range of treatment patterns in Japan makes it difficult to identify the cause of shortened DoT. Therefore, we assessed the predictive factors that shorten DoT at threshold of <3, <6 and <12 months by applying machine learning (ML) model using real-world clinical data of MM patients from the MDV database. Methods: This retrospective cohort study was conducted on 4848 individual treatments (2,762 patients; 1L for stem cell transplant-not conducted, 2L/3L) in patients (aged ≥18 years) with transplant-ineligible (newly diagnosed or relapsed/refractory) MM between 2003-21. An explainable deep learning model (point-wise linear model, PWL) was developed using 647 feature variables (evaluated before, during, and after treatment; Table) from the MDV database to identify the important predictors associated with DoT. The PWL model generated a custom-made logistic regression model for each sample, which was very familiar to medical researchers and allowed to analyze the importance of the feature variables. Predictive performance of the PWL model was compared with elastic-net regularized logistic regression and XGBoost models and calculated by area under the curve (AUC) and evaluated by 10-fold double cross validation. To stratify the patients with shorter DoT, a clustering analysis of 4848 individual treatment was conducted based on the similarity of coefficients of the custom-made logistic regression models generated from the PWL model. To understand characteristics of samples belonging to each cluster, the relationship between predicted DoT and MM treatment-related comorbidity management was investigated ( Table). Results: The AUC score of the PWL model to predict DoT of <3, <6 and <12 months was 0.61, 0.64 and 0.66, respectively ( Figure). As per clustering analysis, there were 2 clusters (cluster A and B) at DoT of <3 months and 3 clusters (cluster A, B and C) each at DoT of <6 and <12 months, respectively. At <3 months, cluster B showed lower median of prediction probability, and had a significantly (P<0.01) higher previous treatment lines, pre-treatment Charlson Comorbidity Index (CCI) versus cluster A. At <6 months, cluster C showed lower median of prediction probability, and had significantly (P<0.01) higher CCI and comorbidities, and cluster B had significantly (P<0.01) lower estimated glomerular filtration rate, among the clusters. At <12 months, cluster C showed lower median of prediction probability, and had significantly (P<0.01) higher lactate dehydrogenase (LD), previous treatment lines, pre-treatment CCI, degree of care requirement at diagnosis of MM, pre-treatment tube and parenteral nutrition, and comorbidities, among clusters. Additionally, in cluster B (at <3 months), and cluster C (at <6 and <12 months), use of immunomodulatory drugs (IMiDs) in treatment for MM was significantly higher in patients who met predicted DoT at each threshold versus the ones who were not. However, age and history of infectious diseases (antibacterial agents, γ globulin, etc.) was not affected. In addition, IMiDs and aspirin use at <3 and <6 months, and IMiDs use at <12 months had significant differences in events during and after treatment, which are important for considering treatment strategies for MM patients and may lead to the optimization of treatment plans. Study limitation included exclusion of important prognostic factors (cytogenetic profile, R-ISS stage, and presence of all plasmacytomas). Conclusions: TheML technique with PWL model yielded efficient results to understand the trend associated with event in treatment and characteristics of Japanese patients with MM whose DoT were shortened. Patient's condition and management related factors might have associated with shortened DoT, in consistent with clinical findings. These results are critical to continually improving MM management, achieving optimal patients care, and understanding the burden of disease and health services available to Japanese patients with MM in the real-world.

Multicenter Open Label Phase 3 Benefit Study of Isatuximab Plus Lenalidomide and Dexamethasone with/without Bortezomib in the Treatment of Newly Diagnosed Non-Frail Transplant Ineligible Multiple Myeloma Elderly Patients. IFM2020-05

Background. The current standard of care for non-transplant eligible (NTE) newly diagnosed multiple myeloma (NDMM) is the combination of anti-CD38 immunotherapy daratumumab to lenalidomide-dexamethasone (DRd) on the basis of the Maia study (Facon et al. NEJM). This regimen has considerably improved the survival objectives for the study and the patients, PFS and OS. Interestingly, the MRD sustained 10-5 negative rate of DRd in MAIA is lower than 15%, alluding to the hypothesis that DRd may be immunogenic more than profoundly debulking in its main MOAs. We and other have hypothesized that adding a proteasome inhibitor (PI) to antiCD38 IT +Rd combination would significantly increase the sustained MRD negativity rate and might improve even further survivals. Two phase 3 studies for registration investigate the role of adding antiCD38 IT to VRd (antiCD38VRd quadruplet-based combination versus VRd), questioning on the added value of antiCD38 to the old standard of care VRd. We believe it is of importance to study the added value of a PI to antiCD38 IT +Rd combination in comparison to antiCD38 IT +Rd (the optimal standard of care today in the NTE NDMM) to demonstrate the impact in debulking of the PI on top of the immunogenic effect with the study of the MRD negative rate. We therefore have conducted the present study of Isa-VRd compared to Isa-Rd (IFM2020-05/Benefit, (NCT04751877). Benefit has fully enrolled as of September 2022, and there has been no safety warnings from the safety committee with the prolonged use of bortezomib for 18 months on a weekly basis in combination to Isa-Rd. Study Design and Methods. 270 NTE NDMM patients, aged [65-79] years old and non-frail, were randomized 1:1 and assigned to either the anti-CD38 mAb isatuximab + Rd (Isa-Rd) or isatuximab + VRd (Isa-VRd lite). Stratification across arms was done according to high-risk MM, age cutoff of 75 years and study centers. Patients receive isatuximab IV 10 mg/kg on days 1, 8, 15, and 22 of cycle 1, days 1 and 15 from cycle 2 to 12 and day 1 from cycle 13 onward, 28-day cycles. Lenalidomide and dexamethasone were given orally as approved. Bortezomib was administered weekly and subcutaneously on days 1, 8, 15 at 1.3 mg/m² from cycle 1 to 12 and on days 1, 15 from cycle 13 to 18, and then stopped. All patients will discontinue dexamethasone after cycle 12. Patients will then continue receiving Isa-Rd until progression in both arms. The primary objective is to evaluate the MRD negativity rate at 10-5 at 18 months in both arms, sustained MRD being key secondary at [12-24] months. The study will be considered positive if the MRD negativity rate at 10-5 at 18 months is 30% in the Isa-VRd arm, and twice as much as Isa-Rd arm within the same time point. Key secondary objectives include the survival analysis (OS, PFS, EFS, TTNT), response rates, duration of response, and safety. Conclusion. The study is estimated to read out March 2024, 18 months after the last patient enrolls.

Analysis of baseline circulating tumor cells integrated with PET/CT findings in transplant-ineligible multiple myeloma

We aimed to improve prognostic predictors in transplant-ineligible multiple myeloma (TIE-MM) patients by combining baseline circulating clonal tumor cells (CTCs) and positron emission tomography/computed tomography (PET/CT) findings. The factors associated with prognosis were retrospectively investigated in 126 TIE-MM patients who underwent CTC quantification by multiparameter flow cytometry and PET/CT at the initial presentation. The total lesion glycolysis (TLG) level was calculated using Metavol software. The median percentage of CTC was 0.06% (range, 0%–4.82%), and 54 patients (42.9%) demonstrated high CTC levels. High CTC levels were associated with significantly poorer progression-free survival (PFS, 2-year 43.4% vs. 68.1%, P <0.001) and overall survival (OS, 5-year 39.0% vs. 68.3%, P <0.001). Similarly, high TLG levels significantly worsened the PFS (2-year, 41.2% vs. 67.6%, P = 0.038) and OS (5-year, 37.7% vs. 63.1%, P = 0.019). The multivariate analyses showed that Revised International Staging System (R-ISS) III, high CTC and TLG levels, and complete response were significant prognostic factors for PFS and OS. A novel predictive model was constructed using CTCs, TLG, and R-ISS III. The patients were stratified into three groups according to the number of risk factors, revealing an extremely high-risk group with a 2-year PFS of 0% and a 5-year OS of 20%. Patients without any high-risk features had better prognosis, with a 2-year PFS of 78.6% and a 5-year OS of 79.5%. The combination of CTCs and volumetric assessment of PET/CT at diagnosis augments the existing stratification systems and may pave the way for a risk-adapted treatment approach.

Health-Related Quality of Life (HRQoL) in Fit, Unfit and Frail Patients Enrolled in Fitness (UK-MRA Myeloma XIV): A Cross Sectional Study

Introduction In the UK in 2016-2018, more than 4 in 10 new diagnoses of multiple myeloma (MM) were in people aged at least 75 years old. Transplant-ineligible (TNE) patients are a heterogeneous group that is not well-defined by age, but by the interplay of age, physical function, cognition and comorbidity better defined as ‘frailty’. There is little evidence on the effect of frailty on HRQoL in patients with MM. We examined patient-reported outcomes from participants enrolled in the FiTNEss study to understand HRQoL according to frailty group and the contribution of different elements of the International Myeloma Working Group (IMWG) frailty score (FS) to HRQoL. Methods FiTNEss (UK-MRA Myeloma XIV, NCT03720041) is a phase III, multi-centre, randomised controlled trial for newly diagnosed TNE MM patients. Patients receive lenalidomide, ixazomib, and dexamethasone induction and maintenance, comparing frailty score-adjusted up-front dose reductions and standard up-front dosing followed by toxicity dependent reactive dose adjustments. Frailty was defined using the IMWG FS. It includes age (&amp;lt;75y, 75-80y, &amp;gt;80y), Katz Activity of Daily Living (ADL&amp;lt;=4), Lawton Instrumental Activity of Daily Living (IADL&amp;lt;=5), and the Charlson Comorbidity Index (CCI&amp;lt;=1). The UK-MRA Myeloma Risk Profile (MRP) 1 was scored using age, performance status (PS), ISS and CRP. HRQoL was measured by EORTC QLQ C30 and MY20 completed at trial entry. We used a one-way ANOVA and two-sample unequal variance t-tests to compare subscales in different frailty groups. We sought minimally important differences that were at least medium size 2, and adjusted p-values using the Bonferonni correction for the 19 subscales (adjusted P = 0.05/19 = 0.0026). Results Baseline HRQoL was available for 559 trial participants. Median age was 77y (&amp;lt;75y: 183 [32.7%], 75-80y: 248 [44.4%], &amp;gt;80y 128 [22.9%]), 307 (54.9%) were male and 427 (76.2%) ECOG PS0-1. 160 (28.6%) patients were classified as Fit, 182 (32.6%) were Unfit and 217 (38.8%) were Frail according to IMWG FS. 105 (18.8%) patients had CCI &amp;lt;=1, 60 (10.7%) had ADL&amp;lt;=4 and 115 (20.6%) had IADL &amp;lt;=5. 167 (31.0%) patients were classified as low risk, 180 (33.5%) were intermediate risk and 191 (35.5%) were high-risk according to MRP. Contrasting IMWG fit, unfit and frail patients, significant differences were evident in 7 of 15 C30 subscales (Global Health Status [QL], Physical [PF], Role [RF], Cognitive [CF] and Emotional Functioning [EP], Appetite loss [AP], Dyspnoea [DY]) and 1 of 4 MY20 subscales (Side Effects [MYSE]) (Figure A). The largest differences in subscales were between the Fit/Unfit and Frail groups with only a single nominally different subscale (PF) between Fit and Unfit. When comparing the frailty score elements, age group and CCI were not significantly different using C30 or MY20 subscales. However, when considering ADL: 11 of 15 C30 (QL, PF, RF. CF, Social Functioning [SF], Fatigue [FA], Pain [PA], AP, Constipation [CO], DY, Financial Problems [FP]) subscales and 2 of 4 MY20 subscales (Disease Symptoms [MYDS], MYSE) were significantly different. Similarly, when considering IADL: 10 of 15 C30 subscales (QL, PF, RF, CF, SF, FA, PA, AP, CO and DY) and 4 of 4 MY20 subscales (MYDS, MYSE, Body Image, Future Perspective Worries) were significantly different (Figure B). When comparing between MRP risk groups, 10 of 15 C30 subscales (QL, PF, RF, CF, SF, FA, PA, AP, CO and DY) and 2 of 4 MY20 subscales (MYDS, MYSE) were significantly different. Unlike IMWG FS, 5 subscales were nominally significantly different between low and medium risk groups (QL, PF, RF, SF, DY). Conclusion The IMWG FS is associated with several domains from EORTC QLQ-C30 and MY20 at baseline with worse function and symptomatology among frail patients. Examining FS elements show that age and comorbidities do not contribute to heterogeneity in HRQoL. However, ADL and IADL are significantly associated with HRQoL. ADL elements may identify components of frailty that are potentially modifiable through supportive care and rehabilitation and could enhance HRQOL and treatment tolerability in older patients. The MRP risk profile is associated with baseline HRQoL as shown previously and with a number of other subscales as shown here. There is evidence that the MRP can delineate subscales, including QL better than the IMWG FS. 1. Cook G, et al, The Lancet Haematology, 6(3): E154-E166. 2. Cocks K, et al, Journal of Clinical Oncology, 29(1): 89-96.

Outcomes of Patients with Newly Diagnosed Transplant-Ineligible Multiple Myeloma According to Clinical Trials Enrollment: Experience of a Single Institution.

The proportion of non-transplant-eligible (NTE) newly diagnosed multiple myeloma (NDMM) patients excluded from clinical trials (CTs) and their prognosis is unknown. CT results may not be generalizable to real-world practice due to strict recruitment criteria. We analyzed causes of NTE-NDMM patient exclusion form CTs and their outcomes. A total of 211 NTE-NDMM patients were included. They were divided into three periods: 2003-2007, 2008-2012, and 2013-2017. Overall, 50% received non-trial treatment (NCT), while 50% participated in a CT (20% control group (CG) and 30% experimental group (EG)). Main causes for exclusion from CTs were comorbidities, ECOG > 2, and renal insufficiency. In the first two periods, the CR rate was similar regardless of treatment type, but in the last period, the EG group showed improved CR. Median PFS was similar in the first two periods, with a benefit seen only in the EG in the last period. The median OS was significantly longer in CT-included patients compared to NCT group in the last two periods. Conclusions: The presence of comorbidities and worsened ECOG were the main reasons for CT exclusion. Patients included in CTs had a longer OS than NCT. This OS benefit may be influenced by a selection bias, making it challenging to generalize CT results to real clinical practice.

Network Meta-Analysis of Randomized Trials in Relapsed/Refractory Multiple Myeloma: Relative Efficacy for Patients Who Are Lenalidomide-Refractory

Background: Continuous lenalidomide in combination with dexamethasone (Rd), with bortezomib and dexamethasone (VRd) or, more recently, with daratumumab and dexamethasone (DRd) is the standard first-line (1L) therapy for transplant-ineligible multiple myeloma (MM) patients (pts). Lenalidomide maintenance is the standard therapy after ASCT. As a result, more pts with MM become LEN-refractory at relapse, representing a difficult-to-treat population with a high unmet need for effective treatments. Selinexor is a first-in-class, oral, XPO1 inhibitor indicated for use in combination with bortezomib and dexamethasone (SVd) in adults with relapsed and refractory (RR) MM who have received at least one prior line. Efficacy and safety of SVd were evaluated in the BOSTON phase 3 randomized controlled trial (RCT) comparing SVd to bortezomib + dexamethasone (Vd). Extended follow-up of the BOSTON trial showed a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) with SVd vs Vd for the LEN-refractory subgroup (Mateos et al, EHA 2023). In the absence of head-to-head trials comparing SVd with other approved regimens in LEN-refractory subgroups, a network meta-analysis (NMA) was performed to evaluate the relative efficacy (PFS and OS) of SVd vs other treatment options in LEN-refractory pts. Methods: A systematic literature review (SLR) was conducted to identify the clinical efficacy and safety evidence of the approved treatments in Europe for RR MM. Searches were performed in Medline, Embase, Cochrane, and CRD up to February 2023. Following a feasibility assessment, the RCTs reporting PFS and/or OS hazard ratios (HRs) in the LEN-refractory subgroup were summarized in separate PFS and OS networks. Because these networks were disconnected, a two-step approach was implemented, beginning with a matching-adjusted indirect comparison (MAIC) followed by a random-effects Bayesian NMA. Based on clinical input, different prognostic factors and treatment effect modifiers were considered for the matching process in the MAIC: median age, sex, ECOG performance status, Revised-International Staging System, high-risk cytogenetics, prior ASCT, number of prior regimens, and median time since diagnosis. Results: Twelve RCTs (APOLLO, ASPIRE, BOSTON, CANDOR, CASTOR, ENDEAVOR, ELOQUENT-3, ICARIA-MM, IKEMA, MM-002, MM-003, and OPTIMISMM) were identified in the SLR reporting PFS and/or OS results for LEN-refractory pts. Three and two disconnected networks were formed for PFS and OS, respectively, which were linked through a MAIC by matching Vd pts in the BOSTON trial with the pomalidomide + dexamethasone (Pd) population of the MM-002 trial. Anti-CD38-based regimens approved in 2L+ RR MM, ie, daratumumab + Vd (DVd), daratumumab + carfilzomib + dexamethasone (DKd), and isatuximab + Kd (IKd) report the lowest PFS HRs vs Vd for LEN-refractory pts. SVd had the lowest PFS HR vs Vd (0.52, 95% CI 0.23-1.21) compared with the remaining comparators in the network. This includes SVd's direct comparators in the post-DRd population as per current ESMO MM guidelines: PFS HR of Kd vs Vd is 0.80 (95% CI 0.39-1.73) and PFS HR of pomalidomide + bortezomib + dexamethasone (PVd) vs Vd is 0.66 (95% CI 0.32-1.34), Figure 1. In the OS network, among the regimens included (with DKd, DVd and IKd excluded due to the lack of OS data on LEN-refractory pts), SVd also had the lowest OS HR vs Vd (0.53, 95% CI 0.22-1.28) compared with the other regimens, including Kd (HR vs Vd: 0.86, 95% CI 0.41-1.77), Figure 2. Conclusion: This is the first two-step approach NMA linking the disconnected networks of treatments available for LEN-refractory pts using efficacy results for this subgroup from their respective RCTs. Excluding anti-CD38-based regimens, which are unlikely to be used in a 2L+ setting with DRd increasingly prescribed in 1L, SVd is the most efficacious treatment option for LEN-refractory pts among commonly used combinations such as PVd, Kd, and pomalidomide-based regimens, with a reduction of 48% in the risk of progression vs Vd. Moreover, among the regimens included in the OS network, SVd had the largest OS improvement vs Vd. We hypothesize the substantial reduction for LEN-refractory pts in the risk of progression and death of SVd vs Vd compared to most of the regimens included in the NMA is due to the two different mechanisms of action with SVd.

Real-world data on induction therapy in patients with transplant-ineligible newly diagnosed multiple myeloma: retrospective analysis of 598 cases from Kansai Myeloma Forum.

To investigate the real-world clinical outcomes and management of novel drug-containing therapies for newly diagnosed multiple myeloma (MM) patients, we retrospectively analyzed data on the first-line treatment for newly diagnosed transplant-ineligible MM patients from Kansai Myeloma Forum, a registry network in Japan. A total of 598 patients treated with novel drugs between March 2007 and February 2018 were analyzed. Regimens used were VD (n = 305), Rd (n = 103), VMP (n = 97), VCD (n = 71), and VRd (n = 22). Younger patients tended to receive VRd or VCD, whereas the regimen with the highest median patient age was Rd. More than three-quarters of patients in the Rd group received a reduced dose of lenalidomide. The Rd and VRd groups had a relatively high incidence of infection and skin complications, and the VMP group had the highest incidence of peripheral neuropathy. Overall response rate did not differ significantly between regimens. Multivariate analysis in all patients revealed several poor prognostic factors, such as poor performance status. Novel drug-containing regimens for newly diagnosed MM showed a durable response with manageable AEs in the real-world setting.

P-125 Ixazomib versus lenalidomide or ixazomib and lenalidomide combination as maintenance regimen for transplant-ineligible multiple myeloma: update of a multi-center prospective study in China

P-125 Ixazomib versus lenalidomide or ixazomib and lenalidomide combination as maintenance regimen for transplant-ineligible multiple myeloma: update of a multi-center prospective study in China

EE149 Modelling First-Line Daratumumab Use in Newly-Diagnosed, Transplant-Ineligible Multiple Myeloma in Singapore

The study aims to evaluate the costs and outcomes associated with first-line daratumumab use plus lenalidomide (DRd) for transplant-ineligible multiple myeloma patients, compared to reserving its use for second line following treatment with a bortezomib-based regimen (VRd) from the Singapore health system perspective.

First Line Treatment of Newly Diagnosed Transplant Ineligible Multiple Myeloma: Recommendations from the Canadian Myeloma Research Group Consensus Guideline Consortium

Although the availability of effective novel treatments has positively impacted the quality of life and survival of newly diagnosed multiple myeloma (MM) patients, benefits in the transplant ineligible MM population may be limited by functional/frailty status. The Canadian Myeloma Research Group Consensus Guideline Consortium proposes consensus recommendations for the first-line treatment of transplant ineligible MM. To address the needs of physicians and people diagnosed with MM, this document further focuses on eligibility for transplant, frailty assessment, management of adverse events, assessment of treatment response, and monitoring for disease relapse. The Canadian Myeloma Research Group Consensus Guideline Consortium will periodically review the recommendations herein and update as necessary.

Real-world Outcomes With Cumulative Bortezomib Dose and Efficacy in the Treatment of Transplant-ineligible Multiple Myeloma With Cyclophosphamide, Bortezomib, and Dexamethasone.

Higher cumulative dose of bortezomib, a key component of Multiple Myeloma (MM) treatment regimens, has been shown to improve outcomes in MM patients, but must be balanced with toxicities including peripheral neuropathy. In this study, we studied the effect of cumulative bortezomib dose on survival, depth of response, and discontinuation rate in transplant ineligible MM patients. Data from 70 patients treated with Cyclophsophamide, Bortezomib, and Dexamethasone (CyBorD) in a single Canadian center were grouped according to above vs below median cumulative bortezomib dose and analyzed for progression-free survival (PFS), overall survival (OS), depth of response, and discontinuation rate. There was a trend for lower discontinuation rate (45.7% vs. 68.6%, P=.052) and significantly lower rate of neuropathy-related discontinuation (5.7% vs. 22.9%, P=.035) in patients who received higher than 43.1 mg/m² of bortezomib. The higher-dose group showed a trend for higher rate of complete response (14.3% vs. 5.7%, P=.225) and significantly higher rate of very good partial response or better (77.1% vs. 51.4%, P=.024). There was significantly longer PFS (24.3 vs. 9.1 months, P=.012) and a trend for longer OS (22.4 vs. 61.3 months, P=.061) in the higher-dose group. In landmark analysis after 180 days, PFS (23.5 vs. 24.3 months, P=.941) and OS were similar in both groups. Higher cumulative bortezomib dose showed a lower rate of discontinuation, longer survival, and deeper response. Determining risk of treatment intolerance remains important for treatment.

Phase 1b Study of Isatuximab in Combination With Bortezomib, Cyclophosphamide, and Dexamethasone in Newly Diagnosed, Transplant-ineligible Multiple Myeloma Patients.

Phase 1b Study of Isatuximab in Combination With Bortezomib, Cyclophosphamide, and Dexamethasone in Newly Diagnosed, Transplant-ineligible Multiple Myeloma Patients.

CO141 Using LiveSLR Platform to Evaluate the Impact of Duration of Treatment (DOT) on Progression Free Survival (PFS) in Multiple Myeloma (MM)

Despite the innovation of newer agents, MM remains an incurable cancer. We investigated whether optimizing DOT would improve outcomes for patients with transplant-ineligible newly-diagnosed MM (TIE-NDMM), transplant-eligible NDMM with maintenance therapy (TE-NDMM-M), and relapsed/refractory MM (RRMM).

Single-Cell Transcriptomic Analysis Reveals Reduction of Cytotoxic NK Cells in a Subset of Newly Diagnosed Multiple Myeloma Patients Impacting Outcome after Daratumumab Therapy

Introduction Anti-CD38 antibody-based therapies in multiple myeloma (MM) rely to a large degree on natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Classically, NK cells are divided into cytotoxic CD56dim NK cells, important for ADCC, and cytokine-producing CD56bright NK cells. Accumulating evidence in other types of cancer suggests that alterations in the balance between CD56dim and CD56bright NK cells is associated with inferior clinical outcome. We hypothesized that changes in NK cell subset composition in the MM microenvironment would impact therapy-responses during NK cell-driven immunotherapies. Here, we used single-cell RNA sequencing and flow cytometry to investigate the heterogeneity of the NK cell compartment in the bone marrow (BM) of newly diagnosed MM (NDMM) patients, and the effects of altered NK cell subset composition on therapy response in patients undergoing first-line daratumumab-containing therapy. Results We performed single-cell RNA sequencing of the BM CD38+ immune cell compartment from 19 NDMM patients. NK cells were identified in silico resulting in a single-cell transcriptomic dataset of 24,664 NK cells. UMAP dimensionality reduction identified 5 transcriptomic distinct NK cell clusters, present in all NDMM patients. Conventional CD56bright and CD56dim NK cells were identified by increased transcription of GZMK or GZMB, respectively. To study the balance of cytotoxic vs cytokine-producing NK cells in MM we compared the relative abundance of cytokine-producing GZMK+CD56bright NK cells vs cytotoxic GZMB+CD56dim NK cells in individual patients in our cohort. The MM BM was characterized by heterogeneity in the ratio of cytotoxic vs cytokine-producing NK cell cluster composition, in which most patients had a predominance of cytotoxic NK cells, while a subset of patients presented with a relative decrease in cytotoxic NK cell clusters (Figure 1A). The reduction in cytotoxic NK cell subsets in this patient subgroup was reflected in an altered overall transcriptome of the total BM NK cell population, with enrichment for inhibitory receptors such as KLRB1 and KLRC1, and a relative loss of activating receptors such as FCGR3A (CD16), NCR3 (NKp30) and CD226 (DNAM-1), and cytotoxic effector genes including NKG7 and GNLY. To define the relative abundance of a reduced cytotoxic NK cell potential in NDMM patients, we performed flow cytometric analyses of 246 NDMM patients from 2 independent clinical cohorts. This revealed a reduced frequency of cytotoxic CD56dim NK cells, defined as < 90% CD56dim NK cells, in 17.9 % of 162 transplant-eligible treatment-naïve NDMM and in 28.6% of 84 treatment-naïve frail or unfit transplant ineligible MM patients. To test whether such relative decrease in cytotoxic NK cells would impact responses to daratumumab, we tested the association of BM NK cell composition with clinical outcome in the context of first-line daratumumab therapy in a cohort of frail NDMM patients ineligible for transplant from the HO143 trial (n=43). NDMM patients with reduced frequencies of BM cytotoxic NK cells presented with significantly shorter progression-free survival (PFS) (Figure 1B, PFS, p = 0.031, log-rank test), while OS was not impacted (p = 0.18, log-rank test). Univariate Cox regression analyses confirmed the correlation between reduced frequencies of CD56dim NK cells in the BM and significantly shorter PFS (hazard ratio (HR) 1.38; 95% confidence interval: 1.057 - 1.803; P = 0.018). Whether reduced frequencies of cytotoxic CD56dim NK cells affect outcome in transplant-eligible patients warrants additional study. Conclusion Here we show that about 20% of NDMM patients have an altered BM NK cell composition with a relative reduction in cytotoxic NK cells. Such altered NK cell composition correlates with significantly shorter PFS following daratumumab-containing therapy in a cohort of frail NDMM patients. Our data suggest that defining BM NK cell composition could stratify patients and identify a subgroup less likely to benefit from therapies driven by NK cell-mediated ADCC. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy of Frontline Treatments for Newly Diagnosed Transplant-Ineligible Multiple Myeloma, a Network Meta-Analysis

Efficacy of Frontline Treatments for Newly Diagnosed Transplant-Ineligible Multiple Myeloma, a Network Meta-Analysis

More Than 2% of Circulating Tumor Plasma Cells Defines Plasma Cell Leukemia-Like Multiple Myeloma.

Primary plasma cell leukemia (PCL) is the most aggressive monoclonal gammopathy. It was formerly characterized by ≥ 20% circulating plasma cells (CTCs) until 2021, when this threshold was decreased to ≥ 5%. We hypothesized that primary PCL is not a separate clinical entity, but rather that it represents ultra-high-risk multiple myeloma (MM) characterized by elevated CTC levels. We assessed the levels of CTCs by multiparameter flow cytometry in 395 patients with newly diagnosed transplant-ineligible MM to establish a cutoff for CTCs that identifies the patients with ultra-high-risk PCL-like MM. We tested the cutoff on 185 transplant-eligible patients with MM and further validated on an independent cohort of 280 transplant-ineligible patients treated in the GEM-CLARIDEX trial. The largest published real-world cohort of patients with primary PCL was used for comparison of survival. Finally, we challenged the current 5% threshold for primary PCL diagnosis. Newly diagnosed transplant-ineligible patients with MM with 2%-20% CTCs had significantly shorter progression-free survival (3.1 v 15.6 months; P < .001) and overall survival (14.6 v 33.6 months; P = .023) than patients with < 2%. The 2% cutoff proved to be applicable also in transplant-eligible patients with MM and was successfully validated on an independent cohort of patients from the GEM-CLARIDEX trial. Most importantly, patients with 2%-20% CTCs had comparable dismal outcomes with primary PCL. Moreover, after revealing a low mean difference between flow cytometric and morphologic evaluation of CTCs, we showed that patients with 2%-5% CTCs have similar outcomes as those with 5%-20% CTCs. Our study uncovers that ≥ 2% CTCs is a biomarker of hidden primary PCL and supports the assessment of CTCs by flow cytometry during the diagnostic workup of MM.

P-202: Machine learning-assisted identification of optimal first-line treatment for newly diagnosed, transplant ineligible multiple myeloma

P-202: Machine learning-assisted identification of optimal first-line treatment for newly diagnosed, transplant ineligible multiple myeloma