International Myeloma Working Group Research Articles

Dynamic machine learning model to forecast patient availability for clinical trials.

e13641 Background: Patient eligibility is a routine concept in clinical research, comprised of simple or complex set of inclusion or exclusion criteria applied in a specific sequence. Our methodology introduces the concept of ‘availability’ as a narrower term that is closer to the actual number that will be considered for a specific study and who may decide to participate. This specific research develops Machine Learning (ML) model that dynamically predicts likelihood of Multiple Myeloma progression and departure from targeted outcomes to sustain therapy and to indicate potential availability for clinical trials – to reduce screening efforts and improve screening precision of clinical research organizations. Methods: The cohort for training these models was drawn from the ConcertAI Oncology Research database, further enriched by key variables derived from unstructured data sources. Eligible patients for the analysis had a diagnosis of Multiple Myeloma made after Jan 1, 2020. Progressions were labelled using International Myeloma Working Group Criteria. Patients that did not satisfy the criteria were censored. Labels were assigned to patients after initial diagnosis of MM, and the duration between diagnosis to label was computed to build time to event (TTE) models. Over 2000 features were created to build this model, e.g., laboratory values, vitals, biomarkers, medications, ECOG, stage, etc. Variable creation preserved temporality of lab variables and vitals and noted presence of other variables. Several ML methods were employed to build the TTE models, with gradient boosting resulting in the highest c-index (0.8) based on 12 clinically relevant features. A temporal validation of the model was performed on a simulated index date. Results: Cohort used for training the model comprised of N = 4315 patients with average age at diagnosis of 72.3 years, and ~11% of the patients labelled as progressing. Temporal validation was performed on N = 1874 patients, with ~9% progression rate. The area under the curve (AUC) and weighted F1 score for this cohort was 87% and 89% respectively. Conclusions: Patient availability assessments are complex, not supported effectively by existing solutions and often require 100’s of hours from highly trained clinical personnel. An AI model predicting Multiple Myeloma progression built using a large-scale real-world dataset demonstrated 2-4x improvement in forecasting patient availability over other approaches. Integrating these solutions into clinical workflows can improve the effectiveness of research teams; enable more patients to have clinical trials as viable options at the right time; and allow care teams to have forward visibility to choices of standard-of-care and clinical trial alternatives in the best interest of patient outcomes. [Table: see text]

Impact of Extraosseous Extramedullary Disease on Outcomes of Patients with Relapsed-Refractory Multiple Myeloma receiving Standard-of-Care Chimeric Antigen Receptor T-Cell Therapy

The presence of extramedullary disease (EMD) has been associated with poor outcomes in patients with relapsed-refractory multiple myeloma (RRMM). Herein, we report the outcomes of RRMM patients who were treated with standard-of-care (SOC) chimeric antigen receptor (CAR) T-cell therapy and had active extraosseous EMD before the infusion. Data were retrospectively collected from patients at three US institutions with the intent to receive SOC CAR T. Responses were assessed per the International Myeloma Working Group criteria. A total of 152 patients proceeded with infusion, of whom 47 (31%) had EMD (EMD group) and 105 (69%) did not (non-EMD group). Baseline patient characteristics were comparable between the two groups. The EMD group had a higher incidence of high-grade CRS, steroid and anakinra use, and thrombocytopenia on day +30 compared to the non-EMD group. In addition, the EMD group had an inferior overall response rate (58% vs 96%, p < 0.00001), median progression-free survival (PFS) (5.1 vs 12.4 months; p < 0.0001), and overall survival (OS) (12.2 vs 27.5 months; p = 0.00058) compared to the non-EMD group. We further subdivided the non-EMD patients into those with paramedullary disease (PMD-only group, n = 26 [17%]) and those with neither EMD nor PMD (bone marrow-contained group or BM-only group, n = 79 [52%]). Patients with PMD-only had similar median PFS (11.2 vs 13.6 months, p = 0.3798) and OS (not reached [NR] vs 27.5 months, p = 0.6446) compared to patients with BM-only disease. However, patients with EMD exhibited inferior median PFS (5.1 vs 13.6 months, p < 0.0001) and OS (12.2 vs 27.5, p = 0.0008) compared to patients in the BM-only group. Treatment with SOC CAR T yielded meaningful clinical outcomes in real-world RRMM patients with extraosseous EMD, though responses and survival outcomes were suboptimal compared to patients without EMD. The presence of only EMD but not PMD was associated with significantly worse survival outcomes following the CAR T infusion.

The evolving pattern of the monoclonal protein improves the IMWG 2/20/20 classification for patients with smoldering multiple myeloma.

The 2/20/20 International Myeloma Working Group (IMWG) score is the most employed risk score in clinical practice to evaluate the risk of progression from smoldering multiple myeloma (SMM) to symptomatic multiple myeloma. However, it faces a serious limitation: The risk score is applied at diagnosis and cannot be reapplied. Since a dynamic accurate patient risk assessment for progression is necessary, we aimed to investigate whether the detection of an evolving pattern in serum M-protein (SMP) improves the identification of high-risk patients. Eighty-three patients diagnosed with SMM between 2011 and 2020 were included. Patients were initially classified applying the 2/20/20 IMWG score at baseline and later reclassified depending on the presence of an SMP evolving pattern into six groups. We regrouped the patients into three final risk groups: low-risk, intermediate-risk, and high-risk. The risk of progression at two years for the high-risk group was 88% and all patients had progressed at 4 years. The performance measurements were superior for the new 2/20/20-Evolving score independently for the detection of high-risk patients. We show that the sequential measurement of the SMP is a noninvasive and widely available test that improves the 2/20/20 IMWG risk score.

Pembrolizumab and low-dose, single-fraction radiotherapy for patients with relapsed or refractory multiple myeloma: a prospective, single-centre, single-group, open-label, phase 2 pilot trial in the USA

Currently, the use of radiotherapy alone for people with multiple myeloma is limited to palliation of pain, pending fracture, and control of spinal-cord compression. Single immune-checkpoint inhibitors, such as anti-programmed death-1 (anti-PD1), have not been successful. We aimed to evaluate the activity and safety of the combination of pembrolizumab and low-dose, single-fraction, hypofractionated radiotherapy to treat patients with relapsed or refractory multiple myeloma. For this prospective, single-centre, single-group, open-label, phase 2 trial, we recruited patients with relapsed or refractory multiple myeloma from the Winship Cancer Institute (Emory University, Atlanta, GA, USA). Key inclusion criteria were aged 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1, relapsed or refractory multiple myeloma as indicated by progression under International Myeloma Working Group (IMWG) criteria, and adequate candidacy for both pembrolizumab and radiotherapy. Baseline and post-treatment assessments were serial bone-marrow biopsy, peripheral blood collections, staging, serial serum and urine paraprotein analysis, serial PET-CT imaging, and a physical examination. On day 1, patients received hypofractionated 8 gray in 1 fraction (8 Gy/1 fx) radiotherapy to either symptomatic or progressing extra-osseous or osseous myeloma sites. Patients also received pembrolizumab (200 mg/kg intravenously) on day 2 or 3, then once every 3 weeks (±7 days) for 2 years or until progressive disease, unacceptable toxicity, withdrawal of consent, loss to follow-up, or death. Dose reduction and interruptions were not allowed. The primary outcome was acute toxicity defined as grade 3 or worse toxicity at 3 months within the radiated site when used in combination with pembrolizumab. All patients were analysed per protocol and included in safety analyses. This trial is registered on ClinicalTrials.gov (NCT03267888); it is completed and closed to accrual. 32 patients were screened between June 1, 2018, and Sept 2, 2022, and 25 were enrolled in the trial and treated on protocol. Of the 25 treated patients, 11 (44%) were female and 14 (56%) were male. 19 (76%) patients were White and six (24%) were Black or African American. Toxicity, as the primary outcome, was deemed to be acceptable as no grade 4 or 5 adverse events were observed. At 3-month follow-up, eight (32%) of 25 patients had treatment benefit (one had stable disease, three had partial response, two had very good partial response, and two had complete response). There was no grade 3 or worse radiation-related toxicity within irradiated volumes. One (4%) patient of the 25 who received combination treatment had a grade 3 pembrolizumab-related adverse event. There were no treatment-related deaths. Combination treatment of low-dose, single-fraction radiotherapy with pembrolizumab was safe, with early promise of response activity. Our approach could be an option for patients with relapsed or refractory multiple myeloma who have not responded to previous treatment. Larger trials to substantiate our findings are needed. Merck Sharp & Dohme.

A Phase I Trial Evaluating the Addition of Lenalidomide to Patients with Relapsed/Refractory Multiple Myeloma Progressing on Ruxolitinib and Methylprednisolone.

Ruxolitinib (RUX), an orally administered selective Janus kinase 1/2 inhibitor, has received approval for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. We have previously demonstrated the anti-multiple myeloma effects of RUX alone and in combination with the immunomodulatory agent lenalidomide (LEN) and glucocorticosteroids both pre-clinically and clinically. This study aims to evaluate whether LEN can achieve clinical activity among patients with multiple myeloma progressing on the combination of RUX and methylprednisolone (MP). In this part of a phase I, multicenter, open-label study, we evaluated the safety and efficacy of RUX and MP for patients with multiple myeloma with progressive disease who had previously received a proteasome inhibitor, LEN, glucocorticosteroids, and at least three prior regimens; we also determined the safety and efficacy of adding LEN at the time of disease progression from the initial doublet treatment. Initially, all subjects received oral RUX 15 mg twice daily and oral MP 40 mg every other day. Those patients who developed progressive disease according to the International Myeloma Working Group criteria then received LEN 10 mg once daily on days 1-21 within a 28-day cycle in addition to RUX and MP, which were administered at the same doses these patients were receiving at the time progressive disease developed. Twenty-nine subjects (median age 64 years; 18 [62%] male) were enrolled in this part of the study and initially received the two-drug combination of RUX and MP. The median number of prior therapies was six (range 3-12). The overall response rate from this two-drug combination was 31% and the clinical benefit rate was 34%. The best responses were 1 very good partial response, 8 partial responses, 1 minor response, 12 stable disease, and 7 progressive disease. The median progression-free survival was 3.5 months (range 0.5-36.2months). The median time to response was 3.0 months. The median duration of response was 12.5 months (range 2.8-36.2 months). Twenty (69%) patients whoshowed progressive disease had LEN added to RUX and MP; all patients had prior exposure to LEN and all but one patient was refractory to their last LEN-containing regimen. After the addition of LEN, the overall response rate was 30% and the clinical benefit rate was 40%. The best responses of patients following the addition of LEN were 2 very good partial responses, 4 partial responses, 2 minor responses, 8 stable disease, and 4 progressive disease. The median time to response was 2.6 months (range 0.7-15.0 months). The median duration of response was not reached. The median progression-free survival following the addition of LEN was 3.5 months (range 0.3-25.9 months). For patients with multiple myeloma, treatment with RUX and MP is effective and well tolerated, and LEN can be used to extend the benefit of this RUX-based treatment. This study is registered with ClinicalTrials.gov, NCT03110822, and is ongoing.

Real-World Outcomes in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma Treated With Bortezomib/Cyclophosphamide/Dexamethasone and Bortezomib/Lenalidomide/Dexamethasone as Upfront Treatment.

Introduction Multiple myeloma (MM) is a hematological disorder characterized by aberrant multiplication of malignant plasma cells in the bone marrow. The current mainstay of treatment for patients with newly diagnosed MM (NDMM) is a triplet regimen with a proteasome inhibitor, immunomodulatory imide, and dexamethasone. The two most common of these triplet regimens are VLD (bortezomib/lenalidomide/dexamethasone) and VCD (bortezomib/cyclophosphamide/dexamethasone). This study aims to compare the outcomes between these two therapies in transplant-ineligible patients with NDMM. Methods We conducted a retrospective study at the Aga Khan University Hospital in Karachi, Pakistan. All NDMM transplant-ineligible patients either receiving VLD or VCD therapy between January 2015 and December 2022 were included in our study. Hematological parameters before and after treatment were obtained from hospital records. Response to treatment was classified according to the International Myeloma Working Group (IMWG) response criteriaas either complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD), or progressive disease (PD). The response to treatment as well as overall survival (OS) and progression-free survival (PFS) was compared between VCD and VLD therapy.A p-value of 0.05 or less was taken to be statistically significant. Results Twenty (23.8%) patients in the VCD group and 20 (23.0%) in the VLD group underwent complete remission. Seven (8.3%)patients experienced disease progression in the VCD group, while the figure stood at three (3.4%) in the VLD group. There was no statistically significant difference in the overall response rate between the VCD (58; 69.0%) and VLD (70; 80.5%) groups (p=0.086), a difference that was not statistically significant on the Chi-square test. OS was comparable between VCD (69.1 months, 95%CI: 61.3-77.0) and VLD (76.9 months, 95%CI: 69.0-85.0) therapies. Conclusions The study did not identify any statistically significant distinction in the treatment outcomes between the VCD and VLD regimens among NDMM patients ineligible for transplantation. Nevertheless, the study highlights the positive outcomes observed with both treatments in this specific patient cohort. This implies that either regimen could be deemed suitable as a treatment option for patients in low- and middle-income countries. Since both regimens demonstrate comparable effectiveness, assessing the cost-effectiveness of these regimens is crucial. Future research should also explore the economic aspects of the two treatment options.

Prevalence of geriatric impairments and frailty categorization among real-world patients with multiple myeloma: a prospective cohort study (MFRAIL)

There is limited knowledge regarding the prevalence of geriatric impairments and frailty among patients with multiple myeloma (MM) in a real-world setting. This study evaluated the distribution of frailty profiles among 116 patients with newly diagnosed or relapsed MM, using four common frailty scales. The proportion of patients classified as frail varied significantly, ranging from 15.5% to 56.9%, due to differences in how frailty was operationalized between each frailty measure. Functional, cognitive, and mobility impairments were common overall and irrespective of performance status. Analyses between frailty and treatment selection (dose reduction and doublet vs. triplet therapy) demonstrated significant differences in non-steroid MM drug dose reductions between frail vs. non-frail patients, as scored by the International Myeloma Working Group (IMWG) Frailty Index and Simplified Frailty Score (p < .05). A standardized approach to frailty assessment that is practical in application, and beneficial in guiding treatment selection and minimizing treatment related toxicity is necessary to provide optimal tailored care.

Assessment of algorithms for identifying patients with triple-class refractory multiple myeloma using real-world data

Objective: Patients with triple-class refractory (TCR) multiple myeloma (MM) have limited treatment options and poor prognoses. This high unmet need has prompted the development of new therapies allowing for improved outcomes for these patients. Recently, new targeted therapies for the treatment of patients with relapsed or refractory MM have been approved based on single-arm clinical trial results. Real-world (RW) data enable a better understanding of the effectiveness of new therapies in clinical practice and provide external controls for single-arm studies. However, using RW data to identify patients with TCR MM is challenging and subject to limitations. Methods: In this retrospective cohort study of an analysis of the COTA electronic health record (EHR) database, we used four algorithms to define refractory status and created four groups of patients with TCR MM initiating post-TCR therapy. Each algorithm relied on slightly different criteria to identify TCR patients, but all were based on the International Myeloma Working Group (IMWG)-derived and/or healthcare provider (HCP)-reported progressions within the database. Results: A total of 3815 patients with newly diagnosed MM met the eligibility criteria for this study. The choice of the algorithm did not impact the characteristics of identified patients with TCR MM (Algorithm 1 [n = 404], Algorithm 2 [n = 123], Algorithm 3 [n = 404], and Algorithm 4 [n = 375]), including their demographic and disease characteristics, MM treatment history, or treatment patterns received after becoming TCR. However, identifying TCR MM using a combination of IMWG-derived and HCP-reported progressions allowed up to a 70% increase in the size of the identified group of patients compared with using only IMWG-derived progressions. Conclusion: In RW settings, progressions from both IMWG-derived data and physician reports may be used to identify patients with TCR MM.

Early Chimeric Antigen Receptor T Cell Expansion Is Associated with Prolonged Progression-Free Survival for Patients with Relapsed/Refractory Multiple Myeloma Treated with Ide-Cel: A Retrospective Monocentric Study

The outcomes of patients with relapsed and refractory multiple myeloma (RRMM) previously treated with the 3 main classes of myeloma therapy-immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies-remain poor. Recently, based on the phase II pivotal KarMMa trial showing prolonged overall survival (OS) and progression-free survival (PFS) in heavily treated patients, idecabtagene vicleucel (ide-cel), a B cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy (CAR-T) product, was approved in the United States for the treatment of RRMM. In France, since June 2021, an early access program has authorized the use of ide-cel in the setting of RRMM (defined as progressive myeloma after at least 3 previous regimens, including the 3 main antimyeloma therapies). We report the first French experience through this early access program in a retrospective study of 24 consecutive patients treated with ide-cel at our institution. The patients were evaluated according to International Myeloma Working Group criteria and by positron emission tomography computed tomography (PET-CT) at 1, 3, 6, 9, and 12 months after ide-cel infusion. Most patients had adverse cytogenetic abnormalities, and RRMM with triple-refractory drugs were seen in 79%. Bridging therapy was required for 19 of 24 patients. Before CAR-T cell infusion, lymphodepletion with fludarabine and cyclophosphamide was systematically performed. The median follow-up was 15.2 months. At 3 months after ide-cel infusion, 92% of patients achieved at least a partial response, and 50% achieved a complete response or better (≥CR). At 6 months, 70% of patients had a persistent ≥CR. At 3 and 6 months, bone marrow minimal residual disease (10-6 level) was undetectable in 79% and 75% of patients, respectively. At 6 months, CR as assessed by PET-CT was achieved in 15 of 20 patients (75%). The median PFS was 14.8 months, and median OS was not reached. Notably, an expansion of circulating CAR-T cells to >180/mm3 after infusion was strongly associated with prolonged PFS. Additionally, the level of soluble BCMA measured before infusion was identified as a prognostic factor for PFS, likely correlated to the tumor burden. Grade 1-2 cytokine release syndrome (CRS) occurred in 22 of 24 patients (92%). Only 1 patient (4%) experienced grade ≥3 CRS. The occurrence of neurologic toxicity was infrequent (12.5%) and reversible in all cases. Hematologic toxicity was relatively common, and secondary hypogammaglobulinemia occurred in most patients. Infections (mostly viral) were frequent but most often nonsevere. This study echoes the promising results of the KarMMa trial and identifies possible prognostic indicators in RRMM patients treated with ide-cel, potentially refining treatment strategies and improving outcomes in this challenging context.

A Review of Three Cases of Primary Plasma Cell Leukemia: Incidental Finding Discovered by Blood Smear Revision

Introduction: Plasma cell leukemia (PCL) is the most aggressive variant of the monoclonal gammopathies (MG). Its diagnosis is based on standard morphological examination of peripheral blood, by finding plasma cells with an atypical morphology. The International myeloma working group (IMWG) has updated the diagnostic criteria for PCL considering that patients with newly diagnosed MG with 5% or greater plasma cells in peripheral blood should be considered as PCL. Case report: We present three cases of primary PCL that were admitted to the hospital due to the study of an anaemia and whose diagnosis was an incidental finding. All the patients had &gt;5% of circulating plasma cells, whose clonality and aberrant phenotype was determined by peripheral and blood marrow flow cytometry immunophenotype and all of them had high-risk cytogenetics related with a poor and adverse outcomes of the disease. Discussion: This cases highlight the importance of peripheral blood smear revision, because the identification of aberrant plasma cells leaded the diagnosis of the MG and the patients were able to start treatment as soon as possible. Carefully examination and interpretation of peripheral blood smear should be always performed, with special attention in patients with a suspicion of MG, because with the new IMWG definition, it is possible that this entity is underdiagnosed.

Effects of Pre-Transplant CONUT and Post-Transplant MRD on Prognosis of Patients with Multiple Myeloma after Auto-HSCT

To explore the effects of pre-transplant controlling nutritional status (CONUT) and post-transplant minimal residual disease (MRD) on prognosis of patients with multiple myeloma (MM) after autologous hematopoietic stem cell transplantation (auto-HSCT). The clinical data of 79 patients who received auto-HSCT from 2011 to 2020 in The First Affiliated Hospital of Chongqing Medical University were retrospectively analyzed. The patients were divided into Low-CONUT group (n=62) and High-CONUT group (n=17) according to whether the CONUT score was less than 5. The differences in clinical features, hematopoietic reconstruction, adverse reactions, efficacy and survival between the two groups were compared. In addition, the prognostic risk factors were analyzed and verified by time-dependent ROC curve. The proportions of male patients and bone marrow plasma cells>30% at initial diagnosis in High-CONUT group were both higher than those in Low-CONUT group (both P <0.05). While, there were no significant differences in hematopoietic reconstruction and adverse reactions (>grade 2) between the two groups. The complete response (CR) rate and CR+very good partial response (VGPR) rate before transplantation in Low-CONUT group were both significantly higher than those in High-CONUT group (both P <0.05). After 3 months of transplantation, the CR+VGPR rate still remained an advantage in Low-CONUT group compared with High-CONUT group (P <0.01), but CR rate did not(P >0.05). The overall survival (OS) and progression-free survival (PFS) in Low-CONUT group were both superior to those in High-CONUT group (both P <0.05). Low CONUT score (0-4) before transplantation and negative MRD at 6 months after transplantation were favorable factors affecting OS and PFS (both P <0.05), while the International Myeloma Working Group (IMWG) high-risk at initial diagnosis and lactate dehydrogenase (LDH) level>250 U/L before transplantation were only risk factors for PFS (both P <0.05). Time-dependent ROC curve analysis showed that pre-transplant CONUT score and MRD status at 6 months after transplantation could independently or jointly predict 1- and 2-year OS and PFS, and the combined prediction was more effective. The combination of pre-transplant CONUT and post-transplant MRD can better predict the prognosis of MM patients.

Precision in Practice: A Cross-sectional Study Involving MRI T2 Dixon and Conventional Sequence in Detecting Focal Multiple Myeloma Lesions

Introduction: Multiple Myeloma (MM) represents a malignant proliferation of plasma cells derived from a single clone. Imaging of the skeleton beyond symptomatic areas is useful for myeloma staging and subsequent follow-up for treatment response and disease relapse. Despite research comparing the Dixon sequence to conventional sequences in a variety of musculoskeletal disorders, there is a lack of studies regarding the Dixon sequence’s application in MM. Aim: To compare the contrast of MM focal lesions in all four T2- weighted Dixon and Conventional T1-weighted spin-echo and Short Tau Inversion Recovery (STIR) images. Materials and Methods: This cross-sectional study was conducted in the Department of Radiology at Kovai Medical Centre and Hospitals (KMCH), Coimbatore, Tamil Nadu, India. All newly diagnosed and known cases of MM, either biopsyproven or strongly suspected based on other diagnostic testing conforming to International Myeloma Working Group (IMWG) criteria from December 2020 to July 2022, were included in the study. A total of 43 patients with 142 focal MM lesions were included. Contrast between focal MM lesions and surrounding bone marrow was calculated on T1-weighted spin-echo, STIR, and T2-weighted Dixon (all four) images. Statistical analysis was done using repeated measures of Analysis of Variance (ANOVA) with Bonferroni correction to control the type I error on multiple comparisons to find the significant difference between multivariate analyses. A probability value of 0.05 was considered a significant level for all statistical tools. Results: The study population consisted of 21 men and 22 women with a mean age of 65.3±8.6 years {Mean±Standard Deviation (SD)}. Contrast values in all four T2 Dixon images, STIR, and T1-weighted images were as follows: T2 Dixon Fat-only (FO) images (0.86.±0.09) (SD); range: (0.46-0.99), T2-weighted Dixon Water-only (WO) images (0.54±0.14) (SD); range: (0.14-0.82), T2 Dixon In-phase (IP) images (0.20±0.13) (SD); range: (0.02-0.41), T2-weighted Dixon Out-phase (OP) images (0.53±0.19) (SD); range: (0.12-0.87), STIR images (0.47±0.12) (SD); range: (0.12-0.73), and T1 images (0.23±0.12) (SD); range: (0.01-0.55). The mean contrast was highest on T2 Dixon fat-only images (p&lt;0.0005) compared to T1 images, with the lowest contrast seen in IP images and intermediate values in OP images. Conclusion: In conclusion, fat-only images of the T2 multipoint Dixon sequence provide significant contrast compared to conventional T1-weighted imaging. Dixon water-only images provide fat suppression that is not inferior to STIR images. While Dixon techniques in the diagnosis of MM did not significantly differ from the conventional sequence, Dixon stands out from conventional sequences when considering the study duration and contrast between the lesion and normal bone marrow.

Comparative assessment of beta-2 microglobulin as predictor of progression of multiple myeloma in asymptomatic and symptomatic multiple myeloma patients in a tertiary care hospital in Eastern India

Background: Multiple myeloma (MM) is a clonal late B-cell disorder in which malignant plasma cells expand and accumulate in the bone marrow and is associated with paraprotein production, bone lesions, anemia, hypercalcemia, susceptibility to infections, and renal impaired. Beta-2 microglobulin (B2M) is a serum marker of tumor burden in lymphoid malignancies, including MM. The purpose of this study was to find whether increased B2M levels can predict the progression of MM from asymptomatic to progressed symptomatic phase, as it is a less invasive and cost-effective method than the more invasive and costly ones to predict the progression of the disease. Aims and Objectives: This study was taken in a medical college, Kolkata, 50 asymptomatic Stage 1 MM patients were taken along with age and gender-matched 50 symptomatic progressed MM patients, blood samples of both groups were evaluated to estimate the difference in serum B2M (SB2M) level in both groups. Moreover, to study the difference in serum albumin, C-reactive protein, creatinine, immunoglobulin (IG), total protein, calcium, hemoglobin, and percentage of plasma cells in both groups and also their correlation with SB2M level in the progressed disease group. As well as to assess if there is increased B2M in the progressed disease group and if the B2M level correlates with the disease severity (i.e. progression of the disease). Materials and Methods: An observational descriptive non-interventional, hospital-based study conducted at central laboratory, medical college, Kolkata, for 6 months. Patients were chosen by systematic random sampling. Fifty asymptomatic MMs were chosen according to the International Myeloma Working Group criteria and out of 50 patients in the progressed disease group, 75% of patients were in Stage III and 25% of patients were in Stage II according to the Salmon and Durie system. Results: More than 80% in the progressed and symptomatic group had β-2M &gt;3.5 mg/L. Whereas in the newly diagnosed group, all the 50 patients had their β-2M level &lt;3.5 mg/L. Moreover, B2M value in the blood of progressed MM patients was found to be positively correlated with percentage of plasma cells from bone marrow, serum creatinine level, serum protein level, serum calcium level, and IgG level and negatively correlated with Hb level and serum albumin level. Hence, in a nutshell, increased B2M level was found in the progressed MM group, and its level positively correlated with the other predictors of the progression of MM. Conclusion: As per this study, SB2M level (which is a less invasive test than bone marrow testing and less costly) can be used as the predictor of progression of MM from asymptomatic to symptomatic. However, small sample size and cross-sectional pattern of the study were the limitations of this study. Bigger sample size and prospective cohort-type study designing method could be a better method to find a stronger correlation between MM staging and SB2M levels.

Efficacy and safety of generic pomalidomide plus low-dose dexamethasone in relapsed or refractory multiple myeloma: a multicenter, open-label, single-arm trial

This multicenter, open-label, single-arm trial (ClinicalTrials.gov, NCT05236621) was conducted to confirm the efficacy and safety of generic pomalidomide plus dexamethasone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Total 79 eligible RRMM patients were planned to be included. Patients were treated with generic pomalidomide (4 mg daily on days 1–21, orally) and low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally; 20 mg for patients aged > 75 years) in 28-day cycles until disease progression with a maximum treatment duration of 2 years. The primary endpoint is the overall response rate (ORR) assessed by the independent review committee per the 2016 International Myeloma Working Group guidelines. A total of 85 eligible patients were included in this study from 32 centers in China, with a median age of 62.0 (range, 39–76) years, a median prior line of therapy of 4 (range, 1–16), and 41.2% patients with high-risk cytogenetics. The ORR was 38.8% (95% confidence interval (CI), 28.44–50.01). The disease control rate was 67.1% (95% CI, 56.02–76.87), meanwhile, the median progression-free survival was 5.55 months (95% CI, 3.68–7.52). Among the treatment-related adverse events (TRAEs), infective pneumonia (17.6%) was the most frequent non-hematologic adverse event, while a decrease in neutrophil count (52.9%) was the most common grade ≥ 3 TRAE. The study results indicated that the generic pomalidomide demonstrated consistent efficacy and a safety profile similar to the branded pomalidomide when combined with low-dose dexamethasone in Chinese RRMM patients.Registration number ClinicalTrials.gov NCT05236621, retrospectively registered on February 11, 2022.

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.

Treatment Response Assessment in Multiple Myeloma: Histogram Analysis of Total Tumor Apparent Diffusion Coefficient based on Whole‐body Diffusion‐weighted MR Imaging

BackgroundThe International Myeloma Working Group (IMWG) consensus criteria for response assessment in multiple myeloma (MM) has methodological limitations. Whole‐body diffusion‐weighted imaging (DWI) with apparent diffusion coefficient (ADC) histogram analysis may be complementary to response assessment of MM.PurposeTo explore the role of histogram analysis of the ADC based on the total tumor volume (ttADC) in response assessment in patients with newly diagnosed MM (NDMM).Study TypeRetrospective.PopulationThirty‐six patients with NDMM.Field Strength/Sequence3.0T/single‐shot DWI echo planar imaging (EPI) sequence with an integrated slice‐by‐slice shimming (iShim) technique.AssessmentBaseline (median: 1 day before treatment) and post‐treatment (median: five cycles of therapy) whole‐body DWI were analyzed. A region of interest (ROI) containing lesions on every section of baseline image was drawn to derive the per‐patient total tumor data. Post‐treatment image analysis was based on the same ROI as the corresponding baseline. Histogram metrics were extracted from both ROIs. Patients were categorized into the very good partial response or better (VGPR+) group and the less than VGPR group per the IMWG response criteria for response assessment. Progression‐free survival (PFS) was also calculated.Statistical TestsMann–Whitney test and Fisher's exact or Chi‐squared tests, Receiver operating characteristic (ROC) analysis and DeLong test, Kaplan–Meier analysis and Cox proportional hazards model. A two‐tailed P‐value &lt;0.05 was considered statistically significant.ResultsThirty patients were categorized into the VGPR+ group and six into the less than VGPR group. The ttADC histogram changes between post‐treatment and baseline metrics (ΔttADC) revealed significant differences in all percentile values between the VGPR+ and less than VGPR groups. For distinguishing VGPR+, ΔttADC_5th percentile had the largest area under the curve (AUC) (0.950, 95% CI 0.821–0.995). Patients with lower ΔttADC_5th percentile values (cutoff point, 188.193) showed significantly longer PFS (HR = 34.911, 95% CI 6.392–190.677).Data ConclusionttADC histogram may facilitate response assessment in patients with NDMM.Level of Evidence3Technical EfficacyStage 4

Early Peripheral Blood Minimal Residual Disease Status By NGS in Patients with Newly Diagnosed Multiple Myeloma (MM) on a Phase 2 Trial Receiving Elotuzumab, Carfilzomib, Lenalidomide, and Dexamethasone (Elo-KRd)

Background: Assaying for minimal residual disease (MRD) in the peripheral blood (PB) of patients with multiple myeloma (MM) could solve issues of patchy and extramedullary disease leading to false-negative MRD tests based on bone marrow (BM) only assessments. However, PB testing is challenging due to limited circulating myeloma cells and/or paraprotein. Further, early PB assessments for MRD by paraprotein are unreliable due to the extended half-lives of immunoglobulins. In this analysis, we investigated the concordance and prognostic significance of early MRD status after 4 cycles of treatment with Elo-KRd by next generation sequencing (NGS) in both the BM and PB and by International Myeloma Working Group (IMWG) response criteria. Methods: All patients received 12 cycles of Elo-KRd in 28-day cycles without intent for stem cell transplant: Elo per standard dosing; K 56/70 mg/m 2 (highest tolerated) days 1, 8 and 15 (20 mg/m 2 on day 1 of cycle 1) ; R 25 mg days 1-21; and dexamethasone 40 mg days 1, 8, 15, 22. An MRD-adapted design was used to determine the duration of carfilzomib as previously reported (Derman et al. JAMA Oncology 2022). MRD by NGS in BM (sensitivity threshold 10 -6,clonoSEQ, Adaptive Biotechnologies) was performed at multiple timepoints per protocol. PB mononuclear cells were evaluated for MRD using the same assay; any quantifiable signal was considered positive in PB. Conventional response was assessed per IMWG response criteria. Paired IMWG response and MRD status in the PB and BM were assessed for concordance and prognostic significance at the end of cycle 4 (C4). The Kaplan-Meier method was used to assess progression free survival (PFS) based on a landmark assessment at C4. Results: A total of 46 patients initiated treatment with Elo-KRd; patient baseline characteristics were reported previously (Derman et al. JAMA Oncology 2022). With a median follow-up of 39 months, estimated 4-year PFS was 75%. Of the 42 patients in response at C4, 39 (93%) achieved &amp;gt;VGPR, and 13 (31%) reached &amp;gt;CR. When stratified by &amp;gt;CR vs &amp;lt;CR at C4, there was no difference in PFS (HR 1.4, 95% CI 0.3-6.9, p=0.7). BM MRD status at C4 was available for 34 patients: 11 (32%) patients were BM MRD(-)and 23 (68%) were MRD(+). Matched PB MRD samples at C4 were available for 31 patients; 22 (69%) patients were PB MRD(-) using the best available threshold based on sample input (16 at 10 -6, 6 at 10 -5). Of the 9 (31%) patients with PB MRD(+), 6 (67%) had at least one high-risk cytogenetic abnormality (del17p in n=4, +1q in n=2, t(4;14) in n=1). Extramedullary disease relapse was a manifestation of progression in 4 (44%) patients. BM MRD(-) at C4 was associated with superior PFS (HR not estimable, p=0.04; Figure 1A). No patient with MRD(-) BM after C4 had disease progression. PB MRD(+) at C4 was also associated with inferior PFS (HR 21, 95% CI 2.3-184, p=0.002; Figure 1B). In comparing BM and PB MRD status, 8/9 (89%) patients with PB MRD(+) at C4 had BM MRD(+), and 14/22 (61%) patients with BM MRD(+) at C4 had PB MRD(-). 3/9 (33%) patients with PB MRD(+) at C4 were in &amp;gt;CR; 16/22 (73%) patients with PB MRD(-) at C4 were in a PR/VGPR. With progression serving as the reference standard, PB MRD(+) carried a sensitivity of 71%, a specificity of 83%, a positive predictive value of 56%, and a negative predictive value of 91%. There were 19 matched BM MRD(+)/PB MRD(+) samples across all timepoints; Pearson's correlation coefficient of detected cells per million between BM and PB MRD was r=0.93. BM MRD detected aberrant cells at higher concentrations, with a median log difference of 1.38 compared to PB MRD (range 0.07-3). Conclusions: MRD by NGS in the PB was less sensitive compared to the same assessment in the BM by 1-2 logs; however, PB MRD status following 4 cycles of induction therapy was strongly prognostic given its association with PFS. PB MRD status early in treatment may represent a leading indicator of early response and/or a marker of high-risk disease features, and validation of these findings may help to eventually guide intensification of therapy.

Vdpace As Salvage Therapy in Triple Class Relapse/Refractory Multiple Myeloma

Background: Patients that have triple-class relapsed/refractory multiple myeloma (RRMM) have relapsed on each of the following classes: an immunomodulatory drugs (IMiDs), proteasome inhibitors (PI), and anti-CD38 monoclonal antibody (MoAb). RRMM poses a significant challenge with poor prognosis due to limited options. We evaluated VDPACE (bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, etoposide) for efficacy and safety as salvage therapy in heavily pre-treated RRMM. Methods: We retrospectively analyzed 54 patients who had triple-class RRMM and received at least 1 cycle of VDPACE between June 2016 - July 2023 at the University of Kansas Health System in collaboration with the U.S Myeloma Innovations Research Collaborative (USMIRC). VDPACE consisted of bortezomib 1 mg/m2 subcutaneous on days 1,4,8 and 11, doxorubicin 10 mg/m2 continuous infusion (CI) x 4 days, cisplatin 10 mg/m2 CI x 4 days, cyclophosphamide 400 mg/m2 CI x 4 days and etoposide 40 mg/m2 CI x 4 days. Descriptive analysis was performed on available data for patient characteristics, disease course, and outcomes differentiating these two groups. Adverse events were graded based on the CTCAE v5.0 criteria. Responses to therapy, including overall response rate (ORR), complete response or better (≥CR), and very good partial response (VGPR) were evaluated using the International Myeloma Working Group (IMWG) criteria. The Kaplan-Meier method was used for progression-free survival (PFS) and overall survival (OS) assessments. Results: Of the 54 patients in this study, the median age was 62 years (41-75), 81% (n=44) were Caucasian, 48% (n=26) were IgG subtype, 42% of the patients (n=23) had Stage-III disease at treatment, 74% (n=40) had high-risk cytogenetics, and extramedullary disease (EMD) was present in 50% (n=27) of patients. These patients had a median of 5 (2-10) prior lines of therapy;67% (n=36) were penta-drug exposed, 59% (n=32) were penta-RRMM and 19% (n=10) were refractory to BCMA-directory therapy. Patient characteristics are summarized in Table 1. The overall response rate (ORR) for the whole cohort was 54%, 7 (13%) patients achieved ≥ VGPR, median PFS was 4.67 months (95% CI, 2.97 to 8.40), while OS was 7.93 months (95% CI, 6.33 to 14.73), see Figure 1. Regarding efficacy on penta-RRMM (n=32) vs non-penta-RRMM subgroups (n=22), the ORR was 44% vs 68% respectively, while the median PFS was 2.67 months (95% CI, 2-7.6) in the penta-RRMM subgroup compared to 9.28 months(95% CI, 4.67-NA) in the non-penta-refractory subgroup. Treatment post salvage therapy of VDPACE included autologous/allogenic stem cell transplant (SCT), BCMA-directed therapies (CAR-T, T-cell engaging bispecific antibodies and antibody-drug conjugates), other chemotherapies, in addition to enrollment to clinical trials reported at 13%, 26%, 39% and 4%, respectively. 11% patients proceeded to hospice due to progression disease. Most patients experienced hematological adverse events (AEs), including grade III/IV lymphopenia (96%), neutropenia (93%), thrombocytopenia (87%) and anemia (76%). 69% (n=37) required a blood transfusion and 67% (n=36) required platelet transfusion. Neutropenic fever (NF) was reported in 33% (n=18), while the most common cause of infection was bacteremia in 24% of patients, followed by pneumonia in 20% of the patients. Following the initial hospitalization to receive treatment, the readmission rate within 60 days was 50% (n=27), that was mostly due to NF (52%, n=14). Treatment related mortality (TRM) in the first 30 days was reported in 6% (n=3), all due to severe sepsis. See Table 1. Conclusions: Based on our retrospective study, VDPACE is an effective salvage treatment in triple RRMM, and can be used as a bridging therapy prior to CAR-T, prior to enrollment in clinical trials or proceeding to SCT, however, due to TRM secondary to severe infections, careful selection of patients for this intensive therapy must be emphasized.

Treatment Patterns and Outcomes in Patients with Multiple Myeloma Who Received Ixazomib and in Patients with Triple-Class Refractory Multiple Myeloma: A Retrospective, Observational, Real-World Historical Database Analysis Study from China

Background: Multiple myeloma (MM) is a fatal, malignant disease of plasma cells characterized by an abnormal proliferation of monoclonal antibodies. China is estimated to have 22,450 newly diagnosed (ND) cases of MM and 17,360 related deaths in 2022. Emerging novel therapies have significantly improved survival in MM, and treatment guidelines have been updated to reflect these advances. Ninlaro® (ixazomib) is the first oral proteasome inhibitor (PI) approved by the US FDA in 2015 and by China's National Medical Products Administration in 2018 (conditionally) for MM patients receiving ≥1 prior therapy owing to its convincing efficacy and well-tolerated safety profile as seen in the landmark Phase III TOURMALINE-MM1 trial and the China Continuation Study. Novel drugs such as PIs, immunomodulatory drugs (IMDs), and anti-CD-38 monoclonal antibodies are the core component of MM treatment and have improved patient outcomes considerably. However, many patients remain refractory to these drugs (triple-class refractory, TCR) and have poor clinical outcomes. There is a lack of real-world evidence characterizing treatment patterns and outcomes of MM patients receiving ixazomib and TCR-MM patients, in China. The objective of this study is to bridge this data gap by providing vital information on the treatment patterns and outcomes, and healthcare resource utilization in Chinese MM patients receiving ixazomib and TCR-MM patients in real-world clinical practice. Study Design and Methods: This study is an ongoing, single-centre, non-interventional, retrospective database analysis study of MM patients identified from the Chinese National Longitudinal Cohort of Haematologic Diseases (NICHE)-MM registry, a historical and ongoing longitudinal data registry of the Institute of Haematology and Blood Diseases Hospital (IHBDH), and representing the top-tier MM care in China. The patients will be divided into two groups. Patients (aged ≥18 years) with a confirmed MM diagnosis receiving all ixazomib-based regimen as 2nd-line and above therapy (RR-MM), or as a 1st-line therapy (ND-MM) will form group one and TCR-MM patients' refractory to at least one IMiD (lenalidomide, pomalidomide or thalidomide), one PI (bortezomib, ixazomib, or carfilzomib) and one anti-CD-38 monoclonal antibody (daratumumab and isatuximab) will form group two. TCR-MM patients receiving ixazomib will be part of both groups. Patients enrolled in clinical trials will be excluded. The data for analysis will be collected from the ixazomib launch date in China (April 12, 2018) and/or the index date of the first patient enrolled in ixazomib Named Patient Program to September 2023 (tentative). Since 2000 till January 2023, the NICHE-MM registry has enrolled 3,329 MM patients of whom 156 patients have received ixazomib. This is the preliminary sample count and the final sample size will be calculated during data cleaning and analysis phases. The primary objective of this study will be to determine 1) treatment patterns and responses by lines of treatments and 2) time-to-event outcomes. The treatment patterns will include treatment name, dosage, type (induction, consolidation, or maintenance), number of cycles, duration and severe adverse event causing hospitalization. The treatment responses will include complete response (CR), stringent CR, partial response (PR), very good PR, minimal response, stable disease, and progressive disease as defined by the International Myeloma Working Group. The overall response rate of the last line of treatment for both study groups will be calculated as composite endpoint. Time-to-event outcomes will include progression-free survival, overall survival, duration of therapy, and time to next line of treatment in ND/RR-MM and TCR-MM patient groups. Secondary objectives will include assessment of patients' demographic, disease and clinical characteristics. Depending on data availability, the exploratory objective will be to determine the healthcare resource utilization and costs incurred by patients in both groups. Subgroup analysis between ND-MM vs. RR-MM or RR-MM patients receiving ixazomib in 2nd-line setting vs. TCR-MM patients receiving ixazomib in &amp;gt;3rd-line setting is also planned. Descriptive statistics will be used for the analyses. Our findings will also help clinicians in making strategic decision about more apt positioning of ixazomib in the treatment algorithm of MM.

Efficacy of Daratumumab-Based Regimens in Anti-CD38 Treatment-Naïve Relapsed/Refractory Multiple Myeloma with High-Risk Cytogenetics

Background: Daratumumab-based combination with proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs) have revolutionized the treatment outcomes of relapsed/refractory multiple myeloma (RRMM). Several daratumumab-based triplet combinations have been approved for the management of RRMM, but outcomes of daratumumab-based triplets in patients with high-risk cytogenetics RRMM (HC-RRMM) are not well described in the literature. This study aimed to evaluate the clinical outcome of daratumumab-based regimens in patients with HC-RRMM who are daratumumab-naïve. Methods: A retrospective review of 110 patients with HC-RRMM who received daratumumab-containing regimens from 6/2016 through 2/2023 at the University of Kansas Medical Center, in collaboration with the U.S Myeloma Innovations Research Collaborative (USMIRC) was conducted. Daratumumab was combined with bortezomib/dexamethasone (DVd), carfilzomib/dexamethasone (DKd), and pomalidomide/dexamethasone (DPd) for treatment of RRMM. HC-RRMM was defined as patients with one or more cytogenetic abnormalities (on FISH panel) including -17/del(17p), t(4;14), t(14;16), t(14;20), or amplification of 1q. Responses to therapy including overall response rate (ORR), complete response or better (≥CR), and very good partial response (VGPR) were evaluated using the International Myeloma Working Group (IMWG) criteria. Descriptive statistics were used to summarize patient and disease characteristics, along with efficacy outcomes. Progression-free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier methods. Results: Of the 110 patients with HC-RRMM, the median age was 66 years (range 43-84), 83 (75%) were Caucasian, 60 (54%) had IgG isotype, 41 (37%) had revised international staging system (R-ISS) stage III disease, 35 (32%) had extramedullary disease (EMD), 57 (52%) patients had one high-risk cytogenetic (HC) abnormality, 49 (44%) had 2 HC abnormalities, while four (4%) had 3 HC abnormalities. The median number of previous lines of therapy was 2 (1-4). Eighty-eight patients (80%) were lenalidomide refractory, while 53 patients (48%) had double refractory disease to both a PI and IMiD treatment. A total of 19 (17%), 27 (25%), and 64 (58%) patients received DVd, DKd, and DPd, respectively. The overall response rate (ORR) for the entire patient population was 73%, 45% had VGPR or better, and 35% achieved ≥CR. Median follow-up was 28 months (12.07-53.57), the median OS was 28 months (95% CI 23.2 - 43.9) and PFS was 8.03 months (95% CI 5.8 - 12.2) for all treatment groups. The median PFS for 1 HC vs ³ 2 HC was 14.8 vs 4.57 months (HR 1.72, 95%CI 1.17-2.72 p = 0.006), respectively. Similarly, median OS for 1 HC vs ³ 2 HC was 43.93 vs 22.47 months (HR 1.87, 95%CI 1.15-3.05, p = 0.011), respectively. (Figure 1). On multivariate analysis, R-ISS stage III, -17/del(17p), and the presence of more than one HC abnormality were associated with poor OS. The most common cause for treatment discontinuation was progressive disease, accounting for 73% of patients in the whole cohort. As for each daratumumab-based triplet, discontinuation due progression occurred in 78%, 48%, and 83% in DVd, DKd, and DPd, respectively. Other causes of discontinuation included &amp;gt; grade 3 neuropathy, which occurred in 16% of patients receiving DVd, and cardiac events, which occurred in 11% of patients receiving DKd. Treatment-related mortality occurred in 2% of patients in the whole cohort. At the time of evaluation, 14 patients remain on treatment. Conclusion: Advanced stage R-ISS disease at diagnosis, presence of -17/del(17p), and 2 or more HC abnormalities were associated with poor prognosis reflected by worse PFS and OS in HC-RRMM treated with daratumumab-based therapies. A larger cohort or a prospective study in patients with HC-RRMM is needed to compare long-term outcomes between daratumumab-based therapies (DKd, DVd, and DPd).