Characteristics and Outcomes of Patients With Relapsed/Refractory Multiple Myeloma After Exposure to Lenalidomide in First Line of Therapy: A Single Center Database Review in Greece.

BACKGROUND: The increasing use of lenalidomide (Len) in first-line (1L) therapy of multiple myeloma (MM) has led to a significant proportion of patients becoming Len-refractory following 1L treatment. However, there are limited real-world data on treatment strategies and outcomes of patients who become Len-refractory following 1L therapy. PATIENTS AND METHODS: This real-world retrospective cohort study analyzed Len-refractory and non-Len-refractory patients who received 1L Len and initiated second-line (2L) therapy at a Greek MM center. The Len-exposed cohort (n = 249) included 55.4% Len-refractory patients after 1L. RESULTS: Compared to non-Len-refractory patients, Len-refractory patients more frequently had high-risk cytogenetics and Revised-International Staging System-3 disease stage at diagnosis, and had shorter progression-free survival (PFS) following 1L therapy. Len-refractory versus non-Len-refractory patients more frequently received triplets (59% vs. 40%), anti-CD38 agents (20% vs. 9%) and pomalidomide (22% vs. 13%). The overall response rate was 53% for Len-refractory patients and 64% for non-Len-refractory patients in 2L therapy; median PFS was 10.7 vs. 18.3 months, respectively. Median overall survival (OS) was shorter for Len-refractory patients vs non-Len-refractory patients (23.8 vs. 53.6 months). Len refractoriness was an independent prognostic factor for both PFS and OS in Len-exposed patients. CONCLUSION: In this real-world Len-exposed cohort, Len-refractory patients receiving 1L Len experienced poorer survival outcomes than non-Len-refractory patients, highlighting the unmet need in this patient population which has driven the development of novel therapies.

Healthcare Resource Utilization and Cost-of-Illness in Systemic Light Chain (AL) Amyloidosis in Europe: Results From the Real-World, Retrospective EMN23 Study.

OBJECTIVES: To report healthcare resource utilization (HCRU) and safety outcomes in systemic light chain (AL) amyloidosis from the EMN23 study. MATERIALS AND METHODS: The retrospective, observational, multinational EMN23 study included 4,480 patients initiating first-line treatment for AL amyloidosis in 2004-2018 and assessed, among other objectives, HCRU and safety outcomes. HCRU included hospitalizations, examinations, and dialysis; safety included serious adverse events (SAEs) and adverse events of special interest (AESIs). Data were descriptively analyzed by select prognostic factors (e.g., cardiac staging by Mayo2004/European) for 2004-2010 and 2011-2018. A cost-of-illness analysis was conducted for the UK and Spain. RESULTS: HCRU/safety and dialysis data were extracted for 674 and 774 patients, respectively. Of patients with assessed cardiac stage (2004-2010: 159; 2011-2018: 387), 67.9% and 61.0% had ≥ 1 hospitalization, 56.0% and 51.4% had ≥ 1 SAE, and 31.4% and 28.9% had ≥ 1 AESI across all cardiac stages in 2004-2010 and 2011-2018, respectively. The per-patient-per-year length of hospitalization increased with disease severity (cardiac stage). Of patients with dialysis data (2004-2010: 176; 2011-2018: 453), 23.9% and 14.8% had ≥ 1 dialysis session across all cardiac stages in 2004-2010 and 2011-2018, respectively. The annual cost-of-illness was estimated at €40,961,066 and €31,904,386 for the UK and Spain, respectively; dialysis accounted for ∼28% (UK) and ∼35% (Spain) of the total AL amyloidosis costs. CONCLUSIONS: EMN23 showed that the burden of AL amyloidosis is substantial, highlighting the need for early disease diagnosis and effective treatments targeting the underlying pathology.

Exploring the molecular biomarker utility of circCCT3 in multiple myeloma: A favorable prognostic indicator, particularly for R-ISS II patients.

Circular RNAs (circRNAs) are associated with the pathobiology of multiple myeloma (MM). Recent findings regarding circCCT3 support its involvement in the development and progression of MM, through microRNA sponging. Thus, we aimed to examine the expression of circCCT3 in smoldering and symptomatic MM and to assess its clinical importance. Three cell lines from plasma cell neoplasms were cultured and bone marrow aspirate (BMA) samples were collected from 145 patients with MM or smoldering MM. Next, CD138+ enrichment was performed in BMA samples, followed by total RNA extraction and reverse transcription. Preamplification of circCCT3 and GAPDH cDNA was performed. Finally, a sensitive assay for the relative quantification of circCCT3 using nested real-time quantitative polymerase chain reaction was developed, optimized, and implemented in the patients' samples and cell lines. MM patients exhibited significantly higher intracellular circCCT3 expression in their CD138+ plasma cells, compared to those from SMM patients. In addition, MM patients overexpressing circCCT3 had longer progression-free and overall survival intervals. The favorable prognostic significance of high circCCT3 expression in MM was independent of disease stage (either International Staging System [ISS] or revised ISS [R-ISS]) and age of MM patients. Interestingly, circCCT3 expression could serve as a surrogate molecular biomarker of prognosis in MM patients, especially those of R-ISS stage II. In conclusion, our study sheds new light on the significance of circCCT3 as a promising molecular marker for predicting MM patients' prognosis.

Single-cell analysis of MYD88L265P and MYD88WT Waldenström macroglobulinemia patients.

Waldenström macroglobulinemia (WM) is characterized by the expansion of clonal lymphoplasmacytic cells; the MYD88L265P somatic mutation is found in >90% of patients, but malignant B cells may still display intra-clonal heterogeneity. To assess clonal heterogeneity in WM, we generated and performed single-cell RNA sequencing of CD19+ sorted cells from five patients with MYD88 L265P and two patients with MYD88 WT genotype as well as two healthy donors. We identified distinct transcriptional patterns in the clonal subpopulations not only between the two genetically distinct WM subgroups but also among MYD88 L265P patients, which affected the B cell composition in the different subgroups. Comparison of clonal and normal/polyclonal B cells within each patient sample enabled the identification of patient-specific transcriptional changes. We identified gene signatures active in a subset of MYD88L265P patients, while other signatures were active in MYD88 WT patients. Finally, gene expression analysis showed common transcriptional features between patients compared to the healthy control but also differentially expressed genes between MYD88 L265P and MYD88 WT patients involved in distinct pathways, including NFκΒ, BCL2, and BTK. Overall, our data highlight the intra-tumor clonal heterogeneity in WM with potential prognostic and therapeutic implications.

Prognosis of COVID-19 severity using DERGA, a novel machine learning algorithm.

It is important to determine the risk for admission to the intensive care unit (ICU) in patients with COVID-19 presenting at the emergency department. Using artificial neural networks, we propose a new Data Ensemble Refinement Greedy Algorithm (DERGA) based on 15 easily accessible hematological indices. A database of 1596 patients with COVID-19 was used; it was divided into 1257 training datasets (80 % of the database) for training the algorithms and 339 testing datasets (20 % of the database) to check the reliability of the algorithms. The optimal combination of hematological indicators that gives the best prediction consists of only four hematological indicators as follows: neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase, ferritin, and albumin. The best prediction corresponds to a particularly high accuracy of 97.12 %. In conclusion, our novel approach provides a robust model based only on basic hematological parameters for predicting the risk for ICU admission and optimize COVID-19 patient management in the clinical practice.

Biomarker analysis of the ASPEN study comparing zanubrutinib with ibrutinib for patients with Waldenström macroglobulinemia.

ABSTRACT: The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib and ibrutinib, in patients with Waldenström macroglobulinemia (WM). Post-hoc biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P < .05). Patients with CXCR4MUT (frameshift or nonsense [NS] mutations) had lower very good partial response (VGPR) and complete response rates (CR; 17.0% vs 37.2%, P = .020) and longer time to response (11.1 vs 8.4 months) than patients with CXCR4WT treated with BTKis. CXCR4NS was associated with inferior progression-free survival (PFS; hazard ratio [HR], 3.39; P = .017) in patients treated with ibrutinib but not in those treated with zanubrutinib (HR, 0.67; P = .598), but VGPR + CR rates were similar between treatment groups (14.3% vs 15.4%). Compared with ibrutinib, patients with CXCR4NS treated with zanubrutinib had a favorable major response rate (MRR; 85.7% vs 53.8%; P = .09) and PFS (HR, 0.30; P = .093). In patients with TP53MUT, significantly lower MRRs were observed for patients treated with ibrutinib (63.6% vs 85.7%; P = .04) but not for those treated with zanubrutinib (80.8% vs 81.9%; P = .978). In TP53MUT, compared with ibrutinib, patients treated with zanubrutinib had higher VGPR and CR (34.6% vs 13.6%; P < .05), numerically improved MRR (80.8% vs 63.6%; P = .11), and longer PFS (not reached vs 44.2 months; HR, 0.66; P = .37). Collectively, patients with WM with CXCR4MUT or TP53MUT had worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.

Carfilzomib, daratumumab, and dexamethasone (KdD) vs. lenalidomide-sparing pomalidomide-containing triplet regimens for relapsed/refractory multiple myeloma: an indirect treatment comparison.

Nearly all patients with multiple myeloma eventually relapse or become refractory to treatment. Lenalidomide is increasingly administered in the frontline until disease progression or intolerance to therapy, resulting in the need for highly effective, lenalidomide-sparing options. In this study, carfilzomib plus daratumumab and dexamethasone were evaluated against lenalidomide-sparing, pomalidomide-containing triplets using matching-adjusted indirect comparison in the absence of head-to-head data. The analyses utilized long-term follow-up data from the CANDOR study (NCT03158688). Treatment with carfilzomib, daratumumab, and dexamethasone resulted in significantly longer progression-free survival (hazard ratio 0.60 [95% confidence interval: 0.37, 0.88])vs. pomalidomide plus bortezomib and dexamethasone, and numerically longer progression-free survival (hazard ratio 0.77 [95% confidence interval: 0.50, 1.08]) vs. daratumumab plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma and previous lenalidomide exposure, the majority of whom were lenalidomide refractory. Carfilzomib plus daratumumab and dexamethasone offers a highly effective, lenalidomide-sparing treatment option for this population.

Retinopathy in a Patient With IgM MGUS: Causal Association or an Epiphenomenon?

BACKGROUND/AIM: The presence of a monoclonal gammopathy of undetermined significance (MGUS) even in small amounts may trigger tissue damage through immunological or other mechanisms, irrespective of the potential for malignant transformation. The aim of the study was to present a case of monoclonal gammopathy of clinical significance with ocular manifestations and discuss relevant literature. CASE REPORT: In our case, a patient presented with vision disturbances that was eventually attributed to the underlying IgM MGUS after extensive workup to exclude other potential etiologies. The patient showed a clinical response with the fixed-duration DRC (dexamethasone, rituximab, cyclophosphamide) regimen that persisted for at least 1.5 years. Herein, we present, in detail, the patient management and discuss the underlying pathophysiology of this rare entity with few available published data in this field. CONCLUSION: A high level of clinical suspicion is necessary in order to detect the association between MGUS and a clinical sign or symptom that cannot be attributed elsewhere.

Genetic justification of COVID-19 patient outcomes using DERGA, a novel data ensemble refinement greedy algorithm.

Complement inhibition has shown promise in various disorders, including COVID-19. A prediction tool including complement genetic variants is vital. This study aims to identify crucial complement-related variants and determine an optimal pattern for accurate disease outcome prediction. Genetic data from 204 COVID-19 patients hospitalized between April 2020 and April 2021 at three referral centres were analysed using an artificial intelligence-based algorithm to predict disease outcome (ICU vs. non-ICU admission). A recently introduced alpha-index identified the 30 most predictive genetic variants. DERGA algorithm, which employs multiple classification algorithms, determined the optimal pattern of these key variants, resulting in 97% accuracy for predicting disease outcome. Individual variations ranged from 40 to 161 variants per patient, with 977 total variants detected. This study demonstrates the utility of alpha-index in ranking a substantial number of genetic variants. This approach enables the implementation of well-established classification algorithms that effectively determine the relevance of genetic variants in predicting outcomes with high accuracy.

Thrombotic and bleeding complications in patients with AL amyloidosis.

Haemostatic abnormalities and deregulated coagulation are common complications in AL amyloidosis. The relevant risks of thromboembolic and haemorrhagic events have not been thoroughly evaluated. To describe clinically significant thrombotic/haemorrhagic events in 450 consecutive patients with AL amyloidosis. Venous thromboembolic events (VTEs) were reported in 6% and arterial embolic events (AEEs) in 5% of patients, respectively, during a 55-month median follow-up. Lower albumin, lower eGFR, higher BM infiltration, soft tissue involvement, IMiD-based therapy and prior thrombosis were associated with VTE risk. Prior thrombosis was the only independent prognostic variable (HR 9.3, p = 0.001). Coronary arterial disease, prior AEE, 24-h proteinuria and higher platelet counts were associated with AEE risk. Significant bleeding events were reported in 9%, and associated mortality was 19%. Liver involvement, higher serum creatinine and higher baseline VWF:Ag levels were linked to bleeding risk. Using competing risk analysis, the cumulative probability of thrombosis/bleeding was higher during the first year following diagnosis, but a stable lower risk for both events remained for the duration of follow-up. In AL amyloidosis patients, the risk of thrombotic/arterial embolic events is significant, but the bleeding risk is also high. A multiparametric assessment is required to initiate anti-thrombotic or anti-platelet therapy appropriately.

Belantamab mafodotin: an important treatment option for vulnerable patients with triple class exposed relapsed and/or refractory multiple myeloma.

Not available.

Belantamab mafodotin, lenalidomide and dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma: Part 1 results of a phase I/II study.

Preclinical and clinical data demonstrate synergy between belantamab mafodotin (belamaf) and immunomodulatory drugs with limited overlapping toxicities. We investigated the safety and efficacy of belamaf with lenalidomide 25mg on days 1-21 every 28 days and dexamethasone 40mg weekly (belamaf-Rd) in transplant ineligible patients with newly diagnosed multiple myeloma. 36 patients (median age 72.5 years) were randomized to receive belamaf at three different doses (2.5/1.9/1.4 mg/kg) every 8 weeks (q8w). Dosing schedule was extended to every 12 weeks (q12w) to account for ocular toxicity. Most common ≥ Grade (Gr) 3 adverse events were fatigue (n=21, 58.3%), rash (n=6, 16.7%), diarrhea (n=8, 22.2%) and COVID-19 (n=5, 13.9%). Gr 3-4 ocular adverse events (OAEs), comprising of visual acuity decline from baseline and/or keratopathy, were reported in 39/216(18.1%)/ 33/244(13.5%)/ 26/207(12.6%) ophthalmological assessments in cohorts 2.5/1.9/1.4 mg/kg. Importantly, Gr 3-4 keratopathy was identified in 9/216 (4.2%)/ 1/244(0.4%)/ 1/207(0.5%) assessments. Most patients (32/36, 88.9%) were treated in the extended q12w schedule, where dose holds due to OAEs were 40, 33 and 16 in cohorts 2.5/1.9/1.4. Overall, ≥VGPR and ≥CR rates were 83.3% and 52.8%, without significant differences among cohorts. Over a median follow-up of 20.3 months no disease progression was reported; 6 patients discontinued treatment due to infection-related death (n=4 COVID-19, n=2 pneumonia) and 1 patient withdrew consent. Based on toxicity/efficacy balance, the recommended phase 2 dose was 1.9 mg/kg q8w, extended to q12w for toxicity. Belamaf-Rd, with the extended schedule for belamaf, has shown important clinical activity and a significant improvement of OAEs with minimal impact on vision-related functioning in an elderly, non-transplant eligible population.

Efficacy and safety of daratumumab with ixazomib and dexamethasone in lenalidomide-exposed patients after one prior line of therapy: Final results of the phase 2 study DARIA.

The use of lenalidomide in frontline therapy for patients with newly diagnosed multiple myeloma (MM) has increased the number of those who become refractory to lenalidomide at second line. In this context, we assessed the efficacy of daratumumab in combination with ixazomib and dexamethasone (Dara-Ixa-dex) in the prospective phase 2 study DARIA. Eligible patients had relapsed/refractory MM (RRMM) after one prior line with a lenalidomide-based regimen. The primary endpoint was overall response rate (ORR). Secondary endpoints included survival outcomes, safety and changes in biomarkers of bone metabolism. Overall, 50 patients were enrolled (median age 69 years, 56% males). 32 (64%) patients were refractory to lenalidomide, and 17 (34%) had undergone autologous transplant. The ORR was 64% (n = 32); whereas 17 (34%) had a very good partial response or better. The median time to first response was 1.0 month. After a median follow-up of 23.4 months, the median PFS and OS were 8.1 and 39.2 months, respectively. Furthermore, significant changes in markers of bone metabolism became evident as early as at 6 months on treatment. Regarding safety, 21 (42%) patients had ≥1 grade 3/4 adverse event (AE); the most common was thrombocytopenia (n = 9, 18%). 14 (28%) patients had ≥1 serious AE (SAE), the most common being acute kidney injury and pneumonia (n = 2, each). Four patients died due to infections. In conclusion, second-line treatment with Dara-Ixa-dex in patients with RRMM pre-treated with a lenalidomide-based regimen resulted in rapid responses along with a favorable effect on bone metabolism.

A 74-Year-Old Man With Waldenström Macroglobulinemia and Progressive Dyspnea.

CASE PRESENTATION: A 74-year-old man presented to our department with progressive dyspnea on exertion over the last year. The patient did not report any other symptoms. He had previously smoked with a 60 pack-year history. He worked in an office and did not report any environmental, occupational, or domestic exposures. His history included asymptomatic Waldenström's macroglobulinemia that was diagnosed 18 months before respiratory symptoms. He was not receiving any treatment and was monitored regularly by the hematology department.

Isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone in patients with relapsed and refractory multiple myeloma: final overall survival analysis.

The primary and pre-specified updated analyses of ICARIA-MM (NCT02990338) demonstrated improved progression-free survival and a benefit in overall survival (OS) was reported with the addition of isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma. Here, we report the final OS analysis. This multicenter, randomized, open-label, phase 3 study included patients who had received and failed ≥2 previous therapies, including lenalidomide and a proteasome inhibitor. Between January 10, 2017, and February 2, 2018, 307 patients were randomized (1:1) to isatuximab-pomalidomide- dexamethasone (Isa-Pd; n = 154) or Pd (n = 153), stratified based on age (3). At data cutoff for the final OS analysis after 220 OS events (January 27, 2022), median follow-up duration was 52.4 months. Median OS (95% confidence interval) was 24.6 months (20.3-31.3 months) with Isa-Pd and 17.7 months (14.4-26.2 months) with Pd (hazard ratio = 0.78; 95% CI, 0.59-1.02; 1-sided P = 0.0319). Despite subsequent daratumumab use in the Pd group and its potential benefit on PFS in the first subsequent therapy line, median PFS2 was significantly longer with Isa-Pd vs. Pd (17.5 vs. 12.9 months; log-rank 1-sided P = 0.0091). In this analysis, Isa-Pd continued to be efficacious and well tolerated after follow-up of approximately 52 months, contributing to a clinically meaningful, 6.9-month improvement in median overall survival in patients with relapsed/refractory multiple myeloma.

Long-term Survival in a Patient With Transformation of Waldenström's Macroglobulinemia into DLBCL.

Background/Aim: Waldenström's macroglobulinemia (WM) is a rare slow-growing B-cell lymphoma that is characterized by lymphoplasmacytic bone marrow infiltration and the production of monoclonal immunoglobulin M (IgM) paraprotein. In 5-10% of patients, WM undergoes transformation into diffuse large B-cell lymphoma (DLBCL), which is more aggressive, with poor prognosis and a low survival rate. Case Report: Α 69-year-old woman was diagnosed with WM in 2009. She received six cycles of chemoimmunotherapy and a remarkable remission was achieved. However, in 2013 the disease transformed into DLBCL. The patient received chemotherapy and after the completion of the first cycle of therapy, the disease was significantly minimized. At the end of the therapy, there was no evidence of disease, and the patient remains disease-free. The cytogenetic profile of the patient did not reveal expression of BCL2 apoptosis regulator, BCL6 transcription repressor, Epstein-Barr virus small RNA, syndecan 1 nor cyclin D1. According to a staging system based on the platelet count, lactate dehydrogenase and previous treatment for WM, the described patient was classified as being at intermediate risk with an expected 2-year survival probability of 47% after WM transformation into DLBCL. However, the patient unexpectedly exceeded these prognostic indications. Conclusion: The findings for this patient are of great interest compared with the existing literature which suggests that the survival and prognosis for patients with transformed DLBCL are not favorable.

Predictors of early morbidity and mortality in newly diagnosed multiple myeloma: data from five randomized, controlled, phase III trials in 3700 patients.

Early morbidity and mortality affect patient outcomes in multiple myeloma. Thus, we dissected the incidence and causes of morbidity/mortality during induction therapy (IT) for newly diagnosed multiple myeloma (NDMM), and developed/validated a predictive risk score. We evaluated 3700 transplant-eligible NDMM patients treated in 2005-2020 with novel agent-based triplet/quadruplet IT. Primary endpoints were severe infections, death, or a combination of both. Patients were divided in a training (n = 1333) and three validation cohorts (n = 2367). During IT, 11.8%, 1.8%, and 12.5% of patients in the training cohort experienced severe infections, death, or both, respectively. Four major, baseline risk factors for severe infection/death were identified: low platelet count (<150/nL), ISS III, higher WHO performance status (>1), and age (>60 years). A risk score (1 risk factor=1 point) stratified patients in low (39.5%; 0 points), intermediate (41.9%; 1 point), and high (18.6%; ≥2 points) risk. The risk for severe infection/death increased from 7.7% vs. 11.5% vs. 23.3% in the low- vs. intermediate- vs. high-risk groups (p < 0.001). The risk score was independently validated in three trials incorporating quadruplet IT with an anti-CD38 antibody. Our analyses established a robust and easy-to-use score to identify NDMM patients at risk of severe infection/death, covering the latest quadruplet induction therapies. Trial registrations: HOVON-65/GMMG-HD4: EudraCT No. 2004-000944-26. GMMG-MM5: EudraCT No. 2010-019173-16. GMMG-HD6: NCT02495922. EMN02/HOVON-95: NCT01208766. GMMG-HD7: NCT03617731.

Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma.

BACKGROUND: Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed. METHODS: In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)-negative status. RESULTS: At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P = 0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group. CONCLUSIONS: The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.).