7566 Background: B-cell maturation antigen (BCMA)–directed therapies have transformed the treatment landscape in RRMM. Belamaf, a BCMA-targeting antibody-drug conjugate, in combination with Pd significantly improved progression-free survival (PFS) vs PVd (hazard ratio [HR], 0.52; 95% CI, 0.37-0.73; P <0.001) in pts with RRMM in DREAMM-8 (median follow-up, 22 mo). This PFS benefit was maintained with extended follow-up (HR, 0.49; 95% CI, 0.36-0.67; median follow-up 36 mo); median PFS2 also favored BPd vs PVd (47.1 vs 21.7 mo, respectively; HR, 0.52; 95% CI, 0.38-0.70), indicating sustained clinical benefit over time. We report PFS2 outcomes from DREAMM-8 in subgroups based on prior therapy to further understand the long-term impact of BPd and inform treatment sequencing. Methods: DREAMM-8 (NCT04484623) is a phase 3, randomized, open-label study evaluating BPd vs PVd in pts with RRMM with ≥1 prior line of therapy including lenalidomide (LEN). Pts could not have received prior BMCA-targeted therapy. PFS2 was defined as time from randomization to disease progression after initiation of subsequent antimyeloma therapy or death. PFS2 was assessed based on prior-treatment subgroups. Results: In the BPd arm (DCO: Jul 7, 2025; median follow-up, 36 mo), PFS2 benefit was maintained in all subgroups, including pts who were LEN refractory and anti-CD38 exposed/refractory. In LEN-refractory pts, BPd treatment led to almost a 3-fold median PFS2 improvement vs PVd (41.7 vs 15.0 mo). A total of 56/155 pts (36%) in the BPd arm and 93/147 (63%) in the PVd arm received any first subsequent therapy (FST) at data cutoff. Across both arms, 36% of pts received steroids, 28% received anti-CD38 therapies (>50% of pts with any subsequent therapy in each arm), and 23% received proteasome inhibitors as FST. A total of 21 pts (7%) received novel therapies (BPd, n=6 [4%]; PVd, n=15 [10%]) as FST, including BCMA-targeted bispecific antibodies (bsAbs), non-BCMA bsAbs, CELMoDs, venetoclax, and belamaf. Improved median PFS2 was observed in patients who had novel therapies as FST (n=21) vs non-novel agents (n=128) (26.0 vs 20.1 mo; HR, 0.61; 95% CI, 0.34-1.09). Conclusions: BCMA-directed therapy, BPd, resulted in improved PFS2 outcomes vs PVd, demonstrating sustained clinical benefit beyond initial belamaf therapy. This benefit was seen regardless of prior treatment, with LEN-refractory pts experiencing almost a 3-fold PFS2 benefit, and despite a higher proportion of pts receiving novel therapies as FST in the PVd arm. PFS2 benefit with high use of subsequent anti-CD38 agents supports sequencing of belamaf combinations early in the treatment paradigm prior to anti-CD38 agents.

7565 Background: BCMA–directed therapies have changed the RRMM treatment landscape. In the phase 3, open-label, randomized DREAMM-8 trial (NCT04484623), BPd demonstrated significant progression-free survival (PFS) benefit compared with pomalidomide, bortezomib, and dexamethasone (PVd) in patients (pts) with RRMM who received ≥1 prior line of therapy (LOT). This post hoc analysis examined the characteristics of and outcomes in pts achieving sustained clinical benefit with BPd. Methods: DREAMM-8 is an ongoing, phase 3, open label study evaluating BPd and PVd in pts with RRMM with ≥1 prior LOT, including lenalidomide. Pts were randomized 1:1 and treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or death, whichever occurred first. The primary endpoint was PFS; secondary endpoints included minimal residual disease (MRD) negativity (10 -5 ), PFS2, response rates, and safety. LTRs were pts with PFS ≥30 months (data cutoff: July 7, 2025; median follow up 36 months in both arms). Results: Of the 302 pts in DREAMM-8 (BPd, n=155; PVd, n=147), 81 were LTRs. The BPd arm had more than twice the proportion of LTRs (n=59 [38%]) as the PVd arm (n=22 [15%]). Baseline characteristics between treatment arms were generally well balanced. In LTRs, median PFS potentially favored BPd (not reached [NR]; 95% CI, NR-NR) vs PVd (NR; 95% CI, 42.7 months-NR), with a hazard ratio (HR) of 0.72 (95% CI, 0.20-2.53). BPd LTRs continued to demonstrate potential benefits after the first subsequent therapy, with median PFS2 (95% CI) of NR (NR-NR) in the BPd LTR arm and NR (44.2 months-NR) in the PVd LTR arm (HR, 0.33; 95% CI, 0.07-1.69). LTRs treated with BPd vs PVd had deeper responses: 76% vs 59% had complete response or better (≥ CR), 56% vs 32% had MRD negativity plus ≥ CR overall (73% vs 54% of pts with ≥ CR), and 39% vs 18% had sustained MRD negativity for ≥12 months, respectively. A higher proportion of pts with high-risk cytogenetics (ie, ≥1 of t[4;14], t[14;16], or del[17p13]) treated with BPd vs PVd achieved long-term response (27% vs 11%). The safety profile in LTRs was generally consistent with that previously reported. Conclusions: More than one-third of pts treated with BPd achieved LTR status, representing a 2.5-fold higher rate than with PVd, with similar rates in pts with high-risk cytogenetics; median PFS with BPd remains unreached. These findings suggest that this broadly accessible BCMA-targeted regimen delivers potential durable clinical benefit, characterized by deep and sustained disease-free survival. Clinical trial information: NCT04484623 .

We explored single or consecutive chimeric antigen receptor (CAR) T and bispecific antibody (BsAb) treatment modalities as correlates of clinical outcomes, by complementary bias-correction analysis of a retrospective multicenter study of 640 patients with relapsed/refractory multiple myeloma. The sequential use of both modalities seemed to yield the most favorable survival trajectories. Initiating treatment with CAR T [idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel), cesnicabtagene autoleucel (cesni-cel)] was associated with longer remission. However, mortality from early progression was similar regardless of initial modality, suggesting that resistance may negate initial efficacy difference. On the product level, the benefit of CAR T seemed to be driven by cilta-cel and cesni-cel, whereas BsAbs showed at least comparable outcomes with ide-cel. These exploratory findings highlight the critical importance of treatment sequencing in optimizing long-term outcomes and underscore the need for equitable and timely access to both modalities across healthcare systems. SIGNIFICANCE:In this real-world cohort, initiating treatment with CAR T was associated with longer remission, and sequential immunotherapy incorporating both modalities yielded the most favorable outcomes. However, early treatment failure negated initial efficacy differences between modalities. These findings provide a rationale for prospective sequencing trials and equitable access to both treatments. See related commentary by Banerjee, p. 650.

Infections remain a key challenge during treatment of multiple myeloma (MM) patients with anti-BCMA and -GPRC5D bispecific antibodies (bsAbs). However, the underlying mechanism behind different rates and severity of infections induced by the two bsAbs remains poorly understood. Single-cell RNA-sequencing performed in bone marrow aspirates of 11 MM patients and 8 healthy donors revealed BCMA expression on mature B cells and, surprisingly, in small pre-B cells within B-cell precursors. By contrast, GPRC5D expression was restricted to normal and malignant plasma cells (PCs). Next-generation flow cytometry immune profiling showed that anti-BCMA bsAbs severely depleted bone marrow (BM) mature B cells (4.9%→0%; p<0.001) and normal PCs (0.17% → <0.0002%; p<0.001) during treatment of 62 relapsed MM patients. This was observed in early and late time points of therapy. Additional flow cytometry (N=31) and single-cell RNA-sequencing studies (N=8) demonstrated that, in contrast to anti-GPRC5D, anti-BCMA bsAbs also depleted immature and small pre-B cells. The MIcγ1 mouse model was used as a negative control of BCMA expression in all stages of the B-cell lineage, which confirmed no depletion of any B-cell subset after anti-BCMA treatment. In conclusion, we show that while GPRC5D bsAbs selectively target PCs, anti-BCMA bsAbs target both PCs and B cells from the small pre-B stage onwards. Our study provides mechanistic insight into the increased infection risk with anti-BCMA therapy and lays a foundation for individualized bsAb strategies in MM. Moreover, dual targeting of B cells and PCs may have therapeutic potential in other B cell malignancies or autoimmune diseases.

Background Talquetamab, a bispecific antibody targeting GPRC5D and CD3, has led to durable responses in patients with heavily pretreated relapsed or refractory multiple myeloma in phase 1-2 trials, with a limited effect on normal B cells. Methods In a phase 3 trial, we randomly assigned patients with relapsed or refractory multiple myeloma who had previously received at least one line of therapy to receive talquetamab plus daratumumab and pomalidomide (Tal-DP), talquetamab plus daratumumab (Tal-D), or daratumumab plus pomalidomide and dexamethasone (DPd). The primary end point was progression-free survival as assessed by an independent review committee. Key secondary end points were overall response, complete response or better (complete or stringent complete response), measurable residual disease-negative complete response, and overall survival. Results A total of 287, 287, and 290 patients were assigned to the Tal-DP, Tal-D, and DPd groups, respectively. At the interim analysis (median follow-up, 24.6 months), progression-free survival was significantly longer with Tal-DP and Tal-D than with DPd (24-month estimate, 81.3% and 77.6% vs. 51.2%; hazard ratio for disease progression or death, Tal-DP vs. DPd, 0.28 [95% confidence interval {CI}, 0.20 to 0.40], and Tal-D vs. DPd, 0.33 [95% CI, 0.24 to 0.46]; P<0.001 for both comparisons). The overall response was higher with Tal-DP and Tal-D than with DPd (88.2% and 88.5% vs. 77.6%), as was complete response or better (71.1% and 69.0% vs. 34.5%) and measurable residual disease-negative complete response (52.3% and 46.3% vs. 15.9%) (P<0.001 for all comparisons). Overall survival at 24 months was 89.2% with Tal-DP, 87.9% with Tal-D, and 79.1% with DPd (hazard ratio for death, Tal-DP vs. DPd, 0.47 [95% CI, 0.30 to 0.73], and Tal-D vs. DPd, 0.51 [95% CI, 0.33 to 0.78]). Serious adverse events occurred in 63.0%, 52.6%, and 53.7% of the patients in the Tal-DP, Tal-D, and DPd groups, respectively; fatal adverse events occurred in 1.8%, 4.0%, and 4.6%. Conclusions Among patients with relapsed or refractory multiple myeloma who had previously received at least one line of therapy, both Tal-DP and Tal-D led to significantly longer progression-free survival than DPd. (Funded by Johnson & Johnson; MonumenTAL-3 ClinicalTrials.gov number, NCT05455320.)

Induction and consolidation with a quadruplet therapy of a CD38-targeting monoclonal antibody, a proteasome inhibitor, an immunomodulatory drug and dexamethasone are a standard-of-care treatment in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM) with the optimal drugs to be used still under debate. The ongoing, phase 3 EMN24 IsKia trial randomized 302 TE patients with NDMM aged <= 70 years 1:1 to isatuximab-carfilzomib-lenalidomide-dexamethasone (Isa-KRd) versus KRd pretransplant induction and post-transplant consolidation. The primary endpoint was the rate of measurable residual disease (MRD) negativity (sensitivity of 10-5 or better) by next-generation sequencing (NGS) after consolidation. Key secondary endpoints were the rates of NGS-MRD negativity after induction and progression-free survival (PFS). MRD negativity rates at higher sensitivity (10-6 or better) were exploratory. Post-consolidation MRD negativity was significantly higher with Isa-KRd versus KRd at the 10-5 (77% versus 67%; odds ratio (OR) 1.67, P = 0.049) and 10-6 (68% versus 48%; OR 2.36, P = 0.0004) sensitivities. Deep MRD responses were rapid (post-induction Isa-KRd versus KRd: 10-5 46% versus 27%, OR 2.32, P = 0.0007; 10-6 28% versus 14%, OR 2.44, P = 0.0029) and durable (1-year sustained 10-6 MRD negativity 52% versus 38%, OR 1.82, P = 0.012). At current follow-up, PFS data were immature. Grade 3-4 non-hematologic adverse events (AEs), treatment discontinuations and deaths due to AEs were similar in the two arms. Isa-KRd significantly improved NGS-MRD negativity in TE patients with NDMM, with a manageable safety profile. ClinicalTrials.gov registration: NCT04483739.

7515 Background: B-cell maturation antigen (BCMA)–directed therapies have changed the RRMM treatment landscape. In the phase 3 DREAMM-8 trial (NCT04484623), BCMA-directed antibody-drug conjugate (ADC) belantamab mafodotin + pomalidomide and dexamethasone (BPd) demonstrated significant progression-free survival (PFS) benefit and higher rates of complete response (CR)–based MRD negativity vs triplet pomalidomide, bortezomib, dexamethasone (PVd) in pts with RRMM and ≥1 prior line of therapy (LOT). As MRD negativity predicts improved survival in MM, this long-term, postbaseline update describes clinical outcomes and characteristics of pts with sustained MRD negativity. Methods: Pts with ≥1 prior LOT including lenalidomide were randomized 1:1 to BPd or PVd. The primary endpoint was PFS (independent review committee assessed); PFS2 was investigator assessed. CR-based sustained MRD negativity (≥12 mo) was an exploratory endpoint. Pts with ≥ CR were tested for MRD negativity by next-generation sequencing (10 −5 sensitivity). Results: At data cutoff (7/7/2025), with median follow-up of 35.8 mo overall, the intention-to-treat population of BPd (n=155) vs PVd (n=147) was >4× more likely to achieve ≥ CR + MRD negativity (27.7% vs 6.1%) and sustained MRD negativity (15.5% vs 2.7%). In pts with ≥ CR (BPd, n = 67; PVd, n = 25), rates of MRD negativity were also higher with BPd vs PVd (64.2% vs 36.0%), as were rates of sustained MRD negativity (55.8% vs 44.4%) among all ≥ CR + MRD negative pts. Pts with sustained MRD negativity had durable PFS in both arms; 1 of 24 and 0 of 4 pts experienced PFS events with BPd and PVd, respectively. In pts without sustained MRD negativity, median PFS was 21.1 mo with BPd (HR vs sustained MRD negative, 0.04; 95% CI, 0.01-0.32) and 10.2 mo with PVd (HR vs sustained MRD negative, not estimable [NE]). Sustained MRD negativity was also associated with durable PFS2 in both arms; 2 of 25 and 0 of 4 pts experienced PFS2 events with BPd and PVd, respectively. In pts without sustained MRD negativity, median PFS2 was 20.2 mo with BPd (HR vs sustained MRD negative, 0.08; 95% CI, 0.02-0.33) and 9.3 mo with PVd (HR vs sustained MRD negative, NE). Findings were similar in pts with vs without ≥ CR + MRD negativity. Of BPd-treated pts, those with MRD negativity (n=43) received 1-3 prior LOT, of which most (74.4%) had 1. MRD-positive pts (n=112) received up to 6 prior LOT, of which 44.6% received 1 and 17.0% received >3. Almost 40% of pts with CR-based MRD negativity had high-risk cytogenetics. Conclusions: Pts receiving BPd vs PVd were >4× more likely to achieve sustained MRD negativity, which was associated with improved PFS and PFS2. MRD negative vs positive pts in the BPd arm more often had 1 prior LOT. These findings further support BPd, a BCMA-directed ADC regimen, in earlier LOTs for RRMM, including in pts with high-risk cytogenetics. Clinical trial information: NCT04484623 .

ABSTRACT:Belantamab mafodotin (belamaf) combined with standard therapies demonstrated significant progression-free survival (PFS) and overall survival benefits in DREAMM-7 and PFS benefit in DREAMM-8 in relapsed/refractory multiple myeloma. Belamaf dose modifications managed adverse events, including belamaf-related ocular events. Ocular events included ocular adverse reactions (eg, dry eyes, photophobia, eye irritation) and protocol-mandated ophthalmic examination findings. Protocol-recommended dose modifications for ocular events were driven by ophthalmic examination findings and included belamaf dose delays until resolution and reductions. We used descriptive analyses to evaluate the impact of dose modifications on managing ocular events and treatment efficacy. In patients with normal baseline vision who were receiving treatment, dose modifications extended belamaf dosing intervals to a median of 8 to 12 weeks by 9 months; the prevalences of reduced vision to bilateral 20/50 or worse and ocular adverse reactions were highest in the first 3 months and remained low at later time points. The median time to resolution after grade ≥2 ophthalmic examination findings was 12 weeks. Rates of belamaf discontinuations due to ocular events were low. Almost all responders (partial response or better) required dose modifications. Most patients achieved a response before an extended (>2 cycles) dose delay; most who had not, subsequently achieved or deepened their response. In DREAMM-7 and DREAMM-8, the median PFS in patients with ≥1 dose delay of ≥12 weeks was 36.6 months and not reached, respectively. Ocular events were common but effectively managed with dose modifications, allowing for patients to remain on treatment and derive robust efficacy benefit. The trials were registered at www.clinicaltrials.gov as #NCT04246047 (DREAMM-7) and #NCT04484623 (DREAMM-8).

Introduction Material and methods Results Conclusions

Despite significant advancements in therapy of multiple myeloma (MM) over the past 20 years, most patients experience relapse, necessitating new treatment approaches. This study aims to compare the real-world effectiveness of lenalidomide (LEN)-based triplet therapies, specifically daratumumab (DRD), carfilzomib (KRD), and ixazomib (IRD), in relapsed/refractory multiple myeloma (RRMM). A retrospective registry-based study analyzed 538 RRMM patients undergoing therapy for their first to third relapse. The primary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), with a matching-adjusted indirect comparisons (MAIC) employed to address cohort differences. ORR was highest for DRD at 91.4

Abstract Background: Chimeric antigen receptor T cells (CAR-T) represent a groundbreaking therapy in hematologic malignancies. Currently approved products target CD19 (axi-cel, brexu-cel, tisa-cel, liso-cel) and BCMA (cilta-cel, ide-cel). CAR-T expansion was linked to both clinical efficacy and toxicity, however, comparative data across CAR-T products remain limited, particularly longitudinal data on CAR-T kinetics and persistence of both CAR-T and non-CAR-T subsets and its clinical relevance. Aims: To assess and compare longitudinal kinetics of CAR-T and non-CAR-T immune subsets among different CD19 and BCMA CAR-T products and to determine clinical relevance of immune monitoring in CAR-T treated patients. Methods: In this multicenter study, 727 peripheral blood (PB) samples from 123 patients treated with axi-cel (sample/patient counts: 377/71), cilta-cel (177/26), tisa-cel (96/14), and brexu-cel (77/12) were analyzed. Samples were collected at baseline (Day 0 [D0]), then D7, D14, D21, D28, and monthly to Month 15 (M15). Specifically designed and standardized 8-color flow cytometry panel (CD3, CD4, CD8, CD19, CD20, CD45, CD16+CD56, and CAR) was used in routine practice. Results: Diagnoses included B-cell non-Hodgkin lymphoma (B-NHL) (71% [89/123]), multiple myeloma (MM) (21% [26/123]), and B-cell acute leukemia (ALL) (7% [8/123]). Median age was 63, 71, and 40 years for B-NHL, MM, and ALL respectively. Axi-cel was used in 80% (71/89) of B-NHLs. CRS occurred in 91%, 76%, and 75% with grade ≥2 observed in 54%, 28%, and 24%. ICANS occurred in 46%, 40%, and 38%,with grade ≥2 observed in 30%, 8%, and 12% of B-NHL, MM, and ALL cases. CR/VGPR was achieved in 70%, 96%, and 100% cases and 26%, 0%, and 12% progressed (PD). Median follow-up of was 364 days. Median CD45+ leukocytes per sample was 1.74 × 10⁵ and median limit of detection (LOD) was 0.0117%. First, CAR-T product expansion was compared among the products. Axi-cel and brexu-cel counts (cells/µL PB) peaked on D7, while tisa-cel and cilta-cel peaked on D14. Cilta-cel exhibited markedly higher peak counts (median: 599.1), compared to axi-cel (91.4), tisa-cel (86.8), and brexu-cel (35.3). Moreover, persistence in PB was assessed for axi-cel and cilta-cel, which had sufficient sampling. Axi-cel persisted at low levels often near LOD (median 0.8/µL) in 45% (17/38) to 41% (7/17) of patients from M4 to M13-15, while cilta-cel was undetectable from M3 onwards (16/16). Axi-cel patients showed limited B-cell recovery (5% to 35% from M4 to M13-15), while B-cells recovered in 100% of cilta-cel patients on M3 and sustained. Then, CD4/CD8 kinetics in the CAR-T pool were compared between axi-cel and cilta-cel. Axi-cel had initial low CD4+ proportions followed by CD4+ increase in persistence (D7–D21 30.9% vs M4–M15 85.2%; p=0.001), whereas cilta-cel showed early CD4+ dominance declining over time (D7 77.8% vs D28 43.0%; p<0.001). In order to assess the association of CAR-T cell expansion and clinical outcomes, we used our largest cohort of B-NHL patients treated with axi-cel (N=71). As anticipated, CAR-T expansion at D7 was linked to toxicity and efficacy. Increased number of CD8+ CAR-T cellsassociated with CRS ≥2 (p=0.048), with CD4+ showing statistical trend (p=0.06). Total CAR-T counts were elevated in CRS and ICANS ≥2 (p<0.012). CD4+ and CD8+ CAR-T counts were higher in CRS ≥2 (p<0.02), and CD8+ counts increased in ICANS ≥2 (p=0.005). Patients achieving CR had higher D7 CD8+ CAR-T counts (p=0.049); total and CD8+ counts at D14 were also elevated (p<0.024). Using a cutoff (Maxstat) of 129 CAR-T/µL at D7, low expansion predicted worse PFS (1-year PFS: 59% vs. 100%, HR 0.12, p=0.015) and lower CR rates (57% vs 82%, p=0.08). Conclusion: This is the first study comprehensively comparing CAR-T and non-CAR-T cell kinetics across different CAR-T products targeting CD19 and BCMA using a specialized flow cytometry panel. Distinct peak kinetics and persistence patterns were observed, with cilta-cel showing higher peaks and rapid disappearance by M3, accompanied by B-cell recovery, while axi-cel tends to persist for longer time period in a subset of patients, with prolonged B cell aplasia. In axi-cel patients, greater CAR-T expansion was associated with higher toxicity but also improved response and PFS.

Background and objectives: Dimethyl sulfoxide has become the most common cryoprotectant used for cryopreservation of hematopoietic progenitor cells because of its efficiency, regardless of its potentially toxic side effects. Its application is considered safe, provided that the daily dose administered does not exceed 1 gram per kilogram of patient weight. Indications for its reduction after thawing are limited to patients with high risk of malignant arrhythmia and those with severely impaired renal function. However, dimethyl sulfoxide reduction can lead to the loss of viable progenitors. Methods: A retrospective study of viable hematopoietic progenitor cell recovery after dimethyl sulfoxide reduction was performed with 13 patients (nine men, four women) with secondary amyloidosis in multiple myeloma (n = 9), primary amyloid light chain amyloidosis (n = 3), or severe adverse reaction at the beginning of the hematopoietic progenitor cell concentrate infusion (n = 1). The Wilcoxon signed-rank test was used. Results: The results of the dimethyl sulfoxide reduction process showed a high recovery of viable nucleated cells (median: 120.85 %), and of viable mononuclear cells (median: 104.53 %). There was a significant decrease in total number of viable CD34+ cells in comparison with data obtained after original collection (median: 51.49 %). No significant decrease in colony-forming unit capacity was observed after dimethyl sulfoxide reduction (median: 93.37 %). Conclusion: The dimethyl sulfoxide removal process and total process recoveries revealed considerable individual variability. To minimize the risk of prolonged engraftment or non-engraftment, it is important to apply this process only to high-risk patients.

Minimal residual disease (MRD) is one of the most important prognostic factors in multiple myeloma (MM) and a valid surrogate for progression-free survival (PFS) and overall survival (OS). Recently, MRD negativity was approved as an early clinical endpoint for accelerated drug approval in MM. Nevertheless, there is limited evidence of MRD utility in real-world setting. In this retrospective multicenter study, we report outcomes of 331 newly diagnosed MM patients with MRD evaluation at Day+100 after autologous stem cell transplantation using flow cytometry with a median limit of detection of 0.001%. MRD negativity was reached in 47% of patients and was associated with significantly prolonged median PFS (49.2 months vs. 18.4 months; hazard ratios (HR) = 0.37; p < 0.001) and OS (not reached vs. 74.9 months; HR = 0.50; p = 0.007). Achieving MRD negativity was associated with PFS improvements regardless of age, International Staging System (ISS) stage, lactate dedydrogenase (LDH) level, or cytogenetic risk. Importantly, MRD positive patients benefited from lenalidomide maintenance versus no maintenance (18-months PFS: 81% vs. 46%; HR = 0.24; p = 0.002) while in MRD negative patients such benefit was not observed (p = 0.747). The outcomes of our real-world study recapitulate results from clinical trials including meta-analyses and support the idea that MRD positive patients profit more from lenalidomide maintenance than MRD negative ones.

Objectives:The objective of this study was to investigate the relationship between both short-term and long-term tacrolimus exposure and overall survival after allogeneic stem cell transplantation and to propose individualized tacrolimus dosing based on the population pharmacokinetic model. Study design:Tacrolimus exposure during the first 3 months of therapy after transplantation was calculated using therapeutic drug monitoring data from all patients who underwent allogeneic stem cell transplantation from 2016 to 2018. The optimal upper level was determined using ROC analysis, and the impact of cutoff tacrolimus exposure values on overall survival of patients was assessed together with other transplant variables using multivariate analysis. The population pharmacokinetic model was developed using a nonlinear mixed-effects modeling method, and the optimal tacrolimus dose was proposed. Results:A total of 86 patients were included in the outcome analyses. Except for the disease risk category, age ≥55 years, and female-to-male donor, tacrolimus exposures of the area under the curve of trough concentrations (AUCtc) ≥ 222 ng h/mL, ≥258 ng h/mL, and ≥160 ng h/mL during the whole three-month period, second month, and third month of therapy, respectively, were also found to be statistically significant for overall survival in univariate analysis. These AUCtc values were independent variables for overall survival in multivariate analysis, with RR of 3.01 (P = 0.0056), 3.22 (P = 0.0058), and 2.93 (P = 0.0184) for the whole three-month period, second month, and third month of therapy, respectively. The disease risk category (RR 7.11; P < 0.0001), age (RR 2.45; P = 0.0214), and non-myeloablative conditioning (RR 3.39; P = 0.0014) were also significant factors influencing survival in multivariate analysis. Tacrolimus volume of distribution was 127.1 L and was not affected by any of the tested covariates, whereas clearance decreased with age according to the equation CL = 7.94 × e - 0.0085 × age and was reduced by 23% in patients who underwent repeat transplantation. Conclusion:Except for the disease risk category, age, and non-myeloablative conditioning, exposure to tacrolimus is an independent predictor of overall survival and should not exceed trough levels of 10.7 ng/mL during the second month and 6.8 ng/mL during third month after transplantation. In order to reach this target, nomogram for estimation of the maximal initial tacrolimus daily dose was developed based on the population pharmacokinetic model.