Sustained Minimal Residual Disease Negativity Research Articles

Elderly Patients with Newly Diagnosed Multiple Myeloma: Continuous or Fixed Duration Treatment?

Multiple myeloma (MM) presents unique challenges in the elderly population due to increased frailty and comorbidities. Balancing treatment efficacy, safety, and quality of life is essential in managing elderly patients. While two-drug regimens were often favored for elderly patients, recent studies show promising outcomes with anti-CD38 antibody-based therapies, particularly daratumumab and lenalidomide with minimal dexamethasone. Continuous low-intensity treatments have shown improved progression-free survival and overall survival, with significant benefits observed in elderly patients. The DRd combination has now emerged as the standard of care for elderly MM patients, offering a favorable balance of efficacy, safety, and convenience. Ongoing trials are evaluating the addition of bortezomib in an induction phase for fit patients. New-generation immunotherapies hold promise for further refining treatment approaches, potentially leading to treatment discontinuation in select patient populations with sustained minimal residual disease negativity.

Real-world prognostic significance of attaining minimal residual disease negativity in newly diagnosed multiple myeloma

The aim of the study was to evaluate the prognostic impact of minimal residual disease (MRD) in the real-world setting and the interaction between MRD and molecular risk, clinical response and autologous stem-cell transplant (ASCT). A retrospective analysis of 275 newly diagnosed multiple myeloma (NDMM) patients who achieved very good partial remission (VGPR) or better before maintenance were involved. We examined MRD status by multiparameter flow cytometry (MFC). At a median follow-up of 37 months (4–88 months), In patients who achieved ≥ VGPR, those with MRD negativity had significantly longer PFS (51 vs. 26 months; P < 0.001) and OS (Not reached: NR vs. 62 months, P < 0.001) than those with MRD positivity. MRD positivity was the independent prognostic factor for PFS with hazard ratios of 2.650 (95% CI 1.755–4.033, P < 0.001) and OS with hazard ratios of 2.122 (95% CI 1.155–3.899, P = 0.015). Achieving MRD negativity was able to ameliorate a poor prognosis associated with genetic high risk. MRD negativity was associated with better PFS regardless of ASCT treatment. MRD status was more predictable for clinical outcome than conventional clinical responses. Moreover, Sustained MRD negativity ≥ 12 or ≥ 24 months improved both PFS and OS. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes regardless of high-risk cytogenetics, ASCT and clinical responses in a real-world setting.

Contribution of post-transplantation therapy to sustained MRD negativity in multiple myeloma: a retrospective analysis.

Post-transplantation therapy is commonly performed in patients with myeloma and can prolong progression-free survival (PFS). However, whether post-transplantation therapy contributes to achieving and continuing MRD-negativity remains controversial. This retrospective analysis aimed to evaluate the clinical impact of post-transplantation therapy, including tandem autologous stem cell transplantation (ASCT), in myeloma patients. The subjects were 79 patients (median age: 62years) who received induction therapy, including bortezomib and/or lenalidomide, of whom 58 underwent post-transplantation therapy. At the median follow-up time of 50months, the 4-year PFS rate was significantly higher in patients who underwent post-transplantation therapy than those who did not (60.6% vs. 28.6%, P = 0.012). Multivariate analysis revealed post-transplantation therapy to be a significant prognostic factor for long PFS. Tandem ASCT followed by consolidation and/or maintenance therapies improved PFS and OS. The minimal residual disease (MRD)-negative rate was significantly higher in patients who underwent post-transplantation therapy than those who did not (50.9% vs. 16.7%, P = 0.006). Post-transplantation therapy contributed to sustained MRD-negativity, which predicted long PFS and overall survival. Patients frequently discontinued post-transplantation therapy due to adverse events within 4months. In conclusion, post-transplantation therapy improved PFS and contributed to sustained MRD-negativity in myeloma patients.

Efficacy Outcomes and Characteristics of Patients with Multiple Myeloma (MM) Who Achieved Sustained Minimal Residual Disease Negativity after Treatment with Equecabtagene Autoleucel (Eque-cel, CT103A) in Fumanba-1

Background: Equecabtagene autoleucel (eque-cel, CT103A), which is designed with a fully human BCMA-specific CAR structure, was recently granted NMPA approval for the treatment of adult patients (pts) with relapsed/refractory multiple myeloma (RRMM) after ≥3 prior lines of therapy (LOT). The pivotal phase 2 FUMANBA-1 study (NCT05066646) demonstrated deep and durable responses with eque-cel in heavily pretreated patients with RRMM. Recent studies have demonstrated the utility of minimal residual disease (MRD) as a prognostic biomarker for long-term outcomes of RRMM, wherein achievement of sustained MRD-negative status was associated with an improvement in PFS of pts treated by eque-cel in FUMANBA-1 study. We sought to characterize the baseline and disease characteristics of pts with sustained MRD negativity (pts who continued to remain MRD negative ≥6 mo and ≥12 mo). Methods: FUMANBA-1 study enrolled RRMM pts who received ≥ 3 lines of prior therapies containing at least a proteasome inhibitor and an immunomodulatory agent and were refractory to their last line of treatment. All pts received a single infusion of eque-cel at the dose of 1.0 x 10 6 CAR-T cells/Kg. Pts who had progressed on previous BCMA CAR-T cell therapy were not included in this analysis. The primary endpoint was ORR. Additional endpoints included ≥CR rate (key secondary), DOR, PFS, and safety. ORR and CR were assessed per IMWG criteria; DOR and PFS were analyzed via Kaplan-Meier methods. MRD negativity was a secondary objective and was assessed on bone marrow samples at baseline; day 14, 28; and 2, 3, 6, 9, 12, 15, 18, 21 and 24 mo using EuroFlow next-generation flow, regardless of disease status. Evaluable samples passed calibration and quality control and included sufficient cells for evaluation at 10 -5 testing threshold. Characteristics were analyzed in pts who had MRD negativity &amp;lt;6 mo, or sustained ≥6 mo and ≥12 mo. Pts who did not achieve MRD negativity at any time point were considered to be MRD positive. Results: Of the 88 pts who achieved MRD negativity in FUMANBA-1, 74 had at least 6 mo follow up without progression after initial MRD-negativity and 43 had at least 12 mo follow up without progression after initial MRD-negativity. MRD negativity was sustained for ≥6 mo in 78.4% (58 of 74 with at least 6 mo follow-up without progression after initial MRD-negativity) and ≥12 mo in 74.4% (32 of 43 with at least 12 mo follow-up without progression after initial MRD-negativity; 7 pts evaluable for sustained MRD at ≥6 mo but not ≥12 mo had PD). Pts with sustained MRD negativity (≥6 mo, and ≥12 mo) had longer progression free survival (PFS; Figure 1A) compared with pts who did not (MRD negative &amp;lt;6 mo). Key pt and disease characteristics in these different groups (Figure 1B), and potential associations with sustained MRD negativity were analyzed descriptively. Baseline R-ISS disease stage III was more common in pts with MRD sustained for ≥6 mo (8.6%) and ≥12 mo (9.4%) compared with pts who had MRD negativity &amp;lt;6 mo (3.3%). Baseline high tumor burden diseases were less common in pts with MRD sustained for ≥6 mo (70.7%) and ≥12 mo (65.6%) compared with pts who had MRD negativity &amp;lt;6 mo (90%). Triple-class exposure was also less common in pts with MRD sustained for ≥6 mo (12.1%) and ≥12 mo (12.5%) compared with pts who had MRD negativity &amp;lt;6 mo (30%). Pts with sustained MRD negativity had trends toward shorter median time since diagnosis (38.6 mo and 40.2 mo for pts with MRD negativity sustained ≥6 and ≥12 mo, respectively versus 43.5 mo for those with MRD negativity &amp;lt;6 mo). Other baseline characteristics, including presence of high-risk cytogenetics, ECOG performance status, extramedullary disease and number of prior LOT did not differ across MRD subgroups, and were similar to the overall FUMANBA-1 population. Conclusions: Based on our descriptive analysis, pts receiving eque-cel achieved MRD negativity irrespective of their high-risk cytogenetics, extramedullary disease, number of prior LOT and performance status. Presence of high tumor burden at baseline, and prior triple-class exposure might be factors that impact achievement of sustained MRD negativity. These data suggest that while eque-cel is effective for a broad range of pts, specific pt and disease characteristics may be associated with sustained MRD negativity and better long-term outcomes. Sustained MRD negativity might be a promising prognostic indicator for RRMM pts treated by eque-cel.

Free from Drug Therapy in Multiple Myeloma (FREEDMM): MRD-Based Cessation of Maintenance

Background. Treatment of newly diagnosed multiple myeloma (NDMM) consists of induction therapy followed by autologous stem cell transplant (ASCT) and indefinite maintenance. Continuous lenalidomide carries both significant clinical and financial toxicity. Minimal residual disease (MRD) has proven to be a powerful surrogate for PFS and OS but is not yet used to guide treatment. We hypothesize that MRD could be used to predict a subset of patients who can safely stop maintenance therapy and enter into a disease surveillance phase. Study Design and Methods. This prospective phase 2 study (NCT 05192122) is designed to stop post-ASCT maintenance therapy once sustained MRD negativity is achieved. MM patients are eligible if they have completed ≥2 years of maintenance therapy post-ASCT, and meet IMWG criteria for ≥ PR. Bone marrow (BM) MRD testing is performed twice, one year apart, using NGS. Sustained MRD-negativity is defined at a threshold of 10 -6, with negative MRD sustained between the Year 1 and Year 2 interval. Patients with sustained MRD negativity and absence of new bony lesions on PET then undergo maintenance therapy cessation. MRD-positive patients are removed from study. In patients who discontinue maintenance, BM testing to re-assess for MRD is repeated yearly for 3 years. At the time of MRD testing, peripheral blood (PB) samples are collected for MALDI-TOF mass spectrometry testing and circulating multiple myeloma cell (CMMC) enumeration. These are done in parallel with MRD assessment. Health-related quality of life (HRQoL) using the EORTC QLQ-MY20 questionnaire is measured before and after maintenance cessation. This study plans to enroll 50 patients to meet the primary objective of assessing sustained MRD-negativity 1 year after maintenance cessation. For all patients, 5-mL PB and BM samples are collected, processed, and kept frozen until analysis. Cellular indexing of transcriptomes and epitopes (CITE-seq) to simultaneously quantify cell surface protein and transcriptome data is used to characterize differences in the immune microenvironment between MRD-negative, MRD-positive, as well as between patients with biochemical and/or clinical progression and patients with MRD-resurgence but biochemically and clinically stable. Preliminary Results. FREEDMM enrollment began December 2021, and 31 patients have been enrolled, 29 of whom have undergone Year 1 BM for MRD assessment. Median follow up of our cohort is 414 (0-577) days. The median age is 69.5 (40-78) years, and the majority are either Black (n=9; 29%) or Hispanic (n=11; 35%). 18 (58%) patients had R-ISS 1 or 2, while 2 patients had high risk disease with presence of 17p deletion. The median number of years of maintenance therapy completed prior to Year 1 BM is 3.4 (2-7.9) years. 28 (96.6%) were in CR at time of Year 1 BM. Year 1 MRD results are pending in 13 patients. At Year 1, 11 (68.8 %) of 16 patients were found to be MRD-negative, while 5 (31.3%) patients were found to be MRD-positive with a median of 206 (1-9,748) cells per 10 6 nucleated cells detected. 24 (85%) of 28 patients had a negative MALDI-TOF result at the time of the Year 1 BM. MALDI-TOF results were false negative in 3 MRD-positive patients. PB CMMC samples were concordant with MRD results in all 5 (100%) patients who were tested. There was concordance between MALDI-TOF and CMMC results in 9 (75%) of 12 patients. At year 2, 4 patients continued to be MRD negative, while 1 patient who was previously MRD-negative became MRD positive. At most recent follow-up, 3 (42.9%) of 7 MRD positive patients at Year 1 experienced clinical progression and were removed from the study. 2 (50%) of 4 patients with sustained MRD-negativity have undergone maintenance cessation, with the remaining 2 awaiting confirmation of MRD-negative results. 59 paired PB (n=29) and BM (n=30) samples have been collected for CITE-seq analysis. Pilot CITE-seq experiments captured 10,000-15,000 cells with 33,000-56,000 reads/ cell on one MRD-positive BM and paired PB sample. CITE-seq results for remaining patients will be presented at the conference. Conclusion: This phase 2 trial applies a novel clinical trial design with an adaptive strategy to explore use of MRD testing as a guide to maintenance therapy cessation in MM patients and represents one of the first studies introducing transcriptome analysis of the tumor and immune microenvironment in the maintenance setting. Ongoing results will be reported at the conference.

RADAR Trial: MRD Response Adapted Trial for Newly Diagnosed Transplant Eligible Myeloma Patients

Background: Achieving and sustaining minimal disease negativity improves clinical outcomes in newly diagnosed transplant eligible myeloma (NDMM). Outcomes in NDMM are influenced by levels of minimal residual disease (MRD) post therapy and genetic risk by FISH or molecular profiling prior to therapy. Trials exploring response adapted post transplant strategies using MRD as a prognostic tool are going. We provide an update of the current UK-MRA RADAR study. Study Design/Methods: The UK-MRA RADAR study is a national multicentre risk adapted response guided multiarm multistage (MAMS) phase II/III trial which will recruit 1400 patients with NDMM eligible for ASCT. Eligible patients receive induction with 4 cycles of RCyBorD (lenalidomide, cyclophosphamide, bortezomib, dexamethasone), followed by high-dose melphalan and stem cell rescue. Patients with high-risk disease receive Isatuximab in addition to RCyBorD during induction. Genetic risk classification is performed using standard of care FISH testing at local sites. Participants enter the standard or high risk pathway based on presence of atleast two markers: t(4;14), t(14;16), t(14;20), del(17p), del(1p) and gain (1q21). MRD analysis in RADAR uses a multiparametric flow cytometry panel with CD319 and Cd229 used to augment post-isatuximab sample analysis at a central laboratory, with negativity defined at threshold of 10 -5(Figure 1). For standard risk patients, the study addresses two pivotal MRD-related questions: 1) For those with sustained MRD negativity after 12 months of isatuximab maintenance, can treatment be stopped safely to allow patients a treatment-free interval thereby reducing treatment burden? 2) For patients with persistent detectable disease after ASCT, does intensification of consolidation and maintenance therapy augment conversion to MRD negativity compared to lenalidomide maintenance? High risk participants receive intensified consolidation and maintenance regimens post_ASCT aligned to OPTIMUM/MUKnine ( NCT03188172). A further amendment is planned to explore the activity of a BCMA bispecific antibody in high risk patients pre and post transplant. It is hypothesised this will improve both depth (MRD negativity) and ability to sustain response (PFS). Feasibility and benefits of multimodal MRD incorporating imaging and blood-based testing will be tested in the new high risk pathway. In RADAR, we will also gather information on how patients respond to receiving information about their genetic risk assignment and treatment response (MRD). This is a unique opportunity to understand the patients perspective on personalised medicine, which has implications for implementation in clinical care, and future trial design. Trial Progress. RADAR opened to recruitment in May 2021 and is currently recruiting across 87 hospital sites with a further 16 sites in set up. 504 patients have been recruited; 87 are classified as high risk on FISH analysis ( 375 standard risk, 15 unable to determine, 19TBC, 8 withdrawn before FISH analysis). 220 have reached D+100 MRD assessment. Trackable phenotypes were available in 98.2% of patients. Discussion: The RADAR study simultaneously tests escalation and de-escalation strategies, according to disease response, and using MRD to guide post transplant therapy in NDMM patients. Use of central flow cytometry laboratory for MRD has proven feasible in patients to date. Recruitment is on target and outcomes will provide RCT-level evidence for the adaptive use of MRD in treatment allocation and intensification post transplant. The platform design enables adaptation with ability to test new strategies for high risk patients and for standard risk patients who are MRD positive post-transplant. Funding This trial is funded by Cancer Research UK (C9203/A24078), Sanofi Genzyme and Celgene : A BMS company. Sanofi Genzyme and Celgene: A BMS company provide study drug and unrestricted educational grants to support study coordination. This work is also supported by Core Clinical trials unit infrastructure from Cancer Research UK ( C7852/A25447). The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the abstract

Daratumumab Bortezomib and Dexamethasone in Transplant Ineligible Newly Diagnosed Elderly Myeloma Patients - a Trial By Asian Myeloma Network

Background: Transplant ineligible (TI) newly diagnosed Multiple Myeloma (NDMM) patients have inferior outcomes compared to that of a transplant population. This led to investigation of therapies with novel mechanisms of action to improve outcomes in this group. MAIA and ALCYONE studies have showed impressive outcomes in this group of patients. However, significant toxicities are a concern when delivering multiple anti-myeloma drugs concurrently in a continuous schedule in elderly patients. In this context, the efficacy and safety of Daratumumab, Bortezomib (finite) and dexamethasone in NDMM remains unknown. Aims: In this study, we investigated the combination of Daratumumab Bortezomib (in a finite schedule), and dexamethasone (DVd) followed by Daratumumab as maintenance in transplant ineligible TI NDMM patients from Asia (NCT03695744). Methods: This is a prospective, open-label, single-arm, phase 2 study of TI NDMM patients conducted by Asian Myeloma Network across three hospitals in Singapore. The primary end point was overall response rate. Secondary end points included progression free survival, overall survival, toxicity &amp; safety, duration of response, minimal residual disease (MRD) and sustained MRD negativity. The study was approved by SingHealth Centralised IRB (CIRB No 2018/2730). Patients with confirmed diagnosis of MM, fulfilling inclusion / exclusion criteria were enrolled after signing informed consent. Patients received IV daratumumab 16mg/kg weekly in weeks 1-9, Q3 weekly from weeks 10 to 24 and Q4 weekly from week 25 onwards. Subcutaneous Bortezomib 1.3mg/m 2 and Dexamethasone 40mg (20mg for patients &amp;gt;75 years old) once weekly were administered for 9 months, followed by daratumumab maintenance until progression or toxicity. Response assessments were as per IMWG criteria and serial QOL data was also collected. Regular safety reviews were performed from recruitment of first patient by an independent committee. Here we report the protocol specified interim analysis of safety and efficacy end points. Results: From Oct 2019 till Sep 2021, we enrolled 27 patients. Median age was 74.3 years (range 70.5 to 79.2 years; 13/27 patients were &amp;gt;75years). 13 male and 14 were female patients. Ethnic distribution was 20 Chinese, 3 Malay, 3 Indian and 1 Others. ECOG performance status was 0 in 5(19%), 1 in 16(59%) and 2 in 6(22%) patients respectively. 11(41%) and 6(22%) patients belonged to Stage II and III ISS respectively. 14(52%) patients had CrCl &amp;lt;60ml/Min. 26(96%) patients experienced any grade adverse event with 17 experiencing a grade 3/4 event. Most common adverse events were infections, gastrointestinal disorders, peripheral neuropathy, and infusion related reactions. All grade and grade 3/4 AEs were relatively low, particularly haematological, given the absence of drugs known to cause significant myelotoxicity. Detailed AEs and SAEs are tabulated in Table 1. Three patients have died, of which one was due to a treatment related infection, while two others were unrelated (1 - suicide secondary to known mental illness, 1 - accidental fall &amp; cervical spine injury). At data cut off (15 Oct 2022), 26 out of 27 patients had a response with 4(14.8%) sCR, 3 (11.1%) CR, 14 (51.9%) VGPR and 5 (18.5%) PR (1 missing assessment) giving an ORR of 96.3%. Median duration on Daratumumab was 16.3 mos and Bortezomib was 8 mos. 6 patients (22.2%) have experienced disease progression. With a median follow-up of 17.6 months, the 18-month progression free survival and overall survival were 65.4% &amp; 89% respectively (median PFS and OS not estimable). Follow-up is on-going and we aim to report long-term survival, FISH/ cytogenetic &amp; MRD results, toxicity and QOL data in future. Conclusion: DVd with Bortezomib in a finite schedule and Daratumumab maintenance achieved highly efficacious responses in elderly TI NDMM. Though this is a small study, toxicity rates here compare favorably to that noted in larger Phase 3 studies with quadruplets (Alcyone) and continuous triplet regimen as in the MAIA study. Whilst using novel agents like CD38 monoclonals upfront clearly improves responses and survival, minimizing toxicities without compromising efficacy by careful limitation of long-term concurrent exposure to multiple anti-myeloma drugs in an elderly population could help improve safety and quality of life. DVd could be an effective alternative in some elderly TI NDMM patients.

Durable MRD and Imaging-Negative Remission ≥ 5 Years Post-Therapy Predicts Long-Term Progression-Free Survival in Multiple Myeloma Patients - a Single-Center Observational Study

Introduction With the advent of modern multiple myeloma (MM) therapies, a significant proportion of patients can achieve durable clinical remission. Minimal residual disease (MRD) reflects depth of response and is a powerful predictor of progression-free survival (PFS) (Munshi et al, JAMA Oncology 2017). Although sustained MRD negativity (defined by IMWG as MRD-negative on two occasions, minimum one-year apart) is associated with improved PFS, there is continued long-term relapse in these patients. A recent study reported a 10-year PFS of 88% in MM patients who are MRD-negative &amp;gt; 3 years after total therapy (Mohan et al, Blood Advances 2022). In the current era of regular MRD testing in MM care, we aimed to estimate the 10-year PFS of unselected MM patients who are MRD and imaging-negative ≥ 5 years after latest therapy, using our single-center data. Methods MRD testing was introduced for MM patients in remission at the Icahn School of Medicine at Mount Sinai (ISMMS) in 2017. Therefore, we systematically reviewed all patients with MRD results in the ISSMS MM registry between July 2017 and December 2022. Next-generation multi-parametric flow cytometry (NGF) was used to detect MRD from 2017 to 2021, with the addition of next-generation sequencing (NGS) from 2021 onwards. MRD-negativity was defined as &amp;lt;1 in 10 5 by NGF or &amp;lt;1 in 10 6 by NGS, and one representative MRD result per year was taken for analysis. Whole-body positron emission tomography (PETCT) and MRI were used to evaluate bone or extra-medullary (EM) disease. Detailed retrospective chart review of patients with sequential MRD-negative results was conducted to identify those with durable clinical, MRD, and imaging negative remission. PFS was evaluated using Kaplan-Meier curves and survival estimates. Results Between 2017 and 2022, 1703 MM patients underwent MRD testing at our center. Of these patients, we have so far identified 92 patients who were in CR, MRD and imaging-negative ≥ 5 years after the start of latest therapy. The estimated 10-year PFS in our cohort was 91.4% (95% CI [0.833 ,1]; Figure 1). With a median follow-up time of 5.9 years (4.6 to 12.6 years), the majority of our cohort (75%) were off-therapy at last follow-up with a median time-off-therapy of 2.5 years. In terms of baseline patient and disease characteristics (Table 1), 57.6% patients were white and 60.9% were male. Most patients were ISS stage I (51.1%) with standard-risk cytogenetics (78.2%) at diagnosis. A much smaller proportion of our cohort had any adverse cytogenetics, including gain1q (13%) and del17p or TP53 mutation (7.6%). The majority of patients were in their first remission after frontline therapy (52.2%), with 33.7% having received autologous stem cell transplant (ASCT) first-line. A smaller proportion of the cohort had received salvage treatment; 31.5% had received two lines, 16.3% had received ≥ 3 lines. Four patients relapsed in this cohort (4.3%) and one patient died of a non-MM related cause. Of the patients who progressed, 2 relapsed with isolated biochemical disease and 2 with predominantly EM disease. Both biochemical relapses were preceded by conversion to MRD positivity by NGF 6 months to 1 year prior, whereas those relapsing with EM disease remained MRD negative. Three patients had been off-treatment between 1 to 4 years prior to clinical relapse and the fourth patient progressed whilst on maintenance treatment. Conclusion We report single-institution MRD data on unselected MM patients who have durable MRD and imaging-negative remission for at least 5 years from their latest line of therapy. The estimated 10-year risk of disease-progression in our cohort is around 8.6%, with the majority of patients being off-therapy. The low rate of disease-progression at 10 years demonstrates that a proportion of MM patients do not suffer multiple relapses and may therefore be potential candidates for discontinuation of maintenance. From our data, these patients are more often ISS stage I, have standard risk cytogenetics and achieve deep responses to frontline therapy. A smaller proportion of patients are able to achieve this landmark even after salvage therapies. This may be increasingly possible in the era of monoclonal antibodies and T cell redirection therapies. Analysis of larger real-world MM cohorts is needed to elucidate whether sustained MRD-negative remission at 5 years can truly predict long-term disease-free survival and possible cure.

Gut Microbiota Diversity and Composition Is Associated with High-Risk Myeloma

Background: High-dose melphalan conditioning followed by autologous stem cell transplantation (ASCT) is standard therapy for newly diagnosed multiple myeloma (MM) patients with standard-risk (SR) or high-HR disease. Despite significant improvements in the depth of response by induction therapy prior to ASCT and consolidation and maintenance therapy post-ASCT, most MM patients with HR cytogenetics relapse quickly post-ASCT with a median PFS ranging between 1 and 2 years. It remains unclear as to why patients identified as relapse earlier than those with SR disease (SR). We ask whether the variability in outcome is due to differences in the diversity and composition of the gut microbiome given its role as a predictor and modulator of tumorigenesis, anti-tumor immunity and response to therapy. Two preclinical studies have shown progression of MM is accelerated by a T H17-associated gut commensal (Calcinotto et al. Nat Commun, 2018) and nitrogen-cycling bacteria (Zhu et al. Microbiome, 2020). In MM patients, lower peri-engraftment diversity predicted inferior outcomes after ASCT (Khan et al. Blood, 2021) and sustained minimal residual disease-negativity was associated with butyrate-producing bacteria and plant-based diets (Shah et al. Clin Cancer Res, 2022). In this study, we analyzed the association between gut microbiota and HR cytogenetic features in MM patients in the ASCT setting. We also determined the cause-and-effect relationship between gut microbiota and disease progression in the 5TGM1 mouse model. Methods and Results: We prospectively collected stool samples from 55 MM patients at time of melphalan conditioning (pre-ASCT), engraftment (72hrs of absolute neutrophil count ≥ 500/mcL), and 60-120 days post-ASCT. The median age of patients (35 males, 20 females) was 63.1 (range 45.6-77.2) years. After a median follow-up of 54 months (range 1-81), the median PFS of patients was 37 months (range 1- 76). We profiled the gut microbiome of SR (n=29) and HR (n=26) MM patients using 16S rRNA sequencing of the V4-V5 region. Amplicon sequence variants (ASV) were annotated against the NCBI 16S database using BLAST. We chose to identify gut microbiota features associated with HR cytogenetics in samples during peri-engraftment when microbial dysbiosis and impaired immune function is most pronounced. The alpha diversity was higher in HR patients using Inverse Diversity index (p&amp;lt;0.020). However, we did not observe significant differences in beta-diversity between groups. Random forest prediction classifier method and Shapley Additive exPlanations (SHAP), a post-hoc explainability algorithm identified Schaalia, Streptococcus, Bifidobacterium with the highest variable of importance (Fig. 1A) These findings were further validated by linear discriminant analysis of effect size (LEfSe). To establish causality, we generated two isogenic C57BL/KaLwRij strains that harbor differences in the complexity and richness of naturally occurring gut microbiota, using complex microbiota targeted rederivation. We observed significant baseline differences in richness (p&amp;lt;0.001), β-diversity (Bray Curtis, p=0.0001), hierarchical clustering and relative abundance among GM1 (low richness), GM4 (intermediate richness) and our original (Orig) GM strain (high richness) bred in our vivarium. The median overall survival for MM-bearing GM1, GM4 Orig GM mice were 31, 35 and 39 days post-5TGM1 transplantation (Fig. 1B). Conclusions: These studies suggest that distinct gut microbiota signatures are associated with HR and SR disease. Furthermore, our preclinical findings suggest a causal relationship between gut microbiota and severity of disease further highlighting the influence of the gut microbiome on progression of disease. Taken together, these findings provide the rationale for microbiota-centered interventions to improve immune-mediated control of MM and overturn resistance to therapy.

Analysis of Peripheral Blood and Bone Marrow Residual Disease Dynamics during Intensive Treatment and Maintenance in Patients with Multiple Myeloma Included in the GEM12MENOS65 and GEM14MAIN Clinical Trials

Introduction: In patients (pts) with multiple myeloma (MM), analysis of minimal residual disease (MRD) dynamics in bone marrow by Next Generation Flow Cytometry (NGF) has shown that conversion of minimal residual disease (MRD) status modulates the risk of progression. Mass spectrometry measuring low-level monoclonal immunoglobulins has shown potential for Peripheral-blood based Residual Disease (PRD) assessment. In this study, we have analyzed the clinical impact of PRD and MRD dynamics in MM pts receiving intensive treatment as per the GEM2012MENOS65 trial and during maintenance as per the GEM2014MAIN trial. Patients and Methods: In GEM2012MENOS65 trial, pts received six cycles of VRD-GEM induction, autologous stem cell transplantation conditioned with melphalan or busulfan plus melphalan and consolidation with two cycles of VRD-GEM. Patients achieving at least minimal response were offered to be enrolled in the GEM2014MAIN and randomized to maintenance with lenalidomide and low-dose dexamethasone (Rd) or Rd plus ixazomib for two years; if not reaching MRD negativity at this point, pts received three more years of Rd. PRD dynamics were analyzed separately in each trial by Quantitative Immunoprecipitation Mass Spectrometry with anti IgG/A/M, total k and total l beads using the EXENT ® Solution (The Binding Site, part of Thermo Fisher Scientific). MRD was analyzed following the recommendations of the IMWG and according to the Euroflow guidelines. Only those pts with available samples at all the time points analyzed (GEM2012: post-induction, post-ASCT and after-consolidation; GEM014: post-consolidation and after 1 and 2 years of maintenance) were included. Results: 134 out of the 458 pts enrolled in the GEM2012MENOS65 trial and receiving intensive treatment as per protocol were analyzed. At treatment completion (post-consolidation), PRD and MRD status were associated with almost identical prognostic value: median progression-free survival (mPFS) in PRD - not reached (n.r.) vs 3.98 years in PRD + cases (p=0.0006) and in MRD - n.r. vs 3.99 years in MRD + cases (p=0.0001). When dynamics were analyzed, sustained PRD and MRD negativitywas observed in 58 (43.3%) and 44 (33.8%) pts and sustained positivity in 42 (31.2%) and 57 (42.5%) pts, respectively. In 35 (26.1%) and 33 (24.6%) pts, PRD and MRD converted from positive to negative, respectively. Sustained PRD or MRD positivity at the 3 time points analyzed was associated with a significantly shorter PFS (mPFS 4.04 years, p=0.0042 and 3.9 years, p=0.0008, respectively), compared to pts remaining negative or converting from positive to negative, in whom mPFS was not reached (Fig.1A). 109 pts out of the 332 pts enrolled in the GEM2014MAIN trial and receiving maintenance treatment as per protocol were analyzed. At treatment completion (after two years of maintenance), PRD or MRD status were associated with comparable prognostic value: mPFS in PRD - and PRD + cases n.r. (p=0.0039) and in MRD - cases n.r. vs MRD + 2.87 years (p&amp;lt;0.0001). When dynamics were analyzed, sustained PRDand MRD negativity was observed in 68 pts (62.4%) and 61 (55.9%) pts and sustained positivity in 19 (17%) and 19 (17%) cases, respectively. In 17 (15.6%) pts PRD and MRD converted from positive to negative and in 5 (5.6%) and 10 (0.91%) from negative to positive, respectively. Sustained PRD positivity at the 3 time points analyzed was associated with a shorter PFS (p=0.0185), compared to pts who remained PRD - or converted from PRD + to PRD -, in whom mPFS was not reached. The mPFS in pts remaining MRD - or converting from MRD + to MRD - was similar and has not been reached yet; the mPFS in pts with sustained MRD positivity at the 3 time points analyzed or converting from MRD - to MRD + was also similar (2.99 years and 2.88 years, respectively). Interestingly, pts converting from PRD - to PRD + had a poorer PFS (mPFS of 0.86 years) as compared to patients converting from MRD - to MRD + (mPFS of 2.28 years) (Fig.1B). Conclusions: In conclusion, assessment of PRD and MRD dynamics during intensive treatment and maintenance allows to define more precisely the patients' clinical outcome as compared to the analysis of isolated time points. Reaching MRD or PRD negativity post-consolidation or after 2 years of maintenance is associated with a similar prognostic value, thus highlighting the clinical utility of mass spectrometry as an alternative, non-invasive technique for disease evaluation.

Recommendations on Minimal Residual Disease Monitoring in Acute Promyelocytic Leukemia Treated with Combination of All- Trans Retinoic Acid and Arsenic Trioxide

Background All- trans retinoic acid (ATRA)-arsenic trioxide (ATO) combination therapy significantly reduces acute promyelocytic leukemia (APL) relapse compared to ATRA combined with chemotherapy, leading to a cure rate of 80-90% in APL patients. The ideal frequency and duration of minimal residual disease (MRD) monitoring needs to be identified in the era of ATO. Methods A total of 1072 APL patients were enrolled in this study, comprising 855 from the APL2012 trial (NCT01987297) and 217 from our center between January 2018 to June 2022 (APL2018 study). The APL2018 protocol was adjusted for consolidation and maintenance therapy based on APL2012 (Chen et. al. PNAS 2021): In consolidation therapy, low-, intermediate-, and high-risk patients were performed following the ATO-group scheme of corresponding risk stratification in the APL2012 study. From December 2019, chemotherapy was no longer administered to high-risk group during consolidation phase. In maintenance treatment, ATO was replaced with oral arsenic realgar-indigo naturalis formula, and methotrexate was removed. RT-PCR or RQ-PCR was routinely used for MRD monitoring, detecting PML::RARA fusion genes in bone marrow before each consolidation and maintenance therapy. MRD testing was conducted every 3 months within the first year, every 6 months within the second year, and annually from 3 to 5 years after treatment. Results A total of 993 patients achieved complete remission (CR) after induction therapy. The negative MRD rates were observed in 61.7% of patients before 1 st consolidation , 95.4% before 2 nd consolidation, 99.3% before 3 rd consolidation, and 99.5% before maintenance therapy , respectively. The median time to achieve negative MRD was 57 (22-301) days with no significant difference between relapsed and non-relapsed patients (p=0.166). A total of 34 patients (30 in the APL2012 trial and 4 in the APL2018 study) relapsed, including 5 at low risk, 9 at intermediate risk, and 20 at high risk. The median recurrence time was 13.5 (3.5-49.0) months after achieving CR, with 94% (32/34) relapsing within 3 years of achieving CR. After induction remission, the risk of relapse decreased with time (44% occurred within the first year, 29% within the second year, 21% within the third year, and only 6% after three years, Figure 1). The median follow-up for the 179 evaluable patients after achieving CR was 39.7 (3.5 -64.6) months in the APL2018 group. The estimated 5-year disease-free survival (DFS) rates were 95.8% (95% CI 92.8-98.9). Prior to the 1 st, 2 nd, and 3 rd consolidation treatment, and before maintenance therapy, the estimated 5-year DFS rates for MRD positive and negative patients were 92.4% (95% CI 86.1-99.2) versus 97.8% (95% CI 94.8-100), p=0.100; 57.1% (95% CI 30.1-100) versus 97.3% (95% CI 94.7-100), p&amp;lt;0.001; 0 versus 96.5% (95% CI 93.1-100), p&amp;lt;0.001; 0 versus 96.8% (95% CI 94.0-99.6), p&amp;lt;0.001, respectively. The results of the APL2012 study were similar to those of APL2018. In the APL2018 study, the estimated 5-year cumulative incidence of relapse (CIR) was 2.51% (95% CI 2.48-2.54), which was 0%, 1.16% (95% CI 1.13-1.19), and 7.83% (95% CI 7.44-8.22) in the low-risk, intermediate-risk, and high-risk patients, respectively (p=0.057). The estimated 5-year CIR for the low to intermediate risk group was 0.74% (95% CI 0.73-0.75), which was statistically different from high-risk patients (p=0.019). The estimated 5-year CIR for MRD positive and negative patients prior to the 1 st and 2 nd consolidation treatments was 4.92% (95% CI 4.76-5.08) versus 1.10% (95% CI 1.08-1.12), p=0.194; 14.29% (95% CI 10.30-18.28) versus 2.08% (95% CI 2.05-2.11), p=0.010, respectively. Conclusion Our results show that MRD after one course of consolidation treatment, rather than before, is a crucial predictive factor for APL relapse. Patients with positive MRD after 1 st consolidation therapy have a high risk of relapse. ATRA-ATO based treatment has significantly reduced APL relapse, so the value of frequent MRD monitoring may be limited. It is recommended to implement an optimized MRD monitoring for risk stratification. For low to intermediate-risk patients and those with negative MRD after a consolidation treatment, the frequency and duration of MRD testing can be minimized. For high-risk patients with sustained MRD negativity for more than 3 years, MRD testing can be considered for discontinuation.

Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens.

Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole-genome and microenvironment single-cell RNA sequencing from upfront phase 2 trials using carfilzomib, lenalidomide and dexamethasone with daratumumab ( NCT03290950 ), we show how distinct genomic drivers including high APOBEC mutational activity, IKZF3 and RPL5 deletions and 8q gain affect clinical outcomes. Furthermore, evaluation of paired bone marrow profiles, taken before and after eight cycles of carfilzomib, lenalidomide and dexamethasone with daratumumab, shows that numbers of natural killer cells before treatment, high T cell receptor diversity before treatment, the disappearance of sustained immune activation (that is, B cells and T cells) and monocyte expansion over time are all predictive of sustained minimal residual disease negativity. Overall, this study provides strong evidence of a complex interplay between tumor cells and the immune microenvironment that is predictive of clinical outcome and depth of treatment response in patients with newly diagnosed multiple myeloma treated with highly effective combinations containing anti-CD38 antibodies.

Trial in Progress: A Phase 2 Study of Linvoseltamab for the Treatment of High-Risk Smoldering Multiple Myeloma (LINKER-SMM1)

Background and Significance Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder that precedes the development of multiple myeloma (MM). Traditionally, patients with SMM have undergone observation until progression to MM, but this paradigm can result in poor outcomes for some patients. Phase 3 clinical trials have demonstrated that early treatment with lenalidomide with or without dexamethasone can delay the development of end-organ damage and improve overall survival among SMM patients with high-risk features. Linvoseltamab (REGN5458) is a fully human B-cell maturation antigen (BCMA)×CD3 bispecific antibody that targets BCMA on plasma cells and CD3 on T cells, resulting in targeted T-cell-mediated cytotoxicity. In the Phase 1/2 LINKER-MM1 study, linvoseltamab alone induced deep and durable responses with a generally manageable safety profile in patients with relapsed/refractory MM (Lee et al. EHA. 2023). These data highlight the potential of novel immunotherapies with promising single-agent activity to be attractive therapeutics for early intervention to prevent progression to MM. Study Design and Methods LINKER-SMM1 is an open-label, Phase 2 study (NCT05955508) designed to evaluate the safety and efficacy of linvoseltamab monotherapy in adult participants with SMM who are at a high risk of progression to MM. High-risk criteria include having both ≥95% clonal plasma cells in the bone marrow (BM) and immunoparesis and/or ≥2 of the following: serum M-protein &amp;gt;2 g/dL, free light chain ratio &amp;gt;20, and BM plasma cells &amp;gt;20%. Participants must have a confirmed diagnosis of SMM within 5 years of enrollment, Eastern Cooperative Oncology Group performance status ≤1, and adequate organ function to be eligible. Participants will be excluded from enrollment if they have myeloma-defining events, uncontrolled infection, history of allogeneic stem cell transplantation, or received prior treatment for SMM. The study will take place at approximately 15 sites in Spain and will include two parts: Part 1 (safety run-in) to evaluate the preliminary safety and tolerability of linvoseltamab and Part 2 (expansion) to evaluate the clinical activity of the selected dosing regimen. In Part 1, at least 6 participants will receive linvoseltamab starting with a step-up schedule before reaching the full dose. All subsequent treatment with full-dose linvoseltamab will be given over 28-day cycles until completion of 24 cycles or occurrence of a protocol-defined reason for discontinuation. Assuming that initial safety is shown to be acceptable, an additional 34 participants will be enrolled in Part 2 according to the dosing regimen established in Part 1. Post-treatment safety monitoring will continue for up to 90 days after the last dose of linvoseltamab, and participants with an ongoing response will continue routine efficacy assessments until confirmed biochemical progression, start of non-protocol cancer therapy, or death. Long-term follow-up will continue for up to 5 years after the last dose of linvoseltamab. The primary endpoints in Part 1 are frequency of adverse events (AEs) of special interest, including grade ≥2 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and frequency and severity of treatment-emergent AEs. In Part 2, the primary endpoints are complete response (assessed by International Myeloma Working Group criteria) and minimal residual disease (MRD) negativity (10 -5 sensitivity) after 12 and 24 months of treatment. Secondary endpoints include cumulative safety, overall response rate, duration of response, sustained MRD negativity, biochemical and clinical progression-free survival (PFS), time to myeloma-defining event, time to initiation of first-line treatment for MM, and overall survival as well as immunogenicity and serum concentration of linvoseltamab over time. Exploratory endpoints include PFS after the start of first-line treatment for MM, adequacy of stem cell collection, patient-reported outcomes, and various biomarker changes. As this is a proof-of-concept study, results will be analyzed using descriptive statistics and no formal hypothesis testing is planned. Study accrual is planned to begin in Q4 2023.

The Phase 2 CARTITUDE-2 Trial: Updated Efficacy and Safety of Ciltacabtagene Autoleucel in Patients with Multiple Myeloma and 1-3 Prior Lines of Therapy (Cohort A) and with Early Relapse after First Line Treatment (Cohort B)

Introduction: CARTITUDE-2 (NCT04133636) is a phase 2, multicohort study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel), an anti-BCMA chimeric antigen receptor (CAR)-T cell therapy, in various populations of patients with multiple myeloma (MM). We previously reported 17-month median follow-up results from cohort A (1-3 prior lines of therapy [LOT] and lenalidomide [len]-refractory) and 18-month median follow-up results from cohort B (early relapse: ≤12 months after either autologous stem cell transplant [ASCT] or start of initial anti-myeloma treatment, if not transplanted). Cilta-cel is also under evaluation in patients with len-refractory MM after 1-3 LOT in the phase 3 CARTITUDE-4 study, which showed cilta-cel significantly prolonged progression-free survival (PFS) vs standard of care (HR, 0.26) at a median follow-up of 16 months. Here, we present updated efficacy and safety data from CARTITUDE-2 cohorts A and B, both with a median follow-up of ~29 months. Methods: Patients in cohorts A and B, all naive to CAR-T and/or anti-BCMA therapies, received a single cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg) 5-7 days after lymphodepletion. In both cohorts, the primary endpoint was minimal residual disease (MRD)-negativity (10 -5 threshold, by next-generation sequencing or next-generation flow cytometry). Management strategies were implemented after the phase 1b/2 CARTITUDE-1 study to reduce risk of movement and neurocognitive treatment-emergent adverse events (MNTs). Results: As of April 2023, 20 patients in cohort A had received cilta-cel (median follow-up, 29.9 months; 35% with high-risk cytogenetics; median 2 prior LOT; 95% refractory to last LOT; 40% triple-class refractory; 85% with prior ASCT). At the same data cut-off, 19 patients in cohort B hadreceived cilta-cel (median follow-up, 27.9 months; 16% with high-risk cytogenetics; 79% refractory to last LOT; 16% triple-class refractory; 79% with prior ASCT). All (100%) 17 MRD-evaluable patients in cohort A and 14 (93%) of 15 MRD-evaluable patients in cohort B achieved MRD negativity (10 -5 threshold). Eight (40%) of 20 patients in cohort A and 10 (53%) of 19 patients in cohort B sustained MRD negativity at 10 -5 for ≥6 months (Table 1). In the 20 patients in cohort A and 19 in cohort B, cilta-cel led to overall response rates of 95% (complete response or better [≥CR], 90%) and 100% (≥CR, 90%), respectively. Median PFS was not reached in either cohort, and 24-month PFS rates were 75% in cohort A and 73% in cohort B; respective 24-month overall survival rates were 75% and 84%. In cohort A, hematologic treatment-emergent adverse events (TEAEs) occurring between 17.1- and 29.9-month median follow-up included maximum grade (gr) 3/4 leukopenia in 1 patient (all gr,12 total; 60%), maximum gr 3/4 lymphopenia in 2 patients (all gr,16 total; 80%), and maximum gr 3/4 thrombocytopenia in 1 patient (all gr,16 total; 80%). In cohort B, no new patients reported hematologic TEAEs between 18.0- and 27.9-month median follow-up (Table 2). In cohort A, no new patients had CAR-T cell neurotoxicity, and no patients had a second primary malignancy (SPM). In cohort B, no new patients had MNTs, but other neurotoxicity (gr 2 sensory loss) occurred in 1 additional patient (all gr, 5 total; 26%) and resolved; and SPM (gr 4 choroid melanoma) occurred in 1 additional patient (all gr, 2 total; 11%). One new death (total 5) occurred in cohort A on day 666 due to progressive disease, and 1 new death (total 4) occurred in cohort B on day 749 due to cardiac arrest (not treatment related). Conclusions: These longer-term follow-up data show that patients treated with cilta-cel in earlier LOT, both those with len-refractory MM after 1-3 LOT (cohort A) and those with early relapse (cohort B), experienced deep and durable responses. No new CAR-T-related safety signals, except for 1 additional CAR-T cell neurotoxicity in cohort B, were reported. Cohort A provides insight into potential longer-term survival outcomes that may be expected in the phase 3 CARTITUDE-4 trial, which enrolled the same patient population but has shorter follow-up thus far. The long-term cohort B data highlight the durable efficacy of cilta-cel in patients who had early relapse; this is a functionally high-risk population for whom standard risk factors, including a high-risk cytogenetic profile, may not predict risk of relapse and for whom there is significant unmet need.

Immunophenotypic correlates of sustained MRD negativity in patients with multiple myeloma

The role of the immune microenvironment in maintaining disease remission in patients with multiple myeloma (MM) is not well understood. In this study, we comprehensively profile the immune system in patients with newly diagnosed MM receiving continuous lenalidomide maintenance therapy with the aim of discovering correlates of long-term treatment response. Leveraging single-cell RNA sequencing and T cell receptor β sequencing of the peripheral blood and CyTOF mass cytometry of the bone marrow, we longitudinally characterize the immune landscape in 23 patients before and one year after lenalidomide exposure. We compare patients achieving sustained minimal residual disease (MRD) negativity to patients who never achieved or were unable to maintain MRD negativity. We observe that the composition of the immune microenvironment in both the blood and the marrow varied substantially according to both MRD negative status and history of autologous stem cell transplant, supporting the hypothesis that the immune microenvironment influences the depth and duration of treatment response.

Prospective evaluation of minimal residual disease in the phase II FORTE trial: a head-to-head comparison between multiparameter flow cytometry and next-generation sequencing.

Limited data are available on the concordance between multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) for minimal residual disease (MRD) detection in a large trial for multiple myeloma (MM) patients. MRD was explored in the FORTE trial for transplant-eligible MM patients randomised to three carfilzomib-based induction-intensification-consolidation treatments and carfilzomib-lenalidomide (KR) vs R maintenance. MRD was assessed by 8-colour 2nd-generation flow cytometry in patients with ≥very good partial response before maintenance. NGS was performed in case of suspected complete response (CR) in a correlative subanalysis. Biological/prognostic concordance between MFC and NGS, conversion to MRD negativity during maintenance, and 1-year/2-year sustained MRD negativity were explored. Between September 28, 2015 and December 22, 2021, 2020 samples were available for MFC and 728 for the simultaneous MFC/NGS correlation in the "suspected CR population". Median follow-up was 62 months. Biological agreement was 87% at the 10-5 and 83% at the 10-6 cut-offs. A remarkable prognostic concordance was observed: hazard ratios in MFC-MRD and NGS-MRD-negative vs -positive patients were 0.29 and 0.27 for progression-free survival (PFS) and 0.35 and 0.31 for overall survival, respectively (p<0.05). During maintenance, 4-year PFS was 91% and 97% in 1-year sustained MFC-MRD-negative and NGS-MRD-negative patients (10-5), respectively, and 99% and 97% in 2-year sustained MFC-MRD-negative and NGS-MRD-negative patients, regardless of treatment received. The conversion rate from pre-maintenance MRD positivity to negativity during maintenance was significantly higher with KR vs R both by MFC (46% vs 30%, p=0.046) and NGS (56% vs 30%, p=0.046). The significant biological/clinical concordance between MFC and NGS at the same sensitivity suggests their possible use in the evaluation of one of the currently strongest predictors of outcome. Amgen, Celgene/Bristol Myers Squibb, Multiple Myeloma Research Foundation.

CARTITUDE-1 final results: Phase 1b/2 study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma.

8009 Background: Heavily pretreated patients (pts) with relapsed/refractory multiple myeloma (RRMM) treated with standard of care therapy have median overall survival (OS) of ~12 months (mo). In the single-arm, phase 1b/2 CARTITUDE-1 study (NCT03548207), pts received a single infusion of ciltacabtagene autoleucel (cilta-cel), a CAR-T cell therapy targeting BCMA. At the final protocol-specified analysis (27.7-mo median follow-up [MFU]), overall response rate (ORR) was 98%, with 83% stringent complete response (CR); 27-mo rates of progression-free survival (PFS) and OS were 55% and 70%, respectively. Here, we report study closeout results. Methods: Eligible pts received ≥3 prior lines of therapy (LOT) or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD); and had received prior PI, IMiD, and anti-CD38 antibody therapy. Primary endpoint was ORR and safety; secondary endpoints included PFS, OS, and minimal residual disease (MRD) negativity at 10-5. Results: 97 pts received cilta-cel (median age 61 years [y]; median 6 prior LOT; 42% penta-drug refractory; 88% triple-class refractory; 99% refractory to last LOT). As of October 14, 2022, MFU was 33.4 mo (range, 1.5-45.2). Median (m) duration of response was 33.9 mo (95% CI, 25.5–not estimable [NE]). mPFS was 34.9 mo (95% CI, 25.2–NE), with an estimated 47.5% progression free and alive at 36 mo. mOS was not reached (NR), with an estimated 62.9% survival at 36 mo. Of 49 MRD-evaluable pts, 26 had MRD negativity sustained for ≥12 mo, of which 20 had sustained MRD-negative ≥CR. mPFS was NR in these subgroups (Table). 18 pts were MRD negative with ≥CR at 24 mo post infusion. No new safety signals and no new neurotoxicity events were reported since the 27.7-mo MFU. 6 new cases of second primary malignancy were reported, including 2 cases of basal cell carcinoma and 1 case each of myelodysplastic syndrome, B-cell lymphoma, melanoma, and prostate cancer. 5 additional deaths occurred (progressive disease [PD], n=3; pneumonia and sepsis, n=1 each [both unrelated to cilta-cel]), for a total of 35 (PD, n=17; unrelated to cilta-cel, n=12; related, n=6). Conclusions: Longer mPFS was observed after a single infusion of cilta-cel than any previously reported therapy in heavily pretreated pts with RRMM. Achieving CR and/or sustained MRD negativity was associated with prolonged PFS. Pts continue to be followed for safety and survival in the 15-y CARTINUE long-term study (NCT05201781; MMY4002). Clinical trial information: NCT03548207 . [Table: see text]

Evaluation of ctDNA in a phase I/II trial in relapsed or refractory large B‐cell lymphoma of epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T‐cell–engaging antibody

Introduction: The emergence of novel, more potent therapeutics in the treatment of patients with large B-cell lymphoma (LBCL) has resulted in higher rates of responses and highlighted a need for additional methods, such as minimal residual disease (MRD), to determine the depth and quality of response and potentially guide duration of treatment. Epcoritamab (DuoBody®-CD3xCD20) is a subcutaneously (SC) administered bispecific antibody (bsAb) that simultaneously binds to CD3 on T cells and CD20 on malignant B cells, inducing activation and cytotoxic activity of T cells for the killing of malignant CD20 B cells. In the pivotal epcoritamab trial, a correlation was demonstrated between MRD by clonoSEQ® (Adaptive Biotechnologies) and long-term outcomes. These findings led to additional analyses to further clarify the clinical use of ctDNA. As the evaluation of ctDNA in LBCL has not been standardized, we have expanded our investigation of the utility of ctDNA measurements from the initial analysis with the clonoSEQ assay to the AVENIO ctDNA assay (Roche). Here we present additional exploratory analyses of ctDNA using the AVENIO assay. Methods: Patients with relapsed/refractory (R/R) LBCL enrolled in EPCORE NHL-1 expansion phase (NCT03625037) received SC epcoritamab administered in 28-d cycles. ctDNA was measured using the clonoSEQ and AVENIO ctDNA assays at protocol-specified timepoints. Specimens were collected in EDTA and Streck cfDNA tubes, respectively, based on the recommended sample type at the time of study initiation. Plasma ctDNA levels were quantified per sample as count per mL (CPM) and mutant molecules per mL (MMPM) for clonoSEQ and AVENIO, respectively. Results: ctDNA quantification was concordant between the assays when within the dynamic range of the clonoSEQ assay (>80% in paired samples tested); however, a greater sensitivity of the AVENIO assay was observed, allowing further exploratory analyses of ctDNA using this platform. Consistent with prior observations, baseline ctDNA levels were associated with key clinical parameters, including LDH, TMTV, ECOG, and IPI. In patients who responded to epcoritamab, ctDNA levels decreased rapidly, with the majority of patients achieving CR having a deep ctDNA response by C3D1. Additional patients achieved MRD-negative status at later evaluations with continued therapy. MRD-negative status at C3D1, measured as absolute or relative change from baseline, was associated with longer progression free survival (PFS) and sustained MRD negativity throughout the duration of treatment. The research was funded by: Genmab A/S and AbbVie Keywords: Aggressive B-cell non-Hodgkin lymphoma, Liquid biopsy, Minimal residual disease Conflicts of interests pertinent to the abstract. D. Soong Employment or leadership position: Genmab C. Thieblemont Consultant or advisory role: AbbVie, Amgen, BMS/Celgene, Cellectis, Gilead Sciences, Kite, Novartis, Roche, Incyte, Janssen, Takeda Honoraria: AbbVie, Amgen, Bayer, Cellectis, Gilead Sciences, Incyte, Janssen, Kite, Novartis, Takeda Research funding: BMS/Celgene, Hospira, Roche Educational grants: AbbVie, Amgen, BMS/Celgene, Cellectis, Gilead Sciences, Kite, Novartis, Roche J. Karavitis Employment or leadership position: Genmab B. Hess Consultant or advisory role: ADC Therapeutics, BMS P. Caimi Consultant or advisory role: ADC Therapeutics, BMS, Beigene, Genentech, Lilly, Takeda, Kite pharma, Incyte, Novartis, MEI pharma Research funding: Genentech, Abbvie, ADC Therapeutics T. Feldman Consultant or advisory role: AbbVie, AstraZeneca, Epizyme, Genmab, Gilead/Kite, Karyopharm, Takeda, Seagen Other remuneration: Seagen: Speakers Bureau M. Hutchings Consultant or advisory role: AbbVie, Celgene, Genmab, Janssen, Roche, Takeda Research funding: Celgene, Genentech, Genmab, Incyte, Janssen, Novartis, Roche, Takeda (All Paid to Institution) A. Sureda Employment or leadership position: AbbVie Consultant or advisory role: Takeda, BMS/Celgene, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, Kite, Mundipharma, Bluebird Honoraria: Takeda, BMS/Celgene, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, Kite Research funding: Takeda Educational grants: Takeda, BMS/Celgene, Roche Other remuneration: Takeda, BMS/Celgene, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, Kite: Speakers Bureau E. Szafer-Glusman Employment or leadership position: AbbVie M. Sacchi Employment or leadership position: Genmab M. Jure-Kunkel Employment or leadership position: Genmab N. Adya Employment or leadership position: Genmab C. Chiu Employment or leadership position: Genmab

MagnetisMM-7: An open-label, multicenter, randomized phase 3 study of elranatamab versus lenalidomide in post-transplant patients with newly diagnosed multiple myeloma.

TPS8066 Background: Elranatamab is a humanized bispecific antibody targeting B cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells. Elranatamab has shown promising efficacy and acceptable safety in pts with relapsed and/or refractory multiple myeloma (MM). The aim of the MagnetisMM-7 study is to evaluate elranatamab monotherapy vs lenalidomide monotherapy in pts with newly diagnosed MM (NDMM) after undergoing autologous stem cell transplant (ASCT). Methods: MagnetisMM-7 is an ongoing, open-label, 2-arm, multicenter, randomized phase 3 study estimated to enroll ~700 pts. ClinicalTrials.gov ID: NCT05317416. Pts are randomized to receive either subcutaneous elranatamab or oral lenalidomide once daily. After initial step-up dosing, two alternative dosing regimens of elranatamab are examined. The primary endpoint is progression-free survival (PFS) assessed by blinded independent review per International Myeloma Working Group (IMWG) criteria (up to ~5 y). Secondary endpoints include overall survival, minimal residual disease (MRD) negativity rate at 12 mo after randomization per IMWG criteria as assessed via next-generation sequencing (NGS), sustained MRD negativity rate at 24 mo after randomization as assessed via NGS, PFS by investigator, duration of MRD negativity, complete response (CR) rate, duration of CR, safety, quality of life, immunogenicity, and pharmacokinetics. Key inclusion criteria are: ≥18 y; a diagnosis of MM with measurable disease according to IMWG criteria; history of induction therapy for NDMM, followed by high dose therapy and ASCT with or without consolidation; partial response or better according to IMWG criteria; identification of the dominant malignant clone; and Eastern Cooperative Oncology Group performance status ≤1. Randomization must occur ≤120 d from ASCT; for pts who receive consolidation therapy after ASCT, randomization must occur ≤60 d of consolidation and ≤7 mo of ASCT. Key exclusion criteria are: plasma cell leukemia; amyloidosis; Waldenström's macroglobulinemia; POEMS syndrome; known active CNS involvement or clinical signs of myelomatous meningeal involvement; previous MM maintenance treatment; prior treatment with BCMA-targeted therapy; any other active malignancy ≤3 y of enrollment; active, uncontrolled bacterial, fungal, or viral infection; and previous administration of an investigational drug or vaccine ≤30 d or 5 half-lives preceding the first dose of study treatment. As of February 2023, the study is open and enrolling at 29 sites in 13 countries. Clinical trial information: NCT05317416 .

MagnetisMM-6: An open-label, multicenter, randomized phase 3 study of elranatamab + daratumumab + lenalidomide (EDR) versus daratumumab + lenalidomide + dexamethasone (DRd) in transplant ineligible (TI) patients with newly diagnosed multiple myeloma (NDMM).

TPS8065 Background: Elranatamab, a humanized bispecific antibody targeting B cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells, has shown promising efficacy and acceptable safety in clinical studies, as monotherapy (MagnetisMM-3, NCT04649359) and in combination with daratumumab (MagnetisMM-5, NCT05020236), in the treatment of patients with relapsed/refractory multiple myeloma (RRMM). Despite recent advances in the treatment of NDMM, MM remains incurable and more effective treatment options are needed. The aim of the MagnetisMM-6 study (NCT05623020) is to evaluate EDR versus DRd for TI patients with NDMM. Methods: MagnetisMM-6 is an ongoing, open-label, 2-arm, multicenter, randomized phase 3 study estimated to enroll ~646 patients. There are 2 parts: Part 1 evaluates the safety and recommended phase 3 dose (RP3D) of EDR: Part 2 evaluates the efficacy and safety of EDR at RP3D vs DRd in TI patients with NDMM. TI is defined as age ≥65 or age &lt; 65 with comorbidities impacting the possibility of transplant. The primary endpoints of Part 2 are minimal residual disease (MRD) at 12 mo and progression-free survival. Secondary endpoints include overall and sustained MRD negativity rates, duration of MRD negativity, objective response rate, complete response (CR) rate, time to response, duration of response, duration of CR, overall survival, safety, quality of life, immunogenicity, and pharmacokinetics. Part 1 includes TI patients with NDMM as well as patients with RRMM who have received 1−2 prior lines of therapy including ≥1 immunomodulatory drug and ≥1 proteasome inhibitor. Part 2 includes only TI patients with NDMM. Key inclusion criteria are: ≥18 y; a diagnosis of MM (according to International Myeloma Working Group [IMWG] criteria); an ECOG performance status ≤2; and measurable disease based on IMWG criteria (serum M-protein ≥0.5 g/dL, urinary M-protein excretion ≥200 mg/24 hr, or involved serum free light chain [FLC] ≥100 mg/L and abnormal serum immunoglobulin κ:λ FLC ratio [ &lt; 0.26 or &gt; 1.65]). Key exclusion criteria are: smoldering MM; monoclonal gammopathy; Waldenström’s macroglobulinemia; plasma cell leukemia; active, uncontrolled bacterial, fungal, or viral infections; previous systemic treatment for MM (NDMM patients only); previous treatment with a BMCA-directed therapy or anti-CD38-directed therapy ≤6 mo of the first dose of study treatment (RRMM patients only); or stem cell transplant ≤3 mo of the first dose of study treatment or active graft versus host disease (RRMM patients only). As of February 2023, the study is open and enrolling at 9 sites in 5 countries. Clinical trial information: NCT05623020 .