Diagnosis Of MM Research Articles

Optimal cut-off values and diagnostic significance of clinical laboratory indicators in newly diagnosed multiple myeloma

ObjectiveThis study aims to identify clinical laboratory parameters for the diagnosis of newly diagnosed multiple myeloma (NDMM), establish optimal cutoffs for early screening, and develop a diagnostic model for precise diagnosis.MethodsThe study conducted a retrospective analysis of 279 NDMM patients and 553 healthy subjects at Zhejiang Province People’s Hospital between January 2008 and June 2023. Multifactor LR was employed to explore clinical laboratory indicators with diagnostic value for NDMM, determine optimal cutoff values and contract a diagnostic model. The diagnostic efficacy and clinical utility were evaluated using receiver operating characteristic curves (ROC), sensitivity, specificity, and other indicators.ResultsMultifactor analysis revealed that hemoglobin (Hb), albumin (Alb), and platelet distribution width (PDW) were significant diagnostic factors for NDMM. Optimal cutoff values for Hb, Alb, and PDW in MM diagnosis were determined, and the results showed a significant increase in the probability of NDMM diagnosis when Alb was below 39.3 g/L, Hb was below 11.6 g/dL, and PDW was below 14.1 fL. The diagnostic model constructed from the development cohort demonstrated a high area under the ROC curve of 0.960 (95% CI 0.942–0.978) and exhibited good sensitivity (0.860), specificity (0.957). The area under the curve (AUC) value of the diagnostic model in the external validation cohort was 0.979, confirming its good diagnostic efficacy and generalization.ConclusionsThe optimal cutoff values for Hb, Alb, and PDW and the diagnostic model designed in the study provided good accuracy and sensitivity for the initial screening and diagnosis of NDMM.

Exploring the role of the combination of FDG-PET plus whole body MRI for staging patients with high-risk smoldering myeloma: A prospective trial.

7569 Background: According to IMWG criteria, Smoldering Multiple Myeloma (SMM) is an asymptomatic stage characterized by M-spike < 3 g/dl serum and/or bone marrow plasma cells infiltration between 10-59% in absence of myeloma-defining events and organ damage. In SMM setting, it is really important to differntiate high risk SMM (HR-SMM), in which treatment could be available thanks to clinical trials. 2016 IMWG criteria state that detection of bone lesions is mandatory for diagnosis of multiple myeloma and essential for diagnosis of SMM. It is really important to clarify in SMM the best imaging analysis in order to perform a correct diagnosis, and particularly it is necessary to define if the combination of FDG-PET/TC and WB-MRI could improve the assessment of lytic lesions and so the discrimination between high risk SMM and symptomatic MM. Methods: In our Institution we conducted a prospective trial, based on integrated new generation imaging, aiming to improve patients’ stadiation and to define its prognostic implications. From January 2021 to January 2024, we performed a prospective trial enrolling 26 consecutive newly diagnosed high risk SMM, according to IMWG, in which WB-MRI was performed according to MY-RADS criteria in combination with FDG PET-CT (median age 56; range 36-85). Results: Our comparison between WB-MRI and FDG PET-CT, showed a discordance between the two imaging modalities in 4/26 (15%) cases. In particular, in 3/26 (12%) cases WB-MRI showed bone lesions that have lead to symptomatic MM diagnosis according to IMWG criteria, while PET-CT was negative. In one case, PET-CT showed a diffuse uptake, not diagnostic for MM, while WB-MRI was negative. WB-MRI showed a 100% of accuracy in detecting SMM and MM. Therefore, WB-MRI has lead to a modification of the prognosis and treatment approach (observation in SMM vs treatment in symptomatic MM) in 3/26 patients (11%) (i.e. Figure 1, with DWI of C2 lesion). Furthermore, in 5/23 (22%) cases of confirmed SMM WB-MRI showed a slight diffuse alteration pattern of bone marrow without any overt lytic bone lesion, which could be a potential prognostic evidence. Conclusions: Our results support a fundamental role of WB-MRI in combination with FDG PET/CT in the stadiation of patients with newly diagnosed high risk SMM, which could modify prognosis and treatment, improving the differentiation with symptomatic MM. In particular, combination of WB-MRI plus FDG PET/CT could be more accurate in the detection of bone lesions than FDG PET/CT alone, being able to anticipate symptomatic MM diagnosis and consequently its treatment. Moreover, a diffuse pattern of marrow involvement could be detected in some HR-SMM patients without any overt lytic lesions: it is questionable if this group of patients is associated with a rapid progression in lytic lesions and so in symptomatic MM diagnosis. Prospective data on evolution of these patients are pending.

Exploring the role of the combination of FDG PET plus whole body MRI for staging newly diagnosed and relapsed/refractory multiple myeloma: A prospective trial.

7512 Background: The integration of FDG-PET/TC and WB-MRI in the diagnosis of MM may results in higher accuracy to detect bone lesion compared to them alone. This could be translated into better outcomes if early detection of myeloma defining events leads to earlier induction or re-induction treatments. Methods: In our Institution, from January 2021 to January 2023, we performed a prospective trial enrolling 73 consecutive newly diagnosed and relapsed/refractory MM (median age 63 years - range 85-35), according to IMWG, in which WB-MRI was performed according to MY-RADS criteria in combination with FDG PET/CT. 31/73 (42%) had a newly diagnosed MM, 25/73 (34%) were in follow-up after autologous stem cell transplantation and 17/73 (23%) patients were affected by relapsed/refractory MM. Subsequently, in 2 cases WB-MRI were aborted and not diagnostic so patients were excluded from the final analysis. Results: In these 71 patients: 52/71 (73%) cases of concordance of WB-MRI and 18F PET-CT, 18/71 (25%) cases of discordance. In this group 15/18 (83%) cases FDG-PET/CT was negative and WB-MRI showed positive findings according to MYRADS criteria (5 micronodular pattern, 9 diffuse pattern e 1 focal pattern) (Figure 1 Newly diagnosed MM – diffuse pattern in WB-MRI, PET negativity), in 3/18 (17%) FDG-PET/CT was positive for focal lesions and WB-MRI was negative. IMWG criteria showed concordance with WB-MRI data in 16/18 (89 %), in 2/18 (11%) case of follow-up after autologous stem cell transplantation PET-CT showed a relapsed focal lesion while WB-MRI was negative. Accuracy of WB-MRI was 69/71 (97%), whilst PET-CT was 55/71 (77%). These results are in agreement with the literature data about the ability of WB-MRI to depict diffuse and micronodular pattern of bone marrow infiltration. Conclusions: Our preliminary results support a potential complementary role of WB-MRI and FDG PET/CT findings, on the management of patients with MM at both diagnosis and relapse. To date, there is no wide availability of WB-MRI because in concerning about costs and technical issues, but data are consistent with its possible future leading role in MM diagnostic work-up.

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

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

MagnetisMM-30: A phase 1b, open-label study of elranatamab in combination with iberdomide in patients with relapsed or refractory multiple myeloma (RRMM).

TPS7577 Background: Elranatamab (ELRA) is a humanized B-cell maturation antigen (BCMA)–CD3 bispecific antibody (BsAb). Single-agent ELRA induced deep and durable responses with a manageable safety profile in patients (pts) with RRMM enrolled in the phase 2 registrational MagnetisMM-3 study (NCT04649359; Lesokhin et al, Nat Med 2023). Iberdomide (IBER) is a novel CELMoD[TM] agent that induces enhanced antimyeloma tumoricidal and immunomodulatory activity in pts with RRMM (Lonial et al, Lancet Haematol 2022). While IBER in combination with ELRA has not been evaluated clinically, it may provide additional benefit to pts with RRMM based on the mechanisms of action of this novel combination. Methods: MagnetisMM-30 is a phase 1b, open-label, prospective study evaluating the safety, efficacy, and pharmacokinetics of ELRA in combination with IBER in pts with RRMM. The study has 2 parts: Part 1 for dose-escalation and Part 2, randomized for dose optimization. After 2 step-up priming doses of ELRA, pts will receive subcutaneous ELRA weekly with IBER given daily for 21 days of each 28-day cycle. After ≥6 months (cycles) of treatment, pts with a partial response or better for ≥2 months are eligible for reduced dosing frequency of ELRA. Once the 2 combination dose levels (dose levels A and B) are selected from Part 1 as the recommended phase 2 doses for ELRA and IBER, pts in Part 2 will be randomized 1:1 (stratified by the number of prior lines of therapy [LOTs; 1 vs >1]) to dose levels A and B. Key inclusion criteria are pts aged ≥18 years with a MM diagnosis per IMWG criteria, Eastern Cooperative Oncology Group performance status of 0-1, adequate organ and bone marrow function, and disease relapsed or refractory to the last antimyeloma regimen per IMWG response criteria. Pts who received 2-4 or 1-3 prior LOTs, including ≥1 immunomodulatory drug (IMiD) and ≥1 proteasome inhibitor (PI), are eligible for Parts 1 and 2, respectively. All pts must have received ≥2 consecutive cycles of an IMiD-containing regimen and ≥2 consecutive cycles of a PI or PI-containing regimen. Key exclusion criteria are pts with stem cell transplant ≤12 weeks prior to enrollment; active, uncontrolled infection; prior treatment with BCMA-directed or CD3 redirecting therapy or prior CELMoD agents (ie, IBER or mezigdomide). This study is ongoing; Part 1 and Part 2 will enroll approximately 27 and 60 pts, respectively. Study endpoints are listed in the table. Clinical trial information: NCT06215118 . [Table: see text]

DNA Sequencing of CD138 Cell Population Reveals TP53 and RAS-MAPK Mutations in Multiple Myeloma at Diagnosis.

Multiple myeloma is a hematologic neoplasm caused by abnormal proliferation of plasma cells. Sequencing studies suggest that plasma cell disorders are caused by both cytogenetic abnormalities and oncogene mutations. Therefore, it is necessary to detect molecular abnormalities to improve the diagnosis and management of MM. The main purpose of this study is to determine whether NGS, in addition to cytogenetics, can influence risk stratification and management. Additionally, we aim to establish whether mutational analysis of the CD138 cell population is a suitable option for the characterization of MM compared to the bulk population. Following the separation of the plasma cells harvested from 35 patients newly diagnosed with MM, we performed a FISH analysis to detect the most common chromosomal abnormalities. Consecutively, we used NGS to evaluate NRAS, KRAS, BRAF, and TP53 mutations in plasma cell populations and in bone marrow samples. NGS data showed that sequencing CD138 cells provides a more sensitive approach. We identified several variants in BRAF, KRAS, and TP53 that were not previously associated with MM. Considering that the presence of somatic mutations could influence risk stratification and therapeutic approaches of patients with MM, sensitive detection of these mutations at diagnosis is essential for optimal management of MM.

An algorithm for conditional-fault local diagnosis of multiprocessor systems under the MM⁎ model

Diagnosis is a crucial subject for maintaining the reliability of multiprocessor systems. Under the MM⁎ diagnosis model, Sengupta and Dahbura proposed a polynomial-time algorithm with time complexity O(N5) to diagnose a system with N processors. In this paper, we propose a (α,β)-trees combination S(u,X,α,β) and give an algorithm to identify the fault or fault-free status of each processor for conditional local diagnosis under the MM⁎ model. According to our results, a connected network with a (α,β)-trees combination S(u,X,α,β) for a node u is conditionally locally (α+2β−3)-diagnosable at node u and the time complexity of our algorithm to diagnose u is O(α2β+αβ2). As an application, we show that our algorithm can identify the status of each node of n-dimensional star graph Sn if the faulty node number does not exceed 3n−8. Compared with existing algorithms, our algorithm allows more faulty nodes in a multiprocessor system.

Comparison of Time to Next Treatment or Death between Front-Line Daratumumab, Lenalidomide, and Dexamethasone (DRd) and Bortezomib, Lenalidomide, and Dexamethasone (VRd) in Transplant Ineligible Patients with Multiple Myeloma

Introduction: Daratumumab, lenalidomide, and dexamethasone (DRd) and bortezomib, lenalidomide, and dexamethasone (VRd) are the only two regimens that are considered as preferred per the National Comprehensive Care Network for transplant ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). While there are no head-to-head studies comparing clinical outcomes of DRd and VRd in this population, an indirect comparison (PEGASUS study [Durie et al., 2020]) has shown that DRd was associated with significantly lower risk of disease progression or death compared with VRd and Rd. This study aims at supplementing this information by comparing real-world time-to-next-treatment (TTNT) or death between NDMM TIE patients treated with front-line (FL) DRd or VRd. Methods: A retrospective cohort study was conducted for patients with NDMM who initiated FL DRd or VRd in Acentrus (1/1/2018 - 5/31/2023), an electronic medical record (EMR) database from academic and non-teaching hospitals in the United States. Patients were included if they had ≥2 records with an ICD-10-CM diagnosis code for MM, ≥6 months of data availability prior to first record with MM diagnosis (without use of antineoplastic agent), initiated FL treatment (initiation of DRd or VRd; index date) within 12 months of first record of MM diagnosis, and ≥90 days of data availability post-index. Patients with pre-index diagnosis of amyloidosis or other cancers and those who participated in a clinical trial before or during FL treatment were excluded. To limit the analysis to the TIE population, patients who had a record of a stem-cell transplant (SCT) before or during FL treatment and those who were <65 years old (used as proxy to SCT eligibility) were excluded. Patient characteristics were evaluated up to 12-months pre-index (baseline period). Patients were followed from the index date until earliest of date of initiation of a next line of treatment, death, or end of data availability. Medications received within 60 days from the date of the first MM antineoplastic agent were considered as FL therapy regimen. Next line of treatment was identified as initiation of a new antineoplastic agent (excluding corticosteroids) outside of FL therapy or re-treatment of FL after >90-day gap. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics between study cohorts, with variables with standardized differences <10% considered balanced. Weighted Kaplan-Meier (KM) curves and a doubly-robust Cox proportional hazards model adjusting for baseline variables remaining imbalanced after IPTW were used compare TTNT or death between study cohorts. Results: Overall, 149 and 494 patients were identified in the DRd and VRd cohorts, respectively. After weighting (N DRd weighted = 302, N VRd weighted = 341), most baseline characteristics in both cohorts were similar, including mean age (DRd: 75.3, VRd: 74.5), female sex (DRd: 48.9%, VRd: 45.8%), white race (DRd: 55.8%, VRd: 58.7%), black race (DRd: 8.8%, VRd: 11.3%), Medicare insurance coverage (DRd: 62.7%, VRd: 65.9%), and mean Quan-Charlson comorbidity index (DRd: 3.8, VRd: 3.6; Table 1). Some imbalances remained for mean age, race, ethnicity, and index year, thus they were additionally adjusted for in doubly-robust Cox model. The median duration of follow-up was 20.2 months and 21.5 months among DRd and VRd patients, respectively. A total of 98 (32.4%) DRd patients and 175 (51.2%) VRd patients received a subsequent line of therapy or died, with the median TTNT or death being 37.8 and 18.7 months in the DRd and VRd cohorts, respectively (hazard ratio: 0.58, 95% CI: 0.35, 0.81; p<0.001; Figure 1). KM estimates for patients remaining on FL therapy were significantly higher for DRd than VRd at 6 months (93.0% vs. 80.1%), 12 months (80.0% vs. 61.0%), 18 months (64.9% vs. 51.3%), and 24 months (60.2% vs. 42.9%). Conclusion: In this retrospective cohort study using EMR data, TIE NDMM patients who initiated DRd had a significantly longer time to next treatment or death than patients who initiated VRd. Results from this real-world study fills an unmet data gap by providing information on the comparative effectiveness evidence for DRd versus VRd among TIE NDMM patients. These findings support the use of DRd as an effective treatment option in the TIE NDMM patient population.

Safety of Elranatamab in Patients with Triple-Class Refractory Relapsed/Refractory Multiple Myeloma (RRMM) in Magnetismm-17, a North American Expanded Access Protocol

BACKGROUND In the phase 2, registrational MagnetisMM-3 (NCT04649359) trial, patients with RRMM who had not previously received a B cell maturation antigen (BCMA)-directed therapy (n=123) achieved an objective response rate of 61% with single-agent elranatamab (ELRA), a BCMA-CD3 bispecific antibody. Common treatment-emergent adverse events (TEAEs) included infections (70%; 40% grade [G] 3/4) and CRS (58%; all G1/2). Here we report on the safety of ELRA in the MagnetisMM-17 (MM-17; NCT05462639) trial, a North American Expanded Access Protocol (EAP). METHODS MM-17 is an ongoing, single-arm, open-label study for patients with triple-class refractory RRMM (refractory to ≥1 proteasome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 antibody), and who had no prior BCMA-directed therapy. Patients must be ≥18 years of age and have a confirmed diagnosis of MM, measurable disease by IMWG criteria, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1, adequate organ function, and no active, uncontrolled infection. The study is being conducted in the US and Canada. The primary objective is to provide access to ELRA for patients with RRMM and no access to comparable/alternative therapy. The secondary objective is to evaluate the safety and tolerability of ELRA. Patients received subcutaneous ELRA 76 mg once every week on a 28-day cycle after step-up doses of 12 and 32 mg during week 1. Dose frequency was reduced to once every 2 weeks (Q2W) after ≥6 cycles in patients with persistent response (≥partial response), and then from Q2W to Q4W after ≥6 Q2W cycles. Patients received ELRA until disease progression, unacceptable toxicity, withdrawal of consent, study termination, or ELRA becomes commercially available. TEAEs were graded by NCI CTCAE v5.0, except cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) which were graded according to the American Society for Transplantation and Cellular Therapy criteria (ASTCT). RESULTS As of April 28, 2023, 20 patients had enrolled in the trial. Median patient age was 72.5 years (range 53-82); 50% male, 85% white, and 15% Black/African American. At baseline, most patients had an ECOG PS of 1 (95%), and 40% had R-ISS disease stage III. Patients had a median of 4 prior lines of therapy (range 2-8); 95% and 35% of patients had triple-class and penta-drug refractory disease, respectively. At the time of data cut-off, 2 patients had discontinued due to progressive disease. Median treatment duration was 0.95 months (range 0.26-2.83); median relative dose intensity was 98.3% (range 48-105). TEAEs were reported in all 20 patients, with G3 or G4 events reported in 13 (65%). There were no G5 events. Thirteen (65%) patients developed CRS, all events were G1 (50%) or G2 (15%); no events G ≥3 were reported. After the first step-up dose, 11 (55%) patients had a CRS event. CRS events occurred in 3 patients (15%) and 1 patient (5%) after the second step-up dose and first treatment dose, respectively. The median time to onset was 2 days (range 1-4), and the median time to resolution was 3 days (range 1-5). ICANS occurred in 2 of the 20 patients (10%), both events were G1, with 1 occurring after the first step-up dose and the other after the second step-up dose. The median time to onset was 3 days (range 3-3) and the median time to resolution was 2.5 days (range 2-3). Four (20%) patients had infections, including 1 event each of G1 sinusitis, G2 acute sinusitis, G2 folliculitis, G2 upper respiratory tract infection and G3 bacterial conjunctivitis. Cytopenias were reported in 11 (55%) patients. The most common (occurring in ≥3 [15%] patients) cytopenias were neutropenia (30%; G3/4 25%), lymphopenia (20%; G3/4 15%), and thrombocytopenia (15%; G3/4 10%). CONCLUSIONS Early safety data (median treatment duration <1 month) from this ongoing expanded access protocol of elranatamab in patients with RRMM are consistent with results from the phase 2, registrational MagnetisMM-3 trial, with no new safety signal identified.

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 & 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 >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 >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 <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 & 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% & 89% respectively (median PFS and OS not estimable). Follow-up is on-going and we aim to report long-term survival, FISH/ cytogenetic & 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.

Fluoroquinolone-Resistant Enterobacteriaceae Prevalence for Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation (aHSCT) in the Treatment of Multiple Myeloma (MM)

Background: Fluoroquinolones (FQL) are commonly used in antimicrobial prophylaxis in immunocompromised cancer patients (pts) during prolonged neutropenia. A possibly high and increasing proportion of pts harboring FQL-resistant Enterobacteriaceae (FRE) challenges the assumption that prophylaxis with FQLs is still of benefit in preventing sepsis. Previous studies reported that colonization of FRE in allogeneic transplant patients may be an infection risk factor (cf. Satlin et al. Clin Infect Dis 202;73:1257-65). This prospective study aims to determine the prevalence of FRE in defined pt populations in two metropolitan areas treated with dose-intense melphalan with autologous peripheral blood stem cell (PBSC) transplantation, and to determine the possible clinical effects of FRE in the host microbiome on transplant outcomes. Methods: Pts eligible for this prospective, ongoing study have a diagnosis of MM and are undergoing autologous PBSC transplantation after conditioning with dose-intense melphalan 200 mg/m 2 at Hackensack University Medical Center (HUMC) and MedStar Georgetown University Hospital (MGUH). Peri-rectal swabs are scheduled before chemotherapy mobilization of PBSC given with FQL prophylaxis, before transplant admission with initiation of antimicrobial prophylaxis, at time of hospital discharge, and 3 months after aHSCT. Prophylaxis is discontinued with fever or hospital discharge. Blood cultures are obtained at time of fever (>38 °C) with adjustments in antibiotics per standard of care. A central catheter is placed for venous access in all patients throughout their transplant course. Pts are discharged after achieving neutrophil (ANC) engraftment and control of conditioning regimen toxicities. Bacterial cultures from perirectal swabs (fresh or frozen for shipping) were purified on CHROMagar™ Orientation Plates and grown in the presence of ≥5 ug/ml ciprofloxacin to select for quinolone-resistant organisms. Results: To date, 39 pts are evaluable (Table 1). PBSC were mobilized using filgrastim/plerixafor (G-Moz) or cyclophosphamide/etoposide/dexamethasone (CDE) followed by filgrastim with levofloxacin prophylaxis. The quantity of CD34+ cells infused is in Table 1. All pts achieved ANC engraftment at a median of 10.8 days (range 9-14) and were hospitalized for a median of 13 days (range 11-24). 37/39 pts collected swabs before transplant admission (and swabs were obtained at discharge for the other 2 pts). 13/37 (35%) admission swabs demonstrated FRE colonization (Table 2). 6/33 swabs at time of discharge were positive for FRE including for 4 pts negative for FRE on transplant admission with a total of 17/39 pts (44%) showing FRE colonization at some point during the transplant admission. Samples collected at 3 months after transplantation for 24 pts reaching that timepoint showed FRE colonization for 4 pts including 2 pts not previously testing positive at time of transplantation. 27/107 samples tested positive for FRE and 21/39 pts (54%) had at least one FRE positive culture. Seven pts (20%) developed neutropenic fever but no pt experienced a blood-stream infection (BSI). One pt developed Clostridium difficile colitis during the period of neutropenia. One pt tested positive for MRSA colonization at admission but did not develop fever or BSI. One pt was readmitted after initial hospital discharge for evaluation of fever without a source of infection determined. Ten pts (5 FRE colonized during transplant course) were given prednisone for persistent diarrhea attributed to engraftment syndrome (cf: Spitzer TR. Bone Marrow Transplant 2001;27:893-8) commencing at a median of 10 (range, 8-13) days after aHSCT and not associated with CDE mobilization or detection of FRE. Nineteen other patients, 8 of whom tested positive for FRE, did not receive corticosteroids for management of regimen-related toxicities (an additional 7 pts received preplanned corticosteroids starting at day +8). No center effect is yet evident. Conclusions: FRE are detected in a high proportion of pts undergoing aHSCT in the treatment of MM. However, FQL prophylaxis is not associated with FRE BSI in this ongoing study. FRE colonization is not predictive of delayed engraftment or prolonged hospitalization, and does not appear predictive of non-infectious diarrhea.

Genomic Profiling to Interpret the Outcomes of Early Intervention for High-Risk Smoldering Myeloma

Introduction Early intervention for High-Risk Smoldering Multiple Myeloma (HR-SMM) achieves deeper and more prolonged responses compared to Newly Diagnosed (ND) MM. Various clinical risk models estimate the risk of SMM progression to MM but there is significant discordance between them (Hill et al., JAMA Onc. 2021). It is unclear if beneficial outcomes of interventional studies in HR-SMM are due to treatment of less complex, susceptible disease or inaccuracy in clinical definition of cases entered. Methods To gain greater biologic insight into treatment outcomes, we performed the first whole genome sequencing (WGS) analysis of treated HR-SMM for 27 patients treated with carfilzomib, lenalidomide, and dexamethasone (KRd) and R maintenance (NCT01572480, presented in parallel). We pooled genomic features from 27 patients with HR-SMM treated with Elotuzumab (Elo)R+/-d; (E-PRISM). Genomic features were compared to those of 701 patients with NDMM from CoMMpass (NCT01454297). Results After a median follow-up of 52.8 months, median PFS was not reached with KRd/R. After 8 cycles of KRd, 19 (70.3%) achieved minimal residual disease (MRD) negativity (LOD 10 -5). At data cutoff, June 13, 2023, 14 patients (51.9%) achieved sustained MRD-negativity, 6 patients (22.2%) lost an initial MRD-negative response and 5 patients clinically progressed (18.5%). Overall, there was discordance between risk models: 3 patients (11.1%) were HR by Mayo2008 criteria, 14 (51.9%) by Mayo 20/2/20, 18 (66.7%) by PETHEMA, and 21 (77.8%) by Rajkumar/Landgren/Mateos criteria (Rajkumar et al., Blood. 2015). Eighteen (66.7%) met criteria for 2 or more scores. The estimated 5-year risk of progression ranged 4.8 to 82.1% (Pangea, median 18.6%). We compared the pooled HR-SMM to NDMM from CoMMpass. The frequency of HR translocations was similar (t(4;14), t(14;16), t(14;20); p>0.05). Consistent with the early disease stage of SMM, mutations of NRAS were lower in SMM (p = <0.001) as were events at the MYC locus (8q24; p <0.001) and gains of 1q (p = 0.039). Next, tumor suppressor genes (TSG) were interrogated together with copy number loss at their loci. Consistent with their late onset in tumor evolution, aberrations at key TSG were less common in HR-SMM (p < 0.05): CDKN2C, CYLD, TENT5C, FUBP1, MAX, NCOR1, NF1, NFKBIA, PRDM1, RB1, RPL5,and TRAF3 (p < 0.05). In a genome-corrected comparison, APOBEC (SBS2+SBS13) mutational signatures were diminished in KRd WGS compared to 60 Dara-KRd-treated NDMM (Maura et al., ASH. 2021; 48% vs 87%, p < 0.001) and in E-PRISM vs CoMMpass (15% vs 45%, p = 0.001). We next related genomic features associated with HR-SMM to treatment outcomes. Patients treated with KRd/R had yearly MRD testing and gain1q, MYC dysregulation via loss of MAX, and t(4:14) were all associated with failure to sustain MRD-negativity. Across pooled HR-SMM, inactivation of CYLD, CREBBP, MAX, and HIST1H2BK; t(4;14), APOBEC expression, loss at select GISTIC peaks ( Fig 1A) and chromothripsis all were associated with HR-SMM progression in the face of triplet therapy (p<0.05). Presence of any one or more of these features was associated with progression (p = 0.005; Fig1B). Conversely, no clinical risk score was able to discern those with this molecular high risk. Conclusion In patients treated on 2 parallel clinical trials for HR-SMM, we found a uniform and relative genomic simplicity. Moreover, non-progressors appear genomically similar to patients with non-progressive/stable MGUS and SMM under observation (Oben et al., Nat Comm 2021). However, within clinical HR-SMM, a set of high-risk genomic features portends progression despite intervention. These results suggest that clinical risk scores do not effectively discriminate between genomically indolent and aggressive disease. Though possible that results reflect treatment before the acquisition of key drivers, prior data suggest that many of these high-risk features are not acquired within the 5 years preceding clinical diagnosis of MM (Bolli et al., Nat Comm. 2018; Bustoros et al., J Clin Onc. 2020). Altogether, these results support the use of genomics to contextualize the advantage of early intervention in SMM (i.e., to avoid overtreatment of non-progressors and to better identify cases likely to progress without therapy). Fig1A: Heatmap of High-Risk Features in Patients treated with KRD/R and EPRISM. Fig1B: Kaplan-Meier curve for time to progression by presence of HR features for KRD/R.

Real-World Outcomes of Medicare Fee-for-Service Beneficiaries Meeting the Eligibility Criteria for the DREAMM-7 and DREAMM-8 Clinical Trials

Introduction: Belantamab mafodotin (belamaf), an investigational first-in-class B-cell maturation antigen-binding antibody-drug conjugate, has demonstrated deep and durable responses as a monotherapy in patients with relapsed/refractory multiple myeloma (RRMM) in the DREAMM-2 and DREAMM-3 trials. Two randomized controlled trials (RCTs) exploring the use of belamaf in combination therapy are ongoing in patients with RRMM treated with at least 1 prior line of therapy (2L+). DREAMM-7 is evaluating the efficacy and safety of belamaf in combination with bortezomib and dexamethasone versus daratumumab in combination with bortezomib and dexamethasone. DREAMM-8 is evaluating the efficacy and safety of belamaf in combination with pomalidomide and dexamethasone versus pomalidomide in combination with bortezomib and dexamethasone. The present study aimed to provide real-world context for DREAMM-7 and DREAMM-8 trial results by reporting treatment outcomes of Medicare Fee-for-Service (FFS) patients with characteristics that meet the inclusion/exclusion criteria for each trial. Methods: A retrospective database analysis was conducted to develop trial-like cohorts (one per trial) using the 100% sample from Medicare FFS administrative claims data spanning 2016-2020. Inclusion/exclusion criteria from each RCT protocol included the presence of an MM diagnosis (based on an ICD-9-CM or ICD-10-CM diagnosis code for MM), ≥1 prior line of therapy (prior lenalidomide treatment required for the DREAMM-8 cohort), and other exclusion criteria related to renal, liver, and cardiovascular function. These criteria were used to identify patients in the Medicare FFS database who would be eligible for trial enrollment. Both RCT protocols restricted the overall study populations to ≤50% of patients with at least 2 prior lines of therapy (3L+). Accordingly, random sampling without replacement was applied across eligible Medicare patient lines of therapy to generate cohorts composed of 50% 2L RRMM patients and 50% 3L+ RRMM patients. Index date was the date the randomized line of therapy was initiated. Overall survival (OS) for each cohort was estimated using time from index date until death. Real-world progression-free survival (rwPFS) for each cohort was estimated as the time from index date until next treatment or death. Results: Overall, 1,911 and 1,280 patients met the DREAMM-7 and DREAMM-8 eligibility criteria, respectively. Following random sampling, the analysis cohorts were composed of 1,232 patients (DREAMM-7) and 1,066 patients (DREAMM-8). For the DREAMM-7 trial-like cohort, median rwPFS was 13.6 months and median OS was 29.6 months(Figure). The most commonly used regimens in this cohort were lenalidomide +/- steroids (21.3%), bortezomib +/- steroids (14.4%), and bortezomib + lenalidomide +/- steroids (8.9%). In the DREAMM-8 trial-like cohort, median rwPFS was 13.2 months and median OS was 30.8 months (Figure). In this cohort, the most common regimens were lenalidomide +/- steroids (21.1%), bortezomib +/- steroids (12.9%), and pomalidomide +/- steroids (8.3%). Over a third of patients in the DREAMM-8 trial-like cohort were retreated with lenalidomide. Conclusions: Real-world outcomes of Medicare FFS patients with RRMM eligible for DREAMM-7 and DREAMM-8 were suboptimal: 57% and 56% died within 3 years of entry into their trial-like cohort, respectively, and median rwPFS was around 1 year for both cohorts. Lenalidomide +/- steroids and bortezomib +/- steroids were most commonly used in each cohort. Retreatment with lenalidomide was common in the DREAMM-8 trial-like cohort. These suboptimal outcomes and frequent retreatment demonstrate a substantial need for new effective treatment modalities to improve patient outcomes and provide further treatment choice in the 2L+ RRMM setting. Funding: GSK (Study 209838). Drug linker technology licensed from Seagen Inc.; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.

Update Analysis of Central Nervous System Multiple Myeloma Prognosis and Survival: A Real-World Multi-Institutional Study of the Greek Myeloma Study Group

Central Nervous System Multiple Myeloma (CNS-MM) is a rare but aggressive complication of MM, and its treatment remains an unmet clinical need. Herein we present a real-world national analysis of incidence, characteristics, prognostic factors and outcome of a large cohort of patients with CNS-MM. We evaluated 53 patients with CNS-MM (M/F: 23/30; median age: 59, range: 20-96 years; IgG: 27, IgA: 10, light-chain: 11, non-secretory: 4, IgD: 1; ISS1: 22, ISS2: 13, ISS3: 18; RISS1: 15, RISS2: 22, RISS3: 16) out of 4352 MM patients (1.2%), who were treated within the Greek Myeloma Study Group centers from 2000 to 2022 (23% of patients were diagnosed after 2016). A control group of MM patients matched for age, gender, and stage (ISS/RISS) who were treated during the same period was used for comparisons. Presence of soft tissue plasmacytomas (STP) and/or plasma cell leukemia (PCL; circulating plasma cells, cPCs: ≥5%) was determined and analyzed as extramedullary involvement (EMI). Median time to CNS-MM from MM diagnosis was 28 months (range 0-149 months); 6/53 (11.3%) patients experienced CNS-MM at initial MM diagnosis. Clinical manifestations of CNS-MM included visual disturbances/diplopia: 32%, paresis/paraplegia: 22%, lethargy/confusion: 37%, headache: 22%, cranial nerve palsy: 13% and dysarthria: 11%. PCL was present in 16/53 (30%) CNS-MM patients, while 29/53 (54.7%) CNS-MM patients had bone and/or STP vs. 13/53 matched controls (p=0.001); EMI was found in 24/53 (45%) patients with CNS-MM vs. 4/53 (7%) in controls (p<0.001). 35/53 (66%) CNS-MM patients had leptomeningeal infiltration (LMI) and 34% had intraparenchymal lesions. Median number of cells in the cerebrospinal fluid (CSF) was 60/μL (range 10-2550) and almost all of them (80%, range: 20-100%) were clonal plasma cells. Out of 53 CNS-MM patients, 14 (26.4%) had only CNS involvement without marrow infiltration by PCs; 51% had ≥1 high-risk molecular features (i.e., del17p, t4:14, t14:16, 1q+), and this was marginally higher vs. controls (36%; p=0.15). CD56 negative marrow PCs did not differ between groups (33% vs. 37%). A binary logistic regression analysis demonstrated that EMI was the strongest prognostic factor for the development of CNS-MM (p=0.01; HzR: 5.7). Median number of lines of treatment before the development of CNS-MM was 2 (range 0-9). First line anti-myeloma treatment in patients who developed CNS-MM included conventional chemotherapy (CT) or thalidomide-based regimens in 19 patients, bortezomib-based triplets in 27 and daratumumab-based regimens (DBR) in 7; this did not differ from controls. Overall response rate (ORR) in first-line therapy was similar between CNS-MM and controls (85% for both groups; CR 41% vs. 36%, respectively). After a median follow-up of 150 months post-MM diagnosis (95% CI: 107-192), 46 CNS-MM patients (87%) deceased (MM progression: 34, infection/sepsis: 10, cerebral hemorrhage: 2). Median overall survival (OS) of CNS-MM patients vs. matched controls from initial MM diagnosis was 43 months (95% CI: 31-54) vs 60 months (95% CI: 34-86) (p=0.002; Figure). Regarding CNS-MM therapy, 17 patients received IMiD-based regimens and 26 received PI-based regimens, 6 received CT and 4 received DBR. Patients with CNS-MM and marrow infiltration by PCs displayed an ORR of 31% only; CNS symptoms improved in 74% of all patients. Median OS of CNS-MM patients from the time of CNS involvement was 4 months (95% CI: 2.6-5.3), and it was longer in 12 patients treated after 2016 [18 months (95% CI: 7-29) vs. 2 months (95% CI: 1-3)]. Cerebrospinal fluid (CSF) infusions were performed in 28 patients (53%); 9 patients (19%) underwent radiotherapy. A multivariate analysis showed that EMI, either at diagnosis or during MM course, was the strongest negative predictor for post CNS-MM OS (p=0.008; HR: 3.4 95% CI: 1.4-8.0). Moreover, LMI was a negative predictor (p=0.02; HR: 2.7, 95% CI: 1.2-6.3) for OS, whereas treatment after 2016 had a positive impact (p=0.02; HR: 0.28, 95% CI: 0.12-0.8); CSF infusions did not affect OS. In conclusion, our analysis representing one of the largest real-world series of CNS MM patients after 2016, showed that, OS of CNS-MM remains poor however, there is a positive impact of treatment after 2016, reflecting the efficacy of modern anti-myeloma therapy; EMI strongly predicts for CNS-MM and induces a 3-fold increase in the probability of post CNS-MM death indicating a potential need for CNS prophylaxis in these patients.

Multiple Myeloma Treatment-Related Decision-Making and Preferences of Patients and Care Partners in the United States

BACKGROUND Multiple myeloma is a largely incurable disease characterized by periods of response followed by relapse and/or refractoriness to therapy. With many new treatments available, patients now have more flexibility to assess treatment benefits and risks and what aspects of a treatment are most important to them. The purpose of this non-interventional qualitative study was to examine treatment-related decision-making in patients with MM and care partners with varying experience with refractoriness. METHODS Patients with MM and care partners were recruited through the Gryt Health Cancer Community, social media, and participant referrals to join a qualitative study centered around a semi-structured interview. Adult patients with MM who self-reported treatment for MM in the United States were eligible; adults who self-reported being the primary care partner to an adult with a MM diagnosis who had received treatment in the United States were also eligible. Participants were stratified based on refractoriness to at least one proteasome inhibitor, immunomodulatory drug, and/or anti-CD38 monoclonal antibody (non-refractory; single or double refractory; triple refractory). An Institutional Review Board approved this study. RESULTS The study was completed by 42 participants, of which 32 were patients with MM (12 non-refractory; 10 single or double refractory; 10 triple refractory) and 10 were MM care partners (3 non-refractory; 3 single or double refractory; 4 triple refractory) (Table). Each care partner was paired to a patient participant, and 80% lived in the same household as the patient. All care partners had provided support since the MM diagnosis, if not before, and at minimum had been providing support for at least 2 years. More than half (60%) of care partners were currently working full-time, relative to only 20% of the paired patients. Patients and care partners made comments supportive of MM being approached as a chronic disease, which suggests an abrupt shift in perspective compared to historical sentiment. Participants wanted to retain or improve their quality of life (QoL) and focus less on the disease itself. Reasons for this shift in perspective include an increased sense of hope brought about by new treatments and community support, documented improvements in long-term survival, and better techniques for monitoring disease relapse, particularly minimal residual disease (MRD) status. More than 70% of participants expressed that treatment-related decision-making was shared, particularly as they were further from diagnosis, and felt comfortable asking their doctor(s) questions related to treatment options, even if treatment options were only discussed on an as-needed basis. Care partners were more actively involved in decision-making around significant events, such as diagnosis, stem cell transplant, and relapses. When making treatment decisions, participants were most concerned about extending remission and overall survival (OS), improving QoL, and minimizing MM symptoms and treatment-related side effects (Figure). Extending remission and OS and improving QoL were rated very important underscoring the value of shared decision-making as patient engagement is key in monitoring and enhancing QoL. Location of care and/or treatment, financial burden, possibility of hospitalization, potential impact on other medical conditions, and frequency and duration of treatment were of lesser concern. Participants were least concerned about the mode of administration of the treatment; none of the patients with double or triple refractory disease considered mode of administration to be fairly or very important. Those with triple refractory disease were more likely to be concerned about frequency and duration of treatment compared with other patients. Patient and care partner participants were generally aligned on priorities when making treatment decisions but had the least alignment on financial burdens with patients expressing more concern. CONCLUSIONS With the availability of new treatment options, patients are seeking therapies that both extend remission and OS and improve QoL, placing more importance on the need for patient engagement in the decision-making process. Treatment of MM is now often being approached from a chronic care perspective, perhaps reflective of changing attitudes about MM as a more treatable disease today.

LGL in MGUS or MGUS in LGL? Lessons of Nature and Their Clinical Implications

Associations between seemingly unrelated entities often reveal important lessons of nature, instructive for the understanding of mutual pathogenic roots. While investigating the clinical features of T-cell large granular lymphocytic leukemia (LGL), we noted the frequent presence of plasma cell dyscrasias/monoclonal gammopathies (MGs), chiefly MGUS. There are several potential explanations for this co-occurrence: 1) similar demographics (both conditions mostly presenting in the elderly); 2) the possibility that the two precursors originate from an initial polyclonal immune response to a common target; and 3) as alternative, that monoclonal plasma cells or the Ig product may be the targets of cytotoxic T-LGL cells in a context of tumor surveillance reaction. For instance, clonal TCR may recognize the M protein idiotype or vice versacausing aberrant activations. In addition, while MGUS should not be associated with cytopenias, responses to anti-myeloma therapies have been observed in LGL with MGUS refractory to traditional immunosuppressive therapies. We hypothesized that the study of clinical and epidemiologic features of MGs and LGL may be helpful to elucidate some of these fundamental questions. To address this, a dual approach was applied: 1) MG-forward strategy: screening of LGL in 2348 individuals with documented diagnosis of MGs and available bone marrow exam; 2) LGL-forward strategy: search of MGs in 235 LGL cases with M protein assessment. Overall, among 2348 cases with MGs, we identified 42 cases (1.8%) with concurrent evidence of LGL. We then selected an exploratory cohort of 787 MG patients with clinical annotations for further phenotypic dissection and comparative analyses. Within 533 patients with non-active MGs (i.e., MGUS or smoldering myeloma -SM), 144 (27%) had cytopenias of any type and grade, which could not be attributable to plasma cell infiltration. Screening for comorbid conditions explaining cytopenias left 32 cases (22%) presumed to be idiopathic. LGL was overrepresented in MGUS-SM with cytopenias (6 vs 0.3% in cases without counts alterations, p< .001). This frequency was higher when considering only cases with idiopathic cytopenias (22 vs 1.8% in cases with cytopenias of other causes, p< .001) ( FigA). Reverse analysis of the LGL cohort demonstrated that 71 (30%) LGL cases had M proteins. Overall, the MG/LGL dyad was more frequently associated with concurrent autoimmune conditions (54%), as well as monoclonal B-cell lymphocytosis and other B-cell lymphoid neoplasms (19%). Next, we compared cases with MG/LGL vs those with MGs (N = 775) or LGL (N = 157) exclusively. When compared to the MGs cohort, MG/LGL cases presented a younger age (median 64 vs 70 years, p < .001), had higher frequency of M protein of the IgM type (21 vs 10%, p= .002), and oftentimes exhibited small/transient paraproteinemia (42 vs 2%, p< .001). No specific features were enriched in the MG/LGL cases when compared to the LGL cohort, except for a higher proportion of proliferations of NK-cell subtype (12 vs 4%, p= .02). Finally, to confirm the observed association, we focused on the subgroup of non-active MGs by excluding cases with initial diagnosis of MM or lymphoma. Multivariable analysis (adjusting by sex, age and MG risk) revealed a lower risk of immunoparesis (aOR: 0.4, 95%CI: 0.2 - 0.7, p= .002) in MG/LGL as opposed to MG without LGL, whereas no effect was found in progression to MM/lymphoma (aHR: 0.9, 95%CI: 0.4 - 2.1, p= .81 in a competitive-risk setting). Moreover, when opposed to its MG and LGL counterparts, MG/LGL more frequently presented with severe cytopenias (aOR vsMGs: 28.9, 95%CI: 14.0 - 59.0, p< .001; aOR vsLGL: 2.7, 95%CI: 1.7 - 5.6, p= .008), and with immune-mediated cytopenias (aOR vsMGs: 10.5, 95%CI: 4.9 - 22.2, p< .001; aOR vsLGL: 2.8, 95%CI: 1.0 - 4.8, p= .04) ( FigB). In conclusion, our study reveals that: 1) the association between MGUS and LGL is more than an age-related epidemiological coincidence; 2) distinctive nosologic features for the MG/LGL dyad; and 3) that even “non-active” MGs associated with LGL might be of hematological clinical significance through humoral or cellular immune mechanisms. These findings point towards alternative treatment strategies of cytopenias in MGUS and LGL (immunosuppression vs anti-myeloma therapies, respectively), and provide impetus for the investigation of tumor surveillance in MGUS vs common etiologic factors intertwining these clonopathies.

Real-World Analysis of Teclistamab in 115 RRMM Patients from Germany

Background Bispecific antibodies and CAR-T cells are currently changing the treatment landscape of relapsed and refractory multiple myeloma (RRMM), having shown high response rates and durable remissions of more than a year in clinical trials. However, some discrepancies to these results have been observed lately, with lower median progression free survival (PFS) and overall survival (OS) in the real-world setting for idecabtagene vicleucel (ide-cel), possibly related to strict entry criteria of the study and known general benefits for patients participating in clinical trials regardless of study arm allocation. Whether this also holds true for Teclistamab, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody approved for treatment of RRMM in 2022 in several countries, has yet to be determined. Therefore, we thought to assess Teclistamab efficacy and tolerability in the real-world setting. Methods Data of 115 patients with RRMM treated with Teclistamab at 18 different German centers from July 2022 to July 2023 were retrospectively collected and analyzed. The patients had received at least one full treatment dose of Teclistamab. Responses were evaluated in accordance with the IMWG response criteria; in addition, near complete response was defined as serological complete remission lacking bone marrow assessment, as this was not always part of clinical routine. In non-secretory disease, response evaluation was based on radiological criteria. Kaplan-Meier methods were applied for time-to-event-analyses. For comparison of survival among groups, the log-rank test and Cox regression analysis were used. For comparison of response rates among groups, the Chi square test was applied. Results The included 115 patients (49 female, 66 male with a median age of 66.0 years) had a median history of MM diagnosis of 6.5 years and were heavily pretreated with a median of 6 (range 3-14) prior lines of therapy. The majority of patients had triple-class (91.3%) or even penta-drug (58.3%) refractory disease. 35.6% (41/115) had received BCMA-directed pretreatment, among them 20 with ide-cel, 21 with belantamab mafodotin and single patients with both or a BCMA-directed study medication. Cytogenetic high-risk features defined as del(17p), t(4;14) and/or t(14;16) and extramedullary disease (EMD) were present in 38.0% and 37.2% of patients, respectively. Around one third of patients had high disease burden with bone marrow infiltration ≥60% (37.0%) or ISS 3 (35.2%) in the latest assessment before initiation of Teclistamab. Overall, a substantial proportion of 40.9% of the treated patients would not have met selected inclusion criteria of the MAJESTEC-1 trial like measurable disease, stable hematopoiesis and kidney function. With median times to response and best response of 4.3 weeks and 8.0 weeks, we observed an ORR, defined as partial remission or better, of 56.8%. 20.9% of all patients reached a near complete or complete response. With a median follow-up of 3.9 months, median PFS was 8.7 months. Median duration of response and median OS were not reached. In the group of patients with BCMA-directed pretreatment, the ORR of belantamab-pretreated patients (70%) was comparable to that in anti-BCMA naïve patients (60.0%), whereas ide-cel pretreated patients showed a significantly lower ORR of 27.8%. Interestingly, PFS did not differ significantly between ide-cel pretreated and ide-cel naïve patients. In further subgroup analyses, the presence of EMD and an ISS of 3 were associated with inferior ORR and PFS in univariable and multivariable analysis. Safety was similar to the experience in MAJESTEC-1. 60.0% of patients developed CRS and 6.9% neurotoxicity with grade 3 or 4 events in 1.7% and 0.9% of patients, respectively. Tocilizumab was administered in 25.2% and dexamethasone in 15.7% of patients. Infections occurred in 49.6% of patients, nearly half of them requiring hospitalization. 53.9% experienced grade 3 or 4 cytopenia according to CTCAE during treatment. Conclusions With an ORR of 56.8% in all patients and 60.0% in anti-BCMA naive patients, Teclistamab showed a similar ORR in the real-world setting to that observed in the MAJESTEC-1 trial. PFS was slightly lower, but our patient collective comprised higher proportions of patients with high risk disease, extramedullary disease, high disease burden, hematopoietic or renal impairment.

Effects of Idecabtagene Vicleucel (Ide-Cel) Versus Standard Regimens on Health-Related Quality of Life (HRQoL) in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Who Had Received 2-4 Prior Regimens: Updated Results from the Phase 3 KarMMa-3 Trial

Background: An interim analysis (data cutoff date April 18, 2022) of the international, open-label, phase 3 KarMMa-3 trial (NCT03651128) showed the chimeric antigen receptor T cell therapy idecabtagene vicleucel (ide-cel) significantly improved progression-free survival and treatment response rates, as well as HRQoL, as compared with standard regimens, in patients with triple-class exposed (TCE) RRMM who had received 2-4 prior regimens (Rodriguez-Otero P, et al. N Engl J Med 2023;388:1002-1014; Delforge M, et al., HemaSphere, 2023;7(S3):P905). The aim of the present study was to analyze the effect of ide-cel versus standard regimens (daratumumab [DARA], pomalidomide, and dexamethasone [DEX]; DARA, bortezomib, and DEX; ixazomib, lenalidomide, and DEX; carfilzomib and DEX; or elotuzumab, pomalidomide, and DEX) on HRQoL in KarMMa-3 trial participants with an extended follow-up of patient-reported outcomes (PRO) data collection (data cutoff date April 28, 2023). Methods: In KarMMa-3, HRQoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-Core 30 (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY20), and EQ-5D-5L. HRQoL assessments were completed at screening (baseline); the day of ide-cel infusion or the first dose of standard treatment; and monthly from 2 to 28 months; and every 3 months thereafter. The prespecified primary outcomes of interest were EORTC QLQ-C30 global health status/QoL, physical functioning, cognitive functioning, fatigue, and pain; EORTC QLQ-MY20 disease symptoms and side effects of treatment; and the EQ-5D visual analog scale (EQ-VAS). Least squares (LS) mean changes from baseline through month 25 for ide-cel and standard regimens were compared by constrained longitudinal data analysis (cLDA). Effect sizes were estimated by Hedges' g. The effect of ide-cel versus standard regimens on time to confirmed improvement and deterioration in HRQoL (defined by prespecified change thresholds and sustained duration) were compared by stratified Cox proportional hazards regression. There was no adjustment for multiple testing, and all P values reported are nominal. Results: Overall, 254 patients were randomized to the ide-cel arm and 132 to the standard regimens arm. Baseline characteristics were well balanced across treatment arms; both arms had a median age of 63 years, a median of 3 prior anti-myeloma regimens, and median time from MM diagnosis to screening was 4 years. The baseline HRQoL scores were generally comparable between treatment arms. Overall LS mean changes from baseline to month 25 showed significant differences (nominal P value < 0.05) in favor of ide-cel for 18 out of 21 HRQoL domains, with effect sizes (Hedges' g) of 0.27 to 0.82 (Table). For 13 of these domains (including 6 primary domains of interest), the difference in overall LS mean change from baseline exceeded the prespecified minimum important difference (MID) threshold. Time to confirmed improvement was significantly shorter in the ide-cel arm than the standard regimens arm for 19 domains, including all primary domains of interest (Table). Time to confirmed deterioration showed trends of being longer in the ide-cel arm than the standard regimens arm for most domains and was significantly longer for emotional functioning, cognitive functioning, social functioning, dyspnea, and constipation as measured by the EORTC QLQ-C30. The time to confirmed deterioration in side effects of treatment (based on the EORTC QLQ-MY20) was significantly longer for patients in the ide-cel arm and time to confirmed improvement was significantly faster, as compared with the standard regimens arm (Table). Conclusions: In the KarMMa-3 trial, patients with TCE RRMM who had received 2-4 prior regimens, ide-cel significantly and meaningfully improved MM-relevant symptoms, functioning, and overall health status/HRQoL compared with standard regimens. Confirmed HRQoL improvements in the ide-cel arm occurred sooner than standard regimens. PRO improvements were sustained over more than 2 years, which is notable after a single infusion treatment with ide-cel. These patient-reported findings further support the benefit of ide-cel in this patient population.

Early Safety Results of P-BCMA-ALLO1, a Fully Allogeneic Chimeric Antigen Receptor T-Cell (CAR-T), in Patients with Relapsed / Refractory Multiple Myeloma (RRMM)

P-BCMA-ALLO1 is an allogeneic CAR-T that targets B-cell Maturation Antigen (BCMA) and is currently being investigated for the treatment of RRMM. P-BCMA-ALLO1 cells are manufactured from healthy donor T-cells using non-viral transposon-based integration (piggyBac® DNA Delivery System) that introduces a human anti-BCMA V H-based CAR and an iCas9 safety switch. The piggyBac® DNA delivery system produces a highly enriched T stem cell memory product. The Cas-CLOVER™ Site-Specific Gene Editing System eliminates endogenous T cell receptor (TCR) expression via knockout of the TCR beta chain 1 gene to prevent graft-vs-host disease (GvHD), and the beta-2 microglobulin gene to reduce Major Histocompatibility Complex (MHC) class I expression to eliminate host-vs-graft responses. P-BCMA-ALLO1 demonstrated compelling activity in MM xenografts, providing rationale for this first-in-human phase I study. The primary objective is to assess the safety and maximum tolerated dose (MTD) of P-BCMA-ALLO1 based on dose limiting toxicity (DLT) in RRMM patients with measurable disease who have received a proteasome inhibitor (PI), immunomodulatory agent (IMiD) and anti-CD38 monoclonal antibody therapy. Key secondary objective will assess the anti-myeloma effect of P-BCMA-ALLO1. Exploratory objectives will assess CAR-T related cytokines, serum BCMA levels and cellular kinetics. The trial utilizes a standard 3 + 3 dose escalation design to test seven planned dose levels of intravenous P-BCMA-ALLO1 ranging from 0.0625 × 10 6 to 15 × 10 6 cells/kg (NCT04960579). Multiple lymphodepletion (LD) strategies and cyclic administration of P-BCMA-ALLO1 are being investigated. Repeat P-BCMA-ALLO1 administration is allowed for patients who do not achieve at least a partial response with the first dose after 4 weeks of follow up. We are currently dosing patients in arm S (Cyclophosphamide (Cy) 300 mg/m 2 + Fludarabine (Flu) 30 mg/m 2 X 3 days), arm P1 (Cy 500 mg/m 2 + Flu 30 mg/m 2 X 3 days), arm P2 (Cy 1,000 mg/m 2 + Flu 30 mg/m 2 X 3 days) and arm C (multiple P-BCMA-ALLO1 doses following Cy 300 mg/m 2 + Flu 30 mg/m 2 X 3 days). The median patient age was 73 (33, 85) years, 61% were female, and median time since MM diagnosis was 6.27 (1.48,18.95) years. Eight (35%) patients had high risk disease by cytogenetic criteria. The enrolled patients were heavily pretreated, having received median 7 (2,16) prior lines of therapy, with 30% having undergone prior BCMA targeting therapy. As of 10 Jul 2023, 24 patients received P-BCMA-ALLO1 at 4 dose levels. Twenty-two were treated in arm S, 1 each in arms P1 and P2. One patient received 0.25 X 10 6 cells/kg (cohort -1, arm S), 7 received 0.75 X 10 6 cells/kg (cohort 1, arm S), 12 received 2 X 10 6 cells/kg (cohort 2, 10 in arm S, 1 in arm P1 and 1 in arm P2), and 4 received 6 X 10 6 cells/kg (cohort 3). One of the cohort 2 patients received a second P-BCMA-ALLO1 infusion at the cohort 2 dose level following disease progression. The median time from enrollment to start of LD chemotherapy was 2 (1-8) days and from enrollment to CAR-T infusion was 7 (6-13) days. No patient needed bridging therapy between enrollment and the start of LD. Twenty-two (all in arm S) of the 24 treated patients completed DLT evaluation by data cutoff. None of the patients treated thus far had DLTs. Most common treatment emergent adverse events (TEAEs) were anemia (36%), neutropenia (36%), constipation (36%) and leukopenia (32%). Most common ≥ grade (G) 3 TEAEs were neutropenia (36%), leukopenia (32%) and anemia (23%). Most of the AEs were considered unrelated to P-BCMA-ALLO1. Three (14%) patients developed grade 1 Cytokine Release Syndrome (CRS). One (4%) patient experienced grade 1 Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS), which resolved with one dose of corticosteroids. None of the patients experienced GvHD by the last follow up. P-BCMA-ALLO1 is a non-viral transposon-generated allogeneic “off-the-shelf” CAR-T that is rapidly available for administration and well tolerated in a heavily pretreated RRMM patient population with minimal CRS/ICANS risk. Updated results including safety, preliminary efficacy, and selected biomarkers will be presented at the American Society of Hematology 2023 meeting.

Natural history, predictors of development of extramedullary disease, and treatment outcomes for patients with extramedullary multiple myeloma.

Extramedullary multiple myeloma (EMM) can present either at initial diagnosis (de novo) or at disease relapse (secondary) and confers an aggressive clinical course. Limited data exist for choosing the optimal therapy for EMM and this remains an area of unmet clinical need. After excluding paraskeletal multiple myeloma and primary plasma cell leukemia, we identified 204 (68%) patients with secondary EMM and 95 (32%) with de novo EMM between January 01, 2000 and 31 December, 2021. The median overall survival (OS) was 0.7 (95% CI: 0.6-0.9) years for secondary EMM and 3.6 (95%CI: 2.4-5.6) years for de novo EMM. The median progression-free survival (PFS) with initial therapy was 2.9 months (95% CI: 2.4-3.2 months) for secondary EMM and 12.9 months (95% CI: 6.7-18 months) for de novo EMM. Patients with secondary EMM treated with CAR-T therapy (n = 20) achieved a partial response (PR) or better in 75% with a median PFS of 4.9 months (3.1 months-not reached; NR). Patients with EMM treated with bispecific antibodies (n = 12) achieved a ≥ PR in 33%, with a median PFS of 2.9 months (95%CI: 2.2 months-NR). In a matched cohort, multivariate logistic regression analysis demonstrated younger age at diagnosis, 1q duplication, and t(4;14) at diagnosis of MM to be independent predictors of development of secondary EMM. Presence of EMM was independently associated with inferior OS in the matched cohorts for both de novo (HR 2.9 [95% CI: 1.6-5.4], p = .0007) and secondary EMM (HR 1.5 [95% CI: 1.1-2], p = .001).