Relapsed Or Refractory Multiple Myeloma Patients Research Articles

Effects of Consolidation Therapy With Autologous Hematopoietic Stem Cell Transplantation After BCMA-CAR T-Cell Therapy on the Survival of Patients With Relapsed or Refractory Multiple Myeloma

Despite the success of chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory multiple myeloma (RRMM), failure after CAR T-cell therapy remains an unmet medical need. An effective consolidation therapy after CAR T-cell therapy may improve the prognosis of RRMM. To investigate the effects of consolidation therapy with autologous hematopoietic stem cell transplantation (AHCT) after B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy on the prognosis of RRMM patients. This retrospective study included 39 RRMM patients who received BCMA-targeted CAR T-cell therapy. Basic clinical, therapy, and outcome data were collected, and factors associated with survival were analyzed. Among the 39 RRMM patients included in the study, 15 had high-risk cytogenetics and 11 had extramedullary disease (EMD). All 39 patients reached peak CAR T-cell expansion within 28 days after infusion. Twenty-six patients developed cytokine release syndrome, including 12 grade 1 and 14 grade 2 cases. Survival analysis revealed that high-risk cytogenetics, high tumor load (International Staging System [ISS] stage III), and EMD were negatively associated with progression-free survival (PFS) and overall survival (OS). Thirteen patients received consolidation AHCT therapy 50-276 days after CAR T-cell therapy, with a median interval of 92 days. No serious complications occurred after consolidation AHCT. Survival analysis showed that consolidation AHCT effectively improved OS and PFS over maintenance chemotherapy. Moreover, Cox regression analysis identified low tumor load (ISS stage I/II) and consolidation AHCT as independent predictors of superior PFS and OS and high-risk cytogenetics as an independent risk factor for poor PFS. Consolidation AHCT after CAR T-cell therapy in RRMM patients can improve patient survival.

Comprehensive characterization of cytopenia after chimeric antigen receptor-T cell infusion in patients with relapsed or refractory multiple myeloma

BackgroundMany studies have demonstrated the effectiveness of chimeric antigen receptor-T (CAR-T) cell therapy for relapsed or refractory multiple myeloma (RRMM), but the hematologic toxicity has not been well characterized. MethodsA total of 111 adults with RRMM who received BCMA CAR-T cells, BCMA + CD19 CAR-T cells or tandem BCMA/CD19 dual-target (BC19) CAR-T cells infusion were enrolled. We characterized cytopenia and hematologic recovery at different time points after CAR-T-cell therapy, analyzed the effect of cytopenia on prognosis and identified the risk factors. ResultsPatients had a high probability of cytopenia, with anemia, neutropenia and thrombocytopenia occurring in 92%, 95% and 73%, respectively. There were 60 (54%) patients had prolonged hematologic toxicity (PHT) after D28. The median hemoglobin and platelet count were significantly lower at D28 post-CAR-T cell therapy than at baseline. Hemoglobin increased to above baseline at D90. The median absolute neutrophil count was lower than baseline at D0 and D28, and it recovered to baseline at D180. The baseline level of lactate dehydrogenase was associated with thrombocytopenia. Extramedullary involvement was associated with hemoglobin recovery, while the baseline level of albumin and types of CAR-T were related to platelet recovery. Patients with anemia at baseline and at D0, D180 and D360 had shorter progression-free survival (PFS), while anemia at D0, D60, D180 and D360 was associated with shorter overall survival (OS). Neutropenia at D0 was associated with shorter PFS and patients with neutropenia at D90 or D180 had shorter OS. Patients with thrombocytopenia at any time had shorter PFS and OS. Compared to patients without PHT, patients with PHT had shorter PFS and OS. ConclusionsThe majority of RRMM patients treated with CAR-T cells experienced cytopenia. Cytopenia occurred at specific time points was associated with a poorer prognosis.

PD-1 downregulation enhances CAR-T cell antitumor efficiency by preserving a cell memory phenotype and reducing exhaustion

BackgroundDespite the encouraging outcome of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) in managing relapsed or refractory multiple myeloma (RRMM) patients, the therapeutic side effects...

Efficacy and safety of bispecific antibodies therapy for relapsed or refractory multiple myeloma: a systematic review and meta-analysis of prospective clinical trials.

Bispecific antibody (BsAbs) therapy represents a promising immunotherapeutic approach with manageable toxicity and noteworthy preliminary efficacy in treating patients with relapsed or refractory multiple myeloma (RRMM). The objective of this systematic review and meta-analysis was to compare the efficacy and safety of B-cell maturation antigen (BCMA)-targeted BsAbs and non-BCMA-targeted BsAbs in the treatment of RRMM patients. PubMed/MEDLINE, Web of Science, EMBASE, Cochrane Library and meeting libraries were searched from inception to August 16th, 2023. The efficacy evaluation included the complete objective response rate (ORR), complete response (CR) rate, stringent CR (sCR) rate, partial response (PR) rate, and very good PR (VGPR) rate. The efficacy evaluation included any grade adverse events (AEs) and grade ≥ 3 AEs. Fourteen studies with a total of 1473 RRMM patients were included. The pooled ORR of the entire cohort was 61%. The non-BCMA-targeted BsAbs group displayed a higher ORR than the BCMA-targeted BsAbs group (74% vs. 54%, P < 0.01). In terms of hematological AEs, BCMA-targeted BsAbs therapy exhibited higher risks of neutropenia (any grade: 48% vs. 18%, P < 0.01; grade ≥ 3: 43% vs. 15%, P < 0.01) and lymphopenia (any grade: 37% vs. 8%, P < 0.01; grade ≥ 3: 31% vs. 8%, P = 0.07). Regarding non-hematological AEs, there were no significant differences in the risks of cytokine release syndrome (CRS, any grade: 64% vs. 66%, P = 0.84; grade ≥ 3: 1% vs. 1%, P = 0.36) and infections (any grade: 47% vs. 49%, P = 0.86; grade ≥ 3: 24% vs. 20%, P = 0.06) between the two groups. However, non-BCMA-targeted BsAbs therapy was associated with a higher risk of immune effector cell-associated neurotoxicity syndrome (ICANS, any grade: 11% vs. 2%, P < 0.01) and lower risks of fatigue (any grade: 14% vs. 30%, P < 0.01) and pyrexia (any grade: 14% vs. 29%, P < 0.01). This analysis suggest that non-BCMA-targeted BsAbs therapy may offer a more favorable treatment response and tolerability, while BCMA-targeted BsAbs therapy may be associated with diminished neurotoxic effects. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42018090768.

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

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

CD27-Armored BCMA-CAR T Cell (CBG-002) Therapy for Relapsed and Refractory Multiple Myeloma: A Phase I Clinical Trial

Introduction: Several BCMA CAR T-cell products have been approved for relapsed or refractory multiple myeloma (RRMM), but long-term response has not been established. There is growing interest in the use of next-generation CAR T-cell therapy in RRMM. CBG002 is an armored BCMA CAR T-cell product engineered to constitutively express CD27, which binds CD70 to promote T-cell proliferation and differentiation. In vitro, CBG-002 cells exhibited enhanced proliferation, greater cytotoxicity and a higher proportion of memory T cells compared to control BCMA-CAR T cells; in animal models, CBG-002 infusion also resulted in improved tumor control and prolonged survival in MM xenograft mice. Based on the preclinical data, we conducted a phase I clinical trial to evaluate its safety and efficacy in patients with RRMM. Methods: This is a single-arm, open-label, phase I study (NCT04706936). Key eligibility criteria were RRMM patients who had received at least 3 prior regimens, including a proteasome inhibitor and an immunomodulatory drug; the percentage of BCMA expression ≥50% on myeloma cells, detected by either flow cytometry and immunohistochemistry. Patients received 3 days of fludarabine (30 mg/m 2) and cyclophosphamide (300 mg/m 2) followed by a single dose of CBG-002 infusion. The dose-escalation study follows a “3+3” design with 1×10 6/kg, 2×10 6/kg and 3×10 6/kg CAR-T cell cohorts. The primary endpoint was safety, including grade 3 or 4 treatment-emergent adverse events (TEAEs) and dose-limiting toxicities (DLTs); The secondary endpoints were overall response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: As of June 25, 2023, 12 patients were enrolled and 1 patient was later excluded due to &amp;lt;50% BCMA expression. Among the evaluable 11 patients, there were 9 males and 2 females; median age was 52 years (range 36-66), 5/11 (45.5%) patients had high-risk cytogenetics including complex karyotype, t(4;14),1q21 amplification and del(17p), 4 (36.4%) had extramedullary disease (EMD). The median number of prior treatments was 5 (range 3-7); 7/11 pts were triple-agent exposed and refractory; 5/11 underwent ASCT. The most common TEAEs were neutropenia (G3/4 63.6%), thrombocytopenia (G3/4 36.4%) and anemia (G3/4 45.5%). Nine patients developed G1/2 CRS, which resolved spontaneously except for 2 patients who required steroids and tocilizumab, and no patients developed G3/4 CRS or ICANS. The median time to onset of CRS was 7 days (range 5-21) and the median duration was 6 days (range 5-8). At a median follow-up of 9 months, the ORR was 81.8%, including sCR/CR of 63.6%, VGPR 9.1% and PR 9.1%. After infusion, 8 pts were MRD negative in bone marrow by flow cytometry at day 28, 5 pts continued at month 3. The median OS was 14 months and the OS rate was 100%. The median PFS was 9 months and the PFS rate was 60%. The CBG-002 kinetics paralleled peripheral blood sCD27 levels with a median time to peak of 15 days (range 7-14). The fold increase in sCD27 levels was significantly higher in responders (12.1, range 1.2-83.8) than in non-responders (1.68, range 0.81-9.45). Conclusions: In this phase I study, CBG-002, a CD27-armored BCMA-CAR T therapy has demonstrated remarkable safety and clinical activity in RRMM patients.

Isatuximab-Based Regimens As Salvage Therapy for Patients with Multiple Myeloma: Sardinian, Multicenter, Retrospective Clinical Practice Experience with 27 Cases Outside of Controlled Clinical Trials

Introduction: Isatuximab (Isa), a humanized monoclonal antibody directed against the surface antigen CD38, has been available in Italy since October 2021 for the treatment of relapsed or refractory Multiple Myeloma (RRMM) in combination with Pomalidomide (P) and Dexamethasone (d) (IsaPd) after two lines of therapy with lenalidomide and a proteosome inhibitor, and from April 2022 in combination with carfilzomib (K) after one line of treatment. Patients eligible for these therapies must not be refractory to Daratumumab. Here, we report preliminary efficacy and safety data for Isatuximab in a Sardinian study of RRMM patients treated with IsaPd and IsaKda as salvage therapy outside of controlled clinical trials. The primary objective of this study was to evaluate the toxicity profile and quality of response to Isatuximab-based regimens administered as salvage therapy in a real-world setting. Methods: The 2 cohorts included 27 patients with RRMM from 4 Sardinian centers who received at least one cycle of IsaPd (16 patients) or IsaKd (11 patients) as salvage therapy between January 2022 and March 2023. Patients received Isa 10 mg/kg IV weekly for the first 4 weeks (wks), then every 2 weeks in combination with Pomalidomide and Dexamethasone (4mg PO days 1-21; 40mg [20mg at &amp;gt; 75 years] PO or IV weekly) every 28 days for the IsaPd regimen. The IsaKd regimen consisted of administration of 10 mg/kg Isatuximab intravenously once weekly in the first cycle, then once every 2 weeks in subsequent cycles. Both arms received Carfilzomib at a dose of 20 mg/m2 on days 1 and then 56 mg/m2 on days 8, 9, 15, and 16 of the first cycle, then 56 mg/m2 on days 1, 2, 8, 9, 15, and 16 in subsequent cycles, while 20 mg of Dexamethasone was administered on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle. Results: The median age of the 16 IsaPd-treated patients was 67.5 years (range 48-89 years) and 61 years (range 49-84 years) for the IsaKd population; 44% and 64% were male, respectively (Table 1). The median number of prior therapies was 2 (range 2-4) for the IsaPd and 1 (range 1-4) for the IsaKd cohort; 11 (68.75%) and 9 (82%) received prior autologous stem cell transplantation (ASCT), respectively. Four patients in both populations started treatment because of biochemical relapse, and no refractory patients were recorded in the IsaKd cohort. Three patients (2 in the IsaPd population and 1 in the IsaKd cohort) had creatinine clearance ≤30 mL/min. Among the IsaKd-cohort, 5 (46%) had R-ISS 2 stage and three had a 17p deletion. At the last data collection, 13 cases in the IsaPD population were evaluable for response. The median number of courses administered to date was 4 (range, 1-14). The overall response rate (ORR) was 69%, with 2 stringent complete remissions (sCR) (15%) and 1 very good partial remissions (VGPRs) (7.7%). The median time to first response was 1 month, while the median time to best response was 2 months. In the IsaKd population, 10 patients were evaluable with an overall response rate (ORR) of 100%, with 1 complete remission (sCR) (10%), 1 complete remission (10%), and 5 very good partial remissions (VGPRs) (50%). A median time to first response of 1 month was also recorded in this population, whereas the median time to best response was 3 months. Renal insufficiency and age &amp;gt; 70 years had no significant impact on the likelihood of achieving a response in either population.In the IsaPd cohort, after a median follow-up of 6 months (range 1-14 months), 9 patients discontinued treatment, 7 due to disease progression, 1 due to toxicity, and 1 due to patient choice) Six patients died (5 patients from progressive disease and 1 from secondary acute myeloid leukemia). Common grade 3 or 4 adverse events were fatigue (57%), thrombocytopenia (35%), neutropenia (57%), lymphocytopenia (15.9%), anemia (29%), and infection (21%). Infusion reactions occurred in only 2 patients (12.5%) and were grade 1 or 2 without treatment discontinuation. In the IsaKd population, the median follow-up time was 4 months (range 1-8 months). 1 patient discontinued treatment and died due to disease progression. Grade 3 or 4 adverse events were fatigue (18%), thrombocytopenia (18%), neutropenia (18%), anemia (36%), and infection (63%) No infusion reactions occurred. Conclusions: Despite the limited number of cases, our preliminary real-world data confirm that Isa-based treatment is an effective and safe therapy for RRMM patients, broadly consistent with results from controlled clinical trials.

Biomarker Correlates of Response to Ciltacabtagene Autoleucel in Patients with Relapsed or Refractory Multiple Myeloma from CARTITUDE-1, a Phase 1b/2 Open-Label Study, at the ~3 Year Follow-up

Ciltacabtagene autoleucel (cilta-cel) consists of autologous T cells genetically modified to express a two-binding domain chimeric antigen receptor (CAR). The target antigen of the CAR is B-cell maturation antigen (BCMA), which is highly expressed on malignant plasma cells (PC) from multiple myeloma subjects. In the Phase 1b/2 CARTITUDE-1 study, cilta-cel led to early, deep, and durable responses and was approved for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) after four or more prior lines of therapy by FDA. Despite cilta-cel's outstanding overall response rate (97.9%) and duration of response (DOR) in RRMM patients, relapse still occurs. Biomarkers associated with this durable response and acquired resistance remain to be elucidated. We present updated correlative data from the CARTITUDE-1 study. At the ~3 year follow-up (October 2022 data cutoff), 97 patients had received a single infusion of cilta-cel (median 0.71 x10 6 cells/kg [range 0.52 x10 6-0.94 x10 6]); the median follow up was 33.4 months (range 1.5-45.2), median DOR was 33.9 months (95% CI, 25.5-not estimable [NE]) and median PFS was 34.9 months (95% CI, 25.2-NE) (Lin Y et al, ASCO 2023). Drug product (DP), baseline and on-treatment whole blood and bone marrow samples from enrolled patients were analyzed by methods including flow cytometry, MSD immunoassays, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) and TCR sequencing. In CARTITUDE-1, the DP contained a mixture of transduced and non-transduced T cells; the median transduction efficiency was 16% (range 5-32%), with a balanced distribution of CAR+CD4+ and CAR+CD8+ cells, median frequency 12% (range 2-28%) and 6% (range 2-20%), respectively. Further, the DP T cell subset composition was variable but balanced between central (Tcm) and effector memory (Tem) phenotypes. CAR+ T cells expanded reaching a median peak concentration (C max of 730 cells/µL; range 3-13805 cells/µL) in blood between days 12-14 post-infusion and persisted in circulation for a median of 100 days (range 20-912 days). High efficacy (best response) and DOR were achieved despite variable CAR-T cell expansion and lack of detectable CAR-T cell persistence over time. At C max, the CD4:CD8 ratio (based on % of CAR+ cells) was 0.29, demonstrating a CAR+CD8+ T cell preferential expansion, and both CAR+CD4+ and CAR+CD8+ T cells were predominantly of a Tcm phenotype, median 95% (range 62-99.5%) and 96% (range 33-99.7%), respectively. Higher frequency of early-memory T cell phenotypes has been associated with clinical responses to CAR-T therapies in MM (Dancy et al., Blood 2018). CITE-seq analyses showed that DP characteristics such as a high CD8+ stem-like phenotype and a low CD4+ Treg-like phenotype in the CAR+ T cell compartment associated with longer DOR. Some of the most abundant clones in the DP single cell TCR data were CAR+CD8+ T cells expressing granzyme B, suggesting high cytotoxic potential. Additional bulk TCR sequencing data suggest both diversity and individual clonal expansion longitudinally after cilta-cel infusion. We also evaluated tumor and patient intrinsic characteristics at baseline. BCMA expression on bone marrow PC was prevalent and highly variable among RRMM patients; however, expression did not associate with best response or DOR. Further, high ORR was observed in patients with high-risk cytogenetics, high tumor burden (&amp;gt;= 60% bone marrow PC), or baseline plasmacytomas, although with a non-statistically significant shorter PFS. Sustained MRD negativity strongly associated with longer DOR. Conversely, patient-intrinsic characteristics associated with inflammation (CRP, ferritin, neutrophils, pro-inflammatory cytokines) correlated with shorter DOR. Treatment benefit of the magnitude seen with cilta-cel had not been reported with any other approved therapy in this setting. Correlative analyses suggest an emerging profile to help understand such outstanding clinical activity: a balanced CD4/CD8 ratio and Tcm/Tem phenotype of the manufactured DP and preferential expansion of CAR+CD8+ Tcm cells. Further, certain baseline patient-intrinsic and tumor characteristics may explain the longer DOR in the RRMM setting. These investigations help identify markers of response to cilta-cel and may lead to CAR-T cell design or manufacturing strategies that enhance drug product characteristics and thus clinical efficacy.

Elranatamab Exposure-Efficacy Analysis in Patients with Relapsed or Refractory Multiple Myeloma: Insights from Pooled Magnetismm Studies

BACKGROUND Elranatamab (ELRA) is a heterodimeric humanized full-length bispecific antibody comprised of one B-cell Maturation Antigen (BCMA) binding arm and one cluster of differentiation 3 (CD3) binding arm paired through hinge mutation technology. Results from the MagnetisMM-3 (NCT04649359) study indicated deep and durable responses in patients with relapsed or refractory multiple myeloma (RRMM). The current analysis was conducted a) to characterize the relationship between free (ie, unbound) and total (ie, unbound and bound to soluble BCMA - sBCMA) ELRA exposure and objective response rate (ORR), b) to evaluate the effect of potential covariates in the ELRA exposure-response (E-R) relationship with ORR, and c) to characterize the relationship between ELRA exposure and duration of response (DOR). METHODS Data from ELRA monotherapy from the MagnetisMM-1 (first-in-human Ph1, NCT03269136), MagnetisMM-2 (Japan Ph1, NCT04798586), MagnetisMM-3 (Ph2 with pivotal Cohort A in BCMA-naïve patients and Cohort B with BCMA-exposed patients), and MagnetisMM-9 (Ph1/2, NCT05014412) studies were pooled for analyses. The dataset included a wide dose range from 0.1 µg/kg IV to 1000 µg/kg / 76 mg SC weekly (QW) dosing. Free and total exposure metrics (C ave,Day28, ie, average ELRA concentration on Day 28) and (C ave,Event, ie, average ELRA concentration up to the time of first response or progression/end of treatment) were obtained using the individual post-hoc pharmacokinetic (PK) parameters from the population PK model 1. The E-R relationship for the efficacy endpoint ORR by Investigator and the effects of various baseline demographic and disease risk factors (eg, age, sex, baseline sBCMA level, cytogenetics, extramedullary disease [EMD], and number of prior lines of therapy) were characterized using binomial logistic regression method. A Cox proportional hazard model was used to quantify the effects of C ave,Day28 and C ave,Event and the reduction of the dosing intensity from QW to once every two weeks (Q2W) on DOR. The relationship between tertiles and DOR was also explored using Kaplan-Meier (KM) analysis. The analyses were performed with R software. RESULTS A significant E-R relationship was identified between both total and free ELRA C ave,Day28 and C ave,Event and ORR. Higher ELRA exposure was associated with higher ORR. For the total ELRA PK analysis, lower baseline sBCMA level was associated with higher ORR. For both total and free ELRA E-R relationships, number of prior lines of therapy ≤ 5 and absence of baseline EMD were associated with higher ORR. None of the other covariates were significant predictors of ORR. The models developed using either C ave,Day28 or C ave,Event identified same set of significant covariates. Figure 1 shows the results of free ELRA C ave,Day28 E-R analysis. The Cox proportional hazard analysis and KM plots of DOR by tertiles of exposure revealed no significant association between ELRA exposure, Q2W switch, and DOR. CONCLUSION The efficacy endpoint ORR demonstrated E-R relationships with total and free ELRA exposures. Patients with higher ELRA exposure, lower number of prior lines of therapy, , were more likely to achieve objective responses. Lower sBCMA was also a significant predictor of ORR in the total PK analysis. The findings supported the 76 mg QW ELRA, which is the highest tested dose in the MagnetisMM-1 study. This regimen is projected to provide meaningful clinical benefit in the majority of RRMM patients, including those with relatively high baseline sBCMA levels. The identified covariates are known prognostic factors for RRMM, yet the ORR achieved in these subgroups is clinically meaningful. There was no significant association between total or free ELRA exposures, Q2W switch and DOR, which further supports the maintenance of responses with Q2W switch for the RRMM population.

Three-Year Follow-up on Efficacy and Safety Results from Phase 1 Lummicar Study 1 of Zevorcabtagene Autoleucel in Chinese Patients with Relapsed or Refractory Multiple Myeloma

Introduction: Phase 1b of LUMMICAR STUDY 1 was conducted in China (NCT03975907) for zevorcabtagene autoleucel (zevor-cel, CT053), a fully human autologous chimeric antigen receptor (CAR) T-cell therapy comprising a B-cell maturation antigen-specific single-chain variable fragment, in patients with relapsed or refractory multiple myeloma (RRMM). Previously disclosed 1-year follow-up data (ASH 2021 Abstract 2821) demonstrated a tolerable safety profile and deep and durable responses in 14 patients. Here, we present the updated results with 3 years of follow-up after the last patient was infused. Methods: Patients were eligible to be enrolled with a diagnosis of RRMM, ECOG score of 0 or 1, and they had received at least 3 prior regimens including at least one proteasome inhibitor and one immunomodulatory drug. A single infusion of zevor-cel (two dose levels, 100 × 10 6 CAR + T cells and 150 × 10 6 CAR + T cells) was administered 5-7 days after the start of lymphodepletion. Response was assessed by investigator per IMWG 2016 criteria. Bone marrow aspirates were tested for minimal residual disease (MRD) by the EuroFlow assay with a minimum sensitivity of 1 in 10 5 nucleated cells. Results: Starting July 23, 2019, 14 patients with a median age of 54 years (range 34, 62), received a single infusion of zevor-cel (100 × 10 6 CAR + T cells in 3 patients, 150 × 10 6 CAR + T cells as the recommended phase 2 dose in 11 patients). The median number of prior lines of therapy was 6. A total of 50.0% of the infused patients had high-risk cytogenetics, 14.3% had extramedullary disease, 14.3% had ISS stage III, and no patients received bridging therapy. By the data cutoff date (July 17, 2023), the median survival follow-up duration was 37.7 months (range:14.8, 44.2). Overall response rate was 100% (95% CI 76.8, 100.0), in which 11 (78.6%) patients achieved complete response (CR) or stringent complete response (sCR); 2 (14.3%) patients achieved very good partial response and 1 (7.1%) patient had partial response. All patients who achieved CR or better were MRD negative. The median progression-free survival was 25.0 months (14.9, not evaluable [NE]) for all patients and 26.9 months (15.5, NE) for patients with sCR/CR (Figure 1A). The median duration of response was 24.1 months (14.0, NE) for all patients and 26.0 months (14.6, NE) (Figure 1B) for patients with sCR/CR. At data cutoff, 5 subjects still had ongoing responses, and 7 patients progressed and were still in survival follow-up. Two patients had died at month 42.6 and 32.6, respectively, and their deaths were deemed unrelated to zevor-cel. All patients experienced treatment related adverse events and grade 3 or 4 hematologic toxicity. Thirteen patients (92.9%) had cytokine release syndrome (all grade 1 or 2). No immune effector cell-associated neurotoxicity syndrome, no second primary malignancy, and no autoimmune disease were reported. All patients have been tested negative for replication competent lentivirus to date. Conclusions: At approximately 3 years of follow-up, heavily pre-treated RRMM patients maintained deep and durable responses after receiving a single infusion of zevor-cel, which showed a well-managed safety profile in the ongoing long-term follow-up.

Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial

BackgroundAponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, is a potential death receptor 4/5-targeted antitumour candidate. Previous phase 1/2 studies have demonstrated the efficacy of aponermin in patients with relapsed or refractory multiple myeloma (RRMM). To confirm the superiority of aponermin plus thalidomide and dexamethasone (aponermin group) over placebo plus thalidomide and dexamethasone (placebo group) in RRMM, a randomized, double-blinded, placebo controlled phase 3 trial was performed.MethodsFour hundred seventeen patients with RRMM who had previously received at least two regimens were randomly assigned (2:1) to receive aponermin, thalidomide, and dexamethasone or placebo, thalidomide, and dexamethasone. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and overall response rate (ORR).ResultsA total of 415 patients received at least one dose of trial treatment (276 vs. 139). The median PFS was 5.5 months in the aponermin group and 3.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.49–0.78; P < 0.001). The median OS was 22.4 months for the aponermin group and 16.4 months for the placebo group (hazard ratio, 0.70; 95% CI, 0.55–0.89; P = 0.003). Significantly higher rates of ORR (30.4% vs. 13.7%, P < 0.001) and very good partial response or better (14.1% vs. 2.2%, P < 0.0001) were achieved in the aponermin group than in the placebo group. Treatment with aponermin caused hepatotoxicity in some patients, as indicated by the elevated alanine transaminase, aspartate transaminase, or lactate dehydrogenase levels (52.2% vs. 24.5%, 51.1% vs. 19.4% and 44.9% vs. 21.6%, respectively), mostly grade 1/2, transient and reversible. The main grade 3/4 adverse events included neutropenia, pneumonia and hyperglycemia. The incidence of serious adverse events was similar between the two groups (40.6% vs. 37.4%). There was no evidence that aponermin leads to hematological toxicity, nephrotoxicity, cardiotoxicity, or secondary tumors.ConclusionsAponermin plus thalidomide and dexamethasone significantly improved PFS, OS and ORR with manageable side effects in RRMM patients who had received at least two prior therapies. These results support the use of aponermin, thalidomide, and dexamethasone as a treatment option for RRMM patients.Trial registrationThe trial was registered at http://www.chictr.org.cn as ChiCTR-IPR-15006024, 17/11/2014.

Incidence of Second Primary Malignancies (SPMs) in Patients in the US with Triple-Class-Exposed (TCE) Relapsed or Refractory Multiple Myeloma (RRMM)

Background Therapeutic advances have increased life expectancy for patients with RRMM. As survival has improved, SPMs have become an increasingly important safety consideration for RRMM patients. Prior studies have demonstrated that treatment with alkylators, autologous stem cell transplantation (ASCT), and immunomodulatory drugs (IMiDs), specifically lenalidomide, are associated with increased SPM risk. Patients who are TCE (exposure to ≥1 IMiD, ≥1 proteasome inhibitor [PI], and ≥1 anti-CD38 monoclonal antibody [mAb]) represent an increasingly large subgroup of RRMM patients. The objective of this study was to describe the incidence of SPMs in patients with TCE RRMM. These data may inform development and selection of novel treatments for these patients. Methods Data were from two large US health-insurance claims databases: the Optum Clinformatics® Data Mart and the IQVIA PharMetrics® Plus Health Insurance Claims database. TCE RRMM patients were selected if they had ≥1 confirmed diagnosis of multiple myeloma (MM) on or after December 1, 2015 (date of approval by the US Food and Drug Administration of 1st anti-CD38 mAb for RRMM) and evidence of being TCE. The first line of therapy (LOT) after becoming TCE was identified ("index LOT") and the date of initiation of this LOT was defined as the "index date". Patients who experienced SPMs prior to the index date were excluded. SPMs were identified based on having at least one inpatient or two outpatient diagnoses (of the same cancer type) of invasive malignancies or myelodysplastic syndromes (MDS) other than MM, Waldenstrom macroglobulinemia, plasma cell leukemia, non-melanoma skin cancers, or primary bone malignancies that were preceded by a diagnosis of bone metastases. The incidence of SPM was calculated per 100 person years (PY) of follow-up, considering only the first SPM for each patient. Cumulative incidence of SPM with death as competing risk was calculated for patients in Optum database (data on mortality was unavailable in the PharMetrics database). Results A total of 1,110 TCE RRMM patients were identified in the two databases, of whom 726 had no evidence of SPM prior the index date (Table). These 726 patients had a mean age of 66.6 y; 45% were female, with a mean of 3 prior LOTs and 3.2 years since diagnosis. Over a mean (SD) follow-up of 11.7 (10.4) months, 96 patients (14.8 per 100 PY) experienced a new SPM, including 47 (7.2 per 100 PY) with solid tumor and 51 (7.9 per 100 PY) with a hematologic malignancy. The latter included 22 (3.4 per 100 PY) with acute myeloid leukemia (AML) and 17 (2.6 per 100 PY) with myelodysplastic syndrome. Among patients in the Optum database (N=416), the cumulative incidence of SPM (95%CI) was estimated to be 10.3% (7.4% , 13.7%), 14.9% (10.8% , 19.6%), and 20.1% (13.9% , 27.2%) at 12, 24, and 36 months, respectively (Figure). Conclusions The incidence of SPM in TCE RRMM patients is clinically significant. Many SPMs in these patients are potentially serious malignancies, including AML and MDS. There is a need for effective treatments for TCE RRMM that are not associated with increased risks of SPMs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Updated results from a matching-adjusted indirect comparison of efficacy outcomes for ciltacabtagene autoleucel in CARTITUDE-1 versus idecabtagene vicleucel in KarMMa for the treatment of patients with relapsed or refractory multiple myeloma

Objective This study used the latest available data cuts from the CARTITUDE-1 and KarMMa clinical trials to update previously published matching-adjusted indirect treatment comparisons (MAICs) assessing the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus the FDA-approved idecabtagene vicleucel (ide-cel) dose range of 300 to 450 × 106 CAR-positive T-cells in the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody (i.e. triple-class exposed). Methods MAICs were performed with the latest available individual patient data for cilta-cel (CARTITUDE-1) and published summary-level data for ide-cel (KarMMa). The analyses included treated patients from CARTITUDE-1 who satisfied the eligibility criteria for KarMMa. The MAIC adjusted for unbalanced baseline covariates of prognostic significance identified in the literature and by clinical expertise. Comparative efficacy was assessed for overall response rate (ORR), complete response or better (≥CR) rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Results Cilta-cel was associated with statistically significantly improved ORR (odds ratio [OR]: 94.93 [95% confidence interval [CI]: 21.86, 412.25; p < .0001]; relative risk [RR]: 1.34), ≥CR rate (OR: 5.65 [95% CI: 2.51, 12.69; p < .0001]; RR: 2.23), DoR (hazard ratio [HR]: 0.52 [95% CI: 0.30, 0.88; p = .0152]), PFS, (HR: 0.38 [95% CI: 0.24, 0.62; p < .0001]), and OS (HR: 0.43 [95% CI: 0.22, 0.88; p = .0200]) compared with ide-cel. Conclusions These analyses demonstrate improved efficacy with cilta-cel versus ide-cel for all outcomes over longer follow-up and highlight its therapeutic potential in triple-class exposed RRMM patients.

Efficacy and safety of pomalidomide and low-dose dexamethasone in Chinese patients with relapsed or refractory multiple myeloma: a multicenter, prospective, single-arm, phase 2 trial

BackgroundPomalidomide in combination with dexamethasone has demonstrated positive results in patients with relapsed or refractory multiple myeloma (RRMM), but no data are available in China. We conducted a multicenter, single-arm trial to examine the efficacy and safety of bioequivalent generic pomalidomide plus low-dose dexamethasone in Chinese RRMM patients.MethodsAdult (≥ 18 years of age) RRMM patients who progressed after at least two previous treatments, including bortezomib and lenalidomide, were eligible. Pomalidomide was given orally at 4 mg/day on days 1 to 21 of a 28-day cycle. Dexamethasone was given at 40 mg/day (either orally or intravenously; 20 mg/day at 75 years or older) on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression or intolerable adverse events (AEs). The primary end point was objective response rate (ORR).ResultsSeventy-four patients were enrolled between February 2017 and February 2019. All patients had progressed within 60 days of their last therapy. 74.3% of the patients were resistant to lenalidomide, 31.1% had renal insufficiency and 33.8% had high-risk cytogenetic RRMM. The median follow-up duration was 33.0 months (range 31.1–34.8 months). The ORR was 37.8% in the overall analysis, 32.7% in lenalidomide-refractory patients, 36.0% in patients with high-risk cytogenetics and 34.8% in RRMM patients with renal impairment. The median progression-free survival was 5.7 months (95% CI 3.7–8.8 months). The median overall survival was 24.3 months (95% CI 14.4–41.1 months). The most common grade 3 and 4 treatment-emergent adverse events (TEAEs) were neutropenia (63.5%), leukopenia (37.8%), thrombocytopenia (28.4%), and anemia (31.1%). Pulmonary infection (27.0%) was the most frequent grade 3 and 4 nonhematologic TEAE. No previously unreported AEs were observed. No venous thromboembolism was reported.ConclusionsPomalidomide in combination with low-dose dexamethasone is effective and safe in Chinese RRMM patients.Trial registrationThe study is registered at Chinese Clinical Trial Registry (ChiCTR) (ChiCTR-OIC-17013234, first registered on 03/11/2017).

Preclinical Assessment of CDR101 - a BCMAxCD3xPD-L1 Trispecific Antibody with Superior Anti-Tumor Efficacy

BCMAxCD3 targeting therapies have demonstrated anti-myeloma activity, and high minimal residual disease negativity rates can be achieved with this approach in heavily pre-treated patients with relapsed or refractory multiple myeloma (RRMM). Despite these promising clinical results, patients eventually develop resistant disease and relapse. Thus, there is a high need for novel BCMA therapies that can evade the resistance mechanisms and provide more durable responses. Recently, we reported on the promising activity of the Local Activator and T cell Engager (LocATE) technology, a trispecific molecule that targets CD3, BCMA and PD-L1, redirecting T cells to multiple myeloma (MM) cells while selectively counteracting PD-L1/PD-1 induced immunosuppression at the immune synapse (ASH, 2020). Here we present CDR101, an optimized LocATE candidate with potential for clinical development.First, we analyzed the ability of CDR101 to induce PBMC-mediated cytotoxicity in two MM cell-lines expressing BCMA (U-266 and NCI-H929) and compared it to four BCMAxCD3 bispecific formats currently in clinical development (a half-life extended BCMAxCD3 BiTE, a BCMA-TCB, and two different BCMAxCD3 bispecific monoclonal antibodies) alone or in combination with a separate PD-L1 blocking antibody. CDR101 resulted in at least 10-fold increased T cell-mediated target cell lysis compared to control BCMAxCD3 bispecifics. Strikingly, CDR101 also resulted in increased MM cell killing when compared to free, independent combinations of BCMAxCD3 bispecifics and the PD-L1 inhibitor. These results, together with the observation that MM cells upregulate the expression of PD-L1 in response to treatment with BCMAxCD3 bispecifics, suggest that the superior effect of CDR101 could be attributed to preferential and highly selective inhibition of the PD-1/PD-L1 axis at the cellular interaction within the immune synapse.Next, bone marrow aspirates from newly diagnosed and RRMM patients were treated with increasing concentrations of CDR101 or a BCMAxCD3 bispecific control. After 24h of incubation, percentage of viable CD138-positive cells and activation status of autologous T cells were analyzed by FACS. Overall, CDR101 potently induced lysis of primary MM cells independently of the E:T ratio (range of E:T ratio between 1.3:1 and 33:1). CDR101 achieved higher target cell killing in all samples compared to the bispecific control, with at least 2-fold difference in 3 out of 4 samples at the highest concentration tested. Concomitantly, CDR101 induced a dose-dependent increase of the T cell activation marker CD25, corroborating the ability of CDR101 to counteract PD-L1/PD-1 induced immunosuppression.In vivo anti-tumor activity of CDR101 was evaluated using a human MM (NCI-H929) xenograft model in NPG mice. Treatment with four different doses of CDR101 or BCMAxCD3 bispecific control demonstrated that CDR101 induced stronger and more durable responses compared to the bispecific control leading to complete tumor regression in 55 out of 60 mice at the last day of treatment (day 29) with no relapse until the end of the observation time (day 41).Collectively, CDR101 demonstrated that targeting BCMA with simultaneous blockade of PD-L1 leads to improved myeloma cell killing compared to clinically validated therapies. In contrast to high-affinity PD-L1 immune checkpoint inhibitors, CDR101 selectively inhibits PD-L1 at the immune synapse preventing on-target off-tumor effects. This is expected to translate into a decreased incidence of immune related adverse events (irAEs) and better efficacy arguing for a high clinical potential and swift translation into the clinic. DisclosuresVrohlings: CDR-Life Inc: Current Employment, Current holder of stock options in a privately-held company. Jungmichel: CDR-Life Inc: Current Employment, Current holder of stock options in a privately-held company. Senn: CDR-Life Inc: Current Employment, Current holder of stock options in a privately-held company. Howald: CDR-Life Inc: Current Employment, Current holder of stock options in a privately-held company. Schleier: CDR-Life Inc: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Scheifele: CDR-Life Inc: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Wendelspiess: CDR-Life Inc: Current Employment, Current holder of stock options in a privately-held company. Richle: CDR-Life Inc: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Merten: CDR-Life Inc: Current Employment, Current holder of stock options in a privately-held company. Lenherr-Frey: CDR-Life Inc: Current Employment, Current holder of stock options in a privately-held company. Leisner: CDR-Life Inc: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Manz: CDR-Life Inc: Consultancy, Current holder of stock options in a privately-held company; University of Zurich: Patents & Royalties: CD117xCD3 TEA. Borras: CDR-Life Inc: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.

TIG-007: Study of EOS884448/GSK4428859A Alone, and in Combination with Iberdomide with or without Dexamethasone, in Participants with Relapsed or Refractory Multiple Myeloma

Background: T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory immune checkpoint receptor expressed on subsets of T cells and NK cells. In multiple myeloma (MM), TIGIT expression increases as the disease progresses and correlates with defective T cell effector functions. Higher TIGIT expression was observed in MM bone marrow CD8+ T cells in mice and patients compared to other immune checkpoint inhibitors, including PD-1, TIM-3, LAG-3, or CTLA-4 (Guillerey, C. et al, Blood 2018; Minnie, S. A. et al . Blood 2018). EOS884448/GSK4428859A (EOS-448) is a potent and highly selective fully human antagonist IgG1 antibody targeting TIGIT. Preclinically, anti-TIGIT Ab elicits superior anti-tumor immune responses compared to anti-PD1 mAbs (Guillerey, C. et al, Blood 2018). In murine Vk*Myc MM models, Fc-enabled a-TIGIT Ab elicits effective control of MM disease progression after autologous stem-cell transplant (ASCT), while Fc-disabled version is inactive. Anti-tumor activity is seen with monotherapy after ASCT at high T cell doses and provides significant synergistic activity when combined with an Immunomodulatory imide drug (IMiD) if T cell doses are suboptimal (Minnie, S. A. et al, Abstract submitted ASH 2021). Iberdomide (also known as CC-220) is a novel potent cereblon (CRBN) E3 ligase modulatory compound (CELMoD) that regulates multiple transcription factors within immune cells (Gandhi, A. K. et al . Brit J Haematol 2014). Iberdomide has shown notable clinical activity and acceptable tolerability in heavily pre-treated patients with relapsed or refractory multiple myeloma (RRMM), including those refractory to prior IMiDs (Lonial, S. et al. J Clin Oncol 2019). Given the dominant role of TIGIT in the immune suppression associated with MM, we hypothesize that TIGIT represents an ideal checkpoint to target clinically. EOS-448 alone or the synergistic combination of EOS-448 with iberdomide may provide a therapeutic opportunity to amplify myeloma-specific T-cell anti-tumor responses in difficult to treat RRMM patients previously exposed to IMiD, proteasome inhibitors (PIs) and anti-CD38.Methods: This phase I/II, open-label, multicenter, dose-escalation/expansion study will assess the safety, tolerability and preliminary activity of EOS-448 as monotherapy and in combination with iberdomide with or without dexamethasone in up to 158 adults with RRMM, who have progressed after prior treatments with IMiDs, PI and anti-CD38. EOS-448 will be infused intravenously on Day 1 of 28-day cycles. In Part 1, the safety and tolerability of EOS-448 as monotherapy and in combination with iberdomide with or without dexamethasone will be assessed in cohorts of up to 18 participants to identify the maximum tolerated dose and recommended phase II dose (RP2D) in each of the 3 treatment arms. In Part 2, the safety and anti-cancer activity of the RP2D will be assessed in up to 102 RRMM participants. Primary endpoints are treatment emergent adverse events, laboratory abnormalities, dose-limiting toxicities and clinical activity according to the International Myeloma Working Group (IMWG) Uniform Response Criteria. Secondary endpoints include overall response rates, duration of response, PK, and antidrug antibodies. Exploratory biomarkers including study treatment-mediated pharmacodynamic (PD) effects, PK-PD correlations, and correlative analyses of predictive and PD measurements with response, toxicity, and resistance will be investigated. Minimal residual disease (MRD) status with therapy will also be assessed as clinically indicated. The study is planned to open in November 2021 in North America and Europe. DisclosuresMoreau: Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria. Holmberg: Janssen: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Sanofi: Research Funding; Millennium-Takeda: Research Funding; Bristol Myers Squibb: Research Funding; Up-To-Date: Patents & Royalties. Meuleman: iTeos Therapeutics: Consultancy. Graham: iTeos Therapeutics: Current Employment. De Henau: iTeos Therapeutics: Current Employment, Current equity holder in publicly-traded company; Bristol-Meyer-Squibb: Current equity holder in publicly-traded company. Driessens: iTeos Therapeutics: Current Employment, Current equity holder in publicly-traded company. McGrath: iTeos Therapeutics: Current Employment, Current equity holder in publicly-traded company; Norgine: Other: Spouse Current Employment. Lager: iTeos Therapeutics: Current Employment, Current equity holder in publicly-traded company. Hill: NeoLeukin Therapeutics: Consultancy; Applied Molecular Transport: Research Funding; Syndax Pharmaceuticals: Research Funding; NapaJen Pharma: Consultancy; iTeos Therapeutics: Consultancy, Research Funding; Compass Therapeutics: Research Funding; Generon Corporation: Consultancy; Roche: Research Funding.

Pomalidomide and Dexamethasone Are Effective in Relapsed or Refractory Multiple Myeloma in a Real-Life Setting: A Multicenter Retrospective Study in Taiwan.

BackgroundThe therapeutic options of relapsed or refractory multiple myeloma (RRMM) remain a challenge. The MM-003 trial demonstrated that RRMM patients treated with pomalidomide and dexamethasone (Pom/Dex) have better progression-free survival (PFS) than those treated with high-dose dexamethasone alone. However, the real-world effectiveness of Pom/Dex in these patients in Taiwan remains unclear.MethodsThis multicenter, registry-based study retrospectively reviewed the medical records of 49 consecutive patients undergoing Pom/Dex treatment for RRMM. We investigated the overall response rate (ORR) and PFS in these patients. The patients were stratified into two groups: those who received two (n=33) and those who received more than two (n=16) prior lines of treatment according to the numbers of regimens before Pom/Dex therapy. The differences in ORR and PFS between these two groups were further analyzed. We also analyzed factors attributed to disease progression.ResultsThe ORR was 47.7%, and the median PFS was 4.0 months (range, 0.1−21.1). Patients who received two prior lines of treatment had a higher ORR than those who received more than two prior lines of treatment (55.2% vs. 33.3%; p=0.045). The median PFS of these groups was 4.8 and 3.9 months, respectively (p=0.805). Primary lenalidomide refractoriness reduced the risk of myeloma progression following Pom/Dex treatment (hazard ratio, 0.14; p=0.001).ConclusionsThe median PFS following Pom/Dex treatment in Taiwanese RRMM patients in a real-world setting was similar to that reported by the MM-003 trial. Primary lenalidomide refractoriness should not be an obstacle for Pom/Dex treatment in RRMM.

3-weekly daratumumab-lenalidomide/pomalidomide-dexamethasone is highly effective in relapsed and refractory multiple myeloma

ABSTRACT Objectives Myeloma relapse remains challenging. Daratumumab (dara) with immunomodulatory agents (IMiD) and dexamethasone (dex) was proven highly effective in relapsed or refractory multiple myeloma (RRMM) in randomized controlled trials. The recommended schedule of dara is weekly for eight doses, followed by 2-weekly for eight doses, and then every 4-weekly thereafter. However, the cost of daratumumab is daunting, precluding widespread and prolonged use in some countries. In this study, we aimed to evaluate the efficacy of using a 3-weekly daratumumab regimen in RRMM. Methods Thirteen RRMM patients were treated with dara-IMiD-dex till maximal response, followed by single-agent IMiD maintenance until disease progression. Dara (every 6 weekly) would be added upon significant biochemical disease progression. Results After a median of four daratumumab infusions (range: 3–10), the best responses included complete response (CR) in seven patients (53.8%), very good partial response (VGPR) in four patients (30.8%), and partial response (PR) in two patients (15.4%). The median time to VGPR was four weeks. At 10 months, the overall survival was 90%, and progression-free survival was 54.7%. Two of three patients tested achieved MRD-ve CR. Another patient, who had PET-CT reassessment, showed PET-ve CR. Discussion Despite less frequent daratumumab use, we reported rapid responses with a median time to VGPR of only four weeks, and a response rate of 100% including CR rate of 54%. Despite less frequent daratumumab use, grade ¾ neutropenia remained common with a frequency comparable to that observed in Pollux. Conclusion This 3-weekly dara-IMiD-dex regimen preserves a high efficacy with rapid, deep responses including MRD-ve and PET-ve CR, hence a cost-effective regimen.

Progression Free Survival of Relapsed or Refractory Multiple Myeloma (RRMM) after Failure of Three Prior Lines of Therapy in United States (US) Real-World Practice

Background: Given the approval of a vast array of potent therapies and treatment combinations in multiple myeloma, it is important to understand outcomes of patients who relapse and/or become refractory to these commonly used drugs such as proteasome inhibitors (PI), immunomodulatory agents (IMiD), and CD38 targeting monoclonal antibodies (MoAB; ie. daratumumab). This study aims to describe clinical characteristics and progression free survival (PFS) after failure of at least 1 PI and IMiD +/- daratumumab in US community practice to provide context for the outcomes of RRMM patients after exposure to at least three lines of anti-myeloma therapies. Methods: Data analyzed were from electronic health record (EHR) generated by Flatiron Health (New York, NY). These data represent over 280 cancer clinics representing over 2 million active patients treated at primarily community-based hematology/oncology practices in the US. Inclusion criteria included adult patients ≥18 years with a diagnosis of MM, at least two clinic visits after 2015, failure of a PI and IMiD, ECOG ≤2, adequate hematologic/renal/hepatic function, and no stem cell transplant within three months of study entry. Study eligibility began as early as treatment initiation in ≥ fourth line (4L+) from January 2015 through March 2020. Progression free survival was measured from treatment until death, progression, or start of new line of therapy, and PFS was estimated for patients who were eligible for study inclusion (index date) between 2015-2018. Last follow-up occurred at March 2020. Results: In total, 141 patients had prior daratumumab exposure (64 included in time-to-event analysis) and 294 patients were daratumumab naïve (56 of these 294 had daratumumab exposure in a later line of therapy, at which point they were counted in the 141 daratumumab exposed patients group; 230 included in time-to-event analysis) once meeting the inclusion criteria for this study. Of patients exposed to daratumumab, 50% qualified for the study after 3-4 lines versus 87% of daratumumab naive patients. The median age at study entry was 69-70 years (Table 1). Approximately 36% of daratumumab exposed patients and 33% of non-previously daratumumab exposed patients presented with either intermediate or high-risk cytogenetics at study entry for patients with available cytogenetics. About half (48%) of daratumumab-exposed patients and over a quarter (29%) of non-previously daratumumab-exposed patients had a prior transplant. Median time from diagnosis until study entry was 49 months for the daratumumab exposed and 39 months for the non-previously daratumumab exposed groups. Median follow-up for the daratumumab exposed group was 8 months and 15 months for the non-previously daratumumab exposed group. At study entry for the daratumumab exposed patients, 4% received monotherapy, 18% received a doublet (5% carfilzomib/dexamethasone and 4% daratumumab/dexamethasone), 56% received a triplet (11% daratumumab/pomalidomide/dexamethasone, 7% carfilzomib/pomalidomide/dexamethasone), and 12% a quadruplet. In total, 56 (40%) patients received re-treatment with a daratumumab combination. Among the non-previously daratumumab exposed patients, 12% received monotherapy, 29% received a doublet (8% carfilzomib/dexamethasone, 7% daratumumab/dexamethasone), 48% received a triplet (12% daratumumab/pomalidomide/dexamethasone, 5% bortezomib/daratumumab/dexamethasone), and 8% received a quadruplet. PFS was short in both groups (Figure 1). In the daratumumab exposed group, the median PFS was 3.3 months (95% CI: 2.1-5.8) and the in the non-previously daratumumab exposed group, the median PFS was 4.4 months (95% CI: 3.6-5.9). Discussion: In this study with majority of patients having 3-4 prior lines of treatment, short PFS was observed for RRMM patients regardless of prior daratumumab exposure. Strikingly, many patients received re-treatment with a drug they had previously failed, suggesting many patients may have run out of effective therapies to utilize. Additionally, the daratumumab exposed group had a higher proportion with prior transplant which may also lead to differential outcome between these groups. Overall, these data suggest that these patients have poor outcomes and the need for effective novel classes of therapies remains high within the US community practice setting. Disclosures Kim: Amgen: Current Employment. Braunlin:Amgen: Current Employment. Belani:Amgen: Current Employment. Wheeling:Amgen: Consultancy.

A Phase I Dose Escalation Study of PT-112 in Patients with Relapsed or Refractory Multiple Myeloma

Background: PT-112 is a novel pyrophosphate-platinum conjugate with a multi-modal mechanism of action that induces immunogenic cell death and is not susceptible to DNA-repair drug resistance pathways. In phase I studies in solid tumors, PT-112 demonstrated safety and efficacy as single agent and in combination with PD-L1 checkpoint inhibitor avelumab, crossing a range of dose levels (DL) and tumor types, including in heavily pre-treated patients (pts) non-responsive to immunotherapy and refractory to other modalities. Non-clinical, in vivo research using advanced imaging technology demonstrated that PT-112 reached the highest concentrations in bone tissue (osteotropism). Moreover, PT-112 was highly active in the orthotopic, immune-competent Vk*MYC mouse model of multiple myeloma, including drug-resistant transplant variants. Thus, a rationale for PT-112 as an investigational candidate in multiple myeloma was established. Here, we present results of a phase I dose escalation study of PT-112 in pts with relapsed or refractory multiple myeloma (RRMM). Methods: A 3+3 design was used to determine the recommended phase 2 dose (RP2D) for PT-112 (28-day cycle IV days 1, 8, 15) in pts with evaluable RRMM who had exhausted available therapies (Tx), with adequate bone marrow (abs neutrophil count ≥ 1.0 x 109/L; platelet count ≥ 50 x 109/L; and hemoglobin ≥ 8.0 g/dL) and renal function (calculated creatinine clearance ≥ 30 mL/min), and ECOG PS 0-2. Results: A total of 24 pts were treated with PT-112 monotherapy across 6 DLs: 125 mg/m2, 3 pts; 180 mg/m2, 4 pts; 250 mg/m2, 5 pts; 300 mg/m2, 4 pts; 360 mg/m2, 4 pts; 420 mg/m2, 4 pts. Patients had a median age of 72 years and were heavily pre-treated, with a median of 8 prior lines of systemic Tx: 22 (92%) pts were triple-class refractory with 19 (79%) pts penta-refractory, and 3 (13%) pts refractory to BCMA-based therapies. The most common treatment-related adverse events (TRAEs) were thrombocytopenia (58%), neutropenia (42%), diarrhea (38%), and nausea (38%). 38% of pts had ≥1 grade 3 non-hematologic TRAE, with no grade 4 non-hematologic TRAEs reported. One dose-limiting toxicity (DLT) of grade 4 neutropenia occurred at the 420 mg/m2 DL. In addition, due to frequent dose reductions and modifications at this DL, the safety committee declared 360 mg/m2 as the RP2D. Among 8 patients who received a starting dose at / above the RP2D, 2 had stable disease and 4 experienced responses to PT-112 Tx. These included a confirmed partial response (PR) achieved in a 79-year-old pt with kappa free light chain (FLC) disease treated at 360 mg/m2, whose previous Tx included combination regimens with most approved therapies (penta-refractory) and stem cell transplantation. FLC levels declined by 65% from baseline on PT-112 therapy and the pt remained progression free for 4.5 months. A 72-year-old pt treated at the 420 mg/m2 DL, reduced to 250mg/m2 every other week over the course of Tx due to grade 3-4 cytopenias, had a confirmed minor response. Prior Tx with multiple lines given over 9 years included stem cell transplantation, most approved therapies (penta-refractory), prior investigational antibody and CAR-T cell Tx (primary refractory to CAR-T). The patient was M-protein negative, kappa FLC levels declined by 32% following the first dose reduction, and the pt remained progression free and clinically stable without complaints for 4.5 months. Additionally, two transient, unconfirmed PRs occurred in patients at the 420mg/m2 DL: in a triple-class-refractory 82-year-old previously treated with 5 lines of Tx, with 70% reduction in kappa FLC during cycle 1; and in a penta-refractory 85-year-old, who experienced disappearance of M-protein during cycle 1 and Gr 4 neutropenia (DLT). Conclusions: PT-112 monotherapy was feasible and well tolerated in this heavily pre-treated, multi-refractory multiple myeloma population, and the Phase I clinical data appear to validate the developmental hypothesis, built upon activity in the Vk*MYC mouse model of multiple myeloma. Responses were confirmed in 25% of patients treated at / above the RP2D using single-agent PT-112, an encouraging result in a dose escalation trial conducted in heavily refractory patients. Activity of PT-112 in RRMM patients may be explained by its osteotropism and its unique mechanism of action compared to other drug classes used to treat this disease. Further clinical study of PT-112 in RRMM is warranted in a phase 2 clinical trial. Disclosures Ailawadhi: Celgene: Honoraria; Janssen: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; Medimmune: Research Funding; BMS: Research Funding; Cellectar: Research Funding; Phosplatin: Research Funding; Takeda: Honoraria. Vogl:Janssen: Consultancy; Celgene: Consultancy; MorphoSys: Consultancy; Takeda: Consultancy; Active Biotech: Consultancy, Research Funding; Oncopeptides: Consultancy; Karyopharm: Consultancy. Ames:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Yim:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Price:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Jimeno:Phosplatin Therapeutics: Current Employment, Current equity holder in private company.