Pretreated Multiple Myeloma Patients Research Articles

The preclinical discovery and clinical development of ciltacabtagene autoleucel (Cilta-cel) for the treatment of multiple myeloma

ABSTRACT Introduction Despite remarkable therapeutic advances over the last two decades, which have resulted in dramatic improvements in patient survival, multiple myeloma (MM) is still considered an incurable disease. Therefore, there is a high need for new treatment strategies. Genetically engineered/redirected chimeric antigen receptor (CAR) T cells may represent the most compelling modality of immunotherapy for cancer treatment in general, and MM in particular. Indeed, unprecedented response rates have led to the recent approvals of the first two BCMA-targeted CAR T cell products idecabtagene-vicleucel (‘Ide-cel’) and ciltacabtagene-autoleucel (‘Cilta-Cel’) for the treatment of heavily pretreated MM patients. In addition, both are emerging as a new standard-of-care also in earlier lines of therapy. Areas covered This article briefly reviews the history of the preclinical development of CAR T cells, with a particular focus on Cilta-cel. Moreover, it summarizes the newest clinical data on Cilta-cel and discusses strategies to further improve its activity and reduce its toxicity. Expert opinion Modern next-generation immunotherapy is continuously transforming the MM treatment landscape. Despite several caveats of CAR T cell therapy, including its toxicity, costs, and limited access, prolonged disease-free survival and potential cure of MM are finally within reach.

Characterization of dysgeusia and xerostomia in patients with multiple myeloma treated with the T-cell redirecting GPRC5D bispecific antibody talquetamab.

In recent years, various immunotherapies have improved the survival of patients with multiple myeloma (MM). However, there remains an unmet need for novel agents. Talquetamab is the first-in-class GPRC5D-targeting T-cell redirecting bispecific antibody, which has substantial activity in advanced MM. Rapidly after the start of talquetamab treatment, patients reported taste changes (dysgeusia; 60% of patients), and a feeling of dry mouth (xerostomia; 30-57% of patients), which may be related to expression of the target antigen in healthy tissues, such as taste buds. Here, we aimed at better characterizing these oral toxicities. We measured salivary flow and the ability to taste (objectively and patient-reported), assessed the feeling of dry mouth, and evaluated quality of life before and 8 weeks after the start of talquetamab therapy in eight heavily pretreated MM patients. Talquetamab treatment led to the rapid and significant decrease in objectively measured taste scores (total score 8.8 ± 2.0 vs 4.9 ± 2.5). All patients reported moderate to severe taste changes. Moreover, patients experienced severe xerostomia after the initiation of talquetamab treatment, in the absence of changes in unstimulated and stimulated salivary flow. Because of these oral toxicities a significant impairment in global health status/(oral health related) quality of life was reported. Studying taste changes in patients treated with talquetamab following up on the described leads provides a new and unique opportunity to further unravel the pathophysiology of taste changes after cancer treatment.

Mezigdomide Treatment in Relapsed-Refractory Myeloma Patients Shifts Bone Marrow NK and T Cell Populations from Exhaustion to Activation

Background The effect of immunomodulatory drugs (IMiDs) and novel cereblon E3 ligase modulators (CELMoDs) on the tumour microenviroment (TME) of multiple myeloma (MM) patients remains poorly understood. A recent multi-center phase 1/2 trial (CC-92480-MM-001) of CELMoD Mezigdomide (MEZI) demonstrated clinical response in triple-class refractory, heavily pre-treated MM patients (Richardson et al, EHA abstracts 2020). Here, we report results from high dimensional mass cytometry immune profiling of baseline and treatment samples from relapsed-refractory MM (RRMM) patients to understand the effect of MEZI on the bone marrow (BM) TME. In addition, we analyze baseline samples to evaluate BM immune phenotypes that may correlate with response to MEZI. Methods We identified 45 RRMM patients with paired bone marrow aspirate samples pre- (screening) and post- (cycle 2 onwards) MEZI treatment, and 32 additional patients with isolated screening samples. Of the 45 patients, 39 received a dose of 0.8-1.0mg daily for 14 or 21 days of a 28-day cycle, 6 received 0.2-0.6mg on varying schedules as part of the trial design. CD138-negative BM mononuclear cells were isolated from these patients and profiled at single-cell resolution using a previously described 39-marker TME CyTOF-panel (van Oekelen, ASH 2021). Both manual hierarchical gating and unsupervised computational workflows were used for CyTOF data analysis. Around 5 million total cells were analyzed and over 100 immune populations. Samples with <2500 total events were excluded for quality-control. Population frequencies used for comparison are reported as median percentage of the parent population. Statistical comparisons between groups were assessed using the Wilcoxon test. Results Upon MEZI treatment, both adaptive and innate BM immune compartments demonstrated a significant increase in activated populations and marked reduction in exhausted/senescent populations (Figure 1A). Total NK and NKT populations expanded on MEZI (p<0.01 for both). Both CD4 and CD8 T cell populations shifted towards an effector phenotype with significant increases in effector memory (CCR7-CD45RA-) populations (p<0.001 for both) and concurrent reductions of and naïve (p<0.001), central memory (p<0.01 for CD4, NS for CD8) and TEMRA populations (p<0.001). HLADR-expressing CD4, CD8 and NKT populations significantly increased on MEZI (p<0.001 for all) as did ICOS-expressing CD4 (p<0.01), NK (p<0.001) and NKT cells (p<0.05). Senescent NK, NKT, CD4 and CD8 populations expressing KLRG1 decreased on MEZI treatment (p<0.01 for all) and CD57 positive CD8 and NKT cell populations also reduced (p<0.05). CD8, NK and NKT cells expressing the inhibitory checkpoint molecule TIGIT, showed a near 3-fold reduction of on treatment (p<0.001 for all). Although PD1-positive populations did not change on MEZI, PD1/TIGIT double-positive CD4 and CD8 populations showed significant reduction (p<0.05 for both). A dose-dependent reduction of TIGIT-expressing CD8 and NKT populations was seen at higher doses of MEZI (p<0.05 for both), suggesting a direct effect of MEZI on the BM TME. We further correlated depth-of-response with baseline immune composition in 77 patients (Figure 1B). Patients with progression of disease (n=9) on MEZI, when compared to all other patients (n=68), were found to have higher frequencies of PD1 (p<0.05) and TIGIT (p<0.001) positive, as well as dual PD1 and TIGIT positive (p<0.001), CD8 and NKT populations. Number of prior lines (median = 6) and type of MM therapy prior to MEZI did not significantly affect baseline PD1 or TIGIT positive populations. Conclusion MEZI treatment leads to significant activation of adaptive and innate BM immune populations with concurrent reduction of exhausted and senescent populations. These findings are concordant with prior observations of IMiD-mediated immune-stimulation. Patients progressing through MEZI had higher levels of immune checkpoint expression at baseline, which may be helpful for patient selection for this novel CELMoD. These results also suggest that MEZI may be useful in combination with other agents for increasing immune activation and reducing immune exhaustion. Further analyses comparing the effect of different CELMoDs on the BM TME are ongoing.

Immune Dynamics Associated with Patient Outcomes Identified By Multimodal Single-Cell Analysis in Multiple Myeloma Patients Receiving Talquetamab Monotherapy

Background: Talquetamab (Tal) is a CD3xGPRC5D bispecific antibody (BiAb) that redirects endogenous T cells to mediate killing of GPRC5D-expressing multiple myeloma (MM) cells. In the recent phase I/II MonumenTAL-1 trial (NCT03399799), Tal showed ≥ 70% response rate when given at the recommended phase 2 doses (RP2D) in heavily pretreated MM patients (Chari A et al., NEJM 2022). However, there is still a need to identify predictive biomarkers and better understand the immune dynamics associated with treatment response and durability with this novel agent. Methods:We identified 30 patients who received Tal monotherapy and had bone marrow (BM) and peripheral blood (PB) samples collected at baseline and PB collected at cycle 3 day 1 (C3D1). Cellular indexing of transcriptomes and epitopes (CITE)-seq was performed to understand transcriptional changes and cell surface proteomics. Total cells were isolated by Ficoll separation from PB and BM samples and were then analyzed separately and only samples of good quality were included in the analysis. Samples were filtered for good quality based on total cell count: at least 1000 cells with more than 500 unique molecular identifiers (UMIs) or genes and less than 4-5 standard deviations above median for UMI, genes and mitochondrial transcripts. A total of 60,851 BM cells (15 pts at baseline) and 299,996 PB cells (23 pts at baseline and 17 pts on C3D1) were analyzed. Downstream analysis was performed using the Seurat R package. All patients included in this study had signed consent for an IRB-approved institutional sub-study (GCO # 18-00456). Results: The 30 patients had a median age of 66.2 years and 57% were female. They received a median of 6 prior lines of therapy, with 83% being triple-class refractory and 50% penta-drug refractory. Only 2 patients were previously treated with anti-BCMA CAR-T cell therapy and none were treated with other BiAbs. 43% of patients had high-risk cytogenetics (including t(4;14), t(14;16) and 17p deletion) and 13% had extramedullary disease at time of initiating therapy. Ten patients (30%) received the recommended phase 2 dose (RP2D) of Tal (0.4 mg/kg weekly or 0.8 mg/kg every other week). Patients were followed for a median of 32.5 months and had a median progression-free survival (PFS) of 6.7 months. 22/30 patients (73%) achieved a partial response (PR) or better, and 14 patients had a short PFS of <150 days. There was no association between the prevalence of different immune cell subsets and depth of response, but rather with PFS. In the baseline BM, a longer PFS was associated with a higher percentage of CD8+ cytotoxic T cells (central memory p=0.00031, effector memory p=0.0022, EMRA p=0.014) and a trend towards higher CD4+ cytotoxic T cells (p=0.072). Of note, we did not find the same associations in the baseline PB samples, which may indicate that the PB may not always reflect the tumor microenvironment in the BM. When we next looked at immune changes in the PB of patients with longer PFS, we found that they exhibited higher percentage of NK cells (p=0.0018 for CD56 low, p=0.04 for CD56 high) and Gamma Delta T cells (p=0.04) at C3D1. Gamma Delta T cells are novel players that warrant further investigation, as they only constitute 1-5% of the T cell repertoire yet are involved in early immune response and do not require major histocompatibility complex (MHC) antigen presentation to function. Profiling of activation and exhaustion markers of these immune subsets is underway. Conclusion: Our findings highlight that the baseline BM immune repertoire and the PB immune changes during Tal treatment may predict long term outcomes. Further in vitro mechanistic studies of T cell function and fitness and validation of these results in independent cohorts will be critical to develop these into predictive biomarkers of long-term response to Tal.

A Phase 2b Study of Selinexor in Combination with Carfilzomib, Daratumumab, or Pomalidomide in Patients with Multiple Myeloma Relapsing on Current Therapy

Background: Selinexor is an oral, selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1), leading to retention of tumor suppressor proteins and apoptosis in malignant cells. Preclinical studies suggest synergistic activity when selinexor is combined with other treatments for multiple myeloma (MM). We hypothesize the addition of selinexor can recapture response to patients relapsing on their current carfilzomib (CFZ), pomalidomide (POM) or daratumumab (DARA)-based regimens. Methods: This is an ongoing phase 2b, open-label, multicenter investigator-initiated study to evaluate the safety and efficacy of selinexor plus CFZ, POM, or DARA. MM patients with documented disease progression or refractory disease while on current treatment with any CFZ-containing regimen (Arm 1), any POM-containing regimen (Arm 2), or any DARA-containing regimen (Arm 3) were eligible for this study. Patients were assigned to the respective arm only if their most recent line of therapy contained the specific drug of interest. Arm 1 consists of selinexor 80 mg orally on D1, 8, 15; CFZ 56 mg/m 2 IV on D1, 8, 15; and dexamethasone (DEX) 40 mg or 20 mg if ≥75 years old on D1, 8, 15, 22. Arm 2 consists of selinexor 60 mg orally on D1, 8, 15; POM 4 mg orally on D1-21; and DEX 40 mg or 20 mg if ≥75 years old on D1, 8, 15, 22. Arm 3 consists of selinexor 100 mg orally on D1, 8, 15, 22; DARA 16 mg/kg IV or 1,800 mg SQ dosing as per standard of care; and DEX 40 mg or 20 mg if ≥75 years old on D1, 8, 15, 22. The primary endpoint is overall response rate (ORR), which includes patients who experience partial response (PR), very good partial response (VGPR), complete response (CR), or stringent CR (sCR), based on International Myeloma Working Group response criteria (Kumar 2016). Secondary endpoints include duration of response (DOR), clinical benefit rate (CBR = sCR + CR + VGPR + PR + stable disease [SD]), progression-free survival (PFS), and treatment-emergent adverse events (TEAEs). Results: At data cutoff (July 14, 2023), there were 23 patients enrolled, including 20 patients on trial, 2 screen failures, and 1 in screening. Of the 20 patients on trial, 1 patient was enrolled onto Arm 1, 9 patients onto Arm 2, and 10 patients onto Arm 3. The median age was 66 years (range 52-83), 30% with ISS stage III MM, 75% with high-risk cytogenetics, 90% refractory to the last LOT, 50% triple refractory, and 35% quadruple refractory. Fifteen unique patients had high-risk cytogenetics, which included 9 patients with 1q21 duplication, 7 with t(4;14), 2 with del(17p)/monosomy 17, 4 with TP53 mutation, and 1 with complex karyotype. In 18 patients evaluable for response, the ORR was 33% (6/18; PR, 6 [33%]) and the CBR was 89% (16/18; PR, 6 [33%]; SD, 10 [56%]); 2 patients withdrew consent before response evaluation. For Arm 2, the ORR was 29% (2/7; PR, 2 [29%]) and the CBR was 86% (6/7; PR, 2 [29%]; SD, 4 [57%]). For Arm 3, the ORR was 44% (4/9; PR, 4 [44%]) and the CBR was 100% (9/9; PR, 4 [44%]; SD, 5 [56%]). In the overall cohort, median DOR was 9.46 months (95% CI, 5.1-12.3), and median PFS was 5.98 months (95% CI, 3.9-NR) (Figure 1). There were 18/20 patients who experienced any grade TEAEs (Table 1). No treatment-related deaths occurred. The most common grade 3 TEAEs were neutropenia (25%), thrombocytopenia (15%), pneumonia (10%), and hyperglycemia (10%). One patient experienced a grade 4 TEAE of neutropenia. There were 3 unique patients who experienced SAEs related to study treatment, which included pneumonia (n=2), chest pain (n=1), sepsis (n=1), and lactic acidosis (n=1). Seventeen patients discontinued treatment due to disease progression (n=12) and withdrawal of consent (n=5). Two patients are deceased: one patient died during long-term follow-up unrelated to treatment of disease; and one patient was hospitalized for dehydration, anorexia, and hyponatremia after C1D8 of KCD then experienced progressive cytopenias upon discharge likely due to disease progression. Conclusions: Preliminary results suggest selinexor plus CFZ, POM, or DARA is safe and restores sensitivity to therapy in relapsed/refractory MM patients. In this population of heavily pretreated MM patients relapsing on their most recent line of therapy, the ORR of 33% and CBR 89% highlights the clinical potential and generally manageable side effect profile of selinexor as an add-on drug for patients with relapsed/refractory MM in combination with CFZ, POM, and DARA. Clinical trial information: NCT04661137.

Real-World Treatment Patterns and Clinical Outcomes Among Triple-Class Exposed and B-Cell Maturation Antigen (BCMA) Exposed Multiple Myeloma Patients

Introduction: Despite the development of advanced treatment options, multiple myeloma (MM) remains an incurable disease. Most MM patients relapse and require further treatments. B-cell maturation antigen (BCMA) targeted immunotherapy is a novel MM therapy class that is now available to heavily pre-treated relapse/refractory MM (R/R MM) patients, who were triple class exposed (TCE) to proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies. As BCMA therapies continue to be further utilized and become an integral part of MM treatment, the proportion of TCE patients who are also BCMA exposed (TCE+BCMA exposed) is expected to grow. However, the clinical outcomes of TCE+BCMA exposed RRMM patients have not been previously assessed. The objective of this study was to evaluate the real-world outcomes of TCE+BCMA exposed MM patients who started a subsequent LOT, describing their characteristics, treatment patterns, and clinical outcomes. Subgroups of penta-drug exposed (at least two PIs, at least two IMiDs, and at least one anti-CD38) patients, as well as White and African American patients were also evaluated as penta-drug exposure status and race were known to impact clinical outcomes. Methods: Adult patients with MM who were TCE+BCMA exposed and started a subsequent LOT starting from July 03, 2019 (when additional new treatment options became available) were selected from the Komodo Healthcare Map (a US claims dataset) and were followed until the earliest of death, last claim, or end of study period (December 31, 2022). Index date was defined as the start date of the subsequent LOT following TCE and BCMA exposure. Descriptive statistics were provided for patient characteristics and treatment patterns. Clinical outcomes including time to treatment discontinuation or death (TTD) and time to next treatment or death (TTNT) were estimated using the Kaplan-Meier method. Results: A total of 344 TCE+BCMA exposed patients, who received the next LOT were included in the study, including 152 (44.2%) patients who were penta-drug exposed before index, 57 (16.6%) African American, and 185 (53.8%) White patients. Key baseline demographic characteristics and treatment history for the overall group and the three subgroups are listed in Table 1. The mean (SD) and median number of prior LOTs for the overall group before index date were 5.7 (1.7) and 6.0, respectively. The most prevalent prior treatments before the index date for the overall group were daratumumab (99.1%), belantamab mafadotin (91.9%), pomalidomide (84.3%), carfilzomib (83.1 %), bortezomib (76.2%) and lenalidomide (72.1%). Excluding corticosteroids, the most frequently used index treatments (i.e., treatment used post TCE+BCMA exposure) were carfilzomib- (21.9%), bortezomib- (20.8%), pomalidomide- (18.3%), and belantamab mafadotin- (18.3%) based regimens. The median (95% confidence interval [CI]) TTD was 3.7 (3.3, 4.4) months, and the median (95% CI) TTNT was 6.4 (5.5, 7.6) months. TTD and TTNT estimates for the three subgroups are listed in Table 2. Conclusions: To our knowledge, this is the first real-world study of treatment patterns and outcomes for TCE+BCMA exposed MM patients who started a subsequent LOT. The findings showed that this group of heavily pretreated MM patients were often retreated with the same therapies or therapies in the same classes, as they have limited effective treatment options. TCE+BCMA exposed patients exhibited poor clinical outcomes, as demonstrated by the rapid treatment discontinuation and moving on to the next treatment shortly after initial treatment. Many patients were already penta-drug exposed, and they appear to have worse clinical outcomes than the overall patient group. A shorter TTD was observed, and a trend for shorter TTNT was observed among African American patients than White patients. The findings highlight the continued need for effective treatments for heavily treated MM patients and particularly those with poor outcomes.

Treatment with low-dose, single-agent belantamab mafodotin is safe and provides long-term responses in heavily pretreated multiple myeloma patients.

To evaluate whether low-dose belantamab mafodotin (B-MAF) dosing results in lower toxicity and better overall outcome. We retrospectively evaluated nine consecutive patients treated with low-dose (1.9 mg/kg) B-MAF. The median age was 70 years. Most patients were penta-refractory. Ocular toxicity was observed in 77.7%. Adverse events resulting in treatment delays were recorded in 9 out of 124 cycles being given. Overall response rate was 66% (6/9), and all responding patients achieved very good partial response or better. Within a median follow-up of 12 (range 0.5-13.8) months, median progression-free survival and overall survival were 14 (CI95% 6-22) and 20 (95%CI 0-41) months, respectively. Low-dose B-MAF regimen showed high-efficacy and low-toxicity profile.

Sequencing bispecific antibodies and CAR T cell therapy in multiple myeloma with prior exposure to BCMA-targeted therapies.

e20049 Background: In patients with heavily pretreated relapse and refractory multiple myeloma (MM), novel approaches such as immunotherapies and B-cell maturation antigen (BCMA) targeted therapies have been utilized to show favorable responses Despite these therapies however, patients continue to have disease progression leaving them with fewer options. A need exists to investigate the optimal sequencing strategies in the treatment approach for MM with novel bispecific antibodies (BsAbs) and CAR T cell therapy in patients previously exposed to BCMA-directed therapies. Methods: A comprehensive review of active clinical trials, published primary literature, and meeting abstracts was performed to gather efficacy endpoints and overall response rates (ORR) in patients receiving BsAbs or CAR T therapy with previous exposure to BCMA directed therapy. Results: A variety of BCMA and non-BCMA directed BsAbs along with CAR T cell therapy have been evaluated for ORR in patients who received previous BCMA-targeted therapies. Teclistamab, a BCMA BsAb induced an adequate response of 40% in patients who received previous BCMA directed antibody drug conjugate (ADC) or CAR-T- cell therapy, with a deepening of response observed in 28%. Elranatamab, an investigational BCMA-targeted BsAb demonstrated a preliminary ORR of 54% in a cohort of 13 pts. Talquetamab, a first in class GPRC5D BsAb induced an ORR of 50% in pts with previous BCMA-directed therapy as monotherapy and resulted in an ORR of 72% in combination with daratumumab. Cevostamab, an investigational FcRH5 directed BsAb demonstrated an adequate ORR of 47% in 20 pts who received previous BCMA-directed therapy. In parallel to evaluating responses for BsAbs, CAR T cell therapies including cilta-cel and ida-cel have also induced favorable and durable responses in their prior BCMA therapy exposed cohorts with an ORR of 60.0% and 74% respectively. Comparable safety profiles across both BCMA treatment exposed and BCMA treatment-naive cohorts were observed among all studies. Additional endpoints including minimal residual disease and incidence of infections are to be included in final results. Conclusions: This analysis indicates that sequencing BsAbs and CAR -T cell therapy after previous BCMA-targeted treatments offers meaningful clinical benefit with durable response rates in patients who have few other options. Longer follow up and larger studies are needed to further evaluate their enhanced benefit and generate greater insight for optimal sequencing strategies in heavily pretreated MM patients who have exhausted other options. [Table: see text]

Outcomes with panobinostat in heavily pretreated multiple myeloma patients

Panobinostat is an oral pan histone-deacetylase inhibitor used in the treatment of relapsed and refractory multiple myeloma. Previously published studies of panobinostat demonstrated synergy with bortezomib but included few patients exposed to newer agent combinations (ie, panobinostat plus daratumumab or carfilzomib). Here, we report outcomes of panobinostat-based combinations at an academic medical center among patients whose disease had been heavily pretreated with modern agents. We retrospectively analyzed 105 patients with myeloma treated with panobinostat at The Mount Sinai Hospital in New York City between October 2012 and October 2021. These patients had a median age of 65 (range 37–87) and had received a median of 6 prior lines of therapy while in 53% the disease was classified as triple class refractory and in 54% the disease had high-risk cytogenetics. Panobinostat was most commonly utilized at 20 mg (64.8%) as part of a triplet (61.0%) or quadruplet (30.5%). Aside from steroids, panobinostat was most commonly administered in combination with lenalidomide, pomalidomide, carfilzomib, and daratumumab in descending order of frequency. Among the 101 response-evaluable patients, the overall response rate was 24.8%, clinical benefit rate (≥minimal response) was 36.6%, and median progression-free survival was 3.4 months. Median overall survival was 19.1 months. The most common toxicities ≥grade 3 were hematologic, primarily neutropenia (34.3%), thrombocytopenia (27.6%), and anemia (19.1%). Panobinostat-based combinations produced modest response rates in patients with heavily pretreated multiple myeloma, over half of whom had triple-class refractory disease. Panobinostat warrants continued investigation as a tolerable oral option for recapturing responses in patients whose disease has progressed after receipt of standard-of-care therapies.

An elevated systemic inflammation index is related to an inferior response to pomalidomide and dexamethasone treatment in patients with relapsed and refractory multiple myeloma.

The systemic inflammation index (SII) might serve as an indicator of the equilibrium between the inflammatory and immune responses. The aim of the study was to determine the clinical value and prognostic significance of SII in the cohort of multiple myeloma (MM) patients treated with a regimen of pomalidomide and dexamethasone (Pd). This retrospective, real-life study included patients who received a Pd regimen in our centre between November 2018 and July 2022. The systemic inflammation index was calculated from peripheral blood counts of platelets, neutrophils, and lymphocytes collected shortly before commencement of Pd treatment using the equation: SII = N × P/L, where N, P, and L are the respective counts per litre of peripheral blood for neutrophils, platelets, and lymphocytes. The study group consisted of 54 patients. Most patients received Pd as the third (38.9%) or fourth (37.0%) line of treatment. The median number of completed treatment cycles was 5 (IQR: 1-12). The median progression-free survival (PFS) was 6.8 months and overall survival (OS) 14.8 months. High SII (> 374) was an independent prognostic factor for PFS (HR = 3.0, 95% CI: 1.4-6.3, p < 0.01) and OS (HR = 2.2, 95% CI: 1.0-4.6, p = 0.04). In the low SII group, the respective median PFS and OS values were 9.6 and 21.7 months, compared to 2.6 (p = 0.018) and 5.5 months (p = 0.035) in the high SII group. The systemic inflammation index has prognostic significance in MM patients treated with Pd. A high SII predicts a poorer outcome in pretreated MM patients undergoing Pd treatment evaluation. As such, it may well be a key factor for guiding subsequent treatment decisions.

Phase 1 Safety and Dose Escalation of Purinostat Mesylate, a Uniquely Potent and Selective Inhibitor of HDAC I and IIb in Relapsed or Refractory Lymphoma and Multiple Myeloma

Introduction Current treatment options for patients with relapsed or refractory (RR) lymphoma and multiple myeloma (MM) are limited, highlighting the unmet need for effective therapies in these disease settings. Purinostat Mesylate (PM) is a small molecule that is designed to selectively inhibit histone deacetylase (HDAC) enzymes class I and IIb, which are members of common oncogenic pathways in hematologic malignancies. This study examined PM monotherapy in patients with RR lymphoma and MM. Methods This open-label, non-randomized, first-in-human, phase 1 two-center trial enrolled adult patients with lymphoma or MM who were refractory to or relapsed after ≥1 prior regimens. PM was administered by 30-minute intravenous infusion in a standard 3+3 dose escalation design. The trial was conducted in three stages sequentially as follows: the first stage as a single dose (Day 1), the second stage as multiple doses (Day 8,11, and 15), and the third stage as extended doses (Day1, 4, 8, 11 in 21-day cycles). The decision to proceed to the third stage is based on patient tolerability in the previous two stages, disease status, and continued benefit determined by investigators. Initially dosing started at 1.2 mg/m2, escalated to 2.4 mg/m2, 4.0 mg/m2, 6.0 mg/m2, 8.4 mg/m2, 11.2 mg/m2 and finally 15.0 mg/m2. Patients continued to receive PM until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum-tolerated dose and recommended phase 2 dose (RP2D); secondary objectives were to assess the safety and tolerability, pharmacokinetic profiles, and preliminary anti-tumor activity. This ongoing trial is registered at Chinese Clinical Trial Registry, number ChiCTR20191121. Results A total of 11 heavily pretreated MM patients(11/27,41%) and 16 lymphoma patients(16/27,59%) were enrolled to receive PM up to a maximum of 15.0 mg/m2 in the dose escalation. Most adverse events (AEs) were grade 1 to 2 and recovered with observation or symptomatic management. The most common Grade ≥3 AEs were thrombocytopenia (n=48.1%), neutropenia (n=48.1%), and anemia (11.1%), which occurred primarily during the extended dosing stages. AEs led to dose reductions in 4 patients. Dose limiting toxicities (DLTs) have not been observed. Twenty-seven patients were evaluable for responses. Eleven patients with RR MM had a disease control rate (DCR) of 72.7%. Eight patients had stable disease (SD) in cycle 1 and entered the third stage with a maximum of 6 extended cycles, of which 1 patient achieved a minimal remission (MR) in cycle 2. Nine out of 16 patients with RR lymphoma achieved objective responses rates (ORR) of 56.2%. Among them, six of 10 patients with diffuse large B-cell lymphoma (DLBCL) achieved objective responses (3 complete remissions [CR], 2 partial remissions [PR], and 1 MR). CRs occurred in 2 patients with DLBCL in cycle 3 (8.4mg/m2, 11.2 mg/m2) and 1 patient in cycle 2 (11.2 mg/m2). PRs occurred in 4 patient in cycle 1 (2 in 8.4 mg/m2, 2 in 11.2 mg/m2 ) and another patient who relapsed after 2 lines of prior therapy including autologous stem cell transplantation(ASCT) in cycle 3 (11.2 mg/m2). One MR and 1 SD have been observed in patients with double-expression DLBCL in cycle 1(15.0 mg/m2, 8.4 mg/m2) . Thus, the ORR in patients with RR DLBCL was 60.0% (6/10) and DCR was 70.0% (7/10). Two out of 4 follicular lymphoma patients relapsed after 2~4 lines of prior therapy also achieved objective responses (1 MR in cycle 1 and 1 PR in cycle 4). Of note, one patient with peripheral T-cell lymphoma who relapsed after four lines of treatment, including ASCT and Chidamide combination treatment with R-CHOP, obtained PR in cycle 1. Up to date, eight active response patients are still being treated. On the basis of the confirmed objective response and tolerability profile, the RP2D of PM was determined to be 8.4mg/m2 and 11.2mg/m2. Conclusions PM has demonstrated tolerability and good anti-tumor activity across all dosing schedules studied, especially multiple objective responses and disease control in patients with DLBCL. These results support continued development of PM, alone or in combination with other therapies, for the treatment of RR DLBCL. An open-label, non-randomized, phase 2, multicenter trial will be soon conducted in China to evaluate the efficacy of PM monotherapy in RR DLBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Preclinical Activity of Allogeneic CS1-Specific CAR T-Cells (UCARTCS1) in Multiple Myeloma

Introduction: The substantial activity of chimeric antigen receptor (CAR) T-cells in multiple myeloma (MM) has recently been shown by the success of BCMA-CAR T-cell therapy. Nevertheless the difficulties in (timely) generation of CART cells for each patient, the limited availability of manufacturing slots, and the frequent BCMAlow MM relapses after therapy urge the investigators to search for i) alternative, "off the shelf", available sources of CAR T-cells and ii) alternative target antigens than BCMA. UCARTCS1 cells are "off the shelf" allogeneic CAR T-cells derived from healthy donors targeting CS1 (SLAMF7), which is a highly attractive target, due to its overexpression on MM cells. Furthermore, the genes coding for the TCRα chain of the TCRab receptor and for CS1 are disrupted in UCARTCS1 cells using Cellectis' TALEN® gene-editing technology. These modifications aim to minimize the potential risk for allo-TCR-mediated graft-versus-host disease (GvHD) upon infusion in patients and diminish CS1-mediated fratricide. In this study, we evaluated the preclinical activity of UCARTCS1 in MM cell lines, in bone marrow (BM) samples obtained from MM patients and in a MM mouse model. We also investigated the potential impact of previous therapy and tumor characteristics on the in vitro efficacy of UCARTCS1. Methods: Luciferase-transduced MM cell lines with different expression levels of CS1 were incubated with UCARTCS1 cells or control (non-transduced CS1/TCRαβ double knock-out) T-cells at different E:T ratios for 24 hours. MM cell lysis was assessed by bioluminescence. Anti-MM activity of UCARTCS1 was also evaluated in 25 BM samples obtained from newly diagnosed (n=10; NDMM), daratumumab-naïve relapsed/refractory patients (n=10; RRMM; median of 3 prior therapies) and from daratumumab-refractory patients (n=5; DRMM; median of 3 prior therapies) in 24-hour flow cytometry-based cytotoxicity assays. The results were correlated to CS1 expression levels of MM cells, Treg frequency, and several other patient characteristics such as treatment history. Results: UCARTCS1 induced strong CS1 CAR-mediated and dose-dependent lysis of different MM cell lines expressing variable levels of CS1 (MM1s, L363, UM9, U266). UCARTCS1 cells also effectively lysed primary MM cells in a dose-dependent and CAR-mediated manner, with a mean maximal lysis of 96.9% (Figure 1). In these BM samples, UCARTCS1 cells also targeted CS1+ non-malignant hematopoietic cells, such as CD4+ T-cells, CD8+ T-cells, B cells, and NK cells, while sparing the CS1low fraction in each cell subset. However, the lysis of normal cells was less efficient than MM cell lysis, which could be explained by substantially lower CS1 expression on normal cells compared to MM cells (Figure 2). CS1 expression on MM cells and UCARTCS1 cytotoxic activity were both comparable in the different patient subgroups. In addition, baseline tumor and immune characteristics, such as the expression level of CS1 on MM cells, the tumor load (MM cell percentage in BM), or frequency of Treg cells in the BM did not affect CAR T-cell mediated cytotoxicity. Finally, UCARTCS1 exhibited durable dose-dependent anti-MM activity in mouse xenograft models after i.v. injection of CAR T-cells compared to mice treated with CAR- control T-cells. Conclusion: UCARTCS1 has potent anti-MM activity against MM cell lines and primary MM cells, as well as in a MM xenograft model. There was no difference in activity between heavily pretreated and newly diagnosed patients, indicating that mechanisms of resistance to prior therapies do not result in reduced susceptibility to UCARTCS1-mediated lysis in vitro. UCARTCS1 was also effective in samples from patients with relatively low CS1 expression, with high tumor burden, or with high Treg numbers. These data support the ongoing phase 1 clinical trial with UCARTCS1 in heavily pretreated MM patients (NCT04142619). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Genetic Alterations in Members of the Proteasome 26S Subunit, AAA-Atpase (PSMC) Gene Family Transmit Proteasome Inhibitor Resistance in Multiple Myeloma By Impacting the ADP/ATP Binding Pocket

Background For the treatment of Multiple Myeloma (MM), proteasome inhibitors (PIs) are highly efficient and widely used, but resistance is a major obstacle to successful therapy. Several underlying mechanisms have been proposed but were only reported for a minority of resistant patients e.g., mutations in the PI binding domain PSMB5. However, the proteasome is a large and complex machinery and its mechanistic understanding remains incomplete. In this study, we unravel the role of the six ATPases of the 19S proteasome regulator (PSMC1-6) in MM resistance. Methods As an example of cancer evolution and the acquisition of PI resistance, we conducted an in-depth analysis of an index patient applying deep sequencing of immunoglobulin rearrangements (IG), FISH, and WES in serial samples at MGUS, newly diagnosed MM, and five later timepoints including two relapses. Then we expand towards generic meta-analyses of PSMC alterations in our own and other published datasets comprising 1,499 newly diagnosed (NDMM) and 447 PI pretreated MM (PMM) patients for WGS/WES. For RNA sequencing, we analyzed 16 normal plasma cells (NPCs) and 360 NDMM patients. Furthermore, we explore the structural impact of PSMC single nucleotide variants on the proteasome and their relevance for PI resistance using 3D modeling with Chimera and Pymol. Results The WES analysis of our index patient uncovers a PSMC2 Y429S mutation acquired at the second relapse after intensive bortezomib-containing therapy. We functionally confirm this variant to mediate PI resistance in the cell line RPMI 8226. In the meta-analysis, a total of 36 mutations were identified (mutation incidence: 1.85%). The PSMC5 G152S mutation was found in three independent patients, and a G152R in a fourth patient, thus, representing a potential hotspot. Based on 3D structural projections, the identified mutations can be clustered into three main groups: first, mutations affecting the intrinsic conformation of the respective subunit; second, mutations perturbing the PSMC protomer interactions and the proper folding/functioning of the whole complex; and third, mutations impairing the ADP/ATP binding pocket (Figure). Nine mutations belong to the third category interacting with the adenine ring or the phosphate groups of the ATP. The expression analysis reveals a significant upregulation of PSMC3 (P=0.003), PSMC4 (P≤0.001), and PSMC5 (P=0.043) from NPC to NDMM. Conclusions The 19S hexameric AAA ATPase ring of the 26S proteasome is responsible for unfolding and introducing the substrates into the catalytic 20S complex. PSMC gene alterations are structurally often located in regulatory sites for activity e.g. impacting the ADP/ATP binding pocket. The following activation of the 26S proteasome increases the PI tolerance and represents a new PI resistance mechanism. Moreover, changes in the expression level of the PSMC members seem to play a role not only in the development of PI resistance but already in the development of MM, probably by increasing the protein turnover capacity of myeloma cells. This study opens the way to explore new classes of proteasome inhibitors avoiding this kind of mechanism of resistance. Figure:Mutations in the'PSMC' subunits of the 19S Base AAA-ATPase hexamer accumulate in proximity to the ATP/ADP binding pockets. The backbone of the PSMC hexamer is displayed as a ribbon diagram, mutations (red) and ADP (blue) as 3D spheres (PDB 5GJR). The mutations cluster in areas responsible for proper folding and functioning of the complex or in proximity to the ADP/ATP binding pockets, exemplarily shown for PSMC1, PSMC2, and PSMC5. ADP is presented as a wireframe stick in light green (PDB 5GJQ). The PSMC2Y429S mutation of the index patient is indicated in yellow. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract CT186: Pharmacokinetic (PK) profile of a novel IKZF1/3 degrader, CFT7455, enables significant potency advantage over other IKZF1/3 degraders in models of multiple myeloma (MM) and the results of the initial treatment cohort from a first-in-human (FIH) phase 1/2 study of CFT7455 in MM

Abstract Introduction: CFT7455 is a highly potent and novel Ikaros Family Zinc Finger Protein 1/3 (IKZF1/3) degrader. In xenograft models, CFT7455 has more potent IKZF1/3 degradation compared to other degraders. Early observations from the FIH clinical trial (NCT04756726) along with supporting translational studies are presented here. Methods: Pre-clinical studies comparing CFT7455 and CC-92480 in both in vitro and xenograft models were performed. The pre-clinical studies’ results coincided with observations from the on-going clinical trial. The clinical trial is an open-label, Phase 1/2, multi-center, FIH study in heavily pretreated relapsed/refractory (R/R) MM and non-Hodgkin’s lymphoma (NHL) patients evaluating safety, tolerability, and PK of CFT7455. Eligible MM patients are R/R to therapy and are not candidates for regimens known to provide clinical benefit. A starting dose of 50 μg QD 21 days on/7 days off (21/7) in 28-day cycles was administered. Results: CFT7455 and CC-92480 showed similar cereblon binding profiles and in vitro IKZF1/3 degradation kinetics, translating into sub-nanomolar GI50 values in proliferation assays across a panel of MM cell lines. In the NCI-H929 xenograft model, 100 μg/kg/day of CFT7455 resulted in durable tumor regressions, while 1000 μg/kg/day of CC-92480 gave tumor stasis. Similar results were seen in a systemic model of MM, MM1.S. Both compounds achieved &amp;gt;95% IKZF3 degradation in tumors 4h post dose. At 48h post dose, CFT7455 was more effective than CC-92480 in maintaining IKZF3 degradation (65% vs. 6% respectively). When levels of CFT7455 and CC-92480 in plasma and tumor were compared, CFT7455 concentrations were &amp;gt; DC80 in tumor 48h post dose, while CC-92480 levels were undetectable in tumor and plasma, demonstrating CFT7455 has longer exposure resulting in sustained IKZF1/3 degradation in pre-clinical models. In cohort A, 5 heavily pre-treated MM patients (pts) received single agent CFT7455. 4 pts have received at least 3 cycles, with 2 pts receiving 5 cycles. Neutropenia (grade 4) was observed in 3/5 pts without coincident fever or infection. Additionally, a 2-4 fold accumulation in plasma CFT7455 exposure at steady state was observed. Early pharmacodynamic (PD) data demonstrates deep persistent degradation of IKZF3 (~100%) and serum free light chain reduction (up to 72%) in response to treatment. Stable disease has been observed in 34 pts, suggesting clinical benefit. Conclusions: While CFT7455 showed clinical benefit at 50 ug with deep target degradation, neutropenia was dose limiting. PK/PD modeling suggests alternative dosing regimens may result in increased tolerability with preserved efficacy, and evaluation of them is underway. Updated results will be presented at the meeting. Citation Format: Sagar Lonial, Shambavi Richard, Jeffrey V Matous, Andrew J. Yee, Urvi Shah, Neha Mehta-Shah, Thomas Martin, Eli Muchtar, Sikander Ailawadhi, Paul G. Richardson, Manisha Bhutani, Samantha Perino, Jason Kirby, Roman V. Agafonov, Prasoon Chaturvedi, Bradley Class, Matthew Schnaderbeck, Michael R. Palmer, Cathleen Gorman, Oliver Schoenborn-Kellenberger, Amanda Hoerres, Stewart L. Fisher, Roy M. Pollock, Adam Crystal, Michelle Mahler, Jesus Bardeja. Pharmacokinetic (PK) profile of a novel IKZF1/3 degrader, CFT7455, enables significant potency advantage over other IKZF1/3 degraders in models of multiple myeloma (MM) and the results of the initial treatment cohort from a first-in-human (FIH) phase 1/2 study of CFT7455 in MM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT186.

Reduced splenic uptake on 68Ga-Pentixafor-PET/CT imaging in multiple myeloma - a potential imaging biomarker for disease prognosis

Beyond being a key factor for tumor growth and metastasis in human cancer, C-X-C motif chemokine receptor 4 (CXCR4) is also highly expressed by a number of immune cells, allowing for non-invasive read-out of inflammatory activity. With two recent studies reporting on prognostic implications of the spleen signal in diffusion-weighted magnetic resonance imaging in patients with plasma cell dyscrasias, the aim of this study was to correlate splenic 68Ga-Pentixafor uptake in multiple myeloma (MM) with clinical parameters and to evaluate its prognostic impact.Methods: Eighty-seven MM patients underwent molecular imaging with 68Ga-Pentixafor-PET/CT. Splenic CXCR4 expression was semi-quantitatively assessed by peak standardized uptake values (SUVpeak) and corresponding spleen-to-bloodpool ratios (TBR) and correlated with clinical and prognostic features as well as survival parameters.Results: 68Ga-Pentixafor-PET/CT was visually positive in all MM patients with markedly heterogeneous tracer uptake in the spleen. CXCR4 expression determined by 68Ga-Pentixafor-PET/CT corresponded with advanced disease and was inversely associated with the number of previous treatment lines as compared to controls or untreated smouldering multiple myeloma patients (SUVpeakSpleen 4.06 ± 1.43 vs. 6.02 ± 1.16 vs. 7.33 ± 1.40; P < 0.001). Moreover, reduced splenic 68Ga-Pentixafor uptake was linked to unfavorable clinical outcome. Patients with a low SUVpeakSpleen (<3.35) experienced a significantly shorter overall survival of 5 months as compared to 62 months in patients with a high SUVpeakSpleen >5.79 (P < 0.001). Multivariate Cox analysis confirmed SUVpeakSpleen as an independent predictor of survival (HR 0.75; P = 0.009).Conclusion: These data suggest that splenic 68Ga-Pentixafor uptake might provide prognostic information in pre-treated MM patients similar to what was reported for diffusion-weighted magnetic resonance imaging. Further research to elucidate the underlying biologic implications is warranted.

Large-Scale Mass Cytometry Reveals Significant Activation of Innate and Adaptive Immunity in Bone Marrow Tumor Microenvironment of Iberdomide-Treated Myeloma Patients

Background: Iberdomide (IBER) is a potent cereblon E3 ligase modulator (CELMoD agent) with direct anti-tumor and immunomodulatory activities in multiple myeloma (MM). An ongoing phase 1b/2a multicenter, open-label, dose-escalation study has reported favorable efficacy and safety of IBER plus low-dose dexamethasone (DEX) in heavily pretreated patients with relapsed/refractory MM (RRMM). While previous studies focused on IMiD/CELMoD agent immune effects in peripheral blood (Amatangelo, ASH 2019), a large-scale characterization of pharmacodynamics in the bone marrow (BM) tumor microenvironment (TME) has not been reported. Here, we present data on BM aspirates (BMAs) of 99 individuals pre-/post-treatment with IBER in the largest study of TME immune dynamics of RRMM patients to date.Methods: A mass cytometry (CyTOF) panel was designed/validated to capture deep and comprehensive immunophenotyping of T, B, and NK cell subpopulations. In all, staining with 37 metal-tagged Abs characterized 110 supervised cell phenotypes. Paired longitudinal assessment was conducted for viably preserved BMAs of IBER±DEX treated patients in dose-escalation of the CC220-MM-001 Ph 1b/2a study pre (SCREEN) and post treatment (cycle 2 day 15, C2D15). For a subset of patients (n=12), samples were available at disease progression (PD) . A training set analysis (n=64, data reported here) collected in North America, was validated against an independent test set (n=35) recruited in Europe. An R-based computational workflow and manual hierarchical gating identified subpopulations of B, T, NK and myeloid cells. In total, more than 5M immune cells were captured (approx. 40K per specimen). Cell populations are expressed as percentage of non-tumor bone marrow mononuclear cells (BMMC, i.e. CD45+CD66b-). P values are by Mann-Whitney U test for unpaired and Wilcoxon test for paired analyses.Results: IBER treatment resulted in profound immune shifts in the TME. B cells decreased (median SCREEN 3.3% vs C2D15 0.7%, p=0.001), with significant reduction of naïve (p=0.001) and regulatory B cells (p<0.001). Decrease occurred in CD4+ T cells (median 15.3% vs 8.9%, p<0.001), whereas CD8+ T cells increased (median 14.9% vs 17.4%). T cell subtypes showed a shift towards cytotoxic effector-memory phenotype (CCR7-CD45RA) (median 67.6% vs 80.9% of CD4+ T cells, p<0.001 and median 78.2% vs 89.2% of CD8+ T cells, p<0.001) with concurrent reduction of naive (CD45RA+CCR7+), central-memory (CD45RA-CCR7+) and EMRA (CD45RA+CCR7-) T cells. The shift towards a cytotoxic TME is confirmed by significant increases of GZMB+, HLA-DR+, ICOS+, Ki-67+, CXCR3+ and CD38+ activated CD8+ T cells (p≤0.001, paired). Conversely, CD8+ T cells expressing inhibitory checkpoints TIGIT and KLRG1 decreased significantly (p≤0.001, paired). Similar changes (with minor deviations) were noted in the CD4+ T cell compartment.NK cells increased (median 4.2% vs 8.7%, p=0.003), with increase of both CD56hi cytokine-producing (median 1.9% vs 4.5%, p<0.001) and CD16+ cytolytic (median 1.8% vs 2.6%, p=0.06) subsets. NKG2A+ and NKG2D+ subsets were increased (p<0.001, paired), as well as subsets expressing markers of activation: GZMB, ICOS, CD38 and PD-1 (p<0.05, paired). TIGIT+ NK cells decreased significantly. NKT cells were also significantly increased (median 1.4% vs 2.2%, p<0.001). Increase of NK and NKT cells expressing the activating receptor NKG2D was limited to patients achieving best response of PR or better. Additional analyses correlating immune phenotypes at baseline/post-treatment with outcomes are ongoing and will be reported at the meeting, as will data on how prior treatment (e.g. with CD38-mAb) shapes the TME at baseline and affects response.Conclusion: Our analysis on a large cohort of RRMM patients provides unique insights into the heterogeneity of the immune TME of heavily pretreated MM patients and how it changes upon treatment with IBER±DEX. We found significant increases of effector T and NK cells in paired analysis, demonstrating innate and adaptive immune enhancement in the MM bone marrow niche as an important mechanism of action. Importantly, these changes were observed throughout dose escalation and in patients previously refractory to lenalidomide/pomalidomide. The presented platform of large-scale immune profiling demonstrates a strategy to design and study rational combinations with (other) immune-enhancing therapies in MM. [Display omitted] DisclosuresAmatangelo: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Gooding: Bristol Myers Squibb: Research Funding. Jagannath: Legend Biotech: Consultancy; Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. Pierceall: BMS: Current Employment, Current equity holder in publicly-traded company. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding. Thakurta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

Current State of the Art and Prospects of T Cell-Redirecting Bispecific Antibodies in Multiple Myeloma

Multiple myeloma (MM) patients eventually develop multi-drug-resistant disease with poor survival. Hence, the development of novel treatment strategies is of great importance. Recently, different classes of immunotherapeutic agents have shown great promise in heavily pre-treated MM, including T cell-redirecting bispecific antibodies (BsAbs). These BsAbs simultaneously interact with CD3 on effector T cells and a tumor-associated antigen on MM cells, resulting in redirection of T cells to MM cells. This leads to the formation of an immunologic synapse, the release of granzymes/perforins, and subsequent tumor cell lysis. Several ongoing phase 1 studies show substantial activity and a favorable toxicity profile with BCMA-, GPRC5D-, or FcRH5-targeting BsAbs in heavily pre-treated MM patients. Resistance mechanisms against BsAbs include tumor-related features, T cell characteristics, and impact of components of the immunosuppressive tumor microenvironment. Various clinical trials are currently evaluating combination therapy with a BsAb and another agent, such as a CD38-targeting antibody or an immunomodulatory drug (e.g., pomalidomide), to further improve response depth and duration. Additionally, the combination of two BsAbs, simultaneously targeting two different antigens to prevent antigen escape, is being explored in clinical studies. The evaluation of BsAbs in earlier lines of therapy, including newly diagnosed MM, is warranted, based on the efficacy of BsAbs in advanced MM.

BCMA in Multiple Myeloma-A Promising Key to Therapy.

Despite the discoveries of numerous agents including next generation proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, multiple myeloma (MM) remains an incurable disease. The field of myeloma treatment in refractory or relapsed patients after standard therapy entered a new era due to the B-cell maturation antigen (BMCA) targeted approach. BCMA is a member of the tumor necrosis factor receptor family with high expression in mature B-lymphocytes and plasma cells. Given the understanding of BCMA mechanism of action in MM, BCMA plays a promising role as a therapeutic target. Several clinical trials are underway to evolve the current BCMA targeted treatment concept such as antibody-drug conjugates (ADCs), bispecific T cell engagers (BITEs) and chimeric antigen receptor (CAR) T cell therapy. Current results of representative BCMA trials may close the gap of the unmet clinical need to further improve the outcome of heavily pretreated MM patients with the potency to change the paradigm in newly diagnosed and refractory MM. This comprehensive review will give an update on various BMCA targeted treatment modalities (ADCs, BITEs, CAR T cell therapy) and its existing results on efficacy and safety from preclinical and clinical trials.

Salvage Autologous Stem Cell Transplantation in Daratumumab-Refractory Multiple Myeloma.

Simple SummaryMultiple Myeloma (MM) is the most common cancer of the bone marrow and remains incurable despite advances in novel therapy. The disease course is typically characterized by an initial response pattern to treatment followed by eventual relapse and treatment refractoriness. Patients who have progressed on several novel therapies, including the CD38-targeting monoclonal antibody Daratumumab, have a dismal outcome with a median overall survival of less than 10 months and are in dire need of therapies with new mechanisms. While emerging novel modalities have shown promising results, the current study explores the use of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) in heavily pretreated Daratumumab-refractory MM patients. Our results for 69 consecutive patients treated with salvage ASCT indicate that this approach can lead to long-term MM control and should be considered a treatment modality in selected heavily pretreated Daratumumab-refractory patients.Daratumumab, a CD38-targeting monoclonal antibody, has significantly improved survival rates in multiple myeloma (MM), yet patients who progress on Daratumumab have dismal clinical outcomes with an overall median of less than 10 months. While emerging novel modalities have shown promising results, the current study explores the use of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) in heavily pretreated Daratumumab-refractory MM patients. We retrospectively investigated the outcome of 69 consecutive patients who received upfront ASCT. The median progression-free survival (PFS) for the entire patient cohort was 7.2 months with a median overall survival (OS) of 19.3 months. For patients with ≥very good partial response (VGPR), median PFS and OS improved to 9 months and 34 months, respectively. Achievement of MRD negativity in ≥VGPR did not further improve the outcome. A better performance status, younger age, longer time interval from initial MM diagnosis/initial ASCT to salvage ASCT and low-risk GEP70 were all associated with improved PFS and OS after salvage ASCT. Our results suggest a role for salvage ASCT in selected heavily pretreated and Daratumumab-refractory patients.

Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma

Cell surface expression levels of GPRC5D, an orphan G protein–coupled receptor, are significantly higher on multiple myeloma (MM) cells, compared with normal plasma cells or other immune cells, which renders it a promising target for immunotherapeutic strategies. The novel GPRC5D-targeting T-cell redirecting bispecific antibody, talquetamab, effectively kills GPRC5D+ MM cell lines in the presence of T cells from both healthy donors or heavily pretreated MM patients. In addition, talquetamab has potent anti-MM activity in bone marrow (BM) samples from 45 patients, including those with high-risk cytogenetic aberrations. There was no difference in talquetamab-mediated killing of MM cells from newly diagnosed, daratumumab-naïve relapsed/refractory (median of 3 prior therapies), and daratumumab-refractory (median of 6 prior therapies) MM patients. Tumor cell lysis was accompanied by T-cell activation and degranulation, as well as production of pro-inflammatory cytokines. High levels of GPRC5D and high effector:target ratio were associated with improved talquetamab-mediated lysis of MM cells, whereas an increased proportion of T cells expressing PD-1 or HLA-DR, and elevated regulatory T-cell (Treg) counts were associated with suboptimal killing. In cell line experiments, addition of Tregs to effector cells decreased MM cell lysis. Direct contact with bone marrow stromal cells also impaired the efficacy of talquetamab. Combination therapy with daratumumab or pomalidomide enhanced talquetamab-mediated lysis of primary MM cells in an additive fashion. In conclusion, we show that the GPRC5D-targeting T-cell redirecting bispecific antibody talquetamab is a promising novel antimyeloma agent. These results provide the preclinical rationale for ongoing studies with talquetamab in relapsed/refractory MM.