Refractory Multiple Myeloma Research Articles

Salvage Autologous Transplant and Lenalidomide Maintenance Versus Continuous Lenalidomide/Dexamethasone for Relapsed Multiple Myeloma: Long Term Follow up Results of the Randomized GMMG Phase III Multicenter Trial Relapse

Introduction The randomized, controlled, multicenter, phase III GMMG ReLApsE trial compared lenalidomide/dexamethasone (Rd) re-induction, salvage high dose chemotherapy, autologous stem cell transplantation (HDCT/ASCT) and lenalidomide (R) maintenance with standard continuous Rd. We have previously reported the absence of a significant survival benefit in the primary analysis. However, landmark analyses from salvage HDCT performed due to the fact that ~30% of patients in the HDCT arm did not receive salvage HDCT/ASCT suggested a survival benefit in patients undergoing salvage HDCT/ASCT. Here we report long term follow up results from the GMMG ReLApsE trial. Methods Between 2010 and 2016, 282 patients were randomized of whom 277 constituted the intention-to-treat (ITT) population (arm B/A n=139/138). Arm B received 3 cycles of Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1, 8, 15, 22; 4 week cycles) re-induction, HDCT (melphalan 200 mg/m 2), ASCT and R maintenance (10 mg daily) until progression (PD). Arm A was treated with Rd until PD. Key inclusion criteria were 1-3 prior treatment lines, age ≤ 75 years, time to PD ≥ 12 months in case of front-line HDCT/ASCT and WHO PS ≤ 2. R-refractory disease was not permitted and only 30/277 patients (11%) were previously exposed to R. The primary endpoint was progression free survival (PFS). Protocol-specified long term follow up collection included overall survival (OS), further lines of treatment and further salvage HDCT/ASCT after trial participation. ISRCTN16345835, Eudra CT-No: 2009-013856-61. Results Within the extended follow up period of 99 months, 238 PFS events (86%) and 174 deaths (63%) occurred. Median PFS in the ITT population was 20.5 months in arm B and 19.3 months in arm A without a statistically significant difference (HR 0.98; 95% CI 0.76-1.27; p=0.9). Median OS was 67.1 months in arm B vs. 62.7 months in arm A (HR 0.89; 95% CI 0.66-1.20; p=0.44). The absence of a significant PFS and OS benefit was consistent among key disease subgroups according to age, R-ISS, renal function, frontline single vs. tandem HDCT/ASCT, prior lines of treatment and prior maintenance treatment post HDCT/ASCT. Time to progression after frontline HDCT/ASCT was significantly associated with PFS in the total ITT population (p=0.001) as well as in both trial arms independently, but was not associated with a survival benefit from arm B vs. A (interaction test PFS p=1.0, OS p=0.7). Multivariate analyses revealed significant associations of survival with age (PFS: HR 0.8, p=0.045), high risk cytogenetic aberrations (PFS: HR 2.1, p<0.001; OS: HR 2.5, p<0.001), ISS stage III vs. I (OS: HR 2.0, p=0.02), elevated LDH (PFS: HR 1.5, p=0.04; OS: HR 2.1, p<0.001), >1 prior lines of treatment (PFS: HR 2.3, p=0.003), and no prior HDCT/ASCT (PFS: HR 1.8, p=0.04; OS: HR 2.2, p=0.009), but not with treatment arm B vs. A (PFS: HR 0.9, p=0.4; OS: HR 0.9, p=0.37). In landmark analyses from HDCT and the contemporaneous Rd cycle 5 in arm A (median interval from randomization to HDCT/Rd cycle 5: 117/122 days; n=103[B]/114[A]) no significant differences in PFS (23.0 vs. 20.3 months; HR 0.91; 95% CI 0.68-1.22; p=0.52) or OS (76.3 vs. 66.0 months; HR 0.8; 95% CI 0.56-1.13; p=0.2) in arm B vs. A were observed. Further lines of treatment after trial participation were reported in 88/139 (63%) and 96/138 (70%) patients in arm B and A (p=0.31). Significantly more salvage HDCT/ASCT were administered after trial participation in arm A vs. B (48/138 [35%] vs. 19/139 [14%], p<0.001). Immunomodulatory drug (lenalidomide, pomalidomide) based regimens were used comparably after both trial arms. The rate of second primary malignancies was comparable in arm B and A (26/139 [19%] vs. 19/138 [14%], p=0.3). Conclusions The GMMG ReLApsE trial is the only randomized, controlled trial comparing salvage HDCT/ASCT with continuous novel agent treatment. With extended follow up, no significant PFS or OS difference is observed in the overall trial population and the previously reported survival benefit in patients who actually received salvage HDCT/ASCT is not confirmed. Time to progression after frontline HDCT/ASCT which is frequently used to stratify for salvage HDCT/ASCT in clinical practice is a general prognostic parameter for PFS, but does not predict benefit from salvage HDCT/ASCT vs. continuous Rd treatment. The GMMG ReLApsE trial does not support salvage HDCT/ASCT for relapsed or refractory multiple myeloma.

Isatuximab Plus Pomalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM) in Real-Life Context in France: IMAGE Subgroup Analysis Based on Prior Lines of Therapy and Refractory Status in Anti-CD38-Naïve Population

Introduction: Isatuximab, a CD38 monoclonal antibody (mAb), targets a specific CD38 epitope to induce myeloma cell death. Based on the results of the Phase 3 ICARIA-MM study, isatuximab (Isa) plus pomalidomide (P) and dexamethasone (d; Isa-Pd) is approved in adult patients (pts) with relapsed/refractory multiple myeloma (RRMM) who have received ≥2 prior therapies. Prior to Isa-Pd regulatory approval, Isa was available in France under early access programs (EAPs). IMAGE is a non-interventional, retrospective cohort study of pts treated with Isa-Pd under the French EAPs. In the IMAGE overall effectiveness population (median follow-up 14.2 months [mo]), median progression-free survival (mPFS) was 12.4 mo; overall response rate (ORR) was 46.3%; 27.9% of pts achieved a very good partial response (VGPR) and best response was VGPR for 60.3% of pts. In the current myeloma landscape, not all pts with RRMM have received a prior anti-CD38 mAb, particularly where access is difficult; thus, the real-world effectiveness of Isa in daratumumab (dara)-naïve pts needs to be assessed in light of the Phase 3 APOLLO and ICARIA-MM trials investigating dara-Pd and Isa-Pd in dara-naïve populations. Effectiveness results from the IMAGE subgroup analysis of dara-exposed and -refractory pts have been presented previously. Here, we describe results for dara-naïve pts based on prior lines of therapy (LOT) and lenalidomide (len)-refractory status. Methods: Data were collected from medical records of adult pts with RRMM who received ≥1 dose of Isa under the EAPs from 29 Jul 2019-1 Sep 2020. The effectiveness analysis was restricted to pts with ≥1 year of follow-up after Isa initiation. PFS was defined as the time from Isa-Pd initiation to date of disease progression or death. VGPR was defined as a ≥90% reduction in serum or urine M-protein, or in the difference between involved and non-involved free light chain. The description of adverse events (AEs; verbatim) was recorded as a reason for treatment temporary or permanent discontinuation or dose reduction. Data were recorded per the subject's medical file. No specific grading was performed. Results: The safety population included 299 pts who received ≥1 Isa dose under the EAPs; of these, 294 received ≥1 Isa dose and met all inclusion/exclusion criteria, thus comprising the effectiveness population. Within the overall effectiveness population, 216 (73.5%) pts were dara-naïve; among them, 13.4%, 58.8%, and 27.8% received 1, 2, and ≥3 prior LOT, respectively; 72.2% were len-refractory (median 2 prior LOT); and 54.2% were len-refractory at last prior LOT. At a median follow-up of 14.2 mo, mPFS (95% CI) in dara-naïve pts was not reached (NR; 14.6-NR), 15.0 mo (10.6-NR), and 14.8 mo (7.6-NR) with 1, 2, and ≥3 prior LOT, respectively; 13.2 mo (9.0-18.6) in those refractory to len; and 13.2 (9.0-NR) in those refractory to len at last prior LOT. ORR (of which, VGPR) was 41.4% (17.2%), 52.0% (34.6%), and 50.0% (31.7%) in pts with 1, 2, and ≥3 prior LOT, respectively; 49.4% (29.5%) in len-refractory pts; and 50.4% (29.9%) in len-refractory at last prior LOT pts (Table). At least 1 AE was reported in 53 (24.4%) pts in the dara-naïve safety population (n=217): 7 (24.1%), 32 (25.2%), and 14 (23.0%) in the 1, 2, and ≥3 prior LOT subgroups, respectively; 41 (26.1%) in the len-refractory subgroup; and 32 (27.4%) in the len-refractory at last prior LOT subgroup. AEs led to permanent Isa discontinuation in 3 (2.4%) pts with 2 prior LOT; 3 (1.9%) len-refractory pts; and 2 (1.7%) len-refractory at last prior LOT pts. The most common AEs were blood and lymphatic system disorders, occurring in 39 (18.0%) pts. Infections and infestations were reported in 2 (0.9%) pts: 1 had received 1 prior LOT and 1 had 2 prior LOT; both pts were len-refractory at last prior LOT. Conclusions: In the dara-naïve populations from APOLLO (dara-Pd) and ICARIA-MM (Isa-Pd), mPFS was 12.4 and 11.1 mo, respectively. This subgroup analysis of IMAGE provides real-world evidence of Isa effectiveness in dara-naïve subgroups: Isa-Pd demonstrated a high mPFS of 16.6 mo in dara-naïve pts and meaningful mPFS at first and subsequent relapse, including in difficult-to-treat len-refractory pts; mPFS was generally comparable to that of the overall effectiveness population. No new safety signals were observed compared with ICARIA-MM. However, the incidence of some AEs like infections was low, possibly due to the retrospective nature of the study. Funding: Sanofi.

Clinician and Administrator Perspectives on Chimeric Antigen Receptor (CAR) T-Cell Therapy Outpatient Administration in Relapsed or Refractory Multiple Myeloma (RRMM) in the United States (US): A Qualitative Study

Background: The use of CAR-T cell therapy has transformed treatment paradigms in B-cell malignancies. Ciltacabtagene autoleucel (cilta-cel) was approved for use in RRMM after four or more prior lines of therapy in 2022. While the pivotal studies exclusively treated patients in an inpatient setting, robust infrastructure planning at some centers across US has fostered outpatient administration of the commercially available product. Outpatient administration of CAR-T is more desirable due to superior financial sustainability, lower healthcare resource utilization, and greater patient autonomy during the treatment. Hence, we conducted a qualitative study to evaluate clinical and administrative perspectives and trends in outpatient administration of commercialized cilta-cel with an aim to understand best practices from certified CAR-T centers in the USA. Methods: A targeted literature review was conducted to better understand current practices around outpatient administration of CAR-T, and inform the development of primary research materials for designing subsequent interviews. Next, two 60-minute exploratory interviews were conducted with multi-stakeholder participants (n=5) from two certified cilta-cel centers, each with significant volume of outpatient administration of cilta-cel. Following the qualitative analysis of interviews, two 90-minute panels were conducted with multi-stakeholder participants (n=14) from six certified cilta-cel centers, including centers from exploratory interviews, focusing on clinical and administrative topics across the patient journey. Results: Each center in the study treated approximately 15-30 patients with cilta-cel in the outpatient setting. Using Likert scales, participants from all centers ranked space/capacity as the most important factor in decision-making process for outpatient cilta-cel administration, and ranked reimbursement incentives as a highly (67% of participants) or a moderately (33%) important factor. All participants agreed that having a dedicated outpatient infrastructure (dedicated space such as bed availability and internal processes including standard operating procedures (SOPs)), 24/7 support, outpatient bone marrow transplant (BMT) or cell therapy experience, and robust multidisciplinary teams were key to setting-up successful outpatient centers for cilta-cel therapy. The participants agreed that cilta-cel can be administered safely in an outpatient setting due to generally predictable, delayed onset of potential AEs, except in patients with significant comorbidities or organ dysfunction. Participants also considered caregiver support and lodging availability as factors of importance for outpatient administration. Institutionally established AE monitoring protocols are critical for safe use of cilta-cel in an outpatient setting. Over 50% of the centers interviewed have recently started to administer tocilizumab to treat mild grade 1 cytokine release syndrome (CRS) in an outpatient setting. Based on the findings across the phases of research, the patient journey for outpatient administration of cilta-cel was updated (Figure 1). While patients may be admitted for toxicity events, 100% of centers interviewed had 24-hour coverage and bed availability for these patients if needed. Conclusions: Overall, this study further supports the notion that centers can safely administer cilta-cel in an outpatient setting, if appropriate infrastructure is in place. Additional best practices for new outpatient sites include adequate infrastructure, SOPs, a well-trained and multidisciplinary team, and education of patients and caregivers (Table 1). Outpatient management and earlier intervention for low-grade AEs is currently evolving, with more real-world research required. Continued expert sharing of best practices can aid centers in implementing outpatient administration of CAR-T therapies. Funding: This analysis was supported by Janssen Research & Development, LLC and Legend Biotech USA, Inc

Phase I Clinical Study of Humanized BCMA-Single-Domain Antibodies-Targeting CAR T (BCMA-CART) in Patients with Relapsed/Refractory Multiple Myeloma

Background:The CAR structure adopted by CART-BCMA is composed of a single-domain antibody targeting BCMA, CD8 hinge region, transmembrane region, 4-1BB co-stimulatory domain, and CD3-ζ T cell activation domain. In the phase I clinical study (NCT05346198) carried out in China, the safety and efficacy of CART-BCMA were initially evaluated through the dose escalation + dose expansion design, and the recommended dose (RD dose) for follow-up studies was determined as well. Method:Enrolled patients with relapsed and/or refractory multiple myeloma (RRMM) had previously received at least 3 lines of therapy including at least one proteasome inhibitor and one immune modulator. After lymphatic preconditioning chemotherapy (program: fludarabine 30mg/m 2/d and cyclophosphamide 300mg/m 2/d, -5, -4, -3, for 3 consecutive days), all patients received a single dose of CART-BCMA at 2.5×10 6, 5×10 6 and 7.5×10 6 CAR-positive T cells/kg (subject body weight), according to the dose level in which they were enrolled. R esults :Up to June 26, 2023, a total of 15 cases of RRMM received 2.5×10 6 CAR-positive T cells/kg (n=3), 5×10 6 CAR-positive T cells/kg (n=11) or 7.5×10 6 CAR-positive T cells/kg (n=1) dose level of CART-BCMA cell infusion therapy on the basis of the dose level in which they were enrolled. The median follow-up time was 14.42 months (range: 10.2-26.6 months). The median age of the subjects was 63.0 years old (range: 36-73 years old) (Table 1), 73.3% of the subjects (n=11) had previously received ≥4 lines of multiple myeloma therapy, and the median line of treatment was 5 lines (range: 3-9 lines), among which, 2 subjects (13.3%) had previously received autologous hematopoietic stem cell transplantation, and 4 subjects (26.7%) had relapsed/refractory diseases after previous treatment with proteasome inhibitors, immune modulators and CD38 monoclonal antibodies (three-drug relapsed/refractory). Nine subjects (60.0%) had high-risk cytogenetic abnormalities according to sMART 3.0 criteria, and 6 subjects (40.0%) had extramedullary plasmacytoma. The most common grade ≥3 adverse events were hematological toxicity, including decreased neutrophil count (n=13, 86.7%), decreased white blood cell count (n=12, 80.0%), decreased lymphocyte count (n=10, 66.7%), anemia (n=8, 53.3%), decreased platelet count (n=4, 26.7%). The first patient in the 7.5×10 6 CAR-positive T cells/kg dose group had a dose-limiting toxicity (DLT) event of grade 4 platelet count decrease, and no DLT event occurred in the other low-dose groups (2.5 and 5×10 6 CAR-positive T cells/kg). All 15 patients (100.0%) developed grade 1-2 cytokine release syndrome (CRS), no grade ≥3 CRS occurred, and the median time to CRS was 2.0 days (range: 1-13 days) , with a median duration of 7.0 days (range: 2 to 17 days). After the occurrence of CRS, all patients recovered without sequelae after supportive treatment, and 6 patients (40%) received tocilizumab (3 subjects received 2 doses, 3 subjects received 1 dose), 4 patients (26.7%) used glucocorticoids. There was no event of immune effector cell-associated neurotoxicity syndrome (ICANS), and no death event occurred. The median time to the first response (TTR) of the patients was 0.953 months (range: 0.92 to 2.23 months). All 15 patients who received CART-BCMA infusion achieved remission, and the overall remission rate (ORR) ( At least achieve PR or better efficacy) was 100% (95%CI, 78.20%-100.00%), as shown in Figure 1, among which, the best response of 9 patients (60%) was strict complete remission ( sCR), 5 patients (33.3%) achieved very good partial response (VGPR), and 1 patient (6.7%) achieved PR. All sCR patients achieved MRD negativity. The ORR of 6 patients with extramedullary plasmacytoma was 100%, of which 2 achieved sCR and 4 achieved VGPR. Notably, gradual deepening of remission was observed in 12 patients (80%), of which 10 patients (66.7%) further deepened the depth of remission on days 60-90 after infusion, and 2 patients (13.3%) were assessed sCR at day 360. Conclusion:Data from this phase 1 clinical study showed that CART-BCMA is well tolerated and highly efficacious in patients with RRMM. Patients with extramedullary plasmacytoma had the comparable response to those without extramedullary diseases. Notably, 12 patients (80%) patients elicted deeper response after 3 months of CART-BCMA infusion

Active STAT3 Prevents Selinexor-Induced Caspase-Independent Apoptosis in Multiple Myeloma

Multiple myeloma (MM) is an acquired malignant plasma cell disorder that typically develops late in life with a median age at diagnosis of 69 years and results in approximately 12,000 deaths per year. Currently, the standard treatment strategy for MM is a combination of 3 drugs with different mechanisms: dexamethasone, a proteasome inhibitor, and an immunomodulatory agent. Many MM patients acquire a “double-hit” of their TP53 on Chromosome 17p region after multple rounds of treatment and become resistant to these conventional therapeutics. Thus, novel effective treatments for high-risk and relapsed and refractory (RR)-MM are urgently needed to overcome drug-resistance, especially in TP53 null patients. In many cancers, nuclear exporter protein XPO1 overexpression is induced by c-Myc and/or loss of p53. Previous studies have demonstrated that many RR-MM patients show increased expression/activity of XPO1, which is associated with aberrant cytosolic localization of its protein and RNA cargoes. Selective XPO1 inhibitor Selinexor (Sel) has been approved by FDA to treat relapsed and refractory multiple myeloma (RR-MM) in combination with a bortezomib + DEX regimen. Addition of Sel to this regiment significantly improves the overall response rate (~75% vs. ~60%) and progress free survival (13.9 months vs 9.5 months), regardless of risk factors including TP53 status. However, only ~50% of RR-MM patients benefit from Sel treatment. In addition, Sel has significant dose dependent side effects. It is important to determine the mechanism of Sel-resistance in order to identify biomarker(s) to predict Sel-resistance and develop novel effective combination therapies. . In this study, we compared the response of 10 human MM cell lines to Sel treatment and identified Sel sensitive and resistant cell lines. Based on EC50, we divided the cell lines into Sel-sensitive group with EC 50 values between 80.4 nM to 211.8 nM, and Sel-resistant groups with EC 50 values >741.4 nM. We found that Sel sensitivity was notably independent of TP53 mutation status, as well as other genetic mutations and chromosomal translocations. In resistant cells, high dose of Sel induces an off-target Caspase-mediated apoptosis because it could not be influenced by XPO1-knockdown but could be prevented using a pan-caspase inhibitor Z-VAD. In sensitive cell lines, low dose of Sel induces a Caspase-independent type of cell death because it could not prevented by pre-treated with Z-VAD. To investigate which programmed cell death pathways Sel works through, sensitive cells were treated using with Sel + inhibitors for necroptosis, ferroptosis, pyroptosis, and parthanatos. We found only parthanatos inhibitor could significantly prevent Sel-induced cell death. The parthanatos death pathway functions via DNA-damage/poly (ADP-ribose) polymerase-1 (PARP-1) activation. While proper PARP-1 levels are required for DNA damage repair, over-activation results in the release of apoptosis-inducing factor (AIF) from mitochondria to cytoplasm which then trans-localize to the nucleus where it functions with macrophage migration inhibitory factor (MIF) to induce DNA fragmentation and cell death. We show via Western blotting and immunofluorescence imaging that upon Sel treatment, AIF shifts from the cytosol into the nucleus. Sel treatment was further assessed in combination with with Dex, where it showed a low synergistic effect with Dex in the sensitive cells but not in resistant cells, specifically when used sequentially. When assessing mechanisms of Sel resistance, phosphorylated STAT3 was uniquely observed in the resistant cell lines. To determine if STAT3 mediates resistance, resistant cell lines were pre-treated with a STAT3-PROTAC (SD36). Our study suggested that p-STAT3 predicts Sel-resistance, and Sel + STAT3 inhibitor combination is a novel effective regimen for MM, especially for these Sel-resistant cases.

Multicenter Open Label Phase 2 Study of Quadruplet-Based Regimen Iskpd (isatuximab plus pomalidomide and dexamethasone with carfilzomib) in Early Relapsed or Refractory Multiple Myeloma - IFM2018-03

Background. RRMM (relapsed or refractory multiple myeloma) is associated to shortened OS (survival) with subsequent relapses and needs optimized treatment approaches. The current treatment paradigm is based on triplet-based association of antiCD38 immunotherapy (antiCD38 IT) with either Imids (Pomalidomide) and dexamethasone or proteasome inhibitors (PI) such as Carfilzomib and dexamethasone. However, quadruplet-based regimens (antiCD38 immunotherapy +Imids +PI +dexamethasone) have transformed the treatment landscape in the upfront setting, improving MRD (minimal residual disease) and survival. We hypothesized that a quadruplet-based regimens (antiCD38 immunotherapy +Imids +PI +dexamethasone) would further improved MRD and survival in early RRMM. We describe a phase II multicentric, open-label study, of isatuximab, pomalidomide and dexamethasone plus carfilzomib (IsKPd/ IFM2018-03, NCT04287855) for patients with early RRMM. Study design and Methods. Approximately 90 patients will receive the association of isatuximab, pomalidomide and dexamethasone with carfilzomib (IsKPd), and the study has fully enrolled 82 patients as of January 2023. Eligible patients are adults aged ≥18 years old with RRMM previously treated with 1 or 2 lines of therapy, including lenalidomide, prior to the study entry. Patients were excluded if they were refractory to any anti-CD38 monoclonal antibody or to carfilzomib, or if they were previously exposed to pomalidomide. Isatuximab will be given by IV route at 10 mg/kg on days 1, 8, 15, and 22 of cycle 1, on days 1 and 15 from cycle 2 to 12 and on day 1 only from cycle 13, 28-day cycles. Carfilzomib will be given by IV route at 20/27 mg/m² on days 1-2, 8-9, 15-16 during cycle 1, at 56mg/m² on days 1, 8, 15 from cycle 2 to 13 and at 56mg/m² on days 1 and 15 after cycle 13. Pomalidomide will be administered by oral route at 3 mg daily on days 1 to 21 in cycle 1 and at 4 mg daily from cycle 12. Dexamethasone will be given by oral route at 40/20 mg daily on days 1, 8, 15 and 22. The primary objective is to evaluate the MRD rate at 10-5 in patients with RRMM treated with IsKPd. Patients will pursue Isa-KPd until progression or unacceptable toxicity. Key secondary objectives include the survival analysis (OS, PFS, EFS, TTNT), response rates and duration of response and evaluation of the safety profile. The study is expected to read out in January 2024 with sustained MRD reported.

Teclistamab Induces Favorable Responses in Patients with Relapsed and Refractory Multiple Myeloma after Prior BCMA-Directed Therapy

Introduction: Teclistamab (TEC) received regulatory approval for the treatment of patients with Relapsed/Refractory Multiple Myeloma (RRMM) after ≥ 3 prior lines of therapy based on the results of the pivotal MajesTEC-1 trial in which such patients achieved an overall response rate (ORR) of 63%, ≥ complete response (CR) of 39%, and median progression free survival (PFS) of 11.3 months (Moreau et al. N Engl J Med 2022). Patients who had received a prior B-cell maturation antigen-targeted therapy (BCMA-TT) were excluded from MajesTEC-1 trial. Data on the efficacy of TEC in patients who have received and relapsed after prior BCMA targeted therapy is lacking. Several studies have shown reduced efficacy of both FDA approved BCMA targeted chimeric antigen receptor T cell therapies (CAR-T) for myeloma, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), when administered after BCMA targeted bi-specific antibodies. There is a paucity of data on the efficacy of TEC when administered in patients who progress after ide-cel or cilta-cel. We evaluated the real-world outcomes of patients treated with standard of care (SOC) TEC after having previously received a BCMA-TT. Methods We performed a retrospective chart review to find patients treated at our center that were > 30 days from first dose of commercial TEC, received at least one prior BCMA-targeted therapy, and were consented to an IRB approved registry protocol. Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) were graded per ASTCT consensus criteria, while responses were graded based on the International Myeloma Working Group (IMWG) response criteria. Results: A total of 22 patients who had received prior BCMA-TT and TEC were evaluable for response, safety, and survival analyses. Median age was 66 years (range 48-81), 59% were male, and 13% had an ECOG PS ≥2. Beside prior BCMA-TT, other exclusion to MajesTEC-1 would have been cytopenias (27%), performance status ≥2 (9%), creatinine clearance <40 mL/min (5%), and plasma cell leukemia (5%). Eleven pts (50%) had high risk cytogenetics (defined as del17, t(4;14), t(14;16)), and 13 pts (59%) had gain 1q. Patients were heavily pretreated with a median of 8 (5-13) prior lines of therapy, 45% had R-ISS III, 14% had extramedullary disease (EMD), 27% had a high marrow burden (≥60% PCs in the marrow) and 11 (50%) were penta-class refractory. Sixty-eight percent (n=15) had received prior Chimeric Antigen Receptor T-cell Therapy (CAR-T), 9% (n=2) prior Antibody Drug Conjugate (ADC), and 23% (n= 5) both CAR-T and ADC, all BCMA-TT. Median time from prior BCMA-TT to TEC was 12.3 (1.3-33.5) months. With a median follow up of 4.16 (1.07-7.27) months, the best overall and ≥ CR response rates were 63% and 36% (N=8), respectively. Of those who had achieved a ≥ CR, 3 were MRD negative by clonoSEQ® (10 −6). Thirteen (57%) pts received TEC as the next line of therapy from prior BCMA-TT. Thirteen of 14 pts tested for BCMA expression were positive by IHC, with 9 expressors responding to TEC; the non-expressor responded to TEC. Toxicity was comparable to that seen in MajesTEC-1. Cytokine release syndrome (CRS) of any grade occurred in 16 (73%) pts. All events occurred during step-up and cycle 1 doses. All events of CRS were grade 1 (n=13; 59%) and 2 (n=3; 14%). The median time to onset of CRS was 3 (1-12) days after the most recent dose, and the median duration was 3 (1-9) days. Tocilizumab was administered to 4 (18%) pts. Only 1 patient had ICANS, grade 3 and requiring steroids. Infections were seen in 12 (55%) pts, including viral (10), bacterial (1), and fungal (1). 6 (50%) infections were deemed severe and required hospitalization. Prior to TEC, 13 (59%) pts had hypogammaglobulinemia (IgG< 400). After TEC, 6 pts developed new hypogammaglobulinemia. 11 (50%) pts had treatment delays, mainly due to CRS and infections. Four pts died due to progression of disease. Conclusions: This single center study in patients with heavily pretreated and prior BCMA-TT demonstrated favorable ORR (63%) and CR (36%) rates, comparable to pts in the MajesTEC-1 trial, without prior BCMA-TT exposure. No new safety signals were identified. Results on progression free survival (PFS) and overall survival (OS) will be reported with continued follow up and will be presented in the meeting.

Promising Safety and Efficacy of Trovocabtagene Autoleucel (C-CAR088) Followed ASCT in Ultra High-Risk Multiple Myeloma (UHR-MM) Patients Who Failed or Had Suboptimal Response to Standard First Line Triplet Based Therapy

Background: The prognosis of MM has improved significantly nowadays. However, patients with ultra-high-risk features (UHR-MM) had dismal outcomes even treated with standard front-line therapy. This study (NCT05632380) explores the potential of new CAR-T therapy in addressing the unmet need of these patients. Trovocabtagene autoleucel (trovo-cel), an anti-BCMA CAR T-cell manufactured by Cellular Biomedicine Group, Inc., showed deep and lasting responses with a good safety profile in relapsed or refractory multiple myeloma (R/R MM). Hereby, we are reporting a phase I, open-label, single-arm study, assessing the feasibility of trovo-cel followed ASCT in UHR-MM patients who failed or had suboptimal responses to the first-line standard therapy. Methods: Eligible patients are 18-70 years old, transplant-eligible and confirmed as UHR-MM defined as follows: 1) Genetic ultra-high risk: del(17p)≥60%; or ≥2 high-risk cytogenetic abnormalities including TP53 mutation, del(17p)/P53 deletion, t(4;14), t(14;16), t(14;20), 1q21 gain/ amplification, and did not reach CR or better response after 4 cycles standard first-line therapy; 2) Primary refractory: <MR after 2 cycles or <PR after 4 cycles standard first-line therapy; 3) Early relapse: lost best response within 6 months from the standard first-line therapy; 4) primary PCL history and < CR after 4 cycles standard first-line therapy. Standard first-line therapy should be a potent standard triplet-based regimen including one PI, one IMIDs, and glucocorticoid. Quadruplet or quintuplet regimens might be used. Prior ASCT, BCMA-targeted therapy, or CAR-T treatment are excluded. Patients undergo conditioning (melphalan alone or plus fludarabine) followed by ASCT on Day 0 and trovo-cel 3.0 or 6.0×10 6 cells/kg single intravenous infusion on Day 3. Maintenance is allowed after 3 months post-transplantation per investigator's decision. Results: As of July 24, 2023, 8 UHR-MM patients completed ASCT and trovo-cel infusion. Five patients received melphalan and 3 received fludarabine combining melphalan pretreatment. Trovo-cel was administrated at 3 × 10 6 cells/kg for all 8 patients. The median age of patients was 54.5 years (range: 39-66). The median number of prior lines of therapy was 2 (range: 1-2), with VRD exposure rate of 100%. Seven patients (87.5%) had received daratumumab, with six having been treated with dara-based quadruplet or quintuplet therapy as a front setting. Two patients (25%) had genetic ultra-high risk features, four patients (50%) had primary refractory myeloma, two (25%) had early relapse myeloma, and three patients (37.5%) had primary PCL history, two (25%) had extramedullary disease. Five patients (62.5%) received bridging and 6 received maintenance therapy. The combination of ASCT and Trovo-cel was well tolerated. With a median follow-up of 184 days (range: 13-332 days), no unexpected adverse events was observed. Among evaluable 7 patients, six (85.7%) had experienced grade 1 CRS and fully recovered. Two patients (28.6%) received tocilizumab and glucocorticoid for CRS. No ICANS event was reported. As expected, hematological toxicities are the most common AEs. All 7 patients achieved hematopoietic reconstitution successfully, with a median time of 14 days for ANC (≥0.5×10 9/L) and 13 days for PLT (≥20×10 9/L) post ASCT. The ORR was 100%, with 6 CR with MRD negative (NGF, 10 -5) (85.7%), 1 VGPR (14.3%). Robust CAR T-cell expansion was observed in blood of all patients. The median time of peak of CAR-T expansion (T max) was 7 days (range 4~7), the median peak CAR-T copy number (C max) was 891,963 copies /μg gDNA and the median AUC 0~28day was 6,009,475.5 copies /μg gDNA/day. The PK profile is similar to trovo-cel single agent treatment 1] but with earlier peak of CAR-T expansion. Conclusion: The preliminary results of this clinical trial show a promising safety and efficacy profile of trovo-cel followed ASCT in UHR-MM patients. Although the follow-up time is relatively limited, we are looking forward to a consistently good safety and efficacy outcome in long-term follow-up and in more patients recruited later. Research Sponsor: Institute of Hematology & Blood Diseases Hospital Collaborator: Cellular Biomedicine Group, Inc.

Healthcare Resource Utilization and Economic Burden of Cytokine Release Syndrome and Neurotoxicity in Patients with Relapsed and Refractory Multiple Myeloma (RRMM) Receiving Idecabtagene Vicleucel in Earlier-Line Settings in the KarMMa-3 Clinical Trial

Introduction: Adverse events (AE), such as cytokine release syndrome (CRS) and neurological toxicity (NT), have been associated with chimeric antigen receptor (CAR) T cell therapies. Idecabtagene vicleucel (ide-cel, bb2121), a B-cell maturation antigen-directed CAR T cell therapy, demonstrated deep and durable responses in triple-class exposed (TCE) patients (pts) with RRMM in the pivotal, single-arm, open-label phase 2 KarMMa (3 prior lines of therapy [LOTs]; NCT03361748) (Munshi NC, et al. NEJM 2021;384:705-716) and superior progression-free survival with ide-cel vs standard regimens in the phase 3 KarMMa-3 trial (2-4 prior LOTS; NCT03651128) (Rodríguez-Otero P, et al. NEJM 2023;388:1002-1014). Healthcare resource utilization (HCRU) and costs associated with CRS/NT management were estimated previously for pts receiving ide-cel in the KarMMa trial (McGarvey N, et al. Value Health 2023;26:S89) and suggested low rates of severe (grade ≥ 3) CRS/NT following ide-cel infusion and higher HCRU and costs with increasing AE severity. To further assess resource and economic burden associated with care of treatment-emergent AEs, this analysis evaluated HCRU and estimated cost of CRS/NT management among pts treated with ide-cel in earlier-line settings in the KarMMa-3 study. Methods: In this retrospective study, case report forms from the KarMMa-3 clinical trial database among pts experiencing a CRS and/or NT event that initiated within 90 days post ide-cel infusion were assessed. Pt-level HCRU data, including hospitalizations and length of hospital stay (LOS) (standard inpatient [IP], intensive care unit [ICU] days), diagnostics (eg, lab work, imaging), procedures (eg, dialysis, intubation), and medications (eg, oncology supportive care, prophylactics, other AE management) were identified from CRS/NT onset through resolution. AE management costs were estimated using a micro-costing methodology in which unit costs sourced from public databases or literature (eg, United States Centers for Medicare and Medicaid Services, Healthcare Cost and Utilization Project, IBM ® Micromedex ® RED BOOK ®) were adjusted to 2022 US dollars (USD) using the Consumer Price Index and applied to each HCRU identified. Results: Of 225 pts treated with ide-cel in the KarMMa-3 trial, 203 (90.2%) experienced any grade CRS and/or NT event. Pts experiencing a CRS/NT event had a mean (standard deviation [SD]) age of 61.9 (8.9) years and most were male (123/203 [60.6%]), White (138/203 [68.0%]), and non-Hispanic or Latino (138/203 [68.0%]). The majority (187/203 [92.1%]) of pts experienced less severe CRS/NT events (grade ≤ 2), which resolved quicker and relatively few pts (16/203 [7.9%]) had a more severe (grade ≥ 3) event, which took longer to resolve. Among pts who received ide-cel, the estimated median cost of AE management ranged from USD 17,124 (CRS only grade 1) to USD 181,552 (nonconcurrent CRS or NT grade ≥ 3) (Figure 1). Additional median costs for a pt with a grade ≥ 3 CRS/NT event was USD 31,045 higher than a grade ≤ 2 CRS/NT event. Across AE categories, the main contributors to CRS/NT management were facility costs, namely standard IP hospitalizations and ICU stays. Almost all pts (202/203 [99.5%]) had a standard IP hospitalization; 3.9% (8/203) had an ICU stay (Table 1). The trial protocol required a stay of ≥ 15 days post infusion unless admitted to the ICU; some hospitalization days recorded during the AE overlapped with the protocol-required stay. ICU admissions were more common among pts with CRS/NT grade ≥ 3 (7/16 [43.8%]) than those with grade ≤ 2 (1/187 [0.5%]). Median (range) total LOS was 10 days longer among pts with grade ≥ 3 (14.5 [2-84] days) than those with grade ≤ 2 (4 [1-34] days) CRS/NT. Pts with grade ≥ 3 CRS/NT had higher rates of HCRU than those with grade ≤ 2 for several interventions, such as medications (eg, tocilizumab + corticosteroids: 13/16 [81.3%] vs 63/187 [33.7%]), diagnostics (eg, imaging: 14/16 [87.5%] vs 48/187 [25.7%]), and procedures (eg, dialysis:3/16 [18.8%] vs 0/187 [0%]). Conclusions: Most pts with RRMM treated with ide-cel in the KarMMa-3 trial experienced a CRS and/or NT event, however, few were of high severity (grade ≥ 3). HCRU and costs for CRS/NT increased with AE severity and management. CAR T cell therapies associated with lower-severity AEs and planned interventions to prevent higher-grade AEs may provide an opportunity to better manage HCRU and costs.

Treatment Patterns and Healthcare Resource Utilization Among Patients with Triple Class Exposed Multiple Myeloma: A Population-Based Cohort Study

Introduction: Outcomes of patients with relapsed or refractory multiple myeloma (MM) have improved substantially with access to novel therapeutic agents. However, patients with triple class exposed (TCE) MM continue to have poor outcomes. Though newer bispecific antibody and chimeric antigen receptor T-cell immunotherapies have improved outcomes of TCE patients, these therapies are inaccessible outside of clinical trials in many publicly funded healthcare systems, including Canada. This study aimed to describe treatment patterns, outcomes, unplanned health care utilization and quality-of-life impairments of TCE MM patients in Ontario, Canada. These data will provide a crucial benchmark to compare to as novel immunotherapies become available. Methods: This retrospective observational study utilized data from the Institute for Clinical Evaluative Sciences (IC/ES) administrative database, which contains all health records of patients treated within Ontario's publicly funded healthcare system. Drug exposure was determined using the Cancer Activity Level Reporting (ALR) and Ontario Drug Benefit Claims Registry (ODB) databases, housed within IC/ES, which contain data on intravenous and oral MM treatment exposure for standard of care and clinical trial regimens. Patients were defined as TCE if they had prior or current treatment with a regimen containing an immunomodulatory drug (lenalidomide or pomalidomide), a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib), and an anti-CD38 monoclonal antibody (isatuximab or daratumumab). The TCE index regimen was identified as the treatment on which a patient was first identified as having met the TCE definition. Inpatient hospitalization visits did not include planned chemotherapy infusion visits. Quality of life was described using the Edmonton Symptom Assessment System Score with scores ³ 7 corresponding to severe symptoms. Overall survival (OS) was determined using the Kaplan-Meier method. Results: Of the 16,777 patients with a diagnosis of MM between 2007-2021 in Ontario, 1358 patients were classified as TCE during their treatment course. The TCE index regimen was a daratumumab-based regimen in most patients [daratumumab/velcade/dex (n=566, 42%), daratumumab/lenalidomide/dex (n=619, 46%)]. Of the TCE patients, 247 (18%) were still receiving treatment with the TCE index regimen at last follow up, 263 (19%) died without receiving any additional treatment, and 489 (36%) received a subsequent MM treatment after the TCE index regimen. Baseline characteristics of patients (n=489) treated with a subsequent MM regimen after post TCE are summarized in Table 1. The three most commonly administered therapies post TCE were carfilzomib-dexamethasone (n=111, 23%), pomalidomide-dexamethasone (n=77, 16%) and oral cyclophosphamide (n=49, 10%). The next-line treatment regimen was administered in an academic versus community treatment center in 235 (48%) versus 254 (52%) of patients, respectively. The next-line therapy was a clinical trial in only 37 (8%) patients. Regarding healthcare utilization, among TCE patients receiving subsequent therapy, 149 (30%) were evaluated in the emergency department (ED), 126 (26%) were admitted to hospital, and 48 (10%) were referred to palliative care while on treatment with the subsequent therapy. Among patients with available information, the most common severe patient-reported symptoms during the subsequent line of treatment included: tiredness (27%), pain (23%) and overall poor well-being (21%). Additionally, 35% of patients had a ECOG PS of ≥2 on next-line treatment. The median OS patients treated after the TCE index regimen was 1.05 year (95% CI 0.89-1.35) as shown in Figure 1. Of the patients that died during follow up, the majority died in hospital (n=147, 44%) and were referred to palliative care (217, 65%). Conclusion: In this real-world study, we showed that the overall outcomes of TCE MM patients remains poor in Canada, highlighting the urgent need for novel therapies. Furthermore, we demonstrated that TCE patients receiving subsequent therapy had significant unplanned health care utilization and poor quality of life. Future studies will need to assess whether the outcomes, healthcare utilization, and patient-reported quality of life improve as newer immunotherapies become accessible as standard of care treatments within our publicly funded healthcare system.

Functional Characterization of GPRC5D alteration and Its Impact on Talquetamab Resistance in Relapsed/ Refractory Multiple Myeloma

Background T-cell engaging (TCE) antibodies show unprecedented efficacy in heavily pretreated penta-refractory multiple myeloma (MM). Responses however are often not durable as resistance mechanisms can arise despite the initial absence of resistance-conferring mutations. Biallelic loss of GPRC5D on chr.12p is a rare, yet well-established mechanism of acquired resistance to the first-in-class anti-GPRC5D directed TCE talquetamab (Lee et al., 2022). At the same time, monoallelic GPRC5D frameshift and missense mutations are much more common and occur in up to 15% of MM patients (Truger et al., 2021). In this study, we investigated the functional relevance of monoallelic GPRC5D alterations and their impact on talquetamab resistance. Methods GPRC5D alterations were modeled in vitro by using CRISPR-Cas9 editing in the OPM-2 MM cell line. The bioluminescence-based cytotoxic assay was performed using PBMCs as effector cells to measure the resistance to talquetamab. Quantitative PCR (qPCR), immunohistochemistry, bulk whole genome sequencing (WGS), and whole genome bisulfite sequencing (WGBS) were performed for molecular, genomic, and epigenetic characterization in a patient with acquired talquetamab resistance. Results Using CRISPR-Cas9, we generated cell line models with mono- vs. biallelic deletions in the GPRC5D gene. Clones with biallelic alterations (OPM-2 Del/Del) displayed a 96.4%, reduced expression of GPRC5D ( p < .0001), leading to in vitro resistance to talquetamab. GPRC5D expression levels in monoallelic models (OPM-2 Wt/Del) decreased by 57.4% ( p = .0004) compared to the wild type. Sensitivity to talquetamab in these clones was equally impaired, however, less pronounced than in the biallelic knock-outs. To assess the impact of monoallelic GPRC5D deletions in the clinic, we next investigated the case of a heavily pretreated 58-year-old patient with lambda light-chain MM treated at our institution with talquetamab in his 7th line of therapy. qPCR was used to measure GPRC5D expression in CD138+ MM cells from the bone marrow of this patient before and at the time of relapse to talquetamab after 15 months of treatment (best response: CR). At the time of relapse, we observed a 94.0% ( p < .0001) decrease in GPRC5D expression upon qPCR assessment as compared to the pre-treatment time point which was confirmed by immunohistochemistry. WGS revealed a novel monoallelic loss of chr.12p encompassing GPRC5D in talquetamab-resistant CD138+ MM cells. Since monoallelic alterations seem unlikely as the sole drivers of resistance, we hypothesized that epigenetic modifications may have contributed to talquetamab resistance in this patient. To this end, WGBS was performed and uncovered a significant shift towards hypermethylation of two regulatory regions of GPRC5D, most likely resulting in the silencing of the second GPRC5D allele. Time-course experiments are currently ongoing to explore the methylation landscape of our CRISPR-Cas9-generated clones with monoallelic GPRC5D deletions. Data for these validation experiments will be presented at the meeting. Conclusions Our study provides the first evidence of the functional impact of monoallelic GPRC5D alterations resulting in relative resistance to talquetamab in vitro. We further report on epigenetic regulation as a potential second-hit mechanism conferring clinical resistance to anti-GPRC5D-directed TCE therapy. This data suggests that patients with monoallelic GPRC5D deletions may be at particular risk for developing resistance to talquetamab.

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 > 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 > 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.

Meta-Analysis of Randomized Controlled Trials to Evaluate the Incidence of Pneumonia, Upper Respiratory Tract Infections and Febrile Neutropenia in Patients with Multiple Myeloma Treated with Isatuximab

Introduction Multiple myeloma is a cancer of plasma cell and accounts for approximately 13% of all haematologic malignancies. Isatuximab is an anti CD38 IgG1 monoclonal antibody which binds to and kills myeloma cells through antibody-dependent cellular-mediated cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and direct induction of apoptosis. The incorporation of isatuximab to standard treatment in patients with relapsed refractory multiple myeloma (RRMM) has shown to significantly improve efficacy, with notable toxicities. We performed a combined analysis of randomized controlled trials (RCT) to determine the risk of pneumonia and upper respiratory tract infections (URTIs) and febrile neutropenia in patients with RRMM treated with isatuximab. Methods We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing isatuximab in patients with relapsed or refractory multiple myeloma that mention pneumonia, URTIs and febrile neutropenia as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results A total of 600 patients with RRMM from 2 phase III RCTs (ICARIA-MM and IKEMA) were eligible. ICARIA-MM and IKEMA compared isatuximab (I) + pomalidomide (P) + dexamethasone (d) vs Pd, and isatuximab (I) + Carfilzomib (K) + dexamethasone (d) vs Kd respectively. The randomization ratios were 1:1 in ICARIA-MM, and 3:2 in IKEMA studies. The I 2 statistic for heterogeneity was 0, suggesting homogeneity among RCT. The incidence of any-grade pneumonia was 30.1% in study group vs 25.8% in control group (RR, 1.19; 95% CI: 0.91 - 1.54; P=0.20). High-grade pneumonia rate was nearly 4% higher in isatuximab group compared to control arm but RR was not statistically significant at 1.26 (95% CI: 0.90 - 1.75; P = 0.18). More events of any-grade URTIs were reported in study arm (36.8%) versus 23.2% in control arm with RR of 1.55 (95% CI: 1.20- 2.01; P = 0.0008). The incidence of high-grade URTIs was low in both groups: 3.3% in study group versus 1.47% in control arm (RR, 2.25; 95% CI: 0.72 - 6.98; P = 0.16). Febrile neutropenia was noted in 20 (6%) of patients in study group compared to 5 (1.8%) in control group with RR of 3.52 (95% CI: 1.40- 8.83; P = 0.007). Conclusions Our meta-analysis showed that the addition of isatuximab to standard anti-myeloma regimen contributed to higher incidence of any-grade URTIs and febrile neutropenia in patients with RRMM, with RR of 1.55 for any-grade URTIs and RR of 3.5 for febrile neutropenia. However, risks of high-grade URTIs, any-grade and high-grade pneumonia were found to be statistically not significant between the two groups. Early recognition and proper supportive care are required to improve any-grade URTIs and febrile neutropenia.

Selinexor, Venetoclax, and Dexamethasone in t(11;14)-Positive Relapsed/Refractory Multiple Myeloma (SELVEDge Study)

Background and Significance: Patients with multiple myeloma (MM) harboring translocation t(11;14) have been shown to benefit from the apoptosis-inducing drug venetoclax; however, the drug lacks FDA approval for the treatment of multiple myeloma thus far. Selinexor is an inhibitor of nuclear export that is FDA-approved for patients with multiple myeloma refractory to multiple lines of therapy. We recently reported that in four patients with multiple myeloma with t(11;14), the concomitant administration of venetoclax and selinexor was safe and associated with disease response (Nguyen et al. Nature Precision Oncology 2022). Moreover, the combination was synergistic in t(11;14) multiple myeloma cell lines and caused decreased levels of Cyclin D1 (which is overexpressed due to the CCND1-IGH fusion) when given in combination as compared to single agents ( Figure 1). These data suggested that the combination of venetoclax and selinexor is effective and t(11;14) may serve as a therapeutic marker for response and target for future clinical trials. We have therefore developed an investigator-initiated study of selinexor and venetoclax in patients with relapsed, refractory multiple myeloma harboring translocation t(11;14)- the SELVEDge study. Methods and Study Design:This is an investigator-initiated, Phase 2 clinical study (NCT05530421) that is being conducted at the Sylvester Comprehensive Cancer Center at the University of Miami of adult (≥18 years) patients with relapsed refractory MM (RRMM) harboring t(11;14) in which approximately 24 patients will be treated with selinexor, venetoclax, and dexamethasone (SELVEDge) to determine the primary objective of response rate (ORR). Therapy will be given in 28-day cycles. Patients will receive venetoclax orally for cycle 1 only at a dosage of 400 mg daily for the first 7 days followed by 800 mg daily for the remainder of the cycle with oral dexamethasone given weekly. From cycle 2 and beyond, patients will receive oral selinexor 80 mg weekly; venetoclax daily, and dexamethasone weekly. Using a Simon Optimal 2-stage design, in the first stage, 9 patients will be enrolled and if ≥2 clinical responses occur (≥PR), the study will continue to the second stage to enroll a total of 24 patients. Early termination for excessive toxicity has been incorporated. Patients will undergo BM biopsy prior to cycle 2 and between cycle 3-4 and/or at CR and/or PD. PET/CT imaging will be performed at the same time points as bone marrow biopsies. MM serum markers for response will be performed at baseline and the start of every cycle. Exploratory corollary research will be performed on research samples collected at clinical timepoints including BCL2/MCL1 biomarkers. The study design is shown in Figure 2. The primary objective of the study is to determine the overall response rate (ORR) of SELVEDge in t(11;14)-positive RRMM with secondary objectives of durability of response (DoR), measurable residual disease (MRD) negative remission rate, progression-free and overall survival, and safety and tolerability. For patients to be included in the study they must have documented evidence of receiving two prior lines of therapy and be refractory to, not a candidate for (ineligible), or intolerant of at least one immunomodulatory (IMiD), one proteasome inhibitor, and one anti-CD38 monoclonal antibody-based treatments. Patients with prior therapy with selinexor or another specific inhibitor of nuclear exporter (SINE) compound are excluded. Statistical Hypothesis: Historically, in patients who have RRMM and have progressed after receiving IMiD, PI, and anti-CD38 -based regimens, approved experimental agents have been associated with an ORR of ~25%. It would be desirable to demonstrate that XVenD has a substantially higher response rate with a clinically meaningful ORR of 50%. As such, the study would rule out an unacceptably low ORR of 25% (p0=0.25) in favor of an improved response rate of 50% (p1=0.50), with a one sided alpha = 0.05 (probability of accepting a poor treatment=0.05) and beta = 0.20 (probability of rejecting a good treatment=0.20). Current Status: This clinical trial is currently open to enrollment at the Sylvester Myeloma Institute, University of Miami and to date 5 patients have been thus far enrolled and treatment initiated.

Lenalidomide use in multiple myeloma (Review).

Lenalidomide is a second-generation new immunomodulatory medication used to treat multiple myeloma (MM). Its mechanism of action involves affecting the expression of vascular endothelial growth factor, interleukin-6, cytochrome c, caspase-8, as well as other factors including immunological modulation and the direct killing of cells, among others, rendering it a fundamental medication, useful for the treatment of MM. Combining lenalidomide with other medications such dexamethasone, bortezomib, ixazomib, carfilzomib and daratumumab can markedly alleviate MM. When autologous-hematopoietic stem cell transplantation (ASCT) cannot be utilized to treat newly diagnosed individuals with MM (NDMM), monotherapy maintenance following lenalidomide and dexamethasone may be employed. Following ASCT, single-agent maintenance with lenalidomide can be performed as an additional treatment. The combination of bortezomib and lenalidomide has been demonstrated to be associated with favorable response rates, tolerable toxicity, and therapeutic benefits although caution is warranted to prevent the onset of peripheral neuropathy with its use. A new-generation oral drug with an excellent safety profile, ixazomib, is more practical and therapeutically applicable in relapsed refractory MM. However, the frequent occurrence of cardiovascular events, hematocrit, and infections with it require flexible adjustment in its clinical application. Carfilzomib produces a rapid and profound response in patients with NDMM eligible for transplantation, but its cardiovascular side effects need to be closely monitored. The primary aim of the present review was to examine the pharmacological properties and pharmacokinetics of lenalidomide, as well as the efficacy and safety of lenalidomide-based treatments with reference to data from clinical trials and real-world studies.

Selinexor Enhances Natural Killer Cell Function Against Multiple Myeloma Cells

Introduction: Natural killer (NK) cells are innate immune effector cells which can mediate antibody dependent cellular cytotoxicity (ADCC) and lyse cancer cells. Harnessing NK cell function against multiple myeloma (MM) is of high interest and multiple strategies are currently under development. Exportin-1 (XPO1) is a nuclear export protein which inhibits the function of tumour suppressor proteins and facilitates oncogene mRNA translation. Selinexor is a first-in-class XPO1 inhibitor approved for the treatment of relapsed or refractory MM that induces cancer cell apoptosis. In addition, selinexor has recently been shown to promote NK cell cytotoxicity against B cell lymphoma cells. This study aimed to determine whether selinexor augments NK cell activation against MM cells both alone, and in combination with the anti-CD38 antibody daratumumab. Methods: A panel of MM cell lines (MM.1S, U266 and RPMI-8226) were incubated with clinically relevant concentrations of selinexor for 24 hours, then either assessed for expression of ligands for NK cell receptors (KIR, NKG2A, NKG2D and NKp46), or co-cultured with primary human NK cells ± daratumumab. Following co-culture, NK-mediated lysis of MM cells was assessed by propidium iodide staining and NK cell degranulation assessed by CD107a expression. Results: Selinexor pre-treatment of MM cells significantly increased NK cell degranulation (p<0.05) and enhanced NK specific lysis of MM targets (p<0.05). Furthermore, selinexor pre-treatment significantly (p<0.05) enhanced NK cell activation in combination with daratumumab compared to daratumumab alone. Importantly, selinexor did not alter surface expression of CD38 on MM cell lines. To investigate the mechanism behind this enhanced NK cell function, we assessed the effect of selinexor on the expression of NK cell ligands by MM cells. Selinexor increased the expression of ULBP1/2/5/6 (2-fold, p<0.001) which bind to the NK cell activating receptor NKG2D. In addition, selinexor decreased MM cell expression of HLA-E (30% decrease, p<0.05) which binds to the inhibitory NK receptor NKG2A. Conclusions: These data suggest that selinexor may promote the efficacy of NK targeted therapeutics in multiple myeloma.

The Role of Macrophage Migration Inhibitory Factor (MIF) in Regulation of T-Cell Activity in Multiple Myeloma

Background: Multiple myeloma (MM) is the second most common hematological malignancy associated with the overproduction of light chain or monoclonal immunoglobulin. MM remains incurable, with high relapses and refractory disease rates after first-line treatment. Hence, novel therapeutic approaches are needed to improve immune responses to prevent relapses or drug resistance after initial therapies. Immune responses are shaped by several factors, including mutations, pro- and anti-inflammatory cytokines and chemokines, and activation of immune checkpoints in the tumor microenvironment (TME) (Gonzalez et al., 2018). Macrophage migration inhibitory factor (MIF) as a soluble pro-inflammatory cytokine has become one of the most puzzling regulators of innate and adaptive immune responses. In myeloma, MIF was found to be significantly higher in MM cells from relapsed patients than those responding to the treatment. MIF has been implicated in drug resistance and suggested as a biomarker for predicting MM patient responses to proteasome inhibitors (Wang et al., 2020). We previously reported that MIF is highly expressed in MM and regulates CD84 (SLAMF5) expression in MM TME. We showed that MIF secreted from MM cells regulates PD-L1 expression through CD84 on CD14 + monocytic cells in the TME. Inhibition of MIF significantly reduced CD84 and PD-L1 expressions on human CD14 + cells and on myeloid-derived suppressor cells of the mice bearing MM (Lewinsky and Gunes et al., 2021). However, whether MIF directly regulates T-cell activity in MM TME has yet to be explored. Methods and Results: The current study reports that MIF may play a pivotal role in T-cell exhaustion in MM. Ouranalyses in published MM transcriptomic databases show that MM patients with low MIF had significantly longer overall and post-progression survival, indicating the therapeutic potential of MIF in MM. We also noted upregulated MIF gene expression in relapsed or refractory MM (R/RMM) patients (n=2) compared to that in newly diagnosed MM patients (n=7) and healthy individuals (n=9) in our and publicly available MM single-cell RNA sequencing datasets. We detected a profound MIF expression in MM cells and myeloid cell fractions, including monocytes, macrophages, and dendritic cells from the patients' bone marrow (BM) specimens. We previously reported that human MM cell lines highly express MIF. In this study, we assessed the impact of MIF secreted by MM cells on the immune cells, specifically CD8 + T cells. Our results showed that inhibition of MIF reduced the elevated T-cell exhaustion markers, PD1 and CTLA-4, on CD8 + T cells in healthy donors (HDs) peripheral blood mononuclear cells (PBMCs) following the coculturing with MM1.S cells (n=3 *P < 0.05 ). We also found that MIF inhibition induced the T-cell activation marker, LAMP1, on CD8 + T cells in this coculturing setting (n=3, **P < 0.01). Furthermore, we noted MIF inhibition reduced PD1 expression on CD8 + T cells in HDs PBMCs (n=3, **P < 0.01), suggesting MIF may regulate the exhaustion profile of CD8 + T cells. MIF can conduct paracrine or autocrine signalings by binding to its receptors, including CD74 and CD44, and lead to intracellular signaling cascades. Hence, we assessed CD74 gene expression as the counterpart of MIF in R/RMM, MM, and healthy patients. We noted significantly upregulated CD74 expression in R/RMM patients compared to newly diagnosed MM patients and healthy individuals. We also noted higher CD74 expression in CD8 + T cells than in CD4 + T cells in R/RMM patients, suggesting that MIF/CD74 axis may be a potential target to enhance CD8 + T cell-mediated immunity in R/RMM. To further explore the impact of MIF inhibition on MM progression, we performed a pilot in vivo study by inoculating murine 5TGM1 cells into two groups of syngeneic C57BL/KaLwRijHsd mice. After two weeks, the mice were injected with either sterile PBS as a control or a MIF inhibitor. The results of this pilot study showed that MIF inhibition significantly decreased MM cells in BM and PB of myeloma-bearing mice and reduced T-cell exhaustion markers on CD8 + T cells compared to that in the control mice (n=3-4, *P < 0.05, **P < 0.01, ***P < 0.001). Conclusion: Overall, our preliminary data indicate that MIF may have a crucial role in T-cell activity by regulating T-cell exhaustion markers in MM. Further studies are needed to explore the therapeutic potential of MIF to reduce T-cell exhaustion to improve anti-tumor immunity in MM.

Suppression of TRIP13 Induces Metabolic Changes and Potentiates Ferroptosis in Multiple Myeloma

Introduction Despite the remarkable success of combination treatments, multiple myeloma (MM) still poses significant challenges, with a high percentage of patients experiencing relapse over time. Additional metabolic alterations are found in relapsed and refractory MM; however, their impacts have not been fully elucidated. Expression of thyroid hormone receptor interactor 13 (TRIP13) has been identified by Gene Expression Profile (GEP)-70 to correlate with poor prognosis in MM. TRIP13 is an AAA ATPase that regulates the spindle assembly checkpoint in mitosis. Based on GEP data from 34 paired baseline and relapse samples, TRIP13 continuously increased from baseline to first and to second relapse. Overexpression of TRIP13 induces bortezomib resistance. In this study, we aimed to investigate how TRIP13 might regulate MM cell metabolism and to use this information to develop a novel combination strategy to overcome MM resistance. Methods Knockout (KO) of TRIP13 in OPM2 and MM1.S cells was generated by dual gRNAs CRISPR-Cas9 editing deleting a fragment between exon 4 and exon 5. Cell growth curves and response to bortezomib were recorded in the control and TRIP13-KO cells. Metabolomics was performed to reveal cellular metabolic alterations. Seahorse analysis was used to test the mitochondrial stress and glycolysis stress. To investigate whether TRIP13 KO promotes ferroptosis, an intracellular iron-dependent cell death characterized by the accumulation of lipid peroxides, we applied C11-BODIY staining after treatment with Erastin, a ferroptosis-inducer. Expression levels of cyclooxygenase 2 (encoded by PTGS2, a hallmark of ferroptosis), cystine transporter (xCT), and intracellular glutathione peroxidase 4 (GPX4) were analyzed. In addition, the protein levels of iron metabolic molecules, including iron importer transferrin receptor protein 1 (TFRC), iron exporter ferroportin 1 (FPN1), ferritin heavy chain 1 (FTH1), and nuclear receptor coactivator 4 (NCOA4) were assessed. To study whether TRIP13 KO delays MM progression in an immune-competent MM mouse model, Vκ12653 murine MM cells were genetically modified by CRISPR-mediated TRIP13-KO and then injected into C57BL/6 mice. Mouse survival was monitored. Results The cell-doubling rate of TRIP13-KO cells was decreased by 50% compared to control cells. After 24 hours of treatment with 5 nM bortezomib, cell viability of TRIP13-KO cells decreased by 31% compared with control cells. The metabolomic studies revealed that TRIP13-KO OPM2 and MM1.S cells both had significantly decreased intracellular L-serine (FC = 0.57) but increased pyruvate (FC = 1.79), citric acid (FC = 1.76), and isocitric acid (FC = 1.64), indicating TRIP13 may regulate serine metabolism, mitochondrial function, and cellular redox balance. Seahorse analysis indicated that TRIP13-KO MM cells showed decreased glycolysis (decreased by 30%, p < 0.001) and glycolytic capacity (decreased by 33%, p < 0.001) while oxidative phosphorylation showed little change. Moreover, lipid peroxidation and PTGS2 were increased in TRIP13-KO cells after Erastin treatment, indicating that these cells were more vulnerable to ferroptosis. Mechanistically, inhibition of TRIP13 decreased GPX4, FPN1, FTH1, and increased NCOA4, while overexpression of TRIP13 showed the opposite changes, suggesting that targeting TRIP13 sensitizes MM cells to ferroptosis by impairing cellular redox balance and increasing the labile-iron pool. Lastly, TRIP13-KO significantly prolonged mouse survival in the Vκ12653 mouse model (median survival: TRIP13-KO 93 days vs. Control 60.5 days, p < 0.001). Conclusion Our study revealed that TRIP13 plays a critical role in regulating MM cell metabolism. By suppressing TRIP13, we observed increased sensitivity of MM cells to bortezomib, leading to enhanced ferroptosis-mediated cell death and prolonged mouse survival. These findings strongly suggest that targeting TRIP13 could be a promising approach in MM therapy. Moving forward, our future investigations will concentrate on unraveling the precise molecular mechanisms underlying TRIP13-mediated alterations in cell metabolism. Additionally, we plan to explore the potential synergistic effects of TRIP13 inhibition in combination with metabolic targeted treatments, such as venetoclax, to further enhance therapeutic outcomes in MM.

Unveiling the Digital Landscape of CAR-T Therapies in Multiple Myeloma Using Social Media Insights

Introduction: The rapid evolution of novel chimeric antigen receptor T-cell (CAR-T) therapies, including Carvykti (ciltacabtagene autoleucel) and Abecma (idecabtagene vicleucel), have revolutionized the treatment landscape for multiple myeloma (MM) patients. These cutting-edge therapies have demonstrated remarkable efficacy in clinical trials, representing a significant advancement in the field. However, their real-world impact on patient and physician experiences, and perceptions remain important topics of ongoing investigation. In recent years, social media platforms have emerged as valuable sources of real-time data and patient perspectives, providing an unprecedented opportunity for researchers to gain insights into physician and patient perceptions around these emerging CAR-T therapies. This study aims to perform a comprehensive digital analysis to measure sentiment expression by different health care stakeholders and to identify health information needs related to MM CAR-T therapies. Methods: This digital analysis utilized publicly available data related to CAR-T therapies approved for the treatment of relapsed or refractory MM from various online sources related to CAR-T therapies. The data was captured using the web indexing tool Talkwalker. The analysis covered the time period from May 21, 2021 to May 21, 2023. Quantitative analysis involved applying filters and Boolean search terms to segment the data and generate figures such as share of voice, language and media type distribution, and treatment and MM mentions over time. Additionally, a qualitative assessment was conducted by reviewing posts related to the key topics of interest. Individuals who self-identify as healthcare professionals (HCPs) based on their bio, social media name, byline in news articles, or other indications were included in stakeholder analysis. Results: Out of the 471.5K MM posts generated over the 2-year study period, 47,909 posts (10%) were about CAR-T therapy, and 13,117 posts specifically commented on either Carvykti (55%) or Abecma (45%). In terms of specialty, hematologists were the primary contributors (47%), followed by oncologists (16%) and pharmacists (6%). CAR-T therapy was most referenced in posts discussing efficacy, safety, duration, and time to cytokine release syndrome (CRS), with a higher number of posts mentioning Carvykti (57%) compared to Abecma (43%). The most prominent key themes of pressing challenges and needs mentioned among CAR-T therapy posts were cost (60.5%), post-CAR-T care (38.6%), access (37.5%), education (6.7%), and quality of life (6.4%). Both Carvykti and Abecma were frequently mentioned alongside access and cost, although access (60%) was more prominent with Carvykti and cost (61%) with Abecma. Among HCPs, the most significant key theme of pressing challenges and needs was post-CAR-T infusion care considerations (58.6%), such as extended hospital stays to manage immune-mediated toxicities such as CRS and neurotoxicity, the risk of cytopenia and infections, and strategies to mitigate these risks. Management strategies mentioned included earlier and more aggressive supportive care, the use of cytokine-targeting therapies such as tocilizumab for any grade CRS, steroids such as dexamethasone for immune effector cell-associated neurotoxicity syndrome, and prophylactic antiseizure medications for all patients regardless of neurotoxicity. In the category of Diversity, Equity, & Inclusion, both Carvykti and Abecma were mentioned similarly on various topics, including access to CAR-T therapies (87% vs. 74%), diversity in clinical trials (19% vs. 17%), geographic location implications (9% vs. 15%), and racial disparities (3% vs. 4%). Conclusions: The study findings highlight the importance of demystifying cost perceptions against the added value to patients, HCPs and payers, and implementing comprehensive post-CAR-T care protocols aligned with the concerns expressed in social media discussions for improvement in CAR-T therapies for multiple myeloma. By leveraging the power of social media data, this study offers valuable real-world insights that can inform clinical decision-making, enhance patient-centered care, and contribute to the development of strategies to overcome challenges associated with CAR-T therapies in multiple myeloma.

Hdp-101, an Anti-BCMA Antibody-Drug Conjugate with a Novel Payload Amanitin in Patients with Relapsed Multiple Myeloma, Initial Findings of the First in Human Study

Introduction Several antibody-drug conjugates (ADCs) are currently being evaluated in clinical trials in a variety of malignancies. The vast majority of these are based on a few toxic compounds, largely limited to microtubule- or DNA-targeting toxins which impact proliferating cells and have limited efficacy in diseases with a low proliferative fraction such as multiple myeloma. Thus, new compounds with alternative modes of action and the ability to actively induce cell death in non-proliferating tumor cells could enhance the therapeutic potential of ADCs. We are currently developing amanitin based ADCs. Amanitin specifically inhibits RNA polymerase II thereby inhibiting the cellular transcription process at very low concentrations irrespective of the proliferation status of the target cell. Subsequently tumor cells enter apoptosis and are eliminated. HDP-101 an Amanitin based antibody drug conjugate HDP-101 is a new ADC targeting BCMA carrying a synthetic version of amanitin as a payload. In vitro cytotoxic potency of HDP-101 was demonstrated on BCMA-positive myeloma cell lines, as well as on non-proliferating primary CD138+ cells isolated from patients with refractory myeloma The cytotoxic effects of HDP-101 were seen even in non-proliferating myeloma cells with low BCMA density. Toxicity was observed neither in non-BCMA expressing control cells nor in myeloma cells exposed to an amanitin-loaded non-target control antibody. In murine xenograft models of human myeloma, HDP-101 caused dose-dependent tumor regression including complete remissions after a single dose in subcutaneous and as well as in disseminated models. Safety profiling in Cynomolgus monkeys revealed a good therapeutic index after repeated dosing. Our non-clinical studies concluded that this amanitin-based ADC is a novel promising approach in the therapy of multiple myeloma to overcome drug resistance and improve patient outcome. HDP-101-01 Clinical study HDP-101-01 is a first-in-human, open label, non-randomized, multicenter, phase 1/2a trial with HDP-101 in patients with myeloma whose disease has progressed. The aim of the Phase 1 dose escalation part is to determine the Maximum Tolerated Dose and/or establish the Recommended Phase 2 Dose. The primary objective of the phase 2 dose expansion phase is to assess the preliminary anti-tumor activity of HDP-101. An adaptive Bayesian logistic regression model with overdose control principle is used to guide the dose escalation steps. An Interim Analysis is planned after each cohort is completed. The design of the study ensures a safe and adaptive dose escalation to reach a potential clinical benefit in a patient who have limited or no therapeutic options. HDP-101-01 Study progress The study started enrollment in February, 2022. As of 10th of July, 2023, eight (2 female and 6 male) patients were dosed in 3 consecutive dose cohorts. The median age of the patients was 70 years, ranging between 50 and 80. All 8 patients were heavily pre-treated and multidrug-resistant. The median previous lines of treatment were 7 (5 to 15). Table 1 HDP-101-01 Results Seven of 8 patients were evaluable for dose limiting toxicities (DLTs) in the first 3 treatment cohorts. The initial 3 cohorts were well tolerated, without any DLTs, there were no signs of liver and kidney toxicity, no infusion reaction was detected. No reports of keratopathy or visual acuity loss were observed. Free payload was not detected in any of the available pharmacokinetic samples. Based on the limited data, the PK of HDP-101 was in line with our expectation based on the preclinical observations, exposure to HDP-101 is dose proportional. Anti-drug antibody (ADA) was not detected and there's no sign of immunogenicity. Objective responses were not reported in these initial cohorts however in Cohort #3 (60μg/Kg) there was one patient ongoing after 8 cycles of treatment with SD. This patient had a slow decrease in M-protein levels. Image 1 The initial dose cohorts showed good tolerability in late stage relapsed and/or refractory multiple myeloma patients. The study continues to enroll patients to higher dose cohorts at selected sites in the US, Germany, Poland and Hungary. Currently the study is enrolling patients in Cohort #4 at the dose of 80μg/Kg. Additional updates will be provided at the 2023 ASH Annual Meeting.