International Myeloma Working Group Criteria Research Articles

Pembrolizumab and low-dose, single-fraction radiotherapy for patients with relapsed or refractory multiple myeloma: a prospective, single-centre, single-group, open-label, phase 2 pilot trial in the USA

Currently, the use of radiotherapy alone for people with multiple myeloma is limited to palliation of pain, pending fracture, and control of spinal-cord compression. Single immune-checkpoint inhibitors, such as anti-programmed death-1 (anti-PD1), have not been successful. We aimed to evaluate the activity and safety of the combination of pembrolizumab and low-dose, single-fraction, hypofractionated radiotherapy to treat patients with relapsed or refractory multiple myeloma. For this prospective, single-centre, single-group, open-label, phase 2 trial, we recruited patients with relapsed or refractory multiple myeloma from the Winship Cancer Institute (Emory University, Atlanta, GA, USA). Key inclusion criteria were aged 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1, relapsed or refractory multiple myeloma as indicated by progression under International Myeloma Working Group (IMWG) criteria, and adequate candidacy for both pembrolizumab and radiotherapy. Baseline and post-treatment assessments were serial bone-marrow biopsy, peripheral blood collections, staging, serial serum and urine paraprotein analysis, serial PET-CT imaging, and a physical examination. On day 1, patients received hypofractionated 8 gray in 1 fraction (8 Gy/1 fx) radiotherapy to either symptomatic or progressing extra-osseous or osseous myeloma sites. Patients also received pembrolizumab (200 mg/kg intravenously) on day 2 or 3, then once every 3 weeks (±7 days) for 2 years or until progressive disease, unacceptable toxicity, withdrawal of consent, loss to follow-up, or death. Dose reduction and interruptions were not allowed. The primary outcome was acute toxicity defined as grade 3 or worse toxicity at 3 months within the radiated site when used in combination with pembrolizumab. All patients were analysed per protocol and included in safety analyses. This trial is registered on ClinicalTrials.gov (NCT03267888); it is completed and closed to accrual. 32 patients were screened between June 1, 2018, and Sept 2, 2022, and 25 were enrolled in the trial and treated on protocol. Of the 25 treated patients, 11 (44%) were female and 14 (56%) were male. 19 (76%) patients were White and six (24%) were Black or African American. Toxicity, as the primary outcome, was deemed to be acceptable as no grade 4 or 5 adverse events were observed. At 3-month follow-up, eight (32%) of 25 patients had treatment benefit (one had stable disease, three had partial response, two had very good partial response, and two had complete response). There was no grade 3 or worse radiation-related toxicity within irradiated volumes. One (4%) patient of the 25 who received combination treatment had a grade 3 pembrolizumab-related adverse event. There were no treatment-related deaths. Combination treatment of low-dose, single-fraction radiotherapy with pembrolizumab was safe, with early promise of response activity. Our approach could be an option for patients with relapsed or refractory multiple myeloma who have not responded to previous treatment. Larger trials to substantiate our findings are needed. Merck Sharp & Dohme.

A Phase I Trial Evaluating the Addition of Lenalidomide to Patients with Relapsed/Refractory Multiple Myeloma Progressing on Ruxolitinib and Methylprednisolone.

Ruxolitinib (RUX), an orally administered selective Janus kinase 1/2 inhibitor, has received approval for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. We have previously demonstrated the anti-multiple myeloma effects of RUX alone and in combination with the immunomodulatory agent lenalidomide (LEN) and glucocorticosteroids both pre-clinically and clinically. This study aims to evaluate whether LEN can achieve clinical activity among patients with multiple myeloma progressing on the combination of RUX and methylprednisolone (MP). In this part of a phase I, multicenter, open-label study, we evaluated the safety and efficacy of RUX and MP for patients with multiple myeloma with progressive disease who had previously received a proteasome inhibitor, LEN, glucocorticosteroids, and at least three prior regimens; we also determined the safety and efficacy of adding LEN at the time of disease progression from the initial doublet treatment. Initially, all subjects received oral RUX 15 mg twice daily and oral MP 40 mg every other day. Those patients who developed progressive disease according to the International Myeloma Working Group criteria then received LEN 10 mg once daily on days 1-21 within a 28-day cycle in addition to RUX and MP, which were administered at the same doses these patients were receiving at the time progressive disease developed. Twenty-nine subjects (median age 64 years; 18 [62%] male) were enrolled in this part of the study and initially received the two-drug combination of RUX and MP. The median number of prior therapies was six (range 3-12). The overall response rate from this two-drug combination was 31% and the clinical benefit rate was 34%. The best responses were 1 very good partial response, 8 partial responses, 1 minor response, 12 stable disease, and 7 progressive disease. The median progression-free survival was 3.5 months (range 0.5-36.2months). The median time to response was 3.0 months. The median duration of response was 12.5 months (range 2.8-36.2 months). Twenty (69%) patients whoshowed progressive disease had LEN added to RUX and MP; all patients had prior exposure to LEN and all but one patient was refractory to their last LEN-containing regimen. After the addition of LEN, the overall response rate was 30% and the clinical benefit rate was 40%. The best responses of patients following the addition of LEN were 2 very good partial responses, 4 partial responses, 2 minor responses, 8 stable disease, and 4 progressive disease. The median time to response was 2.6 months (range 0.7-15.0 months). The median duration of response was not reached. The median progression-free survival following the addition of LEN was 3.5 months (range 0.3-25.9 months). For patients with multiple myeloma, treatment with RUX and MP is effective and well tolerated, and LEN can be used to extend the benefit of this RUX-based treatment. This study is registered with ClinicalTrials.gov, NCT03110822, and is ongoing.

Early Chimeric Antigen Receptor T Cell Expansion Is Associated with Prolonged Progression-Free Survival for Patients with Relapsed/Refractory Multiple Myeloma Treated with Ide-Cel: A Retrospective Monocentric Study

The outcomes of patients with relapsed and refractory multiple myeloma (RRMM) previously treated with the 3 main classes of myeloma therapy-immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies-remain poor. Recently, based on the phase II pivotal KarMMa trial showing prolonged overall survival (OS) and progression-free survival (PFS) in heavily treated patients, idecabtagene vicleucel (ide-cel), a B cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy (CAR-T) product, was approved in the United States for the treatment of RRMM. In France, since June 2021, an early access program has authorized the use of ide-cel in the setting of RRMM (defined as progressive myeloma after at least 3 previous regimens, including the 3 main antimyeloma therapies). We report the first French experience through this early access program in a retrospective study of 24 consecutive patients treated with ide-cel at our institution. The patients were evaluated according to International Myeloma Working Group criteria and by positron emission tomography computed tomography (PET-CT) at 1, 3, 6, 9, and 12 months after ide-cel infusion. Most patients had adverse cytogenetic abnormalities, and RRMM with triple-refractory drugs were seen in 79%. Bridging therapy was required for 19 of 24 patients. Before CAR-T cell infusion, lymphodepletion with fludarabine and cyclophosphamide was systematically performed. The median follow-up was 15.2 months. At 3 months after ide-cel infusion, 92% of patients achieved at least a partial response, and 50% achieved a complete response or better (≥CR). At 6 months, 70% of patients had a persistent ≥CR. At 3 and 6 months, bone marrow minimal residual disease (10-6 level) was undetectable in 79% and 75% of patients, respectively. At 6 months, CR as assessed by PET-CT was achieved in 15 of 20 patients (75%). The median PFS was 14.8 months, and median OS was not reached. Notably, an expansion of circulating CAR-T cells to >180/mm3 after infusion was strongly associated with prolonged PFS. Additionally, the level of soluble BCMA measured before infusion was identified as a prognostic factor for PFS, likely correlated to the tumor burden. Grade 1-2 cytokine release syndrome (CRS) occurred in 22 of 24 patients (92%). Only 1 patient (4%) experienced grade ≥3 CRS. The occurrence of neurologic toxicity was infrequent (12.5%) and reversible in all cases. Hematologic toxicity was relatively common, and secondary hypogammaglobulinemia occurred in most patients. Infections (mostly viral) were frequent but most often nonsevere. This study echoes the promising results of the KarMMa trial and identifies possible prognostic indicators in RRMM patients treated with ide-cel, potentially refining treatment strategies and improving outcomes in this challenging context.

Comparative assessment of beta-2 microglobulin as predictor of progression of multiple myeloma in asymptomatic and symptomatic multiple myeloma patients in a tertiary care hospital in Eastern India

Background: Multiple myeloma (MM) is a clonal late B-cell disorder in which malignant plasma cells expand and accumulate in the bone marrow and is associated with paraprotein production, bone lesions, anemia, hypercalcemia, susceptibility to infections, and renal impaired. Beta-2 microglobulin (B2M) is a serum marker of tumor burden in lymphoid malignancies, including MM. The purpose of this study was to find whether increased B2M levels can predict the progression of MM from asymptomatic to progressed symptomatic phase, as it is a less invasive and cost-effective method than the more invasive and costly ones to predict the progression of the disease. Aims and Objectives: This study was taken in a medical college, Kolkata, 50 asymptomatic Stage 1 MM patients were taken along with age and gender-matched 50 symptomatic progressed MM patients, blood samples of both groups were evaluated to estimate the difference in serum B2M (SB2M) level in both groups. Moreover, to study the difference in serum albumin, C-reactive protein, creatinine, immunoglobulin (IG), total protein, calcium, hemoglobin, and percentage of plasma cells in both groups and also their correlation with SB2M level in the progressed disease group. As well as to assess if there is increased B2M in the progressed disease group and if the B2M level correlates with the disease severity (i.e. progression of the disease). Materials and Methods: An observational descriptive non-interventional, hospital-based study conducted at central laboratory, medical college, Kolkata, for 6 months. Patients were chosen by systematic random sampling. Fifty asymptomatic MMs were chosen according to the International Myeloma Working Group criteria and out of 50 patients in the progressed disease group, 75% of patients were in Stage III and 25% of patients were in Stage II according to the Salmon and Durie system. Results: More than 80% in the progressed and symptomatic group had β-2M >3.5 mg/L. Whereas in the newly diagnosed group, all the 50 patients had their β-2M level <3.5 mg/L. Moreover, B2M value in the blood of progressed MM patients was found to be positively correlated with percentage of plasma cells from bone marrow, serum creatinine level, serum protein level, serum calcium level, and IgG level and negatively correlated with Hb level and serum albumin level. Hence, in a nutshell, increased B2M level was found in the progressed MM group, and its level positively correlated with the other predictors of the progression of MM. Conclusion: As per this study, SB2M level (which is a less invasive test than bone marrow testing and less costly) can be used as the predictor of progression of MM from asymptomatic to symptomatic. However, small sample size and cross-sectional pattern of the study were the limitations of this study. Bigger sample size and prospective cohort-type study designing method could be a better method to find a stronger correlation between MM staging and SB2M levels.

Precision in Practice: A Cross-sectional Study Involving MRI T2 Dixon and Conventional Sequence in Detecting Focal Multiple Myeloma Lesions

Introduction: Multiple Myeloma (MM) represents a malignant proliferation of plasma cells derived from a single clone. Imaging of the skeleton beyond symptomatic areas is useful for myeloma staging and subsequent follow-up for treatment response and disease relapse. Despite research comparing the Dixon sequence to conventional sequences in a variety of musculoskeletal disorders, there is a lack of studies regarding the Dixon sequence’s application in MM. Aim: To compare the contrast of MM focal lesions in all four T2- weighted Dixon and Conventional T1-weighted spin-echo and Short Tau Inversion Recovery (STIR) images. Materials and Methods: This cross-sectional study was conducted in the Department of Radiology at Kovai Medical Centre and Hospitals (KMCH), Coimbatore, Tamil Nadu, India. All newly diagnosed and known cases of MM, either biopsyproven or strongly suspected based on other diagnostic testing conforming to International Myeloma Working Group (IMWG) criteria from December 2020 to July 2022, were included in the study. A total of 43 patients with 142 focal MM lesions were included. Contrast between focal MM lesions and surrounding bone marrow was calculated on T1-weighted spin-echo, STIR, and T2-weighted Dixon (all four) images. Statistical analysis was done using repeated measures of Analysis of Variance (ANOVA) with Bonferroni correction to control the type I error on multiple comparisons to find the significant difference between multivariate analyses. A probability value of 0.05 was considered a significant level for all statistical tools. Results: The study population consisted of 21 men and 22 women with a mean age of 65.3±8.6 years {Mean±Standard Deviation (SD)}. Contrast values in all four T2 Dixon images, STIR, and T1-weighted images were as follows: T2 Dixon Fat-only (FO) images (0.86.±0.09) (SD); range: (0.46-0.99), T2-weighted Dixon Water-only (WO) images (0.54±0.14) (SD); range: (0.14-0.82), T2 Dixon In-phase (IP) images (0.20±0.13) (SD); range: (0.02-0.41), T2-weighted Dixon Out-phase (OP) images (0.53±0.19) (SD); range: (0.12-0.87), STIR images (0.47±0.12) (SD); range: (0.12-0.73), and T1 images (0.23±0.12) (SD); range: (0.01-0.55). The mean contrast was highest on T2 Dixon fat-only images (p<0.0005) compared to T1 images, with the lowest contrast seen in IP images and intermediate values in OP images. Conclusion: In conclusion, fat-only images of the T2 multipoint Dixon sequence provide significant contrast compared to conventional T1-weighted imaging. Dixon water-only images provide fat suppression that is not inferior to STIR images. While Dixon techniques in the diagnosis of MM did not significantly differ from the conventional sequence, Dixon stands out from conventional sequences when considering the study duration and contrast between the lesion and normal bone marrow.

A Phase 2, Single-Arm, Non-Inferiority Study of Limited-Duration Teclistamab for Relapsed and Refractory Multiple Myeloma (LimiTec)

Background and Significance: Teclistamab, a BCMA-directed T-cell engager (anti-BCMAxCD3 bispecific antibody), is currently approved for relapsed/refractory multiple myeloma (MM) patients with ≥4 prior lines of therapy, including an IMID, proteasome inhibitor, and CD38 antibody. Teclistamab is typically dosed on a regular schedule (every 1-4 weeks) indefinitely until disease progression. Yet continuous exposure, as reported on the phase 1/2 MajesTEC-1 study, was associated with infectious complications in 78% of patients, with 52% grade 3 or 4 events (van de Donk et al, ASCO 2023) and several fatal infections (Moreau et al., NEJM 2022). Sustained off-drug responses have been observed in patients who discontinued teclistamab for reasons other than progression and have also been reported with cevostamab, an anti-FcRH5xCD3 bispecific antibody under investigation as a limited-duration regimen (17 cycles) in MM (Lesokhin et al, ASH 2022). These findings raise the possibility that limited-duration teclistamab might provide comparable efficacy with lower risk compared to continuous therapy. Therefore, we hypothesize that monitored discontinuation of teclistamab in patients with deep response after 6-9 months of continuous therapy, with option to resume upon early sign of MM growth, will be non-inferior to that of historical controls [from the MajesTec-1 trial] who were treated with continuous teclistamab dosing. Study design and methods: This is a single-arm, non-inferiority study in which patients who have achieved a very good partial response (VGPR) or better, according to International Myeloma Working Group (IMWG) response criteria, following 6-9 months of standard-of-care teclistamab, will be offered monitored drug discontinuation. Patients will be monitored monthly off-drug for up to 24 months and will be allowed to resume commercial teclistamab on-study in the event of early disease growth (defined as increase in involved free light chain >20 mg/L with ratio >5) or progression (as defined by IMWG criteria).The primary objective is to preliminarily assess whether the rate of treatment failure of limited-duration teclistamab after 6 months of drug discontinuation is non-inferior to that of historical controls who received continuous therapy, where treatment failure is defined as any of the following events: (1) disease progression after teclistamab re-initiation (for subjects who resume teclistamab for early disease growth), (2) failure to achieve at least minimal response to teclistamab re-initiation (for patients who resume teclistamab for IMWG progression), (3) initiation of non-teclistamab systemic MM therapy, or (4) death due to complications of MM, teclistamab, or infection. Secondary endpoints will evaluate time to progression, rates of re-response, the rate and severity of infections, types of clinical complications with progression, patient reported outcomes, and immune cell subset composition. Analysis of minimal residual disease (MRD), tumor features, and bone marrow microenvironment parameters, which will be pursued as exploratory correlative analyses in this study, may identify factors that predict durable response to limited-duration therapy and thereby enable more precise selection of patients likely to benefit from this approach. A subset of patients will be enrolled in an optional biomarker sub-study for analysis of these exploratory endpoints. We will enroll ~75 subjects to reach the target of 64 evaluable subjects assuming 15% will be not evaluable. The sample size was calculated based on a non-inferiority test for the primary outcome of failure-free probability at six months after the date of discontinuation of teclistamab against the null value of 0.79 that estimated from a historical cohort with 80% power, 0.05 alpha level, and a non-inferiority margin of -0.15. The power was evaluated at the value such that no difference between the historical and early discontinuation values using a one-sided one-sample continuity-corrected Z-test for testing a binomial proportion (normal approximation) with the standard deviation estimated under the null value. Conclusions: This single-arm, phase 2 study is exploring whether limited-duration teclistamab is non-inferior to continuously administered therapy in patients who have received 6 to 9 months of teclistamab and have achieved at least a very good partial response. Accrual started in July 2023.

A Phase 1 Trial Evaluating the Addition of Lenalidomide to Relapsed/Refractory Multiple Myeloma Patients Progressing on Ruxolitinib and Methylprednisolone

Background Ruxolitinib (RUX), an orally administered selective JAK 1/2 inhibitor, has received approval for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. We have previously demonstrated the anti-multiple myeloma (MM) effects of RUX alone and in combination with the immunomodulatory agent lenalidomide (LEN) and glucocorticosteroids both preclinically and clinically. Although we have previously demonstrated that LEN and steroid refractory MM patients respond to the addition of RUX, no studies have evaluated whether LEN can achieve clinical activity among those progressing on the combination of RUX and methylprednisolone. Methods Patients included those with MM showing progressive disease (PD) who had previously received a proteasome inhibitor, LEN, glucocorticosteroids, and at least three prior regimens. Initially, subjects received oral RUX 15 mg twice daily and oral methylprednisolone 40 mg every other day. Those patients who developed PD according to International Myeloma Working Group criteria had LEN 10 mg once daily days 1-21 on a 28-day cycle added to RUX and methylprednisolone which were administered at the same doses they were receiving at the time of PD. Results A total of 29 subjects were enrolled and initially received the combination of RUX and methylprednisolone. Follow up was until June 30, 2023. The median number of prior therapies was 6 (range, 3-12). The overall response rate (ORR) was 31% and the clinical benefit rate (CBR) was 34%. The best responses were 1 very good partial response (VGPR), 8 partial responses (PR), 1 minor response (MR), 12 stable disease (SD), and 7 PD. The median progression-free survival (PFS) was 3.5 mo (range, 0.5-36.2 mo). The median time to response was 3.0 mo (n=10). The median duration of response (DOR) was 12.5 mo (range, 2.8-36.2 mo). Twenty (69%) showed PD and had LEN added to the RUX and methylprednisolone combination: all of these patients were refractory to their last LEN-containing regimen. After the addition of LEN, the ORR was 30% and CBR was 40%. The best responses of patients following the addition of LEN were 2 VGPR, 4 PR, 2 MR, 8 SD, and 4 PD. The majority of patients (71%) who initially achieved a > MR to the two-drug combination responded following the addition of LEN whereas only 23% of patients who did not initially achieve a > MR responded to the addition of the third drug. The median time to response was 2.6 mo (range, 0.7-15 mo). The median DOR was undefined (range, 1.2-10.9 mo). The median PFS was 3.5 mo (range, 0.3-25.9 mo). The median PFS2 (including time from first treatment to end of study or June 30, 2023) was 7.3 mo (range, 0.5-39.9). Treatment was well tolerated with no additional toxicity identified following the addition of LEN. Interestingly, PFS2 was predicted by the patient's baseline serum B-cell maturation level; patients with values above the median (128 ng/mL) had significantly shorter PFS2 than those below it (3.5 mo vs. undefined, p = 0.0337). Conclusion The addition of LEN to heavily, previously treated relapsed/refractory MM patients progressing on RUX and methylprednisolone shows significant clinical activity. This three-drug combination is well tolerated and is able to extend the benefit of RUX-based treatment for these patients. The promising results from this phase 1 clinical trial demonstrate a potential novel, all oral therapeutic approach for treating RRMM patients.

SOR-CART-MM-001 Study: A Phase I, Open-Label, Dose-Escalation, Pharmacokinetic, and Pharmacodynamic Study of Safety and Efficacy of CAR2 Anti-CD38 A2 CAR-T Cells in Patients with Relapsed or Refractory Multiple Myeloma (RRMM)

Background: B-cell maturation antigen (BCMA) directed chimeric antigen receptor (CAR-) T cells, show high response rates in patients with highly refractory and heavily treated myeloma, and have become a standard treatment in this setting. The durability of these responses, however, has been limited with few long term remissions. One approach to potentially improve CAR T outcome is to direct these cells to alternative targets such as CD38 almost universally expressed on malignant plasma cells. In this open-label phase I multi-institutional study we explored the efficacy and safety of CAR2 anti-CD38 A2 CAR-T cells in patients with RRMM. Methods: The SOR-CART-MM-001 study was a multicenter, open-label, “3+3” dose-escalation, phase 1b trial of a single administration of a fully human antibody with lambda light chain generated by transduction of activated T cells with an anti-CD38 A2 CAR expressing retroviral vector. A single dose of CAR2 Anti-CD38 CAR-T cells was administered 2 days post lymphodepletion with single-agent cyclophosphamide 1.5 g/m 2. The primary endpoint was determination of the maximum tolerated dose (MTD) assessed by the occurrence of treatment-emergent dose-limiting toxicities during the 28-day treatment period in the dose-escalation phase of the study. Dosing was divided into three cohorts ranging from 1 × 10 5 cells/kg (Cohort 1) to 1 × 10 7 cells/kg (Cohort 3). Circulating CAR-T cells were measured at different timepoints post infusion. Key eligibility criteria included ≥3 lines of therapy with prior proteasome inhibitor, immunomodulatory IMID drug or daratumumab exposure, measurable and progressive MM per International Myeloma Working Group criteria and ECOG ≤ 2. Results: Between March 2018 and March 2022, 9 patients were enrolled and assigned to each of the three Cohorts. Patient demographics and baseline characteristics are described in Table 1. Hematologic toxicity was the most common treatment emergent adverse event experienced (6/9, 66.7%), all Grade 3 or Grade 4. All cytopenias recovered in 21 days in subjects treated with no more than MTD. Two subjects within Cohort 3 exhibited mild cytokine release syndrome (CRS) (Grade 1 and 2) with one of these two subjects also developing mild neurotoxicity (Grade 2). No CRS or neurotoxicity was observed at either of the lower dose levels. Two serious adverse events (SAEs) were reported: Klebsiella sepsis 60 days after treatment that recovered in 4 days after antibiotics and muscle weakness at 24 days after treatment that received within 1 day without treatment and neither were deemed related to the study medication. The first 2 patients in Cohort 3 met dose limiting toxicity (DLT) criteria after treatment due to grade 3 hematological toxicity and the next lower dose 1 x 10 6 cells/kg (Cohort 2) became the MTD. Pharmacokinetic data showed the percentage of the detectable circulating CAR-T cells in any subject at any time point was low with many showing no detectable cells. 4 deaths were reported after the end of the study period, and none were considered related to the investigated CAR-T cells (3 due to progression and one due to COVID-19). Overall, a total of 3 patients had a partial response (PR) and 3 patients had stable disease (SD) across 3 dose levels. PR constituted the best response in the study and the durations of objective clinical responses were each less than 3 months. These treatment responses are summarized in Table 2. Conclusion: This phase I trial demonstrated that CAR2 anti-CD38 A2 CAR-T cells were generally well tolerated at the Cohort 2 (MTD) dose and demonstrated objective though short responses even in patients progressing after daratumumab and belantamab mafodotin. More clinical studies are needed to optimize the efficacy and tolerability of CAR-T cell therapies for patients with RRMM. This study was completed, and no more patients will be enrolled. DART-RRMM-101 is a phase 1b, open-label, dose-escalation study ongoing to assess allogeneic Anti-CD38 A2 Dimeric Antigen Receptor T Cells in RRMM (ClinicalTrials: NCT05007418).

Impact of Long-Term Treatment with Belantamab Mafodotin on Safety and Efficacy Outcomes in Patients with Relapsed/Refractory Multiple Myeloma in DREAMM-3

Introduction: DREAMM-3 (NCT04162210) is a randomized study comparing single-agent belantamab mafodotin, a first-in-class antibody-drug conjugate targeting B-cell maturation antigen, to a standard-of-care regimen, pomalidomide plus dexamethasone (Pd). This post-hoc analysis from the DREAMM-3 trial evaluated the safety and efficacy of long-term treatment (≥52 weeks) with belantamab mafodotin compared with Pd, as well as the effects of dose modifications, in adult patients with relapsed/refractory multiple myeloma (RRMM) at third line of therapy or later. Methods: Patients were randomized (2:1) to belantamab mafodotin 2.5 mg/kg intravenously once every 3 weeks (Q3W; 21-day cycle) or pomalidomide 4 mg orally once daily (Days 1-21) and dexamethasone 40 mg (20 mg if >75 years) orally once weekly (28-day cycle). Belantamab mafodotin dose reductions or delays were permitted to manage treatment-related Grade 3-4 adverse events (AEs), or Grade 2 AEs that were worsening or had symptoms lasting >7 days. Following AE resolution to Grade ≤1, belantamab mafodotin treatment could resume with or without dose reduction (to 1.9 mg/kg). If no dose delays occurred, patients could receive a maximum of 17 cycles in 52 weeks, hence 17 cycles was used as a threshold to assess long term safety. Ocular exams were performed prior to dosing belantamab mafodotin Q3W up to Cycle 6, then every 3 months if no significant ocular events were reported. Treatment-related ocular AEs were graded per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5 and per the Keratopathy Visual Acuity (KVA) scale. The KVA scale incorporates corneal examination findings and changes in Snellen-equivalent best corrected visual acuity (BCVA) into a composite grade. Ocular AEs are reported as worst-case post-baseline. Efficacy responses (per 2016 International Myeloma Working Group criteria) were assessed Q3W, regardless of treatment delays. Results: As of September 12, 2022, 50/218 (23%) patients were treated with belantamab mafodotin for ≥52 weeks. AEs were reported in all patients treated with belantamab mafodotin for ≥52 weeks. Grade ≥3 AEs occurred in 82% (n=41); the most frequent were reduced visual acuity (24%), thrombocytopenia (18%), and neutropenia (16%). The majority of AEs reported occurred at or before cycle 17. For the most common (>40%) AEs (any grade), few additional events occurred after cycle 17 (1 new occurrence each of dry eye, reduced visual acuity, eye irritation, and thrombocytopenia after cycle 17). Few infections (any grade) occurred after cycle 17 (COVID-19, n=5; viral infection, n=1; pneumonia influenzal, n=1). No patients permanently discontinued treatment due to AEs considered related to belantamab mafodotin. Ocular AEs were reported in 94% (n=47) of patients treated with belantamab mafodotin for ≥52 weeks. The majority of ocular AEs (n=487) were of Grade 1 or 2 severity (88%) and no ocular AEs led to study treatment discontinuation. At the time of data cutoff, 95% (n=41) of patients experiencing Grade ≥2 KVA events had recovered prior to the end of study treatment exposure (defined as last dose + 20 days). Most patients had a dose modification, and no loss of efficacy was observed. The clinical benefit rate (≥minimal response) in these patients was 90% (45/50) and the median time to best response was 6.3 months (range 0.8-18.8). Median duration of response was not reached (NR; 95% CI 17.9, NR) in the subset of patients treated for ≥52 weeks. At the time of data cutoff, 94% (n=47) patients were alive. Conclusions: In patients who received long-term treatment (≥52 weeks), the safety profile of belantamab mafodotin was consistent with previous reports. Despite the need for belantamab mafodotin dose delays and reductions, no patients discontinued study treatment due to belantamab mafodotin-related AEs. During dose delays, clinical responses were maintained or deepened in most cases, demonstrating that management of AEs using dose modifications did not impact clinical activity. Together, this suggests that dose modifications are highly effective in the management of emerging AEs while allowing for sustained clinical benefit. Funding: GSK (207495). Drug linker technology licensed from Seagen Inc.; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.

A Phase II Study of Isatuximab in Combination with Pomalidomide and Dexamethasone in Patients with Multiple Myeloma Progressing on or after One Line of Lenalidomide-Containing Therapy

Introduction Relapse in patients (pts) with multiple myeloma (MM) is a common occurrence, resulting in a continued need for novel treatment approaches. Isatuximab (Isa), a monoclonal antibody (mAb), combined with pomalidomide (Pom) and dexamethasone (Dex), is indicated for the treatment of pts with relapsed/refractory multiple myeloma who have received ≥2 prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on the last therapy. The current study aims to evaluate the efficacy and safety of IsaPomDex in pts with MM relapsing for the first time after one line of treatment containing lenalidomide (Len). Methods EAE115 (NCT05298683) is an ongoing, investigator-initiated, phase II, prospective, open-label, multicenter study aiming to enroll 108 pts. Eligible pts are adults with documented MM who have evidence of progressive disease, by the International Myeloma Working Group criteria, on or after treatment with only one prior line of anti-myeloma therapy with lenalidomide (≥2 cycles, alone or in combination) and a proteasome inhibitor. Pts must also have adequate bone marrow and hepatic function and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Excluded are pts with previous anti-myeloma therapy with any anti-CD38 mAb, pomalidomide, or stem cell transplant within 12 weeks before treatment initiation. Pts receive six 28-day cycles of Isa 10 mg/kg (once weekly [QW] by intravenous [IV] infusion on days 1, 8, 15, and 22 in cycle 1 and days 1 and 15 in subsequent cycles), Pom 4 mg (per Os on days 1-21, each cycle), and Dex 40 mg or 20 mg for pts ≥75 years old (per Os or IV on days 1, 8, 15 and 22, each cycle). Fifteen to 60 minutes before Isa infusions, patients receive pre-medications to mitigate potential infusion-related adverse reactions. Following initial 6 cycles, pts achieving at least very good partial response (VGPR) are randomized 1:1 to receive Isa (Q2W or Q4W) plus PomDex, and pts achieving <VGPR continue treatment with Isa (Q2W) plus PomDex. Treatment is given until progressive disease, death, unacceptable adverse events (AEs), lost to follow-up, or consent withdrawal. The study primarily evaluates the overall response rate (ORR; defined as partial response [PR] or better) to IsaPomDex therapy at six months. Adverse events are classified using the Medical Dictionary for Regulatory Activities. Herein, we present safety and efficacy data for all treated patients (cut-off date 15/05/23. Results Twenty pts had received at least one dose by the cut-off date, of whom 16 (80.0%) were continuing with IsaPomDex treatment; four (20.0%) pts had discontinued due to physician or pt decision or progressive disease or death. At baseline (cycle 1, day 1), pts had a median age of 72.0 years (range: 60.0-85.0), 10 (50.0%) were male, and 13 (65.0%) had ECOG PS 0. Eleven (55.0%) pts were at stage II by the revised International Staging System, 9 (45.0%) pts had lytic bone lesions, 5 (25.0%) pts had high-risk cytogenetics, and 1 (5.0%) pt had soft-tissue plasmacytomas (Table 1). Regarding previous treatment outcomes, 14 (70.0%) pts had achieved ≥VGPR (stringent complete response, 2 [10.0%] pts; complete response, 2 [10.0%] pts; VGPR, 10 [50%] pts). Five (25%) and 1 (5.0%) pts achieved partial and minimal response, respectively. Six (30.0%) pts had received ASCT in the prior line. At a median follow-up of 3.4 (range: 0.6-6.1) months, the median number of IsaPomDex cycles received was 3.0 (range: 1.0-7.0); one (5.0%) pt received six treatment cycles. Of the 18 (90.0%) response evaluable pts (2 pts were ongoing without 2 efficacy assessments) VGPR and PR were achieved by 4/18 (22.2%) and 9/18 (50.0%) pts, respectively. ORR was achieved by 13/18 (72.2%) pts, and the median (range) time from IsaPomDex study dose to first response (≥PR) was 1.0 (range: 0.9-1.3) months. Thirteen (65.0%) pts had ≥1 treatment-emergent adverse events (TEAE). Of these pts, 10 (50.0%) had a ≥1 grade (gr)≥3 TEAE and 4 (15.0%) had ≥1 gr ≥3 serious TEAE. The most common TEAEs were neutropenia in 9 pts (45.0%), anaemia in 3 pts (15.0%) and fatigue in 3 pts (15.0%). The most common gr ≥3 TEAE was neutropenia in 7 pts (35.0%) (Table 2). Conclusions Second-line treatment with IsaPomDex in pts with MM who have progressed on or after one Len-containing line of treatment appears to be effective, although longer follow-up is needed to assess its efficacy. No new safety signals were observed with the combination.

Initial Results from a Phase 1 Dose-Escalation Study of WVT078, a BCMA×CD3 Bispecific Antibody, in Combination with WHG626, a Gamma-Secretase (GS) Inhibitor, in Patients with Relapsed and/or Refractory Multiple Myeloma

Introduction: WVT078, a potent anti-B-cell maturation antigen (BCMA)×anti-CD3 bispecific antibody (BsAb), is being investigated as a single-agent and in combination with a GS inhibitor (GSI), WHG626 (AL102), in patients (pts) with relapsed and/or refractory (r/r) multiple myeloma (MM). Single-agent WVT078 showed an acceptable safety profile in the ongoing first-in-human study with active dose range of 48-250 µg/kg (Raab, Leukemia 2023). Membrane BCMA expressed on surface of MM cells is cleaved by GS. This results in shedding of its extracellular domain (ECD) as soluble BCMA (sBCMA), which may bind to and interfere with activity of BCMA-targeting agents such as WVT078. By preventing this shedding, GSIs are postulated to increase clinical benefit of BCMA-targeting agents. WVT078 combined with WHG626 was shown to enhance anti-myeloma activity of WVT078 in vitro preclinically (Raab, Leukemia 2023), supporting rationale for this combination in r/r MM. Methods: The combination of WVT078 and WHG626 is being investigated as part of above-mentioned phase 1 study (NCT04123418) in pts with MM who are r/r to ≥2 standard-of-care regimens, including an immunomodulatory drug, proteasome inhibitor, and anti-CD38 agent (if available). Pts who received prior BCMA chimeric antigen receptor T-cell therapy or BCMA antibody-drug conjugates therapy are included; pts with prior BCMA×CD3 BsAb treatment are excluded. Primary objectives were to evaluate safety and tolerability and to determine recommended dose for expansion of WVT078 in combination with WHG626. Secondary objectives were to assess preliminary anti-tumor activity and characterize pharmacokinetics (PK) and immunogenicity. Key exploratory objectives included evaluation of sBCMA and characterization of immune-cell activation phenotypes. Dose escalation was guided by Bayesian Logistic Regression Model, and International Myeloma Working Group criteria were used to assess disease response. Flow cytometry was used to study pharmacodynamic (PD) effects on immunophenotype of immune cells. Immunoassay-based platform (Meso Scale Discovery) was used for assessing cytokine production and enzyme-linked immunosorbent assay for quantifying serum sBCMA levels. Results: As of April 29, 2023, a total of 23 pts (median age, 64 years) with r/r MM were treated in dose escalation with intravenous WVT078 at 12-48 µg/kg once weekly, combined with oral WHG626 at 2-4 mg once daily, given 2 days on and 5 days off. Eighteen pts (78.3%) discontinued treatment due to progressive disease (n=15), adverse event (AE), guardian decision and physician decision (n=1 each). Most frequent (≥20%) treatment-related AEs across all doses in the combination were cytokine release syndrome (65.2%; Grade ≥3, n=1), pyrexia (39.1%), diarrhea (34.8%), decreased appetite (26.1%), hypophosphatemia, nausea and neutropenia (21.7% each); 5 pts experienced dose-limiting toxicities (pneumonia, neutropenia, ALT/AST/lipase increase, platelet count decrease, sepsis and shoulder pain). The safety profile is consistent with WVT078 and WHG626 as single agents. A maximum tolerated dose was not reached. The overall response rate (partial response or better; ORR) and overall complete response (CR) rate (stringent CR+CR) across all dose levels tested were 39.1% (n=9; 90% CI, 22.2, 58.3) and 13.0% (n=3; 90% CI, 3.7, 30.4), respectively; ORR at two highest dose levels combined was 57.1% (n=8/14; 90% CI, 32.5, 79.4). PK total (AUC) and maximal (Cmax) exposure to WVT078 in serum increased approximately proportionally to dose in Cycle 1. Evidence of T-cell engagement with WVT078 was demonstrated by upregulated peripheral T-cell proliferation and activation markers. WHG626 decreased serum sBCMA levels by 10% within first 24 hours of treatment prior to WVT078 dosing. WHG626 enhanced WVT078-mediated increases in serum inflammatory cytokine levels, and upregulated T-cell activation phenotype in bone marrow in a dose-dependent manner.Based on preliminary data, cytokine and clinical effects were observed at lower WVT078 doses with WVT078+WHG626 than with WVT078 alone. Conclusions: WVT078 combined with WHG626 has an acceptable safety profile and shows preliminary evidence of clinical activity at highest doses tested. PD biomarker analysis supports postulated mechanism of action of WHG626 combined with WVT078. This is the first clinical report on combination of BCMAxCD3 BsAb and GSI in r/r MM.

BCMA Re-Emergence As a Prognostic Indicator of Clinical Relapse after Chimeric Antigen Receptor T-Cell Therapy (CART) in Multiple Myeloma

Background: The outcomes of patients with triple and penta-class relapsed refractory multiple myeloma (RRMM) are poor. B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-Cell (CAR-T) therapies in RRMM have been shown to improve outcomes since approval in 2021; however, relapses are common. We previously reported that patients lost BCMA expression after BCMA-directed therapy. Early re-emergence of surface BCMA on plasma cells (PC) in bone marrow (BM) may be a prognostic indicator for clinical relapse. Furthermore, there is limited published literature about clinical factors that increase risk of early BCMA re-emergence as well as clinical relapse post-CAR-T therapy. Methods: The study is a prospective cohort study that includes RRMM patients who underwent BCMA CAR-T at the University of Kansas Health System between May 2021 and May 2023 and were followed at regular intervals for the first-year post-infusion. All patients had standard procedure of BM evaluation at 1, 3, and 6 months, and 1 year. Eight-color MFC was performed on the BM specimens. BCMA antibody was purchased from R & D Systems (Minneapolis, MN). Data analysis was performed using FCS Express 5 software (De Novo Software, Los Angeles, CA). 500,000 to up to 2,000,000 events were acquired in all the cases. Responses were evaluated using the International Myeloma Working Group criteria. BCMA re-emergence was defined as BCMA greater than nadir on either polyclonal or monoclonal BM plasma cells. Results: 57 patients were evaluated and 44 patients (77 %) who lost their PC BCMA expression by multicolor flow cytometry (MFC) on bone marrow biopsy (BMBX) at Day 30 from baseline were included in the analysis. Demographic data of all 44 RRMM BCMA CAR-T recipients is shown Table 1. Median follow-up was 7 (4-14) months. Of the 44 patients, BCMA re-emergence was as follows: at 3-months (n=14, 32% of total sample), 6-months (n=5, 11%), 9-months (n=0, 0% of total sample), and 12-months (n=5, 11% of total sample). 14 (32%) of the 44 total patients had clinical relapse within 12 months. Of the 14 patients, 11 (79%) had BCMA re-emergence at any time point. 10 out of 11 (91%) of these patients had BCMA re-emergence before or at the same time as clinical relapse. The median time to BCMA re-emergence was 3 months and the median time to clinical relapse was 6 months. Only 1 patient had clinical relapse prior to BCMA re-emergence.Furthermore, at the 6-month mark, there were no significant clinical or demographic factors between those who relapsed vs. those who had a response to CAR-T therapy other than BCMA re-emergence (p-value 0.0445, Table 1). Conclusion: BCMA re-emergence on BM detected by MFC may be a prognostic indicator for clinical relapse in RRMM recipients of BCMA CAR-T therapies. It may be valuable to carry out close monitoring that includes evaluation of BCMA expression on BMBx at regular intervals post CAR-T therapy. Additional prospective studies with larger cohorts are needed to determine the risk factors for early BCMA re-emergence and clinical relapse in RRMM patients who receive BCMA CAR-T therapy.

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

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

Phase I Trial of Systemic Administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and Human Interferon, in Patients with Relapsed or Refractory Multiple Myeloma, Lymphomas, or Histiocytic/Dendritic Cell Neoplasms

Background: Oncolytic virotherapy, an innovative immunomodulatory therapeutic approach, is currently being investigated for its potential in treating relapsed refractory (R/R) hematologic malignancies. This study focuses on the use of an engineered Vesicular Stomatitis Virus called VSV-IFNβ-NIS, a bullet-shaped rhabdovirus which encodes both interferon beta (IFNβ) and sodium iodine symporter (NIS) with particular tumor cell tropism. Viral IFNβ serves as an indicator of viral proliferation and boosts the host's anti-tumor immune response. This is a phase 1 clinical trial with the identifier NCT03017820, wherein patients (pts) with R/R multiple myeloma (MM), and non-Hodgkin lymphoma (NHL) are treated with a single systemic administration of VSV-IFNβ-NIS. Study Design and Methods: Patient Eligibility Criteria: The Mayo Clinic Institutional Review Board approved the protocol. The study includes adult patients with relapsed or refractory multiple myeloma (MM), or T-cell lymphoma (TCL). For MM or plasmacytoma, patients should have <15% plasma cells and a largest diameter of <5 cm. TCL patients should have a mass <5 cm. Study Design: This is a single-center phase 1 trial aiming to determine the maximum tolerated dose of VSV-IFNβ-NIS in patients with R/R MM, and TCL. Secondary objectives included assessing the safety profile and estimating the clinical response rate of VSV-IFNβ-NIS. Correlative objectives involved monitoring viral replication through plasma IFN-β transgene levels and using SPECT/CT imaging with the NIS gene. Viral genomes were measured through quantitative reverse transcription (qRT) polymerase chain reaction (PCR) of VSV RNA, and any virus shedding was examined in body fluids. The tested doses were 5 × 109 TCID50, 1.7 × 1010, 5 × 1010, and 1.7 × 1011 TCID50. The virus was administered via IV infusion over 30 minutes, and patients received 650 mg acetaminophen and 50 mg diphenhydramine hydrochloride before infusion and every 6 hours for 24 hours to manage fever and hypotension. Two expansion cohorts at DL4 have been added (20 additional PTCL, 10 B-cell lymphoma and histiocytic neoplasms) to obtain additional data on tolerability and efficacy and biomarkers of response in these histologies. Safety and Response Assessments: All patients undergo toxicity evaluation, and adverse events (AEs) assessment using the Common Terminology Criteria for Adverse Events (CTCAE) version 4 criteria, except for cytokine release syndrome (CRS) grading, which follows the 2014 Lee criteria. Dose escalation and tolerability are based on the standard 3+3 phase 1 trial design. Ruxolitinib is added from days 2-5 or day -1 to day 9 depending on the arm to mitigate IFNβ toxicity. Response assessment followed the International Myeloma Working Group criteria for MM and the Lugano Classification for NHL and histiocytic neoplasms. Pharmacodynamic and Pharmacokinetic Analyses: For viremia and viral shedding assessment, RNA is isolated from whole blood, mouth rinse, buccal swabs, and urine samples. Quantitative RT-PCR determined VSV-nucleocapsid (N) RNA copy number, and virus shedding is assessed through coculturing samples on Vero cells. Anti-VSV antibodies are evaluated using the standard plaque reduction neutralization assay. Plasma cytokine levels are measured with a 30-plex human cytokine kit, and human IFN-β levels is quantified using an enzyme-linked immunosorbent assay (ELISA) kit. Statistical Analysis: Incidence of dose-limiting toxicities and AEs are tabulated by dose level (DL). AEs are summarized by type, maximum grade, and duration across patients in each DL. Spearman rank correlation tests are used evaluated correlations between laboratory-based measures, and Wilcoxon rank sum tests compared continuous measures between response groups. Response rates will be summarized by DL and disease group, with estimated response rates and corresponding 95% binomial confidence intervals calculated.

Long-Term Efficacy and Safety of Elranatamab Monotherapy in the Phase 2 Magnetismm-3 Trial in Relapsed or Refractory Multiple Myeloma (RRMM)

BACKGROUND Elranatamab is a humanized, bispecific antibody that targets B-cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells, with the aim of inducing T-cell-mediated cytolysis of the myeloma cells. In the MagnetisMM-3 (NCT04649359) trial, an open-label, multicenter, non-randomized, phase 2 registrational study of elranatamab monotherapy, patients with RRMM who had not received prior BCMA-directed therapy (ie, BCMA-naïve patients; n=123) achieved objective responses with an overall response rate (ORR) of 61%. Here, we report the long-term efficacy and safety of elranatamab. METHODS Eligible patients had previously received at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody. Patients received step-up doses of 12 and 32 mg elranatamab subcutaneously on days 1 and 4 of cycle 1, respectively, followed by 76 mg elranatamab once-weekly (QW), starting on day 8 of the first 4-week cycle. Patients who received ≥6 months of QW dosing and achieved ≥ partial response lasting at least 2 months were transitioned to a once every 2 weeks (Q2W) dosing schedule and from Q2W to once every 4 weeks after at least 6 Q2W cycles. Treatment with elranatamab continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was ORR, assessed by blinded-central review per International Myeloma Working Group criteria. Minimal residual disease (MRD) status was assessed using next-generation sequencing, with MRD negativity defined as <1 myeloma cell in 10 5 nucleated cells. Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) severity were graded by American Society for Transplantation and Cellular Therapy criteria. RESULTS After a median follow-up of 15.9 months (data cutoff, April 16, 2023), 32.5% of patients remained on treatment. The confirmed ORR was 61.0% (n=123; 95% CI, 51.8-69.6), with 35.8% of patients achieving complete responses (CR) or better. Among evaluable patients (those with ≥CR and evaluable for MRD, n=29), 89.7% achieved MRD negativity. Median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) have not been reached, and the probabilities of maintaining a response, being progression-free, and being alive at 15 months were 70.8% (95% CI, 58.2-80.2), 50.2% (95% CI, 40.2-59.3), and 56.3% (95% CI, 47.0-64.6), respectively. All participants (100%) had ≥1 any grade treatment-emergent adverse events (TEAEs), and 70.7% of patients had grade 3/4 TEAEs. The most common any grade (≥25%) and grade 3/4 (≥10%) adverse events (any grade, grade 3/4) were infections (69.9%, 40.7%), CRS (57.7%, 0%), anemia (48.8%, 37.4%), neutropenia (48.8%, 48.8%), diarrhea (41.5%, 1.6%) thrombocytopenia (31.7%, 23.6%), lymphopenia (26.8%, 25.2%), fatigue (36.6%, 4.1%), nausea (26.8%, 0%), injection site reaction (26.8%, 0%), hypokalemia (26.0%, 10.6%), cough (26.0%, 0%) pyrexia (30.9%, 4.1%), decreased appetite (33.3%, 0.8%), leukopenia (15.4%, 13.0%) and COVID-19 pneumonia (14.6%, 11.4%). CONCLUSIONS Extended follow-up from the ongoing phase 2 MagnetisMM-3 trial of elranatamab in heavily pretreated participants with RRMM demonstrated sustained clinical efficacy, with median DOR, PFS, and OS not reached, and no new safety signals.

A Phase 2 Study of Daratumumab in Combination with Thalidomide and Dexamethasone in Relapsed and / or Refractory Myeloma: A Report from the Asian Myeloma Network

Introduction Myeloma is a plasma cell dyscrasia characterised by a relapsing remitting course. Patients with relapsed / refractory myeloma (RRMM) with prior exposure to proteosome inhibitor and an immunomodulatory agent have a poor prognosis. In the last few years, CD38 antibodies such as daratumumab and isatuximab have revolutionised the treatment of multiple myeloma. They appear synergistic with immunomodulatory drugs; triplet combinations with lenalidomide 1 (DRd) or pomalidomide 2 (DPd) and dexamethasone have been approved for treatment of RRMM. However, patients face high out-of-pocket costs when attempting to access these drugs. There is hence a pressing need to develop combinations which harness the therapeutic potential of CD38 antibodies while preserving synergistic action of triplet combinations. Methods This was a multi-national, multi-centre, single arm, phase 2 trial of daratumumab in combination with thalidomide and dexamethasone. Patients with myeloma diagnosed according to the International Myeloma Working Group criteria with measurable disease and relapsing after / refractory to at least one prior line of treatment were eligible for enrolment. Satisfactory organ function (neutrophil count ≥ 1,000/mm 3, platelet ≥ 50,000/mm 3, bilirubin ≤ 1.5 x the upper limit of the normal range (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN and creatinine clearance ≥ 30ml/min) were pre-requisites for inclusion. Patients with plasma cell leukaemia and those with prior CD38 antibody exposure were excluded. Patients received daratumumab IV 16mg/kg weekly for weeks 1 - 8, every 2 weeks from weeks 9 - 24 and every 4 weeks from week 25 onwards, thalidomide 100mg daily and dexamethasone 20mg twice a week. Treatment was continued for as long as tolerated and clinically indicated, based on physician assessment, or until disease progression. Thromboprophylaxis was allowed but not mandated. The primary outcome measure was progression-free survival (PFS), defined as the time from commencement of treatment to disease progression or death from any cause, whichever occurred first. Secondary outcome measures included overall response rate (ORR, the percentage of patients achieving a partial response (PR) or better), overall survival (OS), duration of response (DOR, the time from first evidence of PR or better till disease progression or death, whichever occurred first) and safety, assessed by the frequency and severity of adverse events. Results 70 patients were recruited. The median age was 66.8 (range 39 - 81) years with 62.7% males. 95.5% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The median number of prior therapies was 2 (range 1 - 6). 91% of patients had prior exposure to bortezomib, while 88% had prior exposure to thalidomide, lenalidomide or both. 50.7% had a prior autologous stem cell transplant. 67 patients completed at least one cycle of treatment. Two died prior to completion of the first cycle, while one withdrew consent and was excluded. Patients were treated for a median of 15.9 (interquartile range, IQR 5.1 - 23) months. 67 (95.7%) patients suffered 544 adverse events, of which 256 (47%) were related to the study treatment, 103 (19%) grades 3-4 and 8 (1%) were fatal. The most common adverse event was infection, which occurred in 26 patients; 4 were fatal. 27 patients had peripheral neuropathy, 25 of which were grade 1 - 2. 14 patients had an infusion reaction, 3 of which required hospitalisation. One patient had a deep vein thrombosis. At a median follow-up of 22.0 (IQR, 9.9 - 31.0) months, the median PFS was 16.3 (95% CI, 12.8 - 24.6) months (Figure 1). The median OS was 32.5 (95% CI, 25.4 - not reached) months. The ORR was 82.1% (95% CI, 70.8 - 90.4). This ORR was comparable to DRd and DPd (Table 2). Of these, 43 (78%) of patients achieved a very good partial response (VGPR) or better, with 9 (16%) of patients achieving a stringent complete response (sCR). The median DOR was 19.3 (95% CI, 12.2 - 36.5) months. Conclusion The combination of daratumumab, thalidomide and dexamethasone is effective in RRMM patients. Thalidomide and dexamethasone are cost-effective drugs which can improve the accessibility of daratumumab-based triplet combinations.

Renal Response of Selinexor, Pomalidomide, Bortezomib and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients with Renal Impairment: A Prospective, Open-Label, Multicenter, Phase 2 Study

Background Renal impairment (RI) is one of the cardinal features of newly diagnosed multiple myeloma (NDMM), contributing to dismal outcomes and high risk of early death. Improved renal function is associated with prolonged survival for NDMM. The triplet combination of pomalidomide with bortezomib and dexamethasone (PVD) has been proven to be effective in MM patients with RI [1] (The manuscript in preparation). However, the best renal overall response rate (ORR) was 78.8% and 21.2% of patients had no renal response to PVD. Here we reported an interim analysis to evaluate the renal and hematologic response of SPVD (Selinexor, pomalidomide, bortezomib, dexamethasone) regimen as first-line therapy in NDMM with RI in this prospective, open-label, multicenter, phase 2 study (ChiCTR2200064695). Methods Eligible NDMM with RI (defined as estimated glomerular filtration rate (eGFR) by MDRD < 40ml/min) were enrolled in the study. Sample size was designed to recruit 62 patients. RI caused by other reasons than tubular nephropathy was excluded. Patients received SPVD (Selinexor 40mg on days 1,8,15, pomalidomide 4mg on days1-14, bortezomib 1.3mg/m2 on days 1,4,8,11, and dexamethasone 20mg on day of and after bortezomib, 21days/cycle) for a maximum of 9 cycles. Autologous stem cell transplantation (ASCT) was administrated after 3 to 6 SPVD cycles for transplant-eligible patients. The primary endpoint was renal ORR at 3 months. Secondary endpoints included major renal response (≥partial response) at 3 months, hematological ORR, minimal residual disease (MRD), progression-free survival (PFS), overall survival (OS), and safety. The definition of both hematological response and renal response was according to the International Myeloma Working Group (IMWG) criteria. Results Between Oct 28, 2022 and Jun 23, 2023, 31 patients were enrolled across 17 centers, with a median age of 61 years (range: 45-80). The proportion of R-ISS III was 35.5%. Median serum creatine level and eGFR were 365μmol/L [interquartile range (IQR): 214.5-508] and 14.5 mL/min (IQR: 10.5-22.64), respectively. There were 10/31 (32.3%) patients requiring dialysis at diagnosis and 8 patients with high-risk cytogenetic abnormalities [t(4;14), t(14;16), or del(17p)]. At the data cut-off date of July 11, 2023, the median number of SPVD treatment cycles was 3 (range: 1-8). The median follow-up time was 4 months. Two patients received first-line ASCT after induction therapy. The primary endpoint of renal ORR at 3 months was 74.2%, including 6.5% renal PR, and 25.8% renal CR (Table 1). The ORR of the best hematological response was 70.9% (45.1% ≥VGPR, 16.1% CR)(Table 1). The most common treatment emergent adverse events (TEAEs) (incidence >10%) were infection (45.2%), myelosuppression (45.2%), hepatic impairment (12.9%), nausea (12.9%), and hypokalemia (12.9%) (Table 2). Grade 3 or more hematologic toxicity was seen in 35.5% of the patients, the most common being thrombocytopenia (19.4%)(Table 2). Dose reduction or interruption of pomalidomide occurred in 5 patients due to myelosuppression and infection events. Three patients had dose reduction of selinexor due to nausea or vomiting. Notably, among non-hematologic toxicities, 4 patients developed hepatic impairment, and of those, one patient suffered tumor lysis syndrom, hepatic failure and severe infection and then died. Median PFS and OS were not reached. Conclusion This study demonstrated SPVD is an effective combination in NDMM patients with RI. The toxicity profile was consistent with the reported research, but hepatic impairment during treatment should be noted with caution. Reference [1] JIAN Y, CHANG L, SHI M, et al. Renal Response of Pomalidomide with Bortezomib and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients with Renal Impairment: A Prospective, Open-Label, Multicenter, Phase 2 Study [J]. Blood, 2022, 140(Supplement 1): 10167-9. doi:10.1182/blood-2022-159361.

Outcomes of BCMA-Directed Chimeric Antigen Receptor T-Cell (CART) Therapy in Patients with Relapse-Refractory Multiple Myeloma with Extramedullary Disease

Background: Presence of extramedullary disease (EMD) is associated with poor outcomes for patients with relapsed-refractory multiple myeloma (RRMM) and has been identified as a major risk factor for early progression (≤ 3 months) after CAR T-cell therapy. Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are B-cell maturation antigen (BCMA) targeting CAR T-cell therapies approved for patients with RRMM who have received ≥4 prior lines of therapy (LOT). This is a multicenter retrospective study on the real-world safety and efficacy of commercially available ide-cel and cilta-cel in heavily pretreated RRMM patients with EMD. Methods: Three U.S. academic centers, part of the U.S. Myeloma Innovations Research Collaborative (USMIRC), contributed data to this analysis, which included patients with RRMM who had received an ide-cel or cilta-cel infusion ≥30 days prior to data-cut off (7/1/2023). Baseline patient characteristics were outlined by descriptive analyses. Responses including overall response (ORR), and complete response or better (≥CR) rates were evaluated using the International Myeloma Working Group (IMWG) criteria. Statistical analysis was done with the Fisher's exact test and Kaplan Meier method for progression free (PFS) and overall survival (OS) calculations. Results: A total of 132 patients who received commercial (standard of care) BCMA-directed CAR T-cell therapy between 5/1/2021 and 5/30/2023 were included in this study. Out of these, 64 (48%) patients had a previous history or existing EMD prior to CART infusion. Table 1 summarizes the main patient characteristics and outcomes stratified as EMD and non-EMD groups. Both groups had comparable baseline patient and disease characteristics including median age, ECOG performance status, median bone marrow plasma cell percentage, high-risk cytogenetics, number of prior LOT, refractoriness status prior to CART and type of CAR T-cell product received. CART-related toxicities were comparable between the EMD and the non EMD groups. Cytokine release syndrome (CRS) was seen in 73% (≥ grade 3: 5%) of EMD patients vs 79% (≥ grade 3: 4%) of non-EMD patients (p=0.79). Likewise, immune effector cell-associated neurotoxicity syndrome (ICANS) was noted in 28% (≥ grade 3: 5%) of EMD patients vs 32% (≥ grade 3: 9%) of non-EMD patients (p=0.72). Infections were seen in 39% of the EMD group vs 28% of the non-EMD group (p=0.38). Response rates were also similar between the EMD vs non EMD cohorts: ORR 78% vs 96% (p=0.44); and ≥CR rate 42% vs 51% (p=0.54), respectively. With a median follow up of 7.2 (range 0.5-22.8) months for the entire patient cohort, the estimated median PFS was inferior for the EMD group (6.5 months [95% CI, 5.1-9.6]) compared to the non-EMD group (9.8 months [95% CI, 8.2-16.4]) (p=0.017) (Figure 1). At the time of data cut-off, 43 patients had died, 77% from disease progression, 11.5% from CART-related complications and 11.5% from unrelated causes. The estimated median OS was significantly worse for the EMD group (12.9 months [95% CI, 9.5-NA]) compared to the non-EMD group (19.4 months [95% CI, 1.2-NA]) (p=0.031). Conclusions: This is the largest multicenter retrospective study delineating the real-world outcomes of ide-cel and cilta-cel CAR T-cell therapies in RRMM patients with the high-risk disease feature of EMD. Based on our results, patients with prior history or presence of existing EMD at the time of CART infusion did not have any excessive treatment-related toxicities. However, these patients did experience shorter PFS and OS compared to patients without EMD highlighting the presence of EMD as a risk factor for poor outcomes after CART. Therefore, this group of patients should be considered for pre- and post-CART risk mitigation strategies aiming to prevent disease progression and improve survival outcomes.

A Prospective, Multinational Study of Clinical and Biological Factors Associated with Short Overall Survival in Multiple Myeloma

Introduction: Multiple myeloma (MM) is an incurable cancer, but a subset of patients can achieve long-term remission and overall survival (OS). We aimed to study the clinical and biological factors associated with short OS defined as less than 3 years. Methods: A prospective, observational, multinational study was conducted by Australian and New Zealand (ANZ) and Asia-Pacific (APAC) Myeloma and Related Disease Registry (MRDR) from January 2013 to January 2023, across 5 countries (Australia, New Zealand, Korea, Singapore, Malaysia). Eligible patients were ≥18 years old, diagnosed with MM per International Myeloma Working Group (IMWG) criteria, received a bortezomib-containing triplet, and had at least 3 years of follow-up or had deceased within 3 years. Descriptive analysis was completed using chi-squared test for categorical variables and Wilcoxon rank-sum test for continuous variables. The Kaplan-Meier method was used for analysing OS and follow-up data. The ‘stepwise’ function in Stata was used for the forward stepwise logistic regression, with the p-value set to 0.1. All analyses were completed using Stata 16. Results: Of the 1539 patients enrolled, majority were from ANZ (1071 and 359, respectively), with male preponderance (61.0%). Half were above 65 years old. High risk cytogenetic abnormalities, a criterion of the Revised International Staging System (R-ISS), was unknown for half of the patients (49.4%). 45.3% patients presented as ISS stage 1, 21.9% stage II, and 32.8% stage III, respectively at study entry . The most frequent front-line agent used in combination with bortezomib-based triplet was cyclophosphamide [VCd, 1380 (89.7%)], followed by thalidomide [VTd, 92(6.0%)], lenalidomide [VRd, 63 (4.1%)] and daratumumab [DVd, 4 (0.3%)]. The median follow-up was 29.9 months (95%CI: 28.3-31.8) and the median OS was 87.7 months (95%CI: 80.9-93.2). Thirty percent patients had OS<3 years. Clinical and biological factors associated with long OS (≥3 years) were compared with those <3 years (Table 1). Baseline factors associated with higher odds of short OS included age≥65, Eastern Cooperative Oncology Group performance status (ECOG PS)≥2, ISS III, lower creatinine clearance and platelet count, high LDH and poor cytogenetic abnormalities (Table 1). In a multivariate analysis, age≥65 (OR:2.50; p<0.001), ECOG≥2 (OR:2.08; p<0.001), ISS III (OR:2.48; p<0.001), t(4;14)[OR:2.04; p=0.004], t(14;16)[OR:6.33; p=0.004] and 17p deletion (OR:2.77; p =0.001) were associated with a significantly shorter OS. Conclusion: From clinician perspective, identifying patients with an increased likelihood of shorter OS through the determination of patient- and disease-specific risk factors might be clinically relevant to facilitate better treatment decisions.

Vdpace As Salvage Therapy in Triple Class Relapse/Refractory Multiple Myeloma

Background: Patients that have triple-class relapsed/refractory multiple myeloma (RRMM) have relapsed on each of the following classes: an immunomodulatory drugs (IMiDs), proteasome inhibitors (PI), and anti-CD38 monoclonal antibody (MoAb). RRMM poses a significant challenge with poor prognosis due to limited options. We evaluated VDPACE (bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, etoposide) for efficacy and safety as salvage therapy in heavily pre-treated RRMM. Methods: We retrospectively analyzed 54 patients who had triple-class RRMM and received at least 1 cycle of VDPACE between June 2016 - July 2023 at the University of Kansas Health System in collaboration with the U.S Myeloma Innovations Research Collaborative (USMIRC). VDPACE consisted of bortezomib 1 mg/m2 subcutaneous on days 1,4,8 and 11, doxorubicin 10 mg/m2 continuous infusion (CI) x 4 days, cisplatin 10 mg/m2 CI x 4 days, cyclophosphamide 400 mg/m2 CI x 4 days and etoposide 40 mg/m2 CI x 4 days. Descriptive analysis was performed on available data for patient characteristics, disease course, and outcomes differentiating these two groups. Adverse events were graded based on the CTCAE v5.0 criteria. Responses to therapy, including overall response rate (ORR), complete response or better (≥CR), and very good partial response (VGPR) were evaluated using the International Myeloma Working Group (IMWG) criteria. The Kaplan-Meier method was used for progression-free survival (PFS) and overall survival (OS) assessments. Results: Of the 54 patients in this study, the median age was 62 years (41-75), 81% (n=44) were Caucasian, 48% (n=26) were IgG subtype, 42% of the patients (n=23) had Stage-III disease at treatment, 74% (n=40) had high-risk cytogenetics, and extramedullary disease (EMD) was present in 50% (n=27) of patients. These patients had a median of 5 (2-10) prior lines of therapy;67% (n=36) were penta-drug exposed, 59% (n=32) were penta-RRMM and 19% (n=10) were refractory to BCMA-directory therapy. Patient characteristics are summarized in Table 1. The overall response rate (ORR) for the whole cohort was 54%, 7 (13%) patients achieved ≥ VGPR, median PFS was 4.67 months (95% CI, 2.97 to 8.40), while OS was 7.93 months (95% CI, 6.33 to 14.73), see Figure 1. Regarding efficacy on penta-RRMM (n=32) vs non-penta-RRMM subgroups (n=22), the ORR was 44% vs 68% respectively, while the median PFS was 2.67 months (95% CI, 2-7.6) in the penta-RRMM subgroup compared to 9.28 months(95% CI, 4.67-NA) in the non-penta-refractory subgroup. Treatment post salvage therapy of VDPACE included autologous/allogenic stem cell transplant (SCT), BCMA-directed therapies (CAR-T, T-cell engaging bispecific antibodies and antibody-drug conjugates), other chemotherapies, in addition to enrollment to clinical trials reported at 13%, 26%, 39% and 4%, respectively. 11% patients proceeded to hospice due to progression disease. Most patients experienced hematological adverse events (AEs), including grade III/IV lymphopenia (96%), neutropenia (93%), thrombocytopenia (87%) and anemia (76%). 69% (n=37) required a blood transfusion and 67% (n=36) required platelet transfusion. Neutropenic fever (NF) was reported in 33% (n=18), while the most common cause of infection was bacteremia in 24% of patients, followed by pneumonia in 20% of the patients. Following the initial hospitalization to receive treatment, the readmission rate within 60 days was 50% (n=27), that was mostly due to NF (52%, n=14). Treatment related mortality (TRM) in the first 30 days was reported in 6% (n=3), all due to severe sepsis. See Table 1. Conclusions: Based on our retrospective study, VDPACE is an effective salvage treatment in triple RRMM, and can be used as a bridging therapy prior to CAR-T, prior to enrollment in clinical trials or proceeding to SCT, however, due to TRM secondary to severe infections, careful selection of patients for this intensive therapy must be emphasized.