Citations

Importance Evidence regarding suppressive valacyclovir treatment on postherpetic neuralgia is necessary to guide care. Objective To test the hypothesis that suppressive treatment with 1000 mg/d of oral valacyclovir for 12 months reduces the prevalence, severity, and duration of postherpetic neuralgia compared with placebo at 12 and 18 months in participants with herpes zoster ophthalmicus (HZO). Design, Setting, and Participants Multicenter, placebo-controlled randomized clinical trial including 527 immunocompetent, nonpregnant adults with history of HZO rash, documented keratitis, or iritis within 1 year and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater. The study was conducted at 95 participating sites (in Canada, New Zealand, and the US) from November 2017 to June 2024 and participant visits occurred every 3 months. Intervention Treatment with 1000 mg/d of valacyclovir or placebo for 12 months. Main Outcomes and Measures Prevalence of postherpetic neuralgia, severity as determined by pain score (a score of ≥3 on a scale of 1-10), pain duration (≥3 months after HZO onset), and total daily dose of pain medication. Results Of the 527 participants (490 completed 12 months of treatment and 460 completed 18 months), 73 (14%) had postherpetic neuralgia and were analyzed by age at HZO onset (<60 years or ≥60 years) and disease duration (recent [<6 months] or chronic [≥6 months]). Of the 73 participants with postherpetic neuralgia (34 in the valacyclovir group and 39 in the placebo group), the mean age was 62.4 years (SD, 13.6 years), 59% were female, 5% were Black or African American, and 10% were Hispanic. The prevalence of postherpetic neuralgia at 12 months was not reduced by valacyclovir (12/32 [38%]) compared with placebo (14/35 [40%]) (between-group difference, 2.5% [95% CI, −20.8% to 25.8%]; P >.99). The participants who were younger than 60 years at HZO onset and had a chronic disease duration had lower pain scores in the valacyclovir group (mean score, 0.3 [SD, 0.9]) vs the placebo group (mean score, 0.8 [SD, 1.9]) at 12 months ( P = .045) and at 18 months (mean score, 0.2 [SD, 0.9] vs 1.0 [SD, 2.3], respectively; P = .02). There was a decrease in pain duration in the valacyclovir group at 18 months (mean, 13.6 [SD, 11.4] months) vs the placebo group (mean, 18.7 [SD, 29.5] months) (linear mixed-effects model between-group difference, −3.39 months [95% CI, −6.73 to −0.04 months]; P = .046). The total daily dose of neuropathic pain medication was lower in the valacyclovir group (mean, 271.4 [SD, 593.8] mg/d) vs the placebo group (mean, 363.4 [SD, 592.2] mg/d) at 12 months (linear mixed-effects model P = .006) and at 18 months (mean, 209.0 [SD, 412.8] mg/d vs 286.2 [SD, 577.9] mg/d, respectively; linear mixed-effects model P = .01). Conclusions and Relevance One year of suppressive treatment with valacyclovir was associated with a lower dosage of neuropathic pain medication. Participants in the valacyclovir group, who were younger at HZO onset and had a chronic disease duration, had lower pain scores. These secondary outcomes support consideration of 1 year of suppressive treatment with valacyclovir to reduce dosage of pain medications and pain due to HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

Introduction: Teclistamab (Tec) is the first approved BCMA x CD3 bispecific antibody for the treatment of triple-class-exposed patients with relapsed/refractory multiple myeloma (RRMM) based on the pivotal MajesTEC-1 study. Tec was associated with high overall response rate (ORR) of 63% in heavily pretreated patients. After a longer follow-up of 30.4 months, CR rate was 46.1%, median duration of response (DOR) was 24 months (95% CI, 17.0 - not estimable), and median progression-free survival (PFS) was 11.4 months (95% CI, 8.8 - 16.4). Herein, we present updated analysis of real-world outcomes and safety with tec in RRMM with extended follow-up of more than 12 months. Methods: This is an international multicenter retrospective study of patients with RRMM treated with tec on-label at 9 academic centers from 5 countries (United States, United Kingdom, Greece, Spain, and Canada) through the International Myeloma Working Group (IMWG) Immunotherapy Committee. Patients with RRMM treated with commercial tec at the respective institutions between May 24, 2022 to January 4, 2024 were included. Median follow-up was 14 months with data collected until July 15, 2024. High-risk cytogenetic abnormalities (HRCA) was defined as 1q+, t(4;14), t(14;16), t(14;20), and/or del(17p). Response was assessed using the IMWG consensus criteria. Patient characteristics were summarized by frequency (percentage) or median (interquartile range [IQR] or range). PFS, overall survival (OS), DOR were evaluated using the Kaplan-Meier method. Results: There were 223 patients included in this analysis with the following characteristics: median age of 67 (range 33-91) with 24% ≥75 years; 45% female; 74% White, 10% Black, 9% Asian, and 7% other/unknown; 86 of 176 (49%) with high risk cytogenetics, including del(17p), t(4;14), t(14;16), t(14;20), and gain/amp 1q; 29.4% (37/126) with known extramedullary disease; 14% with creatinine clearance ≤30 ml/min. Patients received a median of 6 (IQR, 4-8) prior lines of therapy with 52% (107/206) being penta-drug refractory. Among 212 patients with available data, 161 (75.9%) patients would have been ineligible for MajesTEC-1. There were 94 (42%) patients who received prior BCMA-directed therapy (29.8% antibody-drug conjugate [ADC] alone; 45.7% CART alone; 6.3% bispecific antibody alone; 17.0% ADC and CART). Median time from diagnosis to tec initiation was 6.1 (range 0.6-29.2) years. For the 206 response-evaluable patients, ORR was 66%, including 25.2% ≥CR, 33.5% VGPR, and 7.3% PR. ORR for the 90 response-evaluable patients with prior BCMA-directed therapy was 54.5% (21.1% ≥CR, 26.7% VGPR, 6.7% PR). After a median follow-up of 14 (95%CI, 13-14) months, median PFS and OS were 8.8 (95% CI, 5.5-14) and 20 (95% CI, 18-not reached [NR]) months, respectively. 12-month PFS estimate was 46% (95% CI, 40%-54%), and 12-month OS rate was 65% (95% CI, 59%-72%). Median DOR was 17 (95% CI, 17-NR) months with 12-month estimate of 68% (95% CI, 60%-77%). Tec step-up dosing occurred in the outpatient setting for 57 (25.6%) patients. CRS occurred in 119 out of 222 (53.6%) patients with almost all being grade 1-2, except for 1 grade 4 event. ICANS occurred in 18 out of 216 (8.3%) patients (grade 1-2: 5.1%; grade 3-4: 2.8%). Any grade infection occurred in 130 (58.3%) patients; 25.1% of patients had grade ≥3 infection, including 10 patients with grade 5 infection. While receiving teclistamab, 79 (35.4%) patients had ≥2 infections. IVIG was given in 114 out of 164 (69.5%) patients. Conclusion: In this multicenter international real-world analysis of outcomes and safety associated with tec, ORR was high at 66% with 25.2% of patients achieving ≥CR. CR rates may be underestimated due to infrequent bone marrow confirmation in the real-world datasets. Encouragingly, ORR was 54.5% in BCMA exposed RRMM patients, including 21.1% with ≥CR. After a median follow-up of 14 months, heavily pretreated patients including patients with prior BCMA therapy had durable responses with median PFS of 8.8 months and median DOR of 17 months. There were no new safety signals noted in this real-world study. This is the largest real-world study to date of teclistamab with long-term follow-up of more than 12 months. Additional data including more patients, longer follow-up and results from difficult to treat subgroups will be presented at the meeting.

Introduction: With improving overall survival among MM patients, there is an increasing need to both understand the absolute risk and identify risk factors for developing a second primary malignancy (SPM). Understanding these risk and potential modulation factors may help guide decisions regarding treatment options, monitoring surveillance strategies, and patient counselling. Furthermore, understanding this baseline SPM risk will help contextualize the future SPM risk associated with newer therapeutics, including chimeric antigen receptor therapies. Thus, we conducted a population-based study with following objectives: 1) to evaluate the rate and distribution of SPMs, and 2) to identify risk factors including a history of prior malignancy associated with an increased risk of SPMs in patients with MM. Methods: We conducted a retrospective population-based study using data from Institute for Clinical Evaluative Sciences (ICES), an administrative database that captures all health records in the publicly funded health care system in Ontario, Canada. Adult patients treated for newly diagnosed MM between 2007-2022 were identified using ICD-O-3 code 9732/3 (MM). The list of secondary cancers (excluding non-melanoma skin cancers) were identified from pathology codes maintained in the Cancer Care Ontario Registry. Additional risk factors were also collected including a history and type of any pre-existing cancer (at least 1 year prior to MM diagnosis), treatment details including history of autologous stem cell transplantation (ASCT) and lenalidomide usage. The Kaplan-Meier method was used to estimate the median overall survival (OS). We estimated the cumulative incidence of secondary cancer accounting for death as a competing risk. To identify the association of prognostic factors on the risk of developing a SPM, we performed competing risks regression and estimated the subdistribution hazard ratios (sHR) accounting for death as a competing risk. Results: A total of 12123 patients . The median age at diagnosis was 70 (IQR 61-77) years, 6860 (57%) of our cohort had a male sex. In our 4511 (37%) received at least one ASCT, 8062 (67%) were lenalidomide exposed and 6917 (57%) were cyclophosphamide exposed at any time post MM diagnosis, and 3017 (16%) received oral melphalan based induction regimens. The median follow up for cohort was 4.53 (95% CI 4.4-4.7) years. A total of 2079 patients (17%) had a prior cancer diagnosis at least 1 year prior to their MM diagnosis. Of these patients, 665 (32%) had received chemotherapy and 553 (27%) had received radiation to treat their prior malignancy. The three most common prior cancers were: prostate cancer (25%), breast cancer (13%) and heme malignancies (4%).The median time from diagnosis of a prior malignancy to MM diagnosis was 6.4 (IQR 2.04-13.26) years. A total of 1070 (8.8%) of the cohort developed a SPM. The cumulative incidence of SPM post MM diagnosis, accounting for death as a competing risk, was 3.7% at 2 years, 7.6% at 5 years, and 11.5% at 10 years. The three most common SPMs were hematologic (21%), prostate (7%), and lung (7%) cancer. The three most common hematological SPMs were acute myeloid leukemia (37%), B-acute lymphoblastic leukemia (16%), and myelodysplastic syndrome (19%). The median OS following after any SPM diagnosis was 1.64 (95% CI 1.36-1.92) years, was 1.85 (95% CI 1.54-2.28) years for patients that developed a non-hematologic SPM, and was 1.05 (95% CI 0.88-1.40) years for patients that developed a hematologic SPM. Conclusion: This study represents one of the largest real-world cohort studies examining the rates, risk factor and outcomes of MM patients developing secondary cancers. We show that a prior malignancy diagnosis increased the risk of SPM after adjusting for ASCT and lenalidomide exposure, sex, and age at MM diagnosis. These data are important for patients and physicians to understand the risks associated with treatment of MM.

Introduction: Talquetamab (Talq) is a GPRC5D targeting bispecific antibody recently approved for the treatment of relapsed refractory multiple myeloma (MM) based on the MonumenTAL-1 study. Real World Evidence (RWE) is needed to understand the safety and efficacy of Talq in patients treated outside of a clinical trial as they may have different outcomes and toxicities. Here we report outcomes of 118 patients treated with Talq. Methods: Patients treated with standard-of-care Talq were included. Data was collected through a retrospective chart review from 01/2023 until 7/2024 from 7 International Myeloma Foundation (IMF) associated MM academic centers. Results: 118 patients were included in the analysis. The median age was 64, 37% had HR disease, 22% had EMD at presentation. The median LOT was 6, median number of immunotherapies before TAL was 2 (range 1,4) and 71% received prior BCMA therapy. 72% were triple refractory and 44% were penta refractory. 25% (n=60) would not have been eligible for TAL clinical trial due to exclusion criteria and15% had an ECOG of 2 or greater. 18% (n=97) received TAL as an outpatient and the median number of hospital days was 9 (0,37) for inpatients. CRS during Step up Dose (SUD) 1 was present in 30% Gr 1 (57%), Gr2 (11%), Gr 3 (6%), CRS during SUD 2 was present in 31%, Gr 1 (65%), Gr 2 (11%), CRS during SUD 3 when administered was present in 14% , Gr 1 (82%), Gr 2 (6%) and with first full dose was 12% , Gr 1 (71%), unknown (29%). ICANS occurred in 6% (7/97), Gr 1 (14%), Gr 2 (29%), Gr 3 (14%) and unknown in 43% there was no evidence of HLH. Skin toxicity was present in 62% of patients (n=105/118) with 4% needing dose interruptions and presented as rash (20%), dryness (42%) and itching (20%). Nail toxicity was present in 20% (n=65/118), with 9% needing dose interruptions. Dysgeusia was present in 51% (n=97/118), with 10% needing dose interruptions. Oral toxicity manifest as stomatitis (10%), glossitis (1%), ulcerations (2%), dry mouth (27%), was present in 34% (n=61/118), with 12.5% needing dose interruptions. Infections were present in 34% (n=82/118) and CMV reactivation in 23% while only 1 patient needed treatment for CMV. The Overall Response Rate (ORR) was 64.9% with a VGPR rate or higher of 43.3% in this population. Updated efficacy data including PFS will be reported at the time of presentation Conclusions: This is the first largest RWE of the safety and efficacy of Talq in a heavily pretreated population with a high prior BCMA exposure. The ORR is consistent with a prior study by Jakubowiak et al which showed an ORR OF 65.7% after prior T cell engagers. The safety profile - CRS, ICANS, skin and oral toxicities was similar to the MonumenTAL study, CMV reactivation was higher and this may be related to treatment with prior immunotherapies and should be monitored in the future. This report shows that Talq has a similar safety and efficacy profile in the real world when sequenced after prior BCMA therapies.

Introduction ABBV-383 is a differentiated BCMA x CD3 bispecific antibody (fully humanized IgG4) T-cell engager composed of a bivalent BCMA binding domain with high avidity, a low-affinity CD3-binding domain, and a present but silenced-Fc tail retaining the FcRn binding allowing for an extended half-life and thereby, enabling dosing convenience. ABBV-383 monotherapy has shown promising activity and improved CRS safety profile with modified dexamethasone (Dex) premedication in patients (pts) with RRMM (NCT03933735; Rodriguez et al., JCO 2024;42[suppl 16]:7531). Here, ER and CRS PK/PD analyses supporting the selection of optimal SUD for ABBV-383 are reported. Methods ER-efficacy (N=286) and -safety (N=290) analyses were conducted using logistic regression methodology (R version 4.3.2) combining data from escalation (0.025-120 mg Q3W) and expansion (20, 40, 60 mg Q3W and 60 mg Q4W) cohorts of phase 1 study NCT03933735 and Arm A of phase 1b study NCT05650632 evaluating step-up dose (2 or 4 mg on Day 1) with a full dose (60 mg on Day 4) in pts with RRMM. Pts received modified Dex with full dose in expansion cohorts of 60 mg Q4W and 2/60 mg Q4W. In all other cohorts with or without SUD, pts received low Dex. Based on prior knowledge (JCO 2024;42[suppl 16]:7541), the safety endpoints (CRS: any-grade and ≥ G2) were modeled with Cycle 1 total (unbound + bound to soluble BCMA) Cmax, while objective response rate (ORR) was modeled with free (unbound + partially bound to soluble BCMA) Cavg. CRS ER models included a priori selected Dex (low vs. modified) and SUD (yes vs. no) as predictors. Relevant pt-specific covariates were tested in all models. CRS PK/PD analyses included total PK, IL-6, and CRS data (N=199) from the first 3 cycles of the above phase 1/1b studies. A semi-mechanistic indirect response PK/IL-6 model was developed to correlate total PK and IL-6 (NONMEM 7.5). Maximal IL-6 concentrations were derived using post hoc estimates from the PK/IL-6 model and correlated with CRS events (logistic regression; R version 4.3.2). The models included effects of time-dependent Dex (low vs. modified) and SUD (yes vs. no). The overall modeling approach was assessed by comparing observed and predicted CRS rates. Simulations were conducted for various dosing regimens, including one or two SUD and Dex premedication scenarios to support the selection of the optimal SUD. Results Consistent with clinical observations (separate abstract submission), any-grade CRS model predicted probabilities suggested two key outcomes: 1) premedication with modified Dex improves the CRS safety profile compared to the low Dex (42% vs 69% for 60 mg Q4W); 2) modified Dex with SUD further improves the CRS safety profile of ABBV-383 compared to low Dex with SUD (29% vs 43% for 2/60 mg Q4W). Consistent with prior work, no ER relationship was observed for ≥ G2 CRS (p > 0.05). The ORR model resulted in a predicted probability of 68% ORR (closely matching with overall observed 64% ORR) with no impact of SUD and modified Dex. Only soluble BCMA was selected as a covariate in the ORR ER model. The final semi-mechanistic PK/IL-6 model well captured the observed IL-6 data, and the CRS rates (predicted by the logistic regression models) closely matched with the observed data. The CRS PK/PD analyses findings were consistent with the clinical observations and ER analyses key outcomes 1 and 2. The CRS PK/PD analyses predictions comparing the 1-SUD vs 2-SUD (untested) regimens with modified Dex suggested that 1) among the 2-SUD regimens with modified Dex, the 2/3/60 mg regimen would have the maximum reduction of 4% points in any-grade CRS compared to the 2/60 mg 1-SUD regimen, however, with substantial overlap of confidence intervals and with no decrease in ≥ G2 CRS (< 0.5% point); 2) 4 mg as an intermediate SUD in a 2-SUD regimen would lead to higher any-grade and ≥ G2 CRS rates (~9% and 3% points higher, respectively), compared to the 2/60 mg Q4W regimen. Conclusions ER and CRS PK/PD analyses suggested that modified Dex and SUD improve the CRS safety profile of ABBV-383 with no impact on efficacy (ORR) in pts with RRMM. The CRS PK/PD predictions indicated that implementation of 2-SUDs provide minimal additional or no improvement in CRS safety profile compared to 1-SUD. Overall, the 1-SUD dosing regimen of 2 mg with modified premedication prior to the full dose of 60 mg Q4W showed promising results and can be considered for future evaluation and studies.

Introduction: Frailty is known to be an important risk factor for adverse outcomes in multiple myeloma (MM) and is often under-represented in clinical trials. Frail patients are known to have increased toxicity, high rates of treatment discontinuation rates and decreased efficacy including worse overall survival in MM. Teclistamab (TEC) is a bispecific BCMA-CD3 directed T-cell antibody (BsAb) that was approved based upon the pivotal MajesTEC-1 study showing high overall response rates in patients with R/R MM. In MajesTEC-1, the median age was 63, and patients with ECOG ≥ 2 were excluded, suggesting that the vast majority of patients in the trial were fit. There is a paucity of data both in clinical trials as well as in the real-world regarding the outcomes of patients, particularly frail patients, with BsAb. This data is needed to both understand current outcomes of frail patients as well as devise strategies for future optimization with BsAb treatment. We performed a retrospective analysis utilizing the International Myeloma Foundation (IMF) immunotherapy database with the objective of understanding the outcomes of older adults (age ≥ 70) including frail patients treated in the real-world with teclistamab. Methods: Data was collected from 7 individual academic sites for patients aged ≥ 70 years treated with teclistamab in the real-world. Data collected include patient demographics, disease characteristics, as well as efficacy and toxicity associated with teclistamab. Frailty score was retrospectively calculated using the simplified/IFM frailty index which includes chronological age, ECOG PS and Charlson Comorbidity Index categorizing the patients into fit (score 0-1) or frail (≥ score 2). Fisher's exact tests were performed to evaluate differences in outcomes between fit and frail patients. Results: A total of 81 pts were included in our total cohort. The median age was 76 year (range 70-91). Among them, 44 (54%) were > age 75 and 23 (28%) > age 80. Twenty-eight (35%) patients had an ECOG performance status of ≥2. Using the simplified/IFM frailty index, 22 (27%) were classified as fit and 59 (73%) were frail. In the frail subgroup, a high proportion of patients (42%) would be classified as ultra frail (frailty score of ≥3). Selected baseline patient and disease characteristics are as follows: high risk cytogenetics including 1q gain/amp (fit 67% vs frail 43%), median prior lines (fit 7 vs frail 5), triple class refractory (fit 81% vs frail 88%), CrCl <30 (fit 5% vs frail 15%). For patients hospitalized for step-up dosing, median number of hospital days was 8 both in the fit and frail group. All grade CRS was noted in 12 (55%) fit and 28 (47%) frail patients. Among the fit patients, only 1 of the 12 patients (8%) had grade 2 CRS, whereas 8 of 28 (29%) frail patients had grade 2 (p-value=0.23). ICANS was reported in 2 (9%) fit patients and 8 (14%) frail patients (p=0.72). The majority of ICANS was grade 1 in both groups, but among the frail group, there was one grade 3 and two grade 4 ICANS cases reported. Infections were reported in 10 (45%) fit patients and 35 (59%) frail patients (p=0.32), with 2 (9%) and 14 (23%) being grade≥3 (p-value=0.21). IVIG was administered in most patients (fit 50% vs frail 58%, p=0.62). Grade 3/4 neutropenia was reported in 10 (45%) fit patients and 19 (32%) frail patients (p=0.30). The overall dosing interval was changed in 32% of fit patient and 34% of frail patients (p=1.00). The overall response rate was 50% for fit patients versus 66% for frail patient (p=0.61). The type of responses noted in the fit patient were as follows: sCR/CR 18%, VGPR 27%, PR/MR 5%, SD 18%, PD/NE 32% and for frail patients : sCR/CR 18%, VGPR 43%, PR/MR 9%, SD 5%, PD/NE 25%. The median follow-up time was 13.1 months. 12-month PFS for fit pts was 47.6% (95% CI 25.7% - 66.7%) and for frail pts 42.4% (29.0% - 55.3%). 12-months OS for fit pts was 64.9% (95% CI 39.9% - 81.6%) and for frail 61.5% (47.0% -73.1%). Conclusions: This is the first real-world study to evaluate the outcomes of teclistamab in frail older adults. With regards to toxicity, frail older adults showed a trend towards higher rates of ≥ grade 2 CRS, ≥ grade 2 ICANS as well as ≥3 grade infections. Efficacy was maintained in both fit and frail older adults similar to the MajesTEC-1 study. Our study highlights that BCMA BsAb can be safely utilized in older adults including frail older adults; however, additional proactive supportive care may be required to further optimize outcomes.

Background:Patients (pts) with multiple myeloma (MM) often receive immunomodulatory drugs (IMiDs; eg, lenalidomide), proteasome inhibitors (eg, bortezomib), and anti-CD38 monoclonal antibodies (mAbs) as part of their initial treatment. However, most pts relapse following initial treatment, with increasing attrition rates observed at each subsequent line of therapy (LOT), creating an unmet need for treatment options for pts with relapsed/refractory MM (RRMM) who have prior exposure to these agents. Current regimens for pts who have prior exposure to lenalidomide and anti-CD38 mAbs include elotuzumab, pomalidomide, and dexamethasone (EPd; approved in Europe and the US) and pomalidomide, bortezomib, and dexamethasone (PVd; approved in Europe and Australia), but disease control, as well as depth and durability of response, could be improved. Talquetamab (tal) and teclistamab (tec), targeting CD3 and either G protein-coupled receptor family C group 5 member D (GPRC5D, tal) or B-cell maturation antigen (tec), are the first T-cell redirecting bispecific antibodies (BsAbs) approved as monotherapies in Europe and the US for the treatment of pts with triple-class exposed (TCE) RRMM. Use of these novel immunotherapies in earlier LOTs, either with a dual-antigen targeting approach or by enhancing the activity of the BsAb with an IMiD (pomalidomide), may provide deeper, more durable responses and improve pt quality of life. Preliminary data using these combination treatments have shown promising results: in the phase 1b MonumenTAL-2 study (NCT05050097), tal+pomalidomide (tal-P) demonstrated overall response rates (ORRs) of >84% in pts with RRMM with ≥2 prior LOTs and in the phase 1b/2 RedirecTT-1 study (NCT04586426), tal+tec (tal-tec) showed ORRs of >77% in pts with TCE RRMM. MonumenTAL-6 (NCT06208150) is a randomized, open-label, multicenter, phase 3 study comparing the efficacy of tal-P vs investigator's choice of EPd or PVd and tal-tec vs investigator's choice of EPd or PVd in pts with RRMM with 1-4 prior LOTs, including lenalidomide and an anti-CD38 mAb. Study Design and Methods: Eligibility includes pts aged ≥18 years with documented MM per International Myeloma Working Group (IMWG) criteria, with measurable disease at screening, an Eastern Cooperative Oncology Group performance status of 0-2, who have received 1-4 prior LOTs (including lenalidomide and an anti-CD38 mAb in any prior LOT), and have progressive disease on or after their last therapy. Pts with prior exposure to pomalidomide, tec, or GPRC5D-directed therapies are excluded. Approximately 795 pts are randomized 1:1:1 to receive tal-P, tal-tec, or investigator's choice of EPd or PVd. Tal is administered subcutaneously at 0.8 mg/kg every other week (Q2W), and tec is administered subcutaneously at 3.0 mg/kg every 4 weeks (Q4W) following step-up doses of each. Pts are permitted to switch from Q2W to Q4W tal dosing following a confirmed very good partial response or better (≥VGPR) at cycle 5. Pomalidomide, EPd, and PVd are administered per approved dosing schedules. Randomization is stratified by number of prior LOTs (1 vs ≥2), International Staging System stage at screening (I vs II/III), and investigator's choice of treatment (EPd vs PVd). Pts receive study treatment until disease progression, start of subsequent anti-MM treatment, death, intolerable toxicity, withdrawal of consent, or end of study, whichever occurs first. A finite dosing approach is employed for tal and tec. The primary endpoint is progression-free survival (PFS). Secondary endpoints include ORR assessed per IMWG 2016 criteria, ≥VGPR rate, complete response (CR) or better rate, rate of minimal residual disease-negative CR, overall survival, PFS on next LOT, time-to-next treatment, and pt-reported outcomes. This study is actively recruiting, with more than 160 locations in 26 countries. Results will provide insights into the efficacy of the combination of BsAbs in therapeutic strategies that exploit their different mechanisms of action to overcome treatment resistance and improve outcomes of pts with TCE RRMM in earlier LOTs.

Introduction: The outcomes of patients diagnosed with multiple myeloma (MM) have improved significantly with the advent of immunomodulatory drugs, proteasome inhibitors, anti-CD38 monoclonal antibodies, and high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT). Further advancements include immune-based approaches such as bispecific antibodies and chimeric antigen T-cell receptor therapy. However, most of these therapies are predominantly available in developed countries, with limited access globally. Our study aimed to ascertain the landscape of interventions being used in developing countries for MM, and their efficacy. Methods: A comprehensive search was conducted on March 13, 2023, using Embase via Elsevier, PubMed, Scopus, CINAHL, and CENTRAL. We included retrospective and prospective studies that were evaluating interventions for patients with plasma cell dycrasias in the developing country setting. We defined developing country according to the United Nations. For comparative studies, we calculated the risk ratio (RR) for binary outcomes such as overall survival (OS) and progression-free survival (PFS), estimating 95% confidence intervals (CIs) and pooling data using the DerSimonian and Laird random effects model. For non-comparative studies, we calculated overall event rates and transformed them using the Freeman-Tukey double arcsine method, then pooled the data using the same random effects model. All statistical analyses were conducted using R version 4.4.0. Results: A total of 448 records were identified, of which 37 studies met the eligibility criteria. The overall risk of bias was moderate. The included studies evaluated induction treatments using doublet and triplet-based therapies, including TD (thalidomide and dexamethasone), VD (bortezomib and dexamethasone), MP (melphalan and prednisone), CTD (cyclophosphamide, thalidomide, and dexamethasone), VTD (bortezomib, thalidomide, and dexamethasone), and VAD (vincristine, doxorubicin, and dexamethasone). Lenalidomide was notably absent in the induction regimens apart from one non-comparative study reported on the use of RVD (lenalidomide, bortezomib, and dexamethasone). Studies were divided into comparative (n=11) and non-comparative groups (n=26). Comparative studies included: HSCT vs. no HSCT, induction with alkylating agents vs. thalidomide or bortezomib, and thalidomide vs. bortezomib or CTD vs. VTD. Lenalidomide use in comparative studies was reported only post-HSCT, compared against observation. High-dose chemotherapy followed by autologous HSCT was commonly utilized, with most studies reporting outcomes for patients who underwent autologous HSCT. Two comparative studies from 2 countries (Colombia and India) compared the overall survival of autologous HSCT in patients diagnosed with MM (N=130) vs. patients who never received ASCT (N=293). At one year of follow-up, there was no significant difference in overall survival (OS) between patients who received autologous HSCT and those who did not (relative risk [RR] = 1.11, 95% CI: 0.93-1.33). However, a significant improvement in OS was observed at five years post-autologous HSCT (RR = 1.59, 95% CI: 1.38-1.82). The pooled estimate for five-year OS in single-arm studies, which included nine cohorts from seven countries (Pakistan, India, Colombia, Algeria, Sri Lanka, Mexico, and Peru), was 62% (95% CI: 48-75). Progression-free survival (PFS) at five years post-HSCT, reported in three cohorts from three countries (India, Algeria, and Mexico), was 44% (95% CI: 23-67). Conclusions: Most of the recent advancements in MM treatment, including immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies, were not widely utilized globally, particularly in developing countries. This limited access is a major issue, hindering the potential improvement in patient outcomes. However, high-dose chemotherapy followed by autologous HSCT showed good outcomes, demonstrating a significant survival advantage at five years follow-up. The lack of survival benefits at one-year post-HSCT may be due to high toxicity and/or limited resources to manage side effects in developing countries. Addressing the disparity in treatment availability is crucial for improving MM management and patient survival globally.

Introduction Patients (pts) with multiple myeloma (MM) eventually become refractory to current treatments. There is an unmet need for new therapies with durable efficacy, favorable safety, and simplified dosing schedules. ABBV-383 is a unique BCMA x CD3 bispecific antibody T-cell engager comprising bivalent high-avidity BCMA binding domains, a low-affinity CD3-binding domain designed to minimize cytokine release and the risk for cytokine release syndrome (CRS), and a silenced Fc tail for extended half-life enabling dosing convenience. In an ongoing first-in-human (FIH) study (NCT03933735) in heavily pretreated pts with relapsed or refractory (RR) MM, ABBV-383 monotherapy (60 mg Q4W) resulted in deep and durable responses. Introduction of a modified dexamethasone (Dex) premedication (premed) schedule in cycle (C) 1 lowered incidence and severity of CRS (43% overall; 5% grade ≥2) vs pts treated with low Dex (71% overall; 20% grade ≥2) (JCO 2024;42[suppl 16]:7531). We now report results of Arm A of the open-label, phase 1b study (NCT05650632) evaluating 1 step-up dose (SUD) of ABBV-383 as a strategy to mitigate the risk of severe CRS and further assess ABBV-383 activity in pts with RRMM. Methods This study is enrolling pts with RRMM, ECOG performance status ≤2, and documented evidence of progression during or after the last treatment. Pts must have received ≥3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Arm A consists of a dose-optimization (DO) and a dose-expansion (DE) part. During DO, pts received a single SUD of intravenous ABBV-383 (2/4 mg) on C1 day (D) 1, followed by the target dose of 60 mg on D4. In the DE, based on DO findings, pts received the recommended ABBV-383 SUD on C1D1, followed by 60 mg on D4. The modified premed schedule that lowered incidence and severity of CRS in the FIH study was also introduced prior to target dose on C1D4. After C1, pts received 60 mg ABBV-383 Q4W on D1 of each cycle for DO and DE until disease progression, withdrawal, or discontinuation. Primary endpoint was grade ≥2 CRS events during C1. Other endpoints included any grade CRS events, treatment-emergent adverse events (TEAEs), immune pharmacodynamics, and clinical activity. Results As of April 2024, 70 pts were enrolled in Arm A: 47 in DO (2 mg SUD, n=26; 4 mg SUD, n=21) and 23 in DE. Median age was 69 years (range: 40-84), 59% were male, and 76% were triple-class refractory. Median prior lines of therapy was 4 (range: 3-10). Median follow-up time (months [mo]) was 6.5, 7.5, and 2.8 for 2 mg DO, 4 mg DO, and DE, respectively. Any grade CRS was reported in 10 (39%) and 11 (52%) pts during DO at 2 and 4 mg SUD; CRS grade ≥2 occurred in 3 (12%) pts in the 2 mg SUD and in 6 (29%) pts in the 4 mg SUD, leading to selection of 2 mg SUD for DE. In the DE, 7 (30%) pts experienced CRS; 1 (4%) pt experienced grade 2 CRS, there were no grade ≥3 events, and only 2 (9%) pts received tocilizumab to treat CRS. Overall, median time to CRS onset and resolution was 14.7 and 9 hours, respectively; no pts had CRS after C1. Immune effector cell-associated neurotoxicity syndrome occurred in 7 (10%) pts (grade 1: 4%; grade 2: 6%; grade 3: 4%). Most common TEAEs were CRS (40%), neutropenia (37%), diarrhea (29%), anemia (24%), and fatigue (20%); most common grade 3/4 TEAEs were neutropenia (31%), anemia (19%), thrombocytopenia (13%), and leukopenia (11%). Grade 5 TEAEs occurred in 5 pts; 1 event was deemed possibly related to ABBV-383 (COVID-19 pneumonia). In the efficacy-evaluable population (n=68), the objective response rate was 62% (95% CI: 49.2, 73.3); 35 (52%) pts had a VGPR or better. Median time to response was 1.1 mo (range: 1-4) and median duration of follow-up was 5.8 mo (range: 1-12). Response rates are expected to improve with longer follow-up. Maximum reduction in peak levels of CRS-related cytokines, including IL-6, were observed in DE compared with DO and 60 mg Q4W without SUD (FIH study). Peak activation and proliferation of CD8 T cells was comparable with ABBV-383 in DO, DE, and 60 mg Q4W-treated pts. Conclusions Introduction of 1 SUD of 2 mg on D1 followed by full dose of 60 mg on D4 in C1 combined with modification to the Dex premed schedule reduced the incidence and severity of CRS in pts with RRMM, further optimizing the safety profile of ABBV-383. Preliminary efficacy data show early and high response rates, consistent with outcomes from other ABBV-383 studies.

Purpose: The aim of this study was to identify successful recruitment strategies and obstacles reported by principal investigators (PIs) of the Zoster Eye Disease Study (ZEDS). Methods: A web-based survey was created by a subset of ZEDS PIs and distributed to ZEDS PIs after study enrollment was closed. The survey queried investigators about recruitment strategies and obstacles, use of prophylactic oral antiviral medication, electronic medical records, telemedicine, COVID-19 effect, turnover of research staff, and recruitment outreach to minority and underserved populations. The survey allowed objective measures and free-text options. Analysis from centers with higher enrollment was compared with centers with lower enrollment to identify successful strategies and common obstacles. Results: The most frequently cited helpful strategies were participation from ophthalmologists within the PI's institution (33/63, 52%), ophthalmology resident referrals (23/63, 37%), and chart review (23/63, 37%). Travel to participating clinical center (42/63, 67%) and ongoing prophylactic use of oral systemic antiviral medication (39/63, 62%) were common obstacles. Research coordinator turnover was identified as a contributor to reduced recruitment success by 49% (31/63) of PIs and made recruitment much harder for 22% (14/63). A small number of investigators used telemedicine (18/63, 29%) and few made efforts to recruit from minority and underserved populations (10/63, 16%). Conclusions: Our survey highlights the importance of internal ophthalmologist referral, chart review, and research coordinator commitment for successful clinical trial recruitment. We discuss the impact of prophylactic use of oral antiviral medication on recruitment. Future randomized clinical trials should mobilize the helpful recruitment strategies and improve outreach to underserved populations.