Chanan‐Khan, Asher

Abstract Background: MM is the second most common hematologic malignancy, which despite significant therapeutic advancements, remains incurable. The complexity of MM and its intricate management creates substantial informational demands for patients navigating their care. Methods: A cross-sectional survey study (Mayo Clinic IRB # 25-004671) was conducted to assess MM patients’ awareness about disease basics. A voluntary English language survey (47 questions) encompassing multiple domains of patient MM awareness was administered (REDCap) via the patient EMR portal (Mayo Clinic) and MM support groups nationally. Responses were analyzed using descriptive and inferential statistics (R; Bluesky Statistics, V 10.3.4). Multiple model logistic regression was used for multivariate analysis using age (≤70 or >70 yrs), gender, education (high school or less vs bachelor's and above), income (≤$74999 vs ≥$75000) and insurance status (private vs public). Results: The survey was completed by 2353 patients (pts) with 2177 MM (83.4% active, 16.6% smoldering) and 176 MGUS. Among MM pts median age was 63 yrs with 52.5% males, 91.5% white and 95.7% non-Hispanic. 17.5% had a prior diagnosis of MGUS and 20.2% of smoldering MM prior to MM, and 79.5% were not aware of MM prior to their own diagnosis. Majority (77%) depended most on their doctors to gain MM information but 24.3% reported not having sufficient discussion about MM at diagnosis. 31.2% were not sure what type of MM they had, 22.9% could not correctly report the cell of MM origin (plasma cell), 40.6% did not receive MM stage information at diagnosis, 45.4% were either unsure or reported wrong risk factors for MM and 22% were unsure or mistaken about MM symptoms. Majority (62.9%) did not understand genetic risk categories of MM, 32.3% did not report adequate understanding of MM tests and 31.9% did not understand the difference between response and remission. 57.5% reported not understanding about MRD status and 57.1% never had MRD testing. Majority (86.8%) felt they got adequate opportunity to participate in treatment decisions but only 54.2% felt confident in managing MM with their current knowledge and 28.2% had not discussed their prognosis although 77.7% wanted to know about it. Majority (64.4%) felt they had knowledge gaps about MM and its management. Multivariate analysis showed that females were less likely (OR 0.67) while those with public insurance were more likely (OR 1.35) to report receiving adequate information at diagnosis. Older pts (OR 0.55), males (OR 0.43), with lower education (OR 0.5), lower income (OR 0.5) and public insurance (OR 0.72) were less likely to identify the cell of MM origin correctly. These same groups were significantly less likely to be aware of types of MM as well. Older pts (OR 0.73), with lower education (OR 0.6), lower income (OR 0.77) and public insurance (OR 0.76) were less likely to be aware of MM genetic risk categories. Females (OR 0.81), with lower education (OR 0.68) and lower income (OR 0.63) were less likely to understand MM lab tests. Females and those with lower income were significantly less likely to report receiving adequate information about treatment options. Females reported that they did not get adequate opportunities to participate in treatment decisions (OR 0.65). Older pts, and those with lower income, lower education or public insurance were less likely to understand minimal residual disease (MRD) and all these groups were less likely to have had MRD testing. Those with lower income (OR 0.75) and lesser education (OR 0.72) felt less confident in managing MM with current knowledge. Older pts, females and those with lesser education, lower income and public insurance were also significantly less likely to have discussed about MM prognosis. Conclusion: This study demonstrates substantial basic knowledge deficits integral to managing and prognosticating MM among patients. Patients from unfavorable sociodemographic-economic groups were more likely to have awareness gaps and report lack of information which is integral to having adequate understanding of MM being provided to them. These findings highlight the critical need for structured, comprehensive educational interventions that address fundamental disease concepts to empower pts, overcome healthcare disparities, and engage pts in shared decision-making.

Abstract Background: The phase II and III GRIFFIN and PERSEUS studies evaluated DVRd vs. VRd in NDMM pts that were transplant eligible (TE). These studies included consolidation (cons) and dual agent maintenance (maint) with dara and len (DR). Little is known about the efficacy of DVRd in RW practice including frequency of bor use, use of cons, use of DR maint, and subsequent treatment after progression (PD) on DVRd. We aim to evaluate the RW efficacy of NDMM pts treated with DVRd across the tri-site Mayo Clinic Comprehensive Cancer (MCCC). Methods: We retrospectively analyzed the medical records of pts treated with DVRd between June 2018 and June 2024 at the MCCC. Outcomes were estimated using the Kaplan-Meier method. Results: 464 pts were included; 278 pts were male, and the median (m) age of MM diagnosis was 64 years (yr). 114 pts had ISS III, 205 pts had R-ISS III, 266 pts had high risk (HR) FISH, 80 pts had extramedullary disease, 165 pts had ultra HR disease (dz) (as per 2025 IMS/IMWG consensus), and 47 pts had renal insufficiency (RI) with creatinine >2 mg/dL. Starting len dose was 25mg in 356 pts, 15 mg in 40 pts and ≤10mg in 65 pts. 399 pts received bor 1x per week and 63 2x per week, 91 pts received 1-2 cycles of a different regimen prior to DVRd due to hospitalization (n=23), RI (n=38), poor performance status (n=6), other (n=34). 315 (67.9%) pts underwent autologous transplant (ASCT). The m number of induction cycles was 5; 4 for pts who underwent ASCT and 6 for pts who did not. The best ORR to induction for pts who underwent ASCT was 98% with 247 (79%) achieving ≥VGPR, and 82 (26%) achieving minimal residual disease negativity (MRD-) to at least 10-5. The best ORR for pts who did not undergo ASCT was 87%. For those who underwent ASCT, (96% with melphalan 200mg/m2), the ORR at day 100 was 97% with 56% achieving MRD-. At 1-yr post ASCT, 30% (93/312) were MRD-. 42 pts (13%) received post ASCT cons with DVRd for a m of 2 cycles. 281 pts received post ASCT maint including 107 (38%) len, 53 (19%) bor-len, 91 (32%) dara-len, 14 (5%) dara, 16 (6%) other. 61(13%) pts had change in treatment, due to change to second line therapy (35; 55%), discontinuation (d/c) of len (11; 17%), d/c of dara (3; 5%), d/c of bor (15; 23%), d/c of dex (0; 0%). The m follow-up time for all pts was 26 months (mo) (17-39). The m PFS of pts who underwent ASCT was not reached (NR), and was 57 mo (52-NA) for pts who did not undergo ASCT. For pts who underwent ASCT, the PFS at 24mo for pts who did not have HR FISH was 93% (88-99%) compared to 80% (73-88%) for pts with HR FISH (p=0.12) and 77% (68-87%) for pts with ultra-HR dz (p=0.013).The PFS at 24mo of pts with RI who underwent ASCT was 81% (66-98%) compared to 86% (82-92%) for those without RI, p=0.57. The PFS at 24mo of pts with RI who did not undergo ASCT was 53% (28-100%) compared to 64% (55-75%) for those without RI, p=0.42. The ORR and MRD- rate for pts who received once-weekly bor was 94% and 24%, compared to 94% and 27% for pts who received 2x weekly bor (p=0.85, p=0.93). For pts who underwent ASCT, the PFS at 24mo for pts who received len maint was 91% vs. 83% for pts who receive dual agent maint (DR or VR) (p=0.25), although pts who got dual agent maint were more likely to have HR FISH than pts who received len maint (p<0.001). The PFS at 24mo for pts that received post-ASCT cons was 91% compared to 85% for those that did not (p=0.53); pts who got post-ASCT cons were more likely to have HR FISH (p=0.07). For pts that underwent ASCT, the 3 yr PFS rate is 85% and the 3 yrs OS rate is 96%. For pts that did not undergo ASCT the 3 yrs PFS rate is 60% and the 3 yr OS rate is 85%. 55 pts had functional HR (FHR) MM (relapse within 18 mo) and m PFS for FHR pts who underwent ASCT was 15 mo (11-NA), while m PFS was NR for pts without FHR MM (p<0.001). 79 pts relapsed after 1st line DVRd. The most common 2nd line therapies (tx) were dara-carfilzomib (K)-D, dara-pomalidomide(P)-D, KPD, and other. The m follow-up time from 2nd line tx was 10 mo, the best ORR to 2nd line tx was 76%, and the m PFS with 2nd line tx was 18 mo (7-NA). Conclusion: In this RW analysis, the efficacy and survival outcomes of NDMM pts treated with DVRd was comparable to that reported in the PERSEUS and GRIFFIN trials, although MRD- rates appear lower. DR maint and post-ASCT cons use was not common and was used more frequently in pts with HR FISH. Pts can be effectively salvaged following PD on front-line DVRd with available tx.

Abstract Introduction: In a multiple myeloma mouse model (MM), we determined that subcutaneous (SC) continuous lenalidomide (Len) delivery demonstrated superior tolerability and efficacy to the active control Len given by daily i.p. over a 28 day cycle. Healthy volunteer studies showed that at a daily dose of 9.6 mg a day (400 mcg/h) the Len AUC0-24 was ∼60% less than that observed with an oral 25 mg Len dose. We hypothesized that this modality could improve Len’s therapeutic index by lowering the hematologic toxicity while maintaining or improving the efficacy. Methods: A phase 1b study in 2nd line or greater relapsed/refractory MM was performed to confirm the animal findings and determine if continuous Len can improve its therapeutic index with no negative impact on the cellular immune system. In brief, an RVd regimen was utilized wherein SC Len 9.6 mg/day was administered with an FDA registered ambulatory pump in a continuous fashion using a 28/28 day cycle. Patients were either trained to operate their pump and change the pre-filled cassettes at home or were managed in the clinic on M-W-F. All patients were seen in the clinic to receive weekly bortezomib 1.3mg/m2 and dexamethasone dosed weekly at 40/20mg, according to age. Patients who received bortezomib in a prior cycle were required to demonstrate sensitivity defined as durability for 6 months after discontinuation of the bortezomib. Results: Between September 2023 and November 2024, 6 relapsed/refractory MM patients were enrolled from 2 US community-based investigational sites in the phase 1b study. Median age was 73, male to female ratio 1/1, Caucasian 100%, and median lines of previous therapy were 2 (range 1-7). Two patients were refractory and 4 were relapsed to their prior treatment. Four patients were previously exposed to Len, one of which was discontinued from a prior regimen because of severe fatigue, and 6 had received prior bortezomib. Patients had received 3-12 cycles of study therapy. No drug-related grade 3/4 hematologic or non-hematologic toxicity occurred within cycle 1. No patients experienced drug-related anemia, neutropenia, leukopenia, or thrombocytopenia greater than grade 2 in up to 12 cycles of therapy. All 6 patients achieved an objective response (CR=1 / PR=5). One patient who achieved a partial response experienced grade 2 skin reaction during cycle 3 and withdrew from the study. Five patients are continuing treatment per protocol with a median PFS of > 10 mo. Len pharmacokinetics produced median steady-state blood levels (Cmax) of 39 ng/mL (range 26-94) (N=6) and were above the minimum target of 25 ng/mL. The Len regimen produced a median AUC0-24 of 921-1h*ng/ml (range 630-1503). Immune profiling did not show significant increases in immune checkpoint expression associated with T-cell exhaustion while CD19+ B cells were significantly depleted. Conclusion: Continuous delivery of low dose Len provides meaningful efficacy and improved tolerability with no grade >3 drug-related hematologic toxicity. Further studies in MM and chronic lymphocytic leukemia are planned. Citation Format: Nash Gabrail, Keith Lerro, Mohamad A. Hussein, Asher A. Chanan-Khan, Jamie C. Oliver. Continuous subcutaneous lenalidomide delivery improves the therapeutic index and avoids drug-related grade 3/4 hematologic toxicity in patients with relapsed/refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB207.

Introduction: Myeloma therapeutics have tremendously improved in recent times, leading to unprecedented outcomes. Timely initiation of effective treatment is vital to improving survival and quality of life. Patient refusal to receive treatment is infrequent but certainly leads to increased morbidity/mortality. We studied factors associated with treatment refusal. Methods: The National Cancer Database (NCDB) was queried for adult patients diagnosed with MM between 2004-2021. Those who refused treatment for initial management despite physician's recommendation were identified. Patients with multiple primary malignancies or unknown treatment status were excluded. Patients' demographics and socioeconomic factors were collected. Kaplan-Meier and multivariate Cox regression were used to evaluate the likelihood of treatment refusal in the whole cohort and in each racial/ethnic group. Results: Out of 86,350 eligible patients with MM who were recommended to initiate therapy, 2,508 (2.9%) did not receive any treatment due to refusal. Of these, 52.6% were females, 64% were non-Hispanic White (NHW), 21.3% were non-Hispanic African American (NHAA), and 5.2% were Hispanic. On multivariate analysis, patients who were treated at comprehensive and integrated facilities were more likely to refuse treatment as compared to those at academic facilities (OR=1.36; 95% CI: 1.22-1.52, p<0.001 and OR=1.22; 95% CI: 1.07-1.4, p=0.004, respectively). Patients on Medicare (OR=1.42; 95% CI: 1.16-1.73, p<0.001), and presence of higher Charlson Comorbidity Index (CCI) also had a higher likelihood of refusing treatment. Lower refusal rates were seen for male gender (OR=0.83; 95% CI: 0.76-0.91, p<0.001), NHW racial/ethnic group (as against NHAA; OR=0.34; 95% CI: 0.16-0.71, p=0.004), being insured (OR=0.69; 95% CI: 0.52-0.93, p=0.015), having private insurance (compared to Medicaid; OR=0.47; 95% CI: 0.38-0.59, p<0.001) and having a higher income level (OR=0.82; 95% CI: 0.70-0.96, p=0.013). Among NHAA patients, 2.8% refused treatment and were more likely to have Medicare (OR=1.4; 95% CI: 1.03-1.9, p=0.032). Having private insurance (compared to Medicaid; OR=0.61; 95% CI: 0.43-0.88, p=0.008) had a lower likelihood of refusing treatment. Among NHW, 2.9% refused treatment and they were more likely to be treated at community, comprehensive and integrated facilities compared to academic facilities (OR=1.39; 95% CI: 1.12-1.73, p=0.003, OR=1.54; 95% CI: 1.33-1.77, p<0.001 and OR=1.38; 95% CI: 1.16-1.64, p<0.001, respectively), be from rural areas (OR=1.43; 95% CI: 1.05-1.96, p=0.025), and have a higher CCI. On the other hand, male gender (OR=0.79; 95% CI: 0.72-0.89, p<0.001), private insurance (compared to Medicaid; OR=0.42; 95% CI: 0.30-0.59, p<0.001) and higher income level (OR=0.80; 95% CI: 0.66-0.98, p=0.029) had a lower likelihood of refusing treatment. Among Hispanic patients, 2.3% refused treatment and were more likely to have Medicare (OR=1.96; 95% CI: 1.13-3.4, p=0.016), while those with private insurance (compared to Medicaid; OR=0.32; 95% CI: 0.14-0.73, p=0.007) had a lower likelihood of refusing treatment. Conclusions: This large real-world analysis highlights the intricate sociodemographic and economic factors that affect the decision of a MM to not proceed with the recommendation for treatment. (1) NHW are less likely to refuse treatment as compared to NHAA. (2) Insurance status is an important driver of refusal and transcends race/ethnicity. Furthermore, in this study, we highlight characteristics that are specific to different racial/ethnic groups like CCI which affect only certain racial/ethnic groups. This provides an opportunity to develop targeted interventions such that the benefit of therapeutic advancements can be realized by all.

Introduction: Ven is a BCL2 inhibitor that has shown clinical efficacy in RRMM patients (pts) particularly those that harbor t(11;14). Ven has been evaluated in clinical trials as a single agent, in combination with dexamethasone (dex), immunomodulatory drugs (IMiD), proteasome inhibitors (PI), and anti-CD38 monoclonal antibodies (MAb) yet its place in the therapeutic landscape remains in question. In this retrospective analysis, we aim to evaluate the real-world efficacy of Ven-based regimens in RRMM pts treated outside of a clinical trial across the 3-site MCCC. Methods: We retrospectively analyzed the medical records of pts with RRMM treated with Ven-based regimens between January 2015 and October 2023 at the MCCC. Refractoriness was defined by progression on or within 60 days of stopping treatment. Categorical variables were compared with Chi-square tests and continuous variables were compared with t-tests. Outcomes were estimated using the Kaplan-Meier method and curves were compared between the groups using log-rank tests. Results: 83 pts were included in the analysis. The median age was 71 (39-93), 63% were male, 93% were white, 27% had ISS III, 18% had high risk cytogenetics (HRCyto), 76% had t(11;14), the median prior lines of therapy (LOT) was 4 (1-15), 68% received ≥ 4 prior LOT, 87% received prior autologous transplant, 58% were triple-class refractory (TCR), 64%/23% were penta-drug exposed/refractory (PDE/R), 8% received prior BCMA-directed therapies (BDT), 58% received Ven+dex, 25% received Ven+PI +/-dex, 6 % received Ven+anti-CD38 MAb+/-dex and 11% received Ven+other. The median follow-up time from start of a Ven-based regimen was 29 months (mo). The median Ven dose was 800mg (20-1600) with 25% of pts receiving Ven ramp-up dosing. The overall response rate (ORR) to a Ven-based regimen was 58% and was 64% for pts with t(11;14) and 40% for pts without t(11;14); p=0.06. Ven-treated pts with HRCyto had inferior PFS (3mo) and OS (8mo) compared to patients who did not have HRCyto who had a PFS of 9mo (p=0.020) and OS of 80mo (p<0.001). The ORR for TCR and PDR pts were 52% and 42%, respectively. No significant ORR differences were noted across the different Ven-based regimens (p=0.32). The median PFS for pts with t(11;14) was 10mo compared to 2mo for pts w/o t(11;14); p=<0.001. The median OS for pts with t(11;14) was 80mo compared to 10mo for pts without t(11;14); p=0.001. Ven-treated pts who received 1-3 prior LOT has superior ORR, median PFS, and median OS; 89%, 25mo, and 99mo, respectively, compared to pts who received ≥4 prior LOT who achieved an ORR of 43% (p<0.001), median PFS of 5mo (p<0.001) and median OS of 25mo (p<0.001). Ven-treated pts that were TCR had inferior PFS (5mo) and OS (26mo) compared to pts who were not TCR who achieved a PFS of 12mo (p<0.001) and a median OS of 80mo (p=0.02).Ven-treated pts that were PDR had inferior PFS (4mo) and OS (22mo) compared to pts who were not PDR who achieved a PFS of 9mo (p<0.001) and a median OS of 80mo (p=0.02).Ven-treated pts who received prior BDT (n=7) achieved an ORR of 29% and had a median PFS and OS of 2mo and 6mo, respectively on a Ven-based therapy. 59 pts received additional therapy in the post Ven-progression setting. The ORR to post-Ven progression therapies was 53% (n=31/59), the median PFS was 9mo and median OS was 35mo. The most common post-Ven progression regimens used were PI-based (n=16; ORR=56%), anti-CD38 MAb-based (n=14; ORR=50%), BDT (n=12; ORR=83%), selinexor-based (n=3; ORR=0%) with BDT resulting in highest ORR (p=0.048) and PFS (p=0.005). Conclusions: Ven-based regimens are effective in heavily pre-treated pts with RRMM however they are more effective when used within 1-3 prior LOT, in pts with t(11;14), and in pts without HRCyto, TCR or PDR MM. BDT appear to be the most efficacious therapies in the post-Ven progression setting.

Introduction MM is characterized by the proliferation of abnormal clonal plasma cells, causing destructive bone lesions, kidney injury, anemia, and hypercalcemia. Treatment of MM involves immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies to achieve disease remission. AL amyloidosis comprises disorders of abnormal extracellular deposition of misfolded proteins in various organs with resultant damage, and the key strategy of treatment is to prolong the time to or reverse organ dysfunction. However, many patients will relapse from the standard triplet or quadruplet therapies, necessitating additional treatments with novel mechanisms of action. Lisaftoclax is a novel investigational BCL-2 inhibitor with strong antitumor activity in hematologic malignancies. Here, we report clinical trial data on lisaftoclax combined with novel therapeutic regimens in pts with R/R MM or R/R AL amyloidosis. Methods Eligible patients had an ECOG performance status ≤ 2, ≥ 1 prior line of therapy, and adequate organ function. Patients with R/R AL amyloidosis had confirmed symptomatic organ involvement, purpura, and/or carpal tunnel syndrome. Lisaftoclax was administered orally daily at doses assigned in repeated 28-day cycles. Pomalidomide, daratumumab, and lenalidomide were administered per label use. Dexamethasone 40 mg (20 mg, pts > 75 years old) was administered on days 1, 8, 15, and 22 of 28-day cycles. This study evaluated the safety and efficacy of lisaftoclax combined with pomalidomide and dexamethasone (Pd; Arm A) or daratumumab, lenalidomide, and dexamethasone (DRd; Arm B) in R/R MM and lisaftoclax combined with Pd in R/R AL amyloidosis (Arm C). Intensive blood samples were collected for pharmacokinetic (PK) analyses. Results As of May 29, 2024, 52 pts were enrolled, including 42 with R/R MM and 10 with AL amyloidosis. In Arm A (n = 35), lisaftoclax was administered orally at dose assigned: 400 mg (n = 3), 600 mg (n = 4), 800 mg (n = 15), 1,000 mg (n = 7), and 1,200 mg (n = 6). In Arm B (n = 7), all pts were treated with lisaftoclax 600 mg. In Arm C (n = 10), lisaftoclax was administered at 400 mg (n = 1), 600 mg (n = 4), 800 mg (n = 3), and 1,000 mg (n = 2). The median (range) age of all patients was 69.5 (24-88) years, of whom 63.5% were male and 63.5% were ≥ 65 years of age. The enrolled patients were heavily treated, with a median (range) number of treatment cycles of 4 (1-26), and a median (range) number of prior therapy lines of 3 (1-19). In Arm A, out of 31 evaluable patients, 3 (9.7%) achieved complete remission (CR), 7 (22.6%) reached very good partial remission (VGPR), and 9 (29.0%) achieved partial response (PR). The overall response rate (ORR) was 19 (61.3%), and the ≥ VGPR rate was 10 (32.3%). In Arm B, of 4 evaluable patients, 2 (50%) achieved CR and 2 (50%) ≥ VGPR. In Arm C, of 7 assessed patients, 1 (14.3%) achieved CR, 4 (57.1%) VGPR, 1 (14.3%) PR, and 5 (71.4%) ≥ VGPR, for an ORR of 6 (85.7%); 2 pts had cardiac response. Among 49 pts in the safety population, 34 (69.4%) reported any-grade lisaftoclax treatment-related AEs (TRAEs; ≥ 5% incidence), including neutropenia (20.4%), thrombocytopenia (6.1%), leukopenia (10.2%), nausea (16.3%), abdominal distension (10.2%), diarrhea (12.2%), and constipation (8.2%). A total of 11 pts experienced grade ≥ 3 TRAEs, including neutropenia (14.3%) and febrile neutropenia (2%), and 3 pts experienced lisaftoclax-related serious AEs (1 each): febrile neutropenia, acute kidney injury, and diarrhea with electrolyte imbalance. In Arm B, 1 pt experienced a dose-limiting toxicity (prolonged QT interval). Pharmacokinetic analyses showed no drug-drug interaction (DDI) in all pts treated with lisaftoclax at all doses in combination with other therapeutic agents used in 3 arms. Conclusions Our findings suggest that lisaftoclax improves the depth of response in pts with R/R MM or AL amyloidosis when combined with Pd or DRd. These combination therapies demonstrated a favorable safety profile with no drug-drug interactions, particularly in hematologic side effects. ClinicalTrials.gov registration: NCT04942067; internal study identifier: APG2575MU101.