Zonder, Jeffrey A.

Background: The COVID-19 pandemic had an outsized impact on individuals with immune compromise, such as multiple myeloma, leading to increased rates of severe COVID, hospitalization, and death in these groups. The pandemic also demonstrated the need for rapid and efficient evidence generation to address rapidly changing medical needs and accelerated the use of innovative trial designs to accomplish this goal. Methods: We designed and established a prospective, decentralized study within a site-based provider network, COVID-19 OutcomeS in Myeloma and the Impact of VaCcines (COSMIC), for patients with multiple myeloma at ASH Research Collaborative sites to monitor outcomes related to COVID-19 infection and vaccination. The direct-to-patient approach was accomplished using a study application accessed with a QR code provided to patients during usual clinical care. All study activities occurred within the patient portal at Baseline, Day 30, and Day 180, minimizing burden on site personnel and staff. Study activities included eligibility confirmation, consenting, electronic health record (EHR) data permissions, and patient-reported outcome (PRO) surveys. PRO data (EORTC QLQ-C30, EORTC QLQ MY-20) were made available to clinicians through the portal to visualize results from their patients. Patients shared if they received a COVID-19 vaccination or booster and if they had a COVID-19 infection. Patients with a history of COVID-19 infection included method of confirmation and if hospitalization was required. Patients were provided compensation for participation. Automated text and email messages were sent at three separate intervals: 24 hours, Day 8, and Day 15 for participants who initiated but did not complete study activities. A personal email reminder per participant was sent for those whose second study visit window was approaching. ASH Research Collaborative clinicians met regularly to share best practices related to enrollment and study conduct, thereby creating an innovative evidence generation learning community. We studied the feasibility of data collection in a decentralized format by focusing on the number of participants who interacted with the system, those who consented, and those who completed baseline PRO assessments. Results: The COSMIC study rapidly accrued and consented 200 patients from eight participating ASH Research Collaborative sites over four months (1/22/2024 through 5/17/2024): 69% self-reported as non-Hispanic White (NHW). Of enrolled participants, 57.5% opted to permission sharing of their EHR data, which included disease and treatment-related clinical data, laboratory results, pathology reports, and imaging reports. A total of 196 patients (98%) provided demographic and COVID-related disease and vaccine data at baseline; nearly all of these patients (n=195) provided baseline PRO data, and 150 patients provided further information at Day 30 at the time of this analysis. Those who did not provide Day 30 data were not significantly different from those who did in terms of age (median: 68 [no Day 30 data] vs. 67 [Day 30 data] years; p=0.44), sex (41% [no Day 30 data] vs. 47% [Day 30 data] Female; p=0.47), or race (65% [no Day 30 data] vs. 71% [Day 30 data] NHW; p=0.60). A higher proportion of Hispanic patients were retained at Day 30 (13/15=87%) vs. 78% of non-Hispanic patients or those who declined reporting ethnicity (2/7=29%; p=0.007). COVID-19 vaccination data were submitted by 196 patients, 186 of whom had ever received a COVID-19 vaccination. Data on number, type, brand, and dates for these vaccinations were provided. Conclusions: The COSMIC study conducted by the ASH Research Collaborative was able to rapidly accrue a diverse cohort of patients using a decentralized workflow within a site-based provider network, with high consent and compliance rates. This platform, and the innovative evidence generation learning community of ASH Research Collaborative investigators and patients, sets a precedent to address a variety of real-world questions related to disease management, infections, vaccinations, and PROs in this population of patients with multiple myeloma.

Background: Data from the ASH Research Collaborative COVID-19 Registry for Hematology demonstrated that patients with multiple myeloma and other immune compromise had elevated risk for severe complications from COVID-19 infection. To address current evidence gaps and to demonstrate proof of concept for a pandemic preparedness and response network, the ASH Research Collaborative Multiple Myeloma Program developed a prospective, decentralized study within a site-based provider network to investigate COVID-19 infections, vaccinations, and quality of life in patients with multiple myeloma. Methods: We designed and established the COVID-19 OutcomeS in Myeloma and the Impact of VacCines (COSMIC) to study COVID-19 in patients with multiple myeloma at ASH Research Collaborative network sites. A study application was accessed with a QR code and shared with patients during usual clinical care. Patients provided consent, optionally gave permission for electronic health record data collection, and completed patient-reported outcomes (EORTC QLQ-C30 and MY20) at baseline, Day 30, and Day 180 through the study portal. Clinicians at participating sites facilitated study enrollment and shared best practices monthly to accelerate study execution. Study objectives related to feasibility of data collection in a decentralized format are reported in a separate abstract. Here, we report interim results related to SARS-CoV-2 vaccination history, COVID-19 infection, and how these relate to patient reported outcomes and clinical outcomes in enrolled participants. Results: The COSMIC study rapidly accrued and consented 200 patients from eight participating ASH Research Collaborative sites over four months (1/22/2024 through 5/17/2024). Consented participants' ages ranged from 29 to 93 years, with median of 67 years; 46% were female, 69% were non-Hispanic White (NHW), 17% were non-Hispanic Black (NHB), and 8% were Hispanic/Latino. Of the 196 patients who reported COVID-19 data, 111 (57%) reported at baseline that they had a history of COVID-19 infection, with 12 having required hospitalization for this (12/111=11%). Overall, 95% (186/196) reported a history of COVID-19 vaccination, where the median number of vaccinations was 4 (range: 1 to 6); 44 patients (23%) expressed willingness to discuss getting a yearly booster vaccine with their provider. At 1-month follow-up, there were 3 additional patients who reported a COVID-19 infection and 18 patients who received an additional COVID-19 vaccination. The baseline EORTC QLQ-C30 median Global Health Status/QOL score was 66.7 (mean=64.4, range: 8.3 - 100, n=196). This overall global QOL score was not significantly different between those who did vs. did not have a history of COVID-19 infection (mean [SD]: 63.7 [19.3] vs. 65.8 [17.6]; p=0.57). In analyses adjusted for age, biological sex, and race/ethnicity group, history of COVID-19 infection was not associated with HRQOL (odds ratio=0.93, 95% CI: 0.78 - 1.10; p=0.38). Data collection is ongoing and final study results will be reported at a later date. Conclusion: COSMIC is a prospective, decentralized study within a site-based provider network conducted by the ASH Research Collaborative Multiple Myeloma Program that demonstrates the feasibility of using an innovative evidence generation strategy to drive rapid accrual of patients to address a rapidly evolving area of need. The COSMIC study also provides proof of concept that a real-world evidence generation network can play an important role in national pandemic preparedness and response. The COSMIC experience reinforces the ability to accrue diverse patient populations representing the demographic of myeloma patients in the US.

Background and significance: Light chain (AL) amyloidosis is a plasma cell malignancy characterized by the production of amyloidgenic clonal light chains that deposit in various tissues. The addition of daratumumab to bortezomib, cyclophosphamide and dexamethasone (Dara-VCD) has improved the depth of hematologic and organ responses and is an approved induction therapy in newly diagnosed AL amyloid patients (DOI: 10.1056/NEJMoa2028631). However, this approach has not yet demonstrated an overall survival (OS) benefit and follow up remains short. With strict adherence to eligibility criteria, in particular severity of cardiac involvement, autologous stem cell transplantation (ASCT) as consolidative therapy is safe with transplant related mortality on par with multiple myeloma. This approach generates deep and sustained responses, but it is unclear if it offers an additional survival benefit following Dara-VCD induction. The only randomized trial evaluating the role of ASCT in AL amyloid is outdated (DOI: 10.1056/NEJMoa070484) and no randomized data exist to inform the optimal use of ASCT in the era of Dara-VCD induction. Furthermore, multi-organ involvement in AL amyloid drives morbidity and mortality thus the impact of any consolidative therapy on cardiac and renal involvement in addition to overall survival but must be defined. Finally, the approval of Dara-VCD therapy was based on complete hematologic response rates but there is increasing data demonstrating that achieving minimal residual disease (MRD) negativity by either bone marrow next generation flow cytometry (DOI: 10.1002/ajh.26562) or peripheral blood mass spectrometry (DOI: 10.1038/s41408-020-0291-8) generates improved organ response, hematologic progression free survival, and possibly OS. Methods: This randomized phase 3 SWOG led intergroup trial (S2213; NCT06022939) is being conducted within the United States and will accrue a total of 143 participants per arm. The primary endpoint will compare MOD-PFS (major organ deterioration progression free survival: defined as time from randomization to death, cardiac/renal progression, or hematologic progression) between participants receiving an ASCT with those receiving 3 cycles of Dara-VCD consolidation following 3 cycles of uniform Dara-VCD induction. Following the assigned consolidation, all patients will receive 18 months of daratumumab maintenance therapy. A median MOD-PFS of 31 months is anticipated in the non-ASCT arm. This study has 90% power and a two-sided significance level of 0.05 to detect a hazard ratio of 0.62 corresponding to a MOD-PFS of 50 months in the ASCT arm. Important additional endpoints include OS, hematologic PFS, cardiac and renal responses, MRD negativity both by peripheral blood mass spectrometry and bone marrow next generation flow cytometry, delayed utilization of ASCT, and quality of life. Key inclusion criteria include non-severe cardiac AL amyloid (NT-proBNP <5000; TnT < 0.06; NYHA I or II, EF ≥ 40%), CrCl ≥30 mL/min, serum dFLC > 2 mg/dL, and supine systolic BP ≥ 90 mmHg. Importantly, patients are permitted to have up to one full cycle or 28 days of any plasma cell directed therapy prior to enrollment. This trial was activated on 12/1/2023 with the first patient enrolled 07/01/2024. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819; and in part by Janssen Pharmaceuticals Inc. of Johnson & Johnson (now J&J Innovative Medicine).

TPS7575 Background: Light chain (AL) amyloidosis is a plasma cell malignancy characterized by the production of amyloidgenic clonal light chains that deposit in various tissues. The addition of daratumumab to bortezomib, cyclophosphamide and dexamethasone (Dara-VCD) has improved depth of hematologic and organ responses. However, this approach has not yet demonstrated an overall survival (OS) benefit with short follow-up. Autologous stem cell transplant (ASCT) consolidation remains safe and is associated with deep and durable hematologic responses with an 83% 2-year progression free survival (PFS) and up to 72% of patients achieving a VGPR or better, comparable to Dara-VCD (79%). In multiple myeloma, ASCT improved PFS even in patients who are MRD negative at the end of standard induction therapy. It is thus reasonable to consider that ASCT might provide similar benefits in AL patients. No randomized data exist to inform the optimal use of ASCT in the era of Dara-VCD. Methods: This randomized phase 3 SWOG led intergroup trial will accrue a total of 143 participants per arm and compare MOD-PFS (major organ deterioration progression free survival: defined as time from randomization to death, cardiac/renal progression, or hematologic progression) between participants receiving an ASCT with those receiving Dara-VCD consolidation following uniform Dara-VCD induction. A median MOD-PFS of 31 months is anticipated in the non-ASCT arm. This study has 90% power and a two-sided significance level of 0.05 to detect a hazard ratio of 0.62 corresponding to a MOD-PFS of 50 months in the ASCT arm. Important additional endpoints include OS, hematological PFS, cardiac and renal responses and progression, MRD negativity both by peripheral blood mass spectrometry and bone marrow next generation flow cytometry, delayed utilization of ASCT, and quality of life. This trial was activated on 12/1/2023. Funding: NIH/NCI/NCTN grants and in part by Janssen Pharmaceuticals. Clinical trial information: NCT06022939 . [Table: see text]

Background: Multiple myeloma (MM) is characterized by somatic mutations involving cancer-associated genes. The MyDRUG trial was initiated to explore the efficacy of specific molecularly-targeted therapies in combination with a standard triplet combination in MM. Methods: MyDRUG (NCT03732703) is a genomically-guided umbrella trial for patients with functional high-risk MM, defined as early relapse following primary therapy (3 years for transplant with maintenance, 18 months without), with specific genetic abnormalities. Patients with no actionable mutation or mutations with allelic burden below 30% were randomly assigned to one of the “non-actionable” arms. Here we present the data for the Y3 arm which combines selinexor (60mg po days 1,8,15), ixazomib (4mg po days 1,8,15), pomalidomide (3mg po days 1-21) and dexamethasone (40mg po weekly) (Seli-IPD), given on a 28-day cycle. The primary objective of the Y3 sub-protocol was to evaluate the overall response rate (ORR) according to the International Myeloma Working Group consensus criteria. Secondary objectives included assessment of adverse events (AEs). Results: 17 patients were enrolled into the Y3 arm. The average age was 62 (51-79), 65% were male with a median of 29 months since initial diagnosis and a median of 2 prior lines of therapy. The ORR (> PR) was 52.9% with a clinical benefit rate (> MR) of 58.8%. The median progression free survival was 10.2 months ( 95% CI: 3.9; 12.9) with a median overall survival which has not yet been reached; with all 17 patients still alive at the current data cutoff. No dose-limiting toxicities were seen. Eight patients (47.1%) experienced a serious AE with 2 patients (11.8%) experiencing an AE leading to treatment discontinuation. Two patients (11.8%) required dose reductions. The most common non-hematologic AEs were fatigue, nausea and constipation; all of which were grade 1 and 2. Conclusions: In this platform study of patients with relapsed, functionally high-risk MM, patients who received Seli-IPd exhibited significant efficacy and a manageable AE profile. Furthermore, this provides an all-oral option for patients wishing to minimize their office visits and parenteral therapy administrations.

Abstract Amyloid light-chain (AL) amyloidosis is a rare, typically fatal disease characterized by the accumulation of misfolded immunoglobulin light chains (LCs). Birtamimab is an investigational humanized monoclonal antibody designed to neutralize toxic LC aggregates and deplete insoluble organ-deposited amyloid via macrophage-induced phagocytosis. VITAL was a phase 3 randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of birtamimab + standard of care (SOC) in 260 newly diagnosed, treatment-naive patients with AL amyloidosis. Patients received 24 mg/kg IV birtamimab + SOC or placebo + SOC every 28 days. The primary composite end point was the time to all-cause mortality (ACM) or centrally adjudicated cardiac hospitalization ≥91 days after the first study drug infusion. The trial was terminated early after an interim futility analysis; there was no significant difference in the primary composite end point (hazard ratio [HR], 0.826; 95% confidence interval [CI], 0.574-1.189; log-rank P = .303). A post hoc analysis of patients with Mayo stage IV AL amyloidosis, those at the highest risk of early mortality, showed significant improvement in the time to ACM with birtamimab at month 9 (HR, 0.413; 95% CI, 0.191-0.895; log-rank P = .021). At month 9, 74% of patients with Mayo stage IV AL amyloidosis treated with birtamimab and 49% of those given placebo survived. Overall, the rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were generally similar between treatment arms. A confirmatory phase 3 randomized, double-blind, placebo-controlled clinical trial of birtamimab in patients with Mayo stage IV AL amyloidosis (AFFIRM-AL; NCT04973137) is currently enrolling. The VITAL trial was registered at www.clinicaltrials.gov as #NCT02312206.