Reagan, John L.

Abstract Background: MyeloMATCH is an NCI-sponsored initiative for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) employing a Master Screening and Reassessment Protocol (MSRP) to assign patients (pts) to a pt and disease biology-specific clinical trial. Several trials evaluating initial therapies are currently open, while subsequent trials dedicated to eradicating measurable residual disease during consolidation and including stem cell transplant are being developed. A pt enrolled at diagnosis may be followed longitudinally and be eligible for trials in sequential tiers throughout the treatment course. We report key data concerning the first cohort of pts enrolled on the MSRP. Methods: After pts with suspected AML or MDS consent for the MSRP, blood and marrow are sent to the myeloMATCH Molecular Diagnostics Network (MDNet) of central CLIA labs operating under a single Investigational Device Exemption to rapidly define molecular, cytogenetic, and immunophenotypic characteristics. These data are catalogued by a bioinformatics team (MATCHBox) and reviewed daily to assign participants to an available trial based on pt and disease features. A Tier Advancement Pathway (TAP) allows standard of care therapy with potential for assignment to subsequent myeloMATCH trials. Since activation in May 2024, 550 patients age≥18 were enrolled on the MSRP from 76 institutions: 48 Academic, 14 NCORP, 11 community, 3 VA. There are currently 4 open randomized AML trials (≥age 60 or unfit with mutant FLT3, ≥age 60 IDH2 mutant AML, fit age<60 ELN 2017 intermediate-risk AML, fit age<60 ELN 2017 adverse risk) and 1 MDS trial(IDH2 mutant). Patients not eligible for an open protocol were assigned to TAP. Results: Of the 550 pts consented, 491 completed screening assays; 49 had no or incomplete samples; 10 withdrew before completed analysis. Median cytogenetic turnaround time (TAT) was 69 hours (91% within 72 hours), and median Next Generation Sequencing (NGS) TAT from receipt was 49 hours (95% within 72 hours). Seventy-six pts (of 491 with assay data) were not assigned due to non-AML or non-MDS diagnoses, the most common being: B-ALL [n=11], MPN [9], benign marrow [9], APML [7], and MPAL [6]. The AML/MDS verified cohort was 415 pts, 366 (89.2%) patients with AML (45% age <60) and 49 (11.8%) with MDS. The median age at screening was 63 years (range:18-95) and 186 (45%) were female. Eighty-two percent identified as White, 7.5% Black, 3% Asian, 7% unknown, and 9% as Hispanic. The most frequent mutations in the AML pts were NPM1 (24.0%), DNMT3A (22.7%), TET2 (19.9%), NRAS (18.0%), FLT3 (18.0% ITD, TKD 7.1%), TP53 (14.5%), and CEBPA (8.7%); IDH1/2 mutation rates were 8.2% and 13.7%, respectively. Co-mutations include FLT3/NPM1 (9.8%), NPM1/IDH2 (4.4%), IDH1/2 and any RAS (3.8%). Karyotypes were normal in 40.4%, complex 20.8%, inv(16) 6.0%, MLL/KMT2A 4.6% and t(8;21) 1.9%. 29% had favorable risk disease, 29% intermediate, and 42% adverse (ELN 2017). In MDS, mutations included: TP53 (36.7%), RUNX1 (20.4%) ASXL1 (20.4%), TET2 (18.4%), spliceosome mutations (SRSF2, SF3B1, U2AF1 and ZRSR2, 28.6%) andIDH1/2 in 4.1% and 6.1%, respectively. Karyotypes were normal in 24.5%; complex in 40.8%. By IPSS-R, 2.4% were low, 73.8% intermediate, 2.4% high, and 21.4% very high risk. 82/415 (20%) pts were assigned to initial therapy protocol, with an increase in assignment rate to 44% in the most recent two months. 71/415 pts (16%) were enrolled in one of the MyeloMATCH studies. Three-hundred forty-four pts (80%) were assigned and enrolled to TAP (296 AML, 48 MDS) for potential assignment to subsequent tier trials. In the TAP AML pts, 99 (33%) have completed initial treatment, including intensive chemotherapy (IC) in 62% of pts and hypomethylating agents/venetoclax (HMA/VEN) in 38%. In pts <60 years of age, 87% received IC v. 13% with HMA/VEN, in >60 34% IC v. 66% HMA/VEN and in age 60-75 42% IC v. 58% HMA/Ven. Conclusion: MyeloMATCH has screened over 500 pts from academic and community sites in the US and Canada in 14 months, meeting the TAT goal of sample acquisition to results of <72 hours. Assignment to treatment protocols has substantially increased recently. As additional trials open (12 in development) we expect the percentage of pts enrolled on MSRP who go on to therapeutic trials will markedly increase, thereby allowing a personalized medicine approach for a broad group of US and Canadian adult pts with AML and MDS.

Background: Randomized studies in newly diagnosed (ND) AML patients with a FLT3 mutation show that adding 14 days of a FLT3 inhibitor to each intensive chemotherapy cycle improves overall survival. For patients unsuitable for intensive chemotherapy due to older age or comorbidities, the presence of a FLT3-ITD mutation is associated with high rates of early relapse and short remission duration. There is a limited survival benefit of venetoclax (ven) plus azacitidine (aza) compared to aza alone among patients with AML with a FLT3-ITD mutation. Accordingly, there is significant interest in adding FLT3-targeted therapy to lower intensity chemotherapy for patients with ND AML and FLT3 mutations, but to date no randomized data have demonstrated a survival benefit for this approach.Gilteritinib (gilt) is a highly potent and FLT3-selective oral tyrosine kinase inhibitor that is the standard therapy of relapsed/refractory FLT3-mutated AML, based upon superior survival in randomized studies. Gilt can also be combined safely with ven and/or aza, though myelosuppression remains a concern. Despite this, single institution studies of ven, aza, and gilt therapy of ND AML patients with FLT3-mutations show that this three-drug regimen is associated with near-universal complete remission rates (CR 90%, CRi 6%) and a majority of studied patients eliminate detectable FLT3-ITD (<1 x10-5) within four cycles by an ultrasensitive, amplicon-based NGS assay (Short, et al. JCO 2024). Rates of CR with full count recovery and survival appear superior to historical comparisons, but myelosuppression is potentially increased with the triplet regimen. These data demonstrate a need for multi-institutional comparative trials, not only to determine whether adding FLT3-inhibitors to ven and aza improve deep remission rates, but also to refine schedules of the triplet combination that improve tolerability for widespread use.Methods: This tier 1 MyeloMATCH substudy is an open-label, randomized phase 2 trial that will enroll ND AML patients older than age 60 or individuals judged by their treating physician to be best served by azanucleoside + ven-based therapy due to comorbidity. Subjects provide samples to the central MyeloMATCH Master Screening and Reassessment Protocol (MSRP, NCT05564390 ) and are assigned to the MM1OA-EA02 substudy (NCT06317649) based upon the presence of a FLT3-ITD or FLT3-TKD (D835) mutation by NGS. Subjects are randomized to one of three arms (regimens 1, 2, or 3), stratified by age (<70 years vs. older) and FLT3-ITD burden (ITD VAF>33% vs. lower VAF or D835). All study arms contain aza and ven administered in 28-day cycles with two study arms also including gilt. Regimen 1 is ven and aza administered as per the pivotal VIALE-A study. Regimen 2 adds gilt 80 mg once daily on days 1-28 and regimen 3 adds gilt on days 8-21 only. A marrow biopsy is performed during the first cycle (day 14-21, depending on study arm) and all chemotherapy is held until count recovery if a morphologic leukemia-free state or aplasia is seen. Patients receive up to two induction cycles to achieve remission and then receive ongoing consolidation cycles of therapy with a similar pattern of gilt administration up to 2 years. To minimize risk of cumulative myelosuppression, during consolidation azacitidine administration is reduced to days 1-5 on regimens 2 and 3 and ven limited to days 1-7 on regimen 2 and days 1-14 on regimen 3. For all arms, treatment-related adverse events prompt further reduction in ven, aza, or gilt dose or duration. Response will be measured after cycles 2 and 4, including centrally-performed MRD by flow cytometry. The primary endpoint is the rate of MRD(-) CR (<1 x 10-3) after up to 4 cycles. Key secondary endpoints include safety data, response rate, EFS, and OS. The study is powered to detect a 25% absolute improvement in MRD(-) CR rate in either triplet arm from a target accrual of 147 patients. A safety run-in for regimens 2 and 3 to confirm tolerability and feasibility will be performed after 20 subjects enroll to these arms; an interim futility analysis will be performed once response assessment of 50% of all planned accrual occurs. Study was activated on June 6, 2024 and is expected to continue until December 2025.

Abstract Introduction: IgM-secreting myeloma is rare, encompassing about 1% of all the myeloma cases. Given its rarity, the characteristics and survival of these patients have not been extensively studied. Therefore, we carried out a multicenter retrospective study in patients with IgM myeloma. Methods: The study protocol was reviewed and approved by the Institutional Review Board of each participating institution. Clinical data were gathered and included age, sex, hemoglobin, calcium, LDH, estimated glomerular filtration rate (GFR), presence of lytic bone lesions, International Staging System score, cytogenetic abnormalities, final outcome and overall survival (OS) time. OS was defined as the time in months from diagnosis to last follow-up or death. The Chi-square and the rank-sum tests were used to compare categorical and continuous variables, respectively. The Kaplan-Meier method was used to estimate OS and the log-rank waas used to compare groups. The Cox proportional-hazard regression method was used to fit univariate and multivariate survival models, reported as hazard ratio (HR) with 95% confidence intervals (CI). All reported p-values are two-sided, and were considered significant if less than 0.05. Results: A total of 159 patients with IgM myeloma from 20 centers from Europe, USA and Latin America were included in this analysis. Patients were diagnosed between 1996 and 2015. The median age at diagnosis was 65 years (range 37-86 years) with a male predominance (68%). The median serum IgM level was 2510 mg/dl (range 27-12,100 mg/dl) with 25% of patients having a serum IgM within normal limits but an IgM monoclonal spike detectable in serum electrophoresis. Hemoglobin levels <10 g/dl were seen in 49 patients (32%), serum calcium was elevated in 24 (16%), estimated GFR of 60 ml/min or less in 56 (37%), lytic lesions were detected in 86 (58%), and serum LDH was elevated in 28 (24%). ISS scores of 1, 2 and 3 were seen in 53 (36%), 63 (43%) and 31 (21%) of patients, respectively. Although immunohistochemistry and/or flow cytometry data were limited, CD20 expression was seen in 15/26 (58%) and cyclin D1 in 10/15 (67%) patients. The most common cytogenetic abnormalities were t(11;14) in 26/67 (39%), del13q in 25/76 (33%) and del17p in 6/76 (8%) patients. 149 patients (94%) received at least one line of systemic therapy for myeloma of which 13 (9%) received rituximab as part of initial therapy. After a median follow-up of 47 months, 74 patients (47%) have died. The median OS was 62 months (95% CI 51-79 months). Cause of death was known in 38 patients, and the most common was myeloma progression (74%). IN the univariate analysis, prognostic factors associated with a worse OS were age (HR 1.03, 95% CI 1.01-1.06; p=0.01) and ISS score (ISS 2: HR 1.43, 95% CI 0.83-2.48; p=0.2, and ISS 3: HR 3.03, 95% CI 1.54-5.98; p=0.001, using ISS 1 as reference group), while male sex was associated with a better OS (HR 0.56, 95% CI 0.34-0.90; p=0.02). Hemoglobin, calcium, estimated GFR and lytic lesions were not associated with OS. In the multivariate analysis, male sex was associated with a better OS (HR 0.57, 95% CI 0.35-0.95; p=0.03) and ISS with worse OS (ISS 2: HR 1.57, 95% CI 0.89-2.74; p=0.12, and ISS 3: HR 2.76, 95% CI 1.38-5.55; p=0.004, using ISS 1 as reference group). Conclusion: Patients with IgM myeloma apparently present with similar clinical characteristics as patients with non-IgM myeloma. Pathologically, CD20 and cyclin D1 expression is common. The most common cytogenetic abnormalities identified were t(11;14) and del13q. Survival does not appear shorter than non-IgM myeloma patients, and the ISS appears to have similar prognostic value. Disclosures Castillo: Millennium: Research Funding; Janssen: Honoraria; Otsuka: Consultancy; Biogen: Consultancy; Abbvie: Research Funding; Pharmacyclics: Honoraria. Ghobrial:Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Noxxon: Honoraria; Amgen: Honoraria. Hájek:Celgene: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; BMS: Honoraria; Takeda: Consultancy. Hungria:International Myeloma Foundation Latin America: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Consultancy; Roche: Consultancy; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding, Speakers Bureau. Reagan:Alexion: Honoraria; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees. Spicka:Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria. Gertz:Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Prothena Therapeutics: Research Funding; Ionis: Research Funding; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria; Annexon Biosciences: Research Funding.

AbstractIgM myeloma is a rare hematologic malignancy for which the clinicopathological features and patient outcomes have not been extensively studied. We carried out a multicenter retrospective study in patients with diagnosis of IgM myeloma defined by >10% marrow involvement by monoclonal plasma cells, presence of an IgM monoclonal paraproteinemia of any size, and anemia, renal dysfunction, hypercalcemia, lytic lesions and/or t(11;14) identified by FISH. A total of 134 patients from 20 centers were included in this analysis. The median age at diagnosis was 65.5 years with a male predominance (68%). Anemia, renal dysfunction, elevated calcium and skeletal lytic lesions were found in 37, 43, 19, and 70%, respectively. The median serum IgM level was 2,895 mg dL−1 with 19% of patients presenting with levels >6,000 mg dL−1. International Staging System (ISS) stages 1, 2, and 3 were seen in 40 (33%), 54 (44%), and 29 (24%) of patients, respectively. The malignant cells expressed CD20 (58%) and cyclin D1 (67%), and t(11;14) was the most common cytogenetic finding (39%). The median overall survival (OS) was 61 months. Higher ISS score was associated with worse survival (P = 0.02). Patients with IgM myeloma present with similar characteristics and outcomes as patients with more common myeloma subtypes.