Highlights of the 66th American Society of Hematology Annual Meeting and Exposition

(#ASH24; December 7-10, 2024, in San Diego, California).

· Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma.

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Among patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring.

The results of this study were presented by Professor M.A. Dimopoulos and published in the New England Journal of Medicine. In this study (AQUILA trial; NCT03301220), patients with high-risk smoldering multiple myeloma (n= 390) were randomly assigned to receive either subcutaneous daratumumab monotherapy (n=194) or active monitoring (n=196). Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary endpoint was progression-free survival (PFS), progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). PFS at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (HR, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified.

· Belantamab Mafodotin, Bortezomib, and Dexamethasone Vs. Daratumumab, Bortezomib, and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Overall Survival Analysis and Updated Efficacy Outcomes of the Phase 3 Dreamm-7 Trial.

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During the presentation of the results, the overall survival (OS) analysis was updated, demonstrating that “belantamab mafodotin, bortezomib, and dexamethasone (BVd) had an early, sustained, and statistically significant benefit in OS vs. daratumumab, bortezomib, and dexamethasone (DVd)”.

This follow-up update was presented by Dr. V. Hungria. DREAMM-7 (NCT04246047) is a global, 1:1 randomized, open-label, phase 3, head-to-head trial comparing the efficacy and safety of 2 triplets—belantamab mafodotin, bortezomib, and dexamethasone (BVd) vs. daratumumab, bortezomib, and dexamethasone (DVd)—in patients with progression of multiple myeloma after ≥1 prior line of therapy.

In total, 494 patients were randomly assigned to receive BVd (n=243) or DVd (n=251).  At a median follow-up of 28.2 (range, 0.1-40.0) months, the primary endpoint was met, with a median progression-free survival of 36.6 months (95% confidence interval [CI]):28.4-not reached [NR]) with BVd and 13.4 months (95% CI: 11.1-17.5 months) with DVd (hazard ratio [HR], 0.41; 95% CI, 0.31-0.53; p<0.001). BVd was associated with higher rates of complete response or better plus measurable residual disease-negativity (25% vs. 10%) and a more favorable restricted mean duration of response (p<0.001) than DVd. Overall survival (OS) rate at 18 months with BVd vs. DVd was 84% vs. 73%, respectively. Median OS was NR in either arm at this first interim analysis. The OS analysis was updated, demonstrating that BVd (n=243; events 68) had an early, sustained and statistically significant benefit in OS vs. DVd (n=251; events 103) (HR 0.58; 95% CI 0.43-0.79; p=0.00023). Median OS was not reached. The model-based predicted median OS is 84 months with BVd and 51 months with DVd.

· Effects of Intravenous Immunoglobulin Supplementation (IVIG) on Infections in Recipients of Teclistamab Therapy for Multiple Myeloma (MM): A Multi-Institutional Study.  

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Administering IVIG within the first 60 days of starting teclistamab or at any time before the first documented infection (“primary IVIG prophylaxis”) reduces the risk of high-grade infections in patients receiving teclistamab therapy. IVIG administration within the past 30 days may lower the risk of high-grade and bacterial infections.

Primary IVIG prophylaxis was defined as administering IVIG within the first 60 days of starting the teclistamab or any time before the first documented infection. Secondary IVIG prophylaxis was defined as IVIG administration before the start of teclistamab. For this analysis, patients who were started on IVIG after a documented infection were included in the “no IVIG prophylaxis” group. Infection data was collected up to 60 days after the last dose of teclistamab.

A total of 168 patients with a median follow up of 8.5 months were included in this analysis. The median age was 70 (range 31-89) years with 49% (n=82) of patients ≥70 years of age. The median number of prior lines of therapy was 5 (range 1-12). Most patients (95%, n=160) had at least one prior autologous stem cell transplantation. A third of the patients had a prior BCMA directed therapy, mostly chimeric antigen receptor T-cell therapy. The median duration of teclistamab therapy was 4.6 months and median number of doses of teclistamab was 15. While all patients received herpes zoster prophylaxis, 73% (n=122) of patients were on primary Pneumocystis jirovecii prophylaxis. 42% (n=71) of patients received IVIG, with the majority being primary IVIG prophylaxis (n=63). The most common dosing schedule for IVIG was 0.4mg/kg every 4 weeks.

In this context, 181 infections were recorded for 92 patients. 53% of the infections were bacterial, occurring in 61 patients. 42% of infections were viral, occurring in 52 patients. There were 9 fungal infections in 7 patients. Among these , 55% were ≥ grade 3 with 57% of these events requiring inpatient hospitalization.  The effects of IVIG are stronger for bacterial infections at earlier time points (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.23-0.77; p=0.005) compared to later time points of 31-60 days and >60 days. Timing of IVIG therapy did not influence the incidence of viral infections. Other factors associated with increased risk of infection on multivariate analysis included use of tocilizumab for cytokine release syndrome (HR 1.54, 95% CI 1.07-2.21; p=0.019) and number of prior infections (HR 1.30, 95% CI 1.14-1.50; p<0.001).

In her presentation, Dr. H. Cheruvalath mentioned an “impact on overall survival in favor of primary IVIG prophylaxis with a mean of 44 months vs. 15 months in the non-primary IVIG prophylaxis group (p=0.007 at 36 months)”.

· Ibrutinib-Rituximab Is Superior to Rituximab-Chemotherapy in Previously Untreated Older Mantle Cell Lymphoma Patients: Results from the International Randomised Controlled Trial, Enrich.

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ENRICH is the first randomised trial to demonstrate a significant improvement in progression-free survival (PFS) for ibrutinib-rituximab (IR) compared to rituximab-chemotherapy (R-chemo) in mantle cell lymphoma (MCL).

This work was presented by Professor D. J. Lewis. In this clinical trial, patients ≥60 years (yrs) with untreated, stage II-IV mantle cell lymphoma (MCL) were randomised to IR or R-chemo, stratified by clinician choice of bendamustine-rituximab (BR) or rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP). Treatment consisted of 6-8 cycles of chemotherapy or daily ibrutinib, both in combination with 6-8 cycles of rituximab in the schedule of pre-randomization choice of chemotherapy. Maintenance rituximab (MR) was given in both arms for 2 yrs and intervention participants continued daily ibrutinib until disease progression or unacceptable toxicity. The primary outcome was PFS.

Between December 2015 and June 2021, 397 patients were randomised to IR (n=199) and R-chemo (n=198; R-CHOP n=53, BR n=145) from 65 United Kingdom and Nordic sites. Median age was 74 yrs, 74.6% were male, 94.5% had ECOG 0-1, 56.5% had a high-risk MIPI (MCL international prognostic index) score, and 6.4% had blastoid MCL. The median follow-up was 47.9 months. The PFS with IR was superior to R-chemo, with a hazard ratio (HR) of 0.69, (95% CI 0.52-0.90, p=0.003), median PFS was 65.3 vs. 42.4 months, respectively. There were 94/199 (47.2%) PFS events in the IR arm compared to 121/198 (61.1%) in the R-chemo arm, of which 49 (52.1%) and 77 (63.6%) were progressive disease, respectively. When PFS was analyzed by choice of chemotherapy, IR was superior to R-CHOP, and comparable to BR despite more Covid-19 events in the IR arm. Hematological toxicity was lower with IR. Grade ≥3 atrial fibrillation was reported in 6.6% of IR and 0.5% of R-chemo participants. Further data on high-risk subgroups, including those with TP53 mutation will be presented. The 5-yr overall survival for IR was 57.7% compared to 54.5% for R-Chemo, HR = 0.87 (95% CI 0.64-1.18). 

· Lack of Benefit of Autologous Hematopoietic Cell Transplantation (auto-HCT) in Mantle Cell Lymphoma (MCL) Patients (pts) in First Complete Remission (CR) with Undetectable Minimal Residual Disease (uMRD): Initial Report from the ECOG-ACRIN EA4151 Phase 3 Randomized Trial.

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In this interim analysis, mantle cell lymphoma (MCL) patients (pts) in first complete remission (CR) with undetectable minimal residual disease (uMRD) at 1 in 10^-6 sensitivity (uMRD6) did not benefit from consolidative autologous hematopoietic cell transplantation (auto-HCT). Pts who remain MRD+ after induction may benefit from auto-HCT.

This research was presented by Dr. T.S. Fenske. EA4151 is a four-arm trial of pts with MCL between the ages of 18 and 70 years in first CR. After induction, pts underwent positron emission tomography/computed tomography, bone marrow biopsy, and the clonoSEQ® MRD assay from peripheral blood. Pts in CR with uMRD6 were randomized 1:1 to Arm A (auto-HCT + 3 years of maintenance rituximab [MR]) or Arm B (3 years of MR alone), stratified by MIPI-c score and intensive vs. non-intensive induction. Pts with either MRD-positive (MRD+) CR or MRD-indeterminate CR (Arm C and Arm D, respectively) both received auto-HCT + 3 years of MR. Pts who were MRD+ pre-transplant had MRD assessment repeated at day 100. The primary endpoint was to compare overall survival (OS) in Arms A and B, with secondary endpoints including progression-free survival (PFS).

From Aug 2017 to July 2024, 650 pts were assigned to a treatment arm with 257, 259, 49, and 85 pts enrolled in Arms A, B, C, and D, respectively. Median age was 60 years (range, 27-70). Induction was intensive (defined as high-dose cytarabine-containing) in 73% and non-intensive in 27%. The estimated OS hazard ratio (HR) for Arm A vs. B in all randomized (n=516) and pts treated as assigned (n=375) was 1.11 (95% confidence interval [CI]  0.71-1.74, p=0.66) and 1.00 (95% CI 0.58-1.74, p=0.99), respectively, and crossed the futility boundary. The 3-year OS for Arms A and B were 82.1% and 82.7%, respectively, in all randomized pts, and 86.2% and 84.8%, respectively, in pts treated as assigned. The estimated PFS HR for Arm A vs. B in all randomized and pts treated as assigned were 1.05 (95% CI 0.71-1.56, p=0.79) and 0.95 (95% CI 0.59-1.54, p=0.84), respectively. The 3-year PFS for Arms A and B were 76.6% and 77.4% in all randomized pts, and 81.5% and 80.4%, respectively, in pts treated as assigned. For Arm C, 3-year OS and PFS were 81.9% (95% CI 69.6-96.4%) and 76.9% (95% CI 64.4-91.7%), respectively. For Arm D, 3-year OS and PFS were 85.1% (95% CI 76.0%-95.4%) and 73.4% (95% CI 62.7-85.9%), respectively. For the intensive induction group, 3-year OS was 83.0% vs. 86.2% for Arm A vs. B (p=0.30), while in the non-intensive induction group, 3-year OS was 79.5% vs. 72.8% for Arm A vs. B (p=0.48).

· Tafasitamab Plus Lenalidomide and Rituximab for Relapsed or Refractory Follicular Lymphoma: Results from a Phase 3 Study (inMIND).

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Addition of tafasitamab (tafa) to lenalidomide plus rituximab (len+R) resulted in significant and clinically meaningful improvement in progression-free survival (PFS), representing a 57% reduction in risk of progression, relapse, or death in patients (pts) with relapsed/refractory follicular lymphoma (R/R FL).

Professor L. Sehn presented the findings. Pts ≥18 years with CD19+ and CD20+ R/R FL (grade 1-3A), requiring treatment after ≥1 prior systemic therapy including an anti-CD20 monoclonal antibody (mAb), were randomized 1:1 to receive intravenous tafa 12 mg/kg or  placebo (pbo) on days (D) 1, 8, 15, and 22 of cycles (C) 1-3 and D1 and D15 of C4-12 with standard dosing of len+R for up to twelve 28-day cycles. Primary endpoint was investigator-assessed PFS, planned for analysis after 174 events were observed. 

548 pts with FL were randomized: tafa, n=273; pbo, n=275.  With median follow-up of 14.1 months (mo), addition of tafa to len+R resulted in significantly lower risk of progression, relapse, or death vs. pbo (median investigator-assessed PFS, 22.4 mo vs. 13.9 m; hazard ratio [HR] [95% CI], 0.43 [0.32, 0.58]; P<0.0001). PFS benefit with tafa was consistent in all prespecified subgroups analyzed, including: pts with progression of disease within 2 years (POD24), pts refractory to prior anti-CD20 mAb, pts receiving multiple prior lines of treatment.  Duration of response was improved with tafa vs. pbo (median 21.2 mo vs. 13.6 mo; HR [95% CI], 0.47 [0.33, 0.68]; P<0.0001), as was time to next treatment (median NR vs. 28.8 mo; HR [95% CI], 0.45 [0.31, 0.64]; P<0.0001). A similar rate of treatment-emergent adverse events (TEAEs), grade 3 or 4 adverse events (AEs) (71% vs. 69.5%), and serious AEs (36% vs. 32%) were observed with tafa and pbo, respectively. Most common grade 3 or 4 AEs with tafa vs. pbo were neutropenia (40% vs. 38%), pneumonia (8% vs. 5%), thrombocytopenia (6% vs. 7%), and COVID-19 pneumonia (5% vs. 1%). TEAEs leading to discontinuation were reported by 11% and 7% of pts in tafa and pbo arms, respectively. In total, 15 pts (5.5%) in the tafa arm and 23 (8.5%) in the pbo arm died during the study, including 5 (2%) vs. 17 (6%) due to disease progression and 6 (2%) in each arm due to fatal AEs.

· Updated Results and Longer Follow-up from the AUGMENT-101 Phase 2 Study of Revumenib in All Patients with Relapsed or Refractory (R/R) KMT2Ar Acute Leukemia.

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Revumenib (an oral, potent, and selective menin inhibitor) monotherapy provides clinically meaningful responses in heavily pretreated patients (pts) with relapsed/refractory (R/R) rearrangements of the lysine methyltransferase 2A (KMT2Ar) acute leukemias, including those with high rates of measurable residual disease (MRD)-negativity and ability to proceed to hematopoietic stem cell transplant (HSCT). Continued treatment and follow-up of pts after the interim analysis demonstrate the durability of ongoing response. The safety profile of revumenib with this longer follow-up is consistent with prior reports.

This work, the largest trial to date evaluating a targeted therapy for pts with R/R KMT2Ar acute leukemias, was presented by Professor I. Aldoss. A total of 116 pts with R/R KMT2Ar AL received ≥1 dose of revumenib and were included in the safety population. Median age was 35.5 years (y) (range, 0.6-75.0); 28 (24%) pts were <18 y, and 14 (12%) were ≥65 y. A total of 95 (82%) pts had acute myeloid leukemia (AML), and 21 (18%) had acute lymphoblastic leukemia (ALL) or  mixed-phenotype acute leukemia (MPAL). Pts were heavily pretreated (median of 2 prior therapies [range, 1-11]), with 51 (44%) receiving ≥3 prior lines, 73 (63%) receiving prior venetoclax, and 59 (51%) underwent prior HSCT.

 In the efficacy population (n=97), 22 pts (23% [95% CI, 15%-32%]) achieved  complete remission (CR) and CR with partial hematologic recovery (CRh) with a median duration of response of 6.4 months (95% CI, 1.9 -months NR). Of 18 CR+CRh responders with available MRD results, 11 (61%) achieved MRD-negativity. Of 62 pts who achieved an overall response rate, 21 (34%) proceeded to HSCT. Nine pts resumed revumenib post-HSCT. The most common (≥10%) grade ≥3 adverse events were febrile neutropenia (45 [39%]), anemia (23 [20%]), platelet count decreased (19 [16%]), differentiation syndrome (17 [15%]; only 1 grade 4, no grade 5), neutrophil count decreased (17 [15%]), sepsis (16 [14%]), and QTc prolongation (15 [13%]; all grade 3).

Professor A. Zeidan conducted a podcast in which he further discussed a phase 1b study of another menin inhibitor (ziftomenib) in combination with azacitidine and venetoclax in the ongoing KOMET-007 study. “This regimen was well tolerated at the doses tested to date and continued to show promising clinical activity in R/R patients with nucleophosmin 1 (NPM1) or KMT2Ar mutated AML”.

· Long-Term Response Analysis of Transfusion Independence in Erythropoiesis Stimulating Agent–Naive Patients with Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes Treated with Luspatercept Vs. Epoetin Alfa in the COMMANDS Trial.

Highlight(s): 

In this analysis of long-term responses in the COMMANDS trial, luspatercept continued to demonstrate sustained and durable clinical benefit vs. epoetin alfa, maintaining responses of ≥1.5 years across multiple clinically relevant subgroups, including patients with ring sideroblast (RS)-negative status, low baseline serum erythropoietin, and non-mutated SF3B1.

The interim analysis of a phase 3 clinical trial was published in The Lancet journal last year Professor G. García-Manero presented the results of the analysis evaluating the long-term clinical value of luspatercept in COMMANDS (NCT03682536), including extended red blood cell (RBC)-transfusion independence (TI) and cumulative response (cumulative duration of RBC-TI was defined as the sum of all durations of RBC-TI for ≥ 12 or ≥ 24 weeks from week 1 to end of treatment [EOT]).

At data cutoff (Sept 22, 2023), 81/182 (44.5%) patients in the luspatercept arm and 50/181 (27.6%) patients in the epoetin alfa arm achieved a longest single RBC-TI period lasting ≥ 1 year, from week 1-EOT (common risk difference 16.7, 95% confidence interval [CI] 7.2-26.1, P = 0.0003; odds ratio [OR] 2.2, 95% CI 1.4-3.5). In all, 55 (30.2%) patients in the luspatercept arm and 25 (13.8%) patients in the epoetin alfa arm achieved a longest single RBC-TI period lasting ≥ 1.5 years (week 1-EOT; common risk difference 16.3, 95% CI 8.0-24.6, P < 0.0001; OR 2.8, 95% CI 1.6-4.8). The ≥ 1.5 year RBC-TI benefit with luspatercept vs. epoetin alfa was observed across prespecified subgroups, including those who were RS-negative (24.5% vs. 16.0%; OR 1.7, 95% CI 0.6-4.6), had baseline serum erythropoietin ≤ 200 U/L (35.9% vs. 15.3%; OR 3.1, 95% CI 1.8-5.5), and had non-mutated SF3B1 (21.5% vs. 13.9%; OR 1.7, 95% CI 0.7-4.2).

· Extended Treatment of Venous Thromboembolism with Reduced- Vs. Full-Dose Direct Oral Anticoagulants in Patients at High Risk of Recurrence.

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In patients with venous thromboembolism who need extended anticoagulation, the noninferiority of a reduced-dose versus a full-dose of direct anticoagulants to prevent recurrent venous thromboembolism could not be proven. In the reduced-dose group, clinically relevant bleeding and the composite of recurrent venous thromboembolism or clinically relevant bleeding were lower than in the full-dose group and did not appear to be offset by an increased risk of death or arterial thromboembolic events.

The Reduced-Dose Versus Full-Dose of Direct Oral Anticoagulant After Unprovoked Venous Thromboembolism (RENOVE) trial (ClinicalTrials.gov Identifier: NCT03285438) is an academic, multicenter, Prospective Randomized Open, Blinded Endpoint (PROBE) trial. This research was presented by Professor F. Couturand. In this study, the authors compared, using hierarchical sequential testing, extended anticoagulation with reduced-dose versus full-dose direct oral anticoagulants in patients with venous thromboembolism at high risk of recurrence initially treated for 6 to 24 months. Primary outcome was recurrent symptomatic venous thromboembolism (noninferiority hypothesis). 

During the 36-month median follow-up, recurrent venous thromboembolism occurred in 19 of 1383 patients in the reduced-dose group versus 15 of 1385 patients in the full-dose group (5-year cumulative incidence 2.2%; 95% confidence interval [CI], 1.1 to 3.3 versus 1.8%; 95% CI, 0.8 to 2.7; hazard ratio, 1.32; 95% CI, 0.67 to 2.60; P=0.23 for noninferiority). Clinically relevant bleeding occurred in 96 and 154 patients in the reduced- and full-dose groups, respectively (5-year cumulative incidence 9.9%; 95% CI, 7.7 to 12.1 versus 15.2%; 95% CI, 12.8 to 17.6). The composite outcome occurred in 113 and 166 patients in the reduced- and full-dose groups, respectively (5-year cumulative incidence 11.8%; 95% CI, 9.4 to 14.3 versus 16.5%; 95% CI, 14.0 to 19.0). All-cause death occurred in 35 (4.3%) and 54 (6.1%) patients in the reduced- and full-dose groups, respectively.

· Identification of Hepatic-like Erythropoietin with Enhanced Activity As a New Cause of Hereditary and Acquired Erythrocytosis.  

Highlight(s): 

this is a report of a new entity of secondary erythrocytosis named hepatic-like erythropoietin (EPO) polycythemia  characterized by the production of liver-like EPO with an atypical glycosylation pattern and increased activity. This new form of EPO has been observed in all patients with hereditary EPO-mutated erythrocytosis, in cases of erythrocytosis associated with liver disease, and in neonates. Thus, it is essential to consider quantitative and qualitative EPO screening as part of the biological tests for the diagnosis of idiopathic and hereditary erythrocytosis.

Professor B. Gardie introduced this interesting work.  In this study, the authors identified six unrelated families with hereditary erythrocytosis associated with circulating EPO levels within the normal range and characterized this condition as a novel molecular and functional entity. Using next-generation sequencing and segregation analysis, they identified three novel non-coding heterozygous mutations in the promoter and intron 1 of the EPO gene in the six families. Experiments with reporter assays and induced pluripotent stem cell-derived hepatocyte-like cells showed that mutations target previously uncharacterized regulatory elements of the EPO gene that exhibit high responsiveness to hypoxia-inducible factor (HIF)-2α. The circulating EPO protein from all patients with hereditary erythrocytosis examined in this study exhibited a unique and distinctive isoelectric focusing (IEF) profile compared to EPO produced by the kidneys of healthy adults. An identical IEF profile was also found in premature neonates, in whom EPO is produced by the liver, as well as in patients with acquired erythrocytosis associated with liver disease. Interestingly, this profile, which shows a shift of the main EPO isoforms to a more basic region, was related to glycosylation modifications. This suggests lower contents of sialic acids and other modifications, indicating a liver-type glycosylation pattern, which differs from the classic kidney-type glycosylation pattern observed in adulthood. Finally, these functional assays of EPO protein purified from patients’ plasma and umbilical cord blood revealed statistically significant enhanced activity, as reflected by increased EPO receptor signaling in a human cell line, pointing to a potential gain-of-function for the liver-type glycosylation of EPO.