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IMROZ: Phase III study of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible NDMM
Over the last decade, the survival rates for patients with newly diagnosed multiple myeloma (NDMM) have improved due to the development of novel agents. For patients with transplant-ineligible disease, current standard of care (SoC) typically involves a proteasome inhibitor-immunomodulatory drug (IMiD) combination, such as bortezomib, lenalidomide, and dexamethasone (VRd). In patients with high-risk disease, quadruplet therapies that include a monoclonal antibody (mAb) are preferred.1
At EHA 2024, Thierry Facon, MD, Lille University Hospital, Lille, France, presented results from the Phase III IMROZ study (NCT03319667), which investigated the safety and efficacy of isatuximab in combination with VRd (Isa-VRd) versus VRd in patients with transplant-ineligible NDMM. 446 patients were randomized in a 3:2 ratio to receive Isa-VRd or VRd. The primary endpoint was progression-free survival (PFS), with key secondary endpoints including complete response (CR), measurable residual disease (MRD) negativity, very good partial response (VGPR) or better, and overall survival (OS).
At a median follow-up of 59.7 months, the median PFS was not reached for Isa-VRd compared with 54.3 months for VRd (HR 0.596, p=0.0005), with a projected median PFS of approximately 90 months for Isa-VRd. The PFS benefit was consistent across subgroups and maintained throughout subsequent lines of therapy.
Isa-VRd led to deep, sustained responses, and was well tolerated in this patient population. Exposure-adjusted grade 5 treatment-emergent adverse event (TEAE) rate was 0.03 for Isa-VRd versus 0.02 for VRd. This is the first Phase III trial demonstrating that Isa-VRd significantly reduces risk of progression or death by 40.4% versus VRd, and may support the use of this quadruplet therapy as a potential new SoC for transplant-ineligible patients.2
First results of the APOLLO trial: ATO-ATRA versus standard ATRA + chemotherapy for patients with newly diagnosed high-risk APL
Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML), which has historically had poor outcomes. The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) into the APL treatment landscape has significantly improved outcomes for patients with this rare disease.3
In this press briefing, Uwe Platzbecker, MD, University of Leipzig, Leipzig, Germany, shared the first results from the Phase III APOLLO trial (NCT0268840), which compared ATO-ATRA to the SoC of ATRA and chemotherapy in patients with newly diagnosed, high-risk APL. Patients were randomized into two groups: the ATO-ATRA arm and the ATRA-chemotherapy arm. The primary endpoint was event-free survival (EFS) at two years, while secondary endpoints included OS, toxicity, MRD status, and quality of life (QoL) assessments.
After a median follow-up of 31 months, the two-year EFS was 89% in the ATO-ATRA arm compared with 72% in the ATRA-chemotherapy arm (p=0.02). The complete remission+complete remission with incomplete count recovery (CR+CRi) rates were similar between both groups (93% in ATO-ATRA versus 91% in ATRA-chemotherapy, p=0.65), and early death rates were comparable. There were no molecular relapses in the ATO-ATRA group and six in the ATRA-chemotherapy group. The two-year OS rates were 93% for the ATO-ATRA arm and 87% for the ATRA-chemotherapy arm (p=0.33). A safety analysis is ongoing, which may support the use of ATO-ATRA as the new SoC for patients with high-risk APL.4
Low molecular weight heparin does not prevent VTE in adults with newly diagnosed ALL: prospective side-study of the HOVON-100 trial
Venous thromboembolism (VTE) is a common complication that can occur in patients with acute lymphoblastic leukemia (ALL), and adult patients can have a 10–40% risk of VTE.5
In this press briefing, Mandy Lauw, MD, PhD, Erasmus Medical Center, Rotterdam, the Netherlands, shared insights into a study which evaluated the efficacy of thromboprophylaxis using low molecular weight heparin (LMWH) in adults aged between 18–70 with newly diagnosed ALL. The primary outcome was the incidence of venous or arterial thrombosis within the first 60 days of treatment, and secondary outcomes included overall thrombosis, major bleeding, and EFS.
Among 369 eligible patients (n=179, 18–40 years of age; n=190, 41–70 years of age), 253 received thromboprophylaxis with LMWH and 116 received no LMWH. Results demonstrated that thrombosis occurred in 15% of patients within the first 60 days, with no significant difference between those receiving LMWH (17%) and those who did not receive LMWH (11%). Bleeding rates were comparable between the groups.
Overall, 33% of patients on LMWH experienced thrombosis during the study, compared with 22% without thromboprophylaxis, and EFS was not significantly impacted by LMWH use. This is the largest prospective, comparative study with thromboprophylaxis using LMWH in adult patients with ALL, highlighting the need for further investigation.5
Development and evaluation of a novel CAR-T cell therapy against CALR mutant neoplasms
Mutant calreticulin (CALR) represents one of the main oncogenic drivers in myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET) and myelofibrosis (MF), making it a promising immunotherapeutic target.6
At EHA 2024, Alex Rampotas, MD, University College London, London, UK, discussed the development of a novel CAR-T therapy for mutant CALR-driven MPNs. To assess the efficacy of this CAR-T product, engineered mutant CALR cell lines of varying expression levels were used alongside peripheral blood samples from patients.
Both 2D liquid cultures and 3D human bone marrow organoids were used to test the killing efficacy of this novel product. For in vivo evaluation, NOD scid gamma (NSG) mice inoculated with mutant CALR-positive MARIMO cells engineered to express the thrombopoietin receptor (TPO-R) were used.
This novel CAR-T product demonstrated selective targeting and almost complete eradication of MARIMO cells expressing both low and high levels of mutant CALR, as well as cells expressing the del52 mutant CALR variant. The study also evaluated the impact of these CAR-T cells on CD34+ stem/progenitor cells from patients with chronic-phase MF, highlighting selective depletion of these cells harboring mutant CALR variants, with minimal toxicity to JAK2V617F+ patient cells. These findings underscore the promising potential of CAR-T therapy for mutant CALR-driven MPNs, paving the way for future clinical trials aimed at validating these pre-clinical results.7
BrECADD regimen is superior in treating advanced HL with improved patient outcomes: results from the HD21 trial
The introduction of immune therapies into the Hodgkin lymphoma (HL) treatment landscape has changed the field and greatly improved survival outcomes for patients.8 In this press briefing, Peter Borchmann, MD, University Hospital Cologne, Cologne, Germany, discussed the results of the HD21 trial (NCT02661503), which aimed to compare the superiority of PFS between the BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) and BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone) regimens in patients with advanced stage classical HL.
In this open-label, randomized, Phase III trial, patients aged between 18–60 years of age were randomized to receive either BEACOPP or BrECADD based on PET2 results. The co-primary endpoints were treatment-related morbidity and PFS, with superiority testing planned over a four-year follow-up period. The intention-to-treat cohort consisted of 1,482 patients, of which 742 received BrECADD and 740 received BEACOPP.
At a median follow-up of 48 months, the four-year PFS was 94.3% in the BrECADD arm compared with 90.9% in the BEACOPP arm (HR=0.66, [95% CI: 0.45–0.97], p=0.035). Additionally, PET2-negative patients in the BrECADD arm achieved a four-year PFS of 95.5%, and PET2-positive patients 92.5%. The four-year OS rate was 98.5% for BrECADD and 98.2% for BEACOPP. These results demonstrate that the BrECADD regimen is more effective than BEACOPP and significantly reduces the risk of disease progression in advanced stage classical HL, which may provide a new treatment option for patients.9
The Phase III STARGLO trial: Glofit-GemOx versus R-GemOx for R/R DLBCL
Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who progress following treatment with R-CHOP tend to have a poor prognosis. The introduction of immune-based therapies, including CAR-T cells and bispecific antibodies, has changed the landscape.10 Glofitamab is a CD20xCD3 bispecific antibody, which has shown promise as a monotherapy in patients with R/R DLBCL.
At EHA 2024, Jeremy Abramson, MD, Massachusetts General Hospital, Boston, MA, presented results from the Phase III STARGLO trial (NCT04408638), which compared the safety and efficacy of glofitamab plus gemcitabine and oxaliplatin (Glofit-GemOx) versus rituximab-GemOx (R-GemOx) in patients with R/R DLBCL after at least one prior line of therapy.
Patients were randomized 2:1 to receive either Glofit-GemOx or R-GemOx, stratified by the number of prior therapies and refractoriness to last treatment. The primary endpoint was OS, with secondary endpoints including PFS and CR rate.
A total of 274 patients were enrolled (183 in the Glofit-GemOx arm and 91 in the R-GemOx arm). At the primary analysis, Glofit-GemOx demonstrated a significant OS benefit over R-GemOx (HR=0.59, [95% CI: 0.40–0.89], p=0.011). At a median follow-up of 11.3 months, median OS was not reached for Glofit-GemOx (95% CI: 13.8–not evaluable) and nine months for R-GemOx (95% CI: 7.3–14.4). Significant benefits were also observed in PFS and CR rate. Follow-up analysis confirmed superior median OS (25.5 versus 12.9 months), PFS (13.8 versus 3.6 months), and CR rate (58.5% versus 25.3%) for Glofit-GemOx. Adverse events (AEs) were higher with Glofit-GemOx, but were similar between both arms after adjusting for exposure differences. Overall, Glofit-GemOx demonstrated significant clinical benefits in OS, PFS and CR rates in patients with transplant-ineligible R/R DLBCL.11
EVI-2: vitamin C supplementation in patients with CCUS or LR-MDS
Research has demonstrated that vitamin C is a key regulator of cellular epigenetic processes, and is known to play a role in the activation of TET2.12 Patients with hematological malignancies are often deficient in vitamin C, and therefore, vitamin C supplementation may be a promising strategy for patients with precursor conditions and early stage myeloid malignancies.
In this press briefing, Stine Ulrik Mikkelsen, MD, PhD, University of Copenhagen, Copenhagen, Denmark, discussed the Phase II EVI-2 study (NCT03682029), which evaluated the safety and efficacy of vitamin C supplementation in 109 patients with low-risk myeloid malignancies and precursor conditions, including clonal cytopenia of undetermined significance (CCUS) and lower-risk myelodysplastic syndromes (LR-MDS). The primary endpoint was the change in variant allele frequency of somatic mutations in bone marrow mononuclear cells from baseline to the end of treatment. Secondary endpoints included changes in plasma vitamin C concentration, the number of serious AEs, and OS.
Between 2017–2022, 55 patients were assigned to the vitamin C arm and 54 to the placebo arm. Baseline vitamin C concentration was inadequate in 57% of the study population. In the vitamin C arm, median plasma concentration increased significantly from 45.85 μmol/L at baseline, to 81.90 μmol/L at 12 months (p<1×10-7), while no significant change was observed in the placebo group.
Serious AEs occurred in 27% of patients in the vitamin C group and 43% in the placebo group. After a median follow-up of 33.5 months, 35 deaths occurred (11 in the vitamin C group and 24 in the placebo group), with a median OS not reached in the vitamin C group, and 42.2 months in the placebo group (HR 2.88, p=0.0025). Data on the primary endpoint are pending. Overall, vitamin C supplementation was significantly associated with longer OS, suggesting the need for further investigation in a Phase III study.13
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References
- Goel U, Usmani S, Kumar S. Current approaches to management of newly diagnosed multiple myeloma. American Journal of Hematology. 2022 May;97 Suppl 1:S3-S25.
- Facon T, Dimopoulos MA, Leleu X, et al. Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ). Presented at EHA 2024. June 13-16;Abstract S100.
- Ryan MM. Acute Promyelocytic Leukemia: A Summary. Journal of the Advanced Practitioner in Oncology. 2018 March;9(2):178-187.
- Platzbecker U, Adès L, Montesinos P, et al. First results of the APOLLO trial: a randomized Phase III study to compare ATO combined with ATRA versus standard AIDA regimen for patients with newly diagnosed, high-risk acute promyelocytic leukemia. Presented at EHA 2024. June 13-16;Abstract S102.
- Lauw M, Rijneveld A, Ko A, et al. Low-molecular-weight heparin does not prevent venous thromboembolism in adults with newly diagnosed acute lymphoblastic leukemia; prospective side-study of the HOVON-100 trial. Presented at EHA 2024. June 13-16;Abstract S325.
- Foßelteder J, Pabst G, Sconocchia T, et al. Human gene-engineered calreticulin mutant stem cells recapitulate MPN hallmarks and identify targetable vulnerabilities. Leukemia. 2023 April;37(4):843-853.
- Rampotas A, Gannon I, Wong Z, et al. Development and evaluation of a novel CAR-T cell therapy against calreticulin mutant neoplasms. Presented at EHA 2024. June 13-16;Abstract S216.
- Nakhoda S, Rizwan F, Vistarop A, et al. Updates in the Role of Checkpoint Inhibitor Immunotherapy in Classical Hodgkin’s Lymphoma. Cancers (Basel). 2022 Jun 14;14(12):2936.
- Borchmann P, Moccia A, Greil R, et al. The randomized study GHSG HD21 shows superior tolerability and efficacy of BrECADD versus BEACOPP in advanced stage classical Hodgkin lymphoma. Presented at EHA 2024. June 13-16;Abstract S225.
- Atallah-Yunes SA, Robertson MJ, Davé UP, et al. Novel Immune-Based treatments for Diffuse Large B-Cell Lymphoma: The Post-CAR T Cell Era. Frontiers in Immunology. 2022 Jun 1;13:901365.
- Abramson J, Ku M, Hertzberg M, et al. Glofitamab plus gemcitabine and oxaliplatin (Glofit-GemOx) for relapsed/refractory (R/R) diffuse large b-cell lymphoma (DLBCL): results of a global randomized Phase III trial (STARGLO). Presented at EHA 2024. June 13-16;Abstract LB3438.
- Ottone T, Faraoni I, Fucci G, et al. Vitamin C Deficiency in Patients With Acute Myeloid Leukemia. Frontiers in Oncology. 2022 Jun 27;12:890344.
- Mikkelsen SU, Vallentin A, Nielsen A, et al. Vitamin C supplementation in patients with clonal cytopenia of undetermined significance or low-risk myeloid malignancies: results from EVI-2, a randomized, placebo-controlled Phase 2 study. Presented at EHA 2024. June 13-16;Abstract LB3444.
Edited by Raffaella Facchini
