Long-Term (≥5-Year) Remission and Survival After Treatment With Ciltacabtagene Autoleucel in CARTITUDE-1 Patients With Relapsed/Refractory Multiple Myeloma [Clinical trial update; prospective cohort]

Highlights:

●      Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell therapy, led to early, deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM) in the phase Ib/II CARTITUDE-1 trial (ClinicalTrials.gov identifier: NCT03548207) and significantly prolonged progression-free survival in patients with 1-3 previous lines in the phase III CARTITUDE-4 trial.

●      In this follow-up, one third of patients remain alive and progression-free for ≥5 years after a single cilta-cel infusion, without maintenance treatment.

●      Together with the LEGEND-2 study, these data from CARTITUDE-1 represent the longest study follow-up after any CAR T-cell therapy in patients with heavily pretreated RRMM.

Here, the authors describe overall survival (OS), ≥5-year progression-free outcomes, associated biomarkers, and safety, with a median study follow-up of 61.3 months. For the 97 treated patients, median OS was 60.7 months (95% confidence interval, 41.9 to not estimable). One third (32/97) of patients remain alive and progression-free for ≥5 years after a single cilta-cel infusion, without maintenance treatment. Twelve of these patients treated at a single center underwent serial minimal residual disease (MRD) and positron emission tomography-computed tomography assessments, and all (100%) were MRD-negative (at least 10^-5 threshold) and imaging-negative at year 5 or later after cilta-cel. The safety profile of cilta-cel remained consistent with previous reports.

Measurable Residual Disease–Guided Therapy in Newly Diagnosed Myeloma [Phase 3 clinical trial]

Highlight:  

●      Among patients who were measurable residual disease (MRD)-negative at 10⁻⁵ sensitivity after induction, the percentage with a pre-maintenance MRD-negative status at 10⁻⁶ sensitivity was not significantly higher with autologous stem-cell transplantation (ASCT) than with Isa-KRd (isatuximab, carfilzomib, lenalidomide, and dexamethasone).

●      Among patients who were MRD-positive at 10⁻⁵ sensitivity after induction, the percentage with a pre-maintenance MRD-negative status at 10⁻⁶ sensitivity was not significantly higher with tandem ASCT than with single ASCT.

In the MIDAS clinical trial (ClinicalTrials.gov number: NCT04934475), patients with transplantation-eligible newly diagnosed multiple myeloma who had completed the induction treatment of Isa-KRd were randomly assigned to receive consolidation therapy according to their MRD status. Patients who were MRD-negative at 10⁻⁵ sensitivity (assessed by next-generation sequencing) were assigned to undergo ASCT and receive Isa-KRd for two cycles (ASCT group) or to receive Isa-KRd for six cycles (Isa-KRd group). Patients who were MRD-positive at 10⁻⁵ sensitivity were assigned to undergo tandem ASCT (two ASCTs within a short period; tandem ASCT group) or to undergo ASCT and receive Isa-KRd for two cycles (single ASCT group). The primary end-point was an MRD-negative status at 10⁻⁶ sensitivity before maintenance therapy.

Among 485 patients who were MRD-negative at 10⁻⁵ sensitivity after induction, a

pre-maintenance MRD-negative status at 10⁻⁶ sensitivity occurred in 86% in the ASCT group and in 84% in the Isa-KRd group (adjusted relative risk [RR] 1.02; 95% confidence interval [CI], 0.95 to 1.10; P=0.64). Among 233 patients who were MRD-positive at 10⁻⁵ sensitivity after induction, a pre-maintenance MRD-negative status at 10⁻⁶ sensitivity occurred in 32% in the tandem ASCT group and in 40% in the single ASCT group (adjusted RR 0.82; 95% CI, 0.58 to 1.15; P=0.31); 15% of the patients in the tandem ASCT group did not undergo a second ASCT. No new safety signals were observed. The median follow-up was 16.8 months in the ASCT and Isa-KRd groups and 16.3 months in the tandem ASCT and single ASCT groups.

First-in-human study of JNJ-79635322 (JNJ-5322), a novel, next-generation trispecific antibody (TsAb), in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Initial phase 1 results

Highlights: 

●      Emerging data suggest that targeting two multiple myeloma (MM) antigens with T-cell redirection may overcome tumor heterogeneity and acquired resistance to further improve clinical outcomes.

●      JNJ-5322 is a next-generation TsAb dually targeting B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GPRC5D) via T-cell redirection, comprising novel binding domains, including low affinity CD3, selected in vitro to enhance on-tumor effects and reduce off-tumor impact.

●      The first clinical data for JNJ-5322 showed a 100% overall response rate (ORR) at the putative recommended phase 2 dose (RP2D) in anti-BCMA/-GPRC5D naïve pts. Tolerability appeared improved, including lower incidence and severity of GPRC5D-associated adverse events (AEs) vs. anti-GPRC5D bispecific antibodies, and manageable grade 3/4 infection rates.

Dose escalation/expansion cohorts enrolled measurable RRMM pts previously exposed to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody. As of January 15, 2025, 126 pts received JNJ-5322; median follow-up (mFU) 8.2 months. Median age 64 years; median 4 prior lines of therapy; 100% triple-class exposed pts (56% refractory); 31% high-risk cytogenetics; 23% had prior anti-BCMA/-GPRC5D therapy (77% naïve). Overall, 99% of pts had  ≥1 AE, most commonly cytokine release syndrome (59%; all grade 1/2; no grade  ≥3), nail AEs (grade 1/2 56%), taste AEs (grade 1/2 56%), neutropenia (48%; grade 3/4 41%), and non-rash skin AEs (47%; grade 3/ 41%). Overall, 16% had weight decreases (no grade  ≥3), 16% had rashes (no grade  ≥3), 2% had immune effector cell-associated neurotoxicity syndrome (all grade 1), and 75% had infections (grade 3/4 28%). Five pts had dose-limiting toxicities; 4 pts died due to AEs. ORR was 100% (89% ≥very good partial response) at the RP2D (identified as 100 mg Q4W) among pts naïve to anti-BCMA/-GPRC5D therapies (n=27), and all pts remained in response (mFU 8.5 months). Median time to first response was 1.2 months.

Combination of zanubrutinib (zanu) + venetoclax (ven) for treatment-naive (TN) CLL/SLL: Results in SEQUOIA arm D [Clinical trial update; prospective cohort]

Highlights: 

●      SEQUOIA arm D data demonstrate promising efficacy and tolerability of zanu + ven combination treatment in TN chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), regardless of del(17p) and/or TP53 mutation status.

●      The safety profile of zanu + ven was consistent with results of prior zanu studies, and no new safety signals were identified.

Arm D, is a nonrandomized cohort of the SEQUOIA study (NCT03336333) in patients aged  ≥65 years (or 18-64 years with comorbidities) with zanu + ven in patients with or without del(17p) and/or TP53 mutation. Patients received zanu + ven from cycle 4 to cycle 28, followed by continuous zanu monotherapy until progressive disease, unacceptable toxicity, or meeting undetectable minimal residual disease (uMRD)–guided early zanu or ven stopping rules (complete response [CR]/CR with incomplete hematologic recovery and uMRD [by flow cytometry] in peripheral blood [PB] and bone marrow on 2 consecutive tests  ≥12 weeks apart). Between 2019 and 2022, 114 patients were enrolled: 66 (58%) with del(17p) and/or TP53 mutation, 47 (41%) without del(17p) and TP53 mutation, and 1 with missing TP53 results. 86 (75%) patients had unmutated immunoglobulin heavy chain variable region gene, and 47 (41%) had complex karyotype. Patients with or without del(17p)/TP53 mutation achieved similar efficacy responses and best PB uMRD. The safety profile of zanu + ven was consistent with results of prior zanu studies, and no new safety signals were identified

Overall survival (OS) and duration of response for transfusion independence (TI) in erythropoiesis stimulating agent (ESA)–naive patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) treated with luspatercept (LUSPA) vs. epoetin alfa (EA) in the COMMANDS trial [Clinical trial update; prospective cohort].

Highlights:

●      In the phase 3 COMMANDS trial (NCT03682536), LUSPA was superior in im- proving red blood cell (RBC)-TI ≥12 weeks with concurrent hemoglobin increase ≥1.5 g/dL in weeks 1 to 24 vs. EA and had durable clinical benefit in patients with ESA-naïve transfusion-dependent (TD) lower-risk MDS.

●      With longer follow up (FU), no new safety concerns emerged. Progression to acute myeloid leukemia was comparable between groups.

As of Nov 4, 2024, median FU was 29.0 and 27.1 months for the LUSPA (n=182) and EA (n=181) groups, respectively. Median OS for LUSPA was not reached and was 46.7 months for EA (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.60-1.24); 3-year OS rates were 63.8% and 62.2%, respectively, and 5-years OS rates were 54.0% and 41.8%. Overall, RBC-TI ≥12 weeks (week 1 to end of treatment [EOT]) was reached by 76.4% (139/182) of patients in the LUSPA group and 55.8% (101/181) in the EA group. Median cumulative duration (95% CI) of longest RBC-TI ≥12 weeks period (from week 1 to EOT) was 126.6 (81.0-184.4) vs. 86.7 (55.9-111.1) weeks (HR, 0.64; 95% CI, 0.44-0.93). With longer FU, no new safety concerns emerged. Progression to acute myeloid leukemia was comparable between groups (3.8% vs. 4.4%).

 Results from VERIFY, a phase 3, double-blind, placebo (PBO)-controlled study of rusfertide for treatment of polycythemia vera (PV)

Highlights:

●      VERIFY (NCT05210790) is a global, ongoing phase 3 study designed to assess rusfertide (a subcutaneous, self-injected, first-in-class peptide hepcidin mimetic that decreases erythrocytosis) vs. PBO in phlebotomy (PHL)-dependent patients with PV receiving standard of care therapy.

●      Rusfertide resulted in a statistically significant reduction in the mean number of PHLs and improved hematocrit  control.

●      Rusfertide had a safety and tolerability profile consistent with prior studies.

A total of 293 pts (median age, 57 [27- 86] years) were randomized to receive rusfertide (n=147) or PBO (n=146). In the rusfertide and PBO groups, 56.5% (n=83) and 55.5% (n=81) of patients, respectively, received concurrent cytoreductive therapy. During weeks 20-32, significantly more patients in the rusfertide group (76.9%) achieved a clinical response vs. PBO (32.9%) (P<0.0001). The mean (SE) number of PHLs (weeks 0-32) was 0.5 (0.2) with rusfertide vs. 1.8 (0.2) with PBO (P<0.0001). More patients treated with rusfertide maintained hematocrit <45% from weeks 0-32 vs. PBO (rusfertide, 62.6%; PBO, 14.4%; P<0.0001). For patient-reported outcomes, patients treated with rusfertide demonstrated a statistically significant improvement in the PROMIS Fatigue SF-8a total T-score and MFSAF TSS (Myelofibrosis Symptom Assessment Form v4 Total Symptom Score) (P<0.03).  Serious adverse events occurred in 3.4% (rusfertide) and 4.8% (PBO) of patients; none were considered related to rusfertide.

IACH Friends and Members Corner

IACH Radio: On Air from EHA 2025

The IACH welcomes you to

#EHA25 in Milan

This corner is yours! Please send us any information you would like to share with the IACH community (Upcoming event, congratulations message, award announcement, call for a grant, new important appointment, vacant position, etc) to info@clinical-hematology.org.