We assessed the overall survival (OS) impact of time to relapse (TTR) in multinational cohorts with independent observational and randomized validation. Patients with nMTCL with frontline complete response were assigned to TTR12 (≤12 months) or without TTR12 based on time to progression or next therapy. OS analyses included modified landmark (m-LM), standard landmark (s-LM), and time-dependent Cox (td-Cox), adjusting for age, histology, and prognostic index for T-cell lymphoma (PIT) score. Across 452 patients, 165 (36.5%) had TTR12, 181 (40%) relapsed at ≥12 months, and 106 (23.5%) remained relapse-free. TTR12 conferred worse OS using m-LM (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.58-2.90; P< .001), s-LM (HR, 1.92; 95% CI, 1.39-2.66; P< .001); and td-Cox (HR, 5.81; 95% CI, 2.94-11.46; P< .001). Results were consistent in the independent validation cohorts. TTR12 consistently conferred worse OS irrespective of frontline stem cell transplantation or PIT score, in peripheral T-cell lymphoma, not otherwise specified (m-LM: HR, 2.32; 95% CI, 1.51-3.55; P< .001; s-LM: HR, 2.10; 95% CI, 1.33-3.31; P = .001), anaplastic large cell lymphoma (m-LM: HR, 3.34; 95% CI, 1.18-9.50; P = .023; s-LM: HR, 2.96; 95% CI, 1.02-8.81; P = .046), and angioimmunoblastic T-cell/T follicular helper cell lymphoma (m-LM only: HR, 1.92; 95% CI, 1.15-3.21; P = .013). Second-line novel therapies improved OS (second-line start to death) vs chemotherapy in TTR12 only (HR, 0.60; 95% CI, 0.37-0.97; P = .038; without TTR12: HR, 0.82; 95% CI, 0.51-1.32; P = .407). TTR12 serves as a prognostic and potential OS surrogate marker, supporting stratification of new risk groups and need for their differential treatment.

We compared daunorubicin/cytarabine plus fractionated gemtuzumab ozogamicin (DAGO2) with CPX-351 (CPX; 1:2 randomization) in 439 patients with acute myeloid leukemia (AML) aged ≥60 years (median age, 68 years) without known adverse-risk cytogenetics. Median follow-up was 35 months. Patients not in measurable residual disease (MRD)-negative remission after course 1 could enter a second randomization between standard and intensified chemotherapy. Post-course 1, the overall response rate (complete remission [CR] + CR with incomplete hematological recovery) was greater after DAGO2 (60% vs 47.5%; odds ratio [OR], 0.61; P = .016). Following course 2, the overall response was not significantly different (85% for DAGO2 vs 78% for CPX; P = .095). More patients attained CR with MRD negativity after course 1 in the DAGO2 arm (47% vs 29% for CPX; OR, 0.46; P = .004). We observed better 3-year event-free survival (34% vs 27%; hazard ratio [HR], 0.73; P = .012) and overall survival (52% vs 35%; HR, 0.62; P = .001) with DAGO2. CPX did not provide a survival benefit in patients with myelodysplasia (MDS)-related mutations and was associated with poorer survival in patients with NPM1 (HR, 2.83) and FLT3 mutations (HR, 2.14). Overall, 37% of patients underwent transplantation in first remission, with no difference in transplantation frequency or survival after transplant between randomization groups. Among patients entering the course 2 randomization (n = 107), survival was equivalent between standard and intensified CPX doses (P = .565). In conclusion, in this population of older patients with AML without known adverse-risk cytogenetics, DAGO2 resulted in superior survival compared with CPX. CPX did not benefit patients with MDS-related mutations over DAGO2. This trial was registered at www.ClinicalTrials.gov as #NCT02272478.

Circulating tumor cells (CTC) represent a high-risk biomarker in newly diagnosed multiple myeloma (NDMM); however, their prognostic value among transplant-eligible (TE) patients receiving daratumumab/bortezomib/lenalidomide/dexamethasone (D-VRd) remains unknown. In this study, we analyzed CTC in the phase 3 PERSEUS/EMN017 trial. TE-NDMM patients were randomized (1:1) to D-VRd with daratumumab/lenalidomide maintenance (D-VRd group) or bortezomib/lenalidomide/dexamethasone (VRd) with lenalidomide maintenance (VRd group), both with transplant. A subset of 451 of 709 patients from PERSEUS (D-VRd, 231/355; VRd, 220/354) had screening blood samples collected for CTC analysis by flow cytometry. CTC were detected in 370 patients (82%; median limit of detection, 0.0004%). CTC were prognostic of progression-free survival (PFS), independent of other factors, as a continuous (hazard ratio [HR], 1.36 [95% confidence interval (CI), 1.15-1.60]; P< .001) and categorical variable (≥0.175% CTC-high, optimal threshold). D-VRd improved PFS vs VRd in CTC-low patients (4-year rates: 88% vs 74%; HR, 0.42 [95% CI, 0.25-0.70]; P = .0013). Regardless of study treatment, minimal residual disease (MRD)-negativity rates were lower in CTC-high vs CTC-low patients (10-5: 52.2% vs 66.2%; 10-6: 34.8% vs 52.4%). D-VRd significantly increased MRD-negativity rates vs VRd among CTC-high (10-5: 69.4% vs 33.3%; 10-6: 47.2% vs 21.2%; both P< .05) and CTC-low patients (10-5: 74.4% vs 57.8%; 10-6: 65.6% vs 38.5%; both P< .001), with similar observations for sustained MRD-negativity. CTC levels are an independent prognostic factor in TE-NDMM treated with standard-of-care frontline quadruplet. D-VRd improved and sustained MRD-negativity rates in CTC-high and CTC-low, and improved PFS for CTC-low with a positive trend in CTC-high patients. This trial was registered at www.clinicaltrials.gov as #NCT03710603.

Diffuse large B-cell lymphoma (DLBCL) poses a challenge in hematology given its varied symptoms, and the complex interplay between disease and treatment effects on health-related quality of life (HRQoL). The phase 3 POLARIX study demonstrated superior progression-free survival and a similar safety profile with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) vs R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with previously untreated DLBCL. Here, we evaluate HRQoL through patient-reported outcome (PRO) instruments to fully characterize the patient experience in the POLARIX study. Changes from baseline in HRQoL, lymphoma symptoms, and gastrointestinal (GI) symptoms were assessed, as well as incidence and severity of common symptoms by PROs vs clinician-reported adverse events (AEs). Baseline characteristics of PRO-evaluable patients (N = 874) were consistent. Comparison between PROs and clinician-reported AEs revealed a notable discordance; patients generally reported a higher incidence of symptoms than clinicians, emphasizing the need for patient-centric tools to accurately capture the patient experience. Both treatments exhibited rapid and sustained improvements in HRQoL and lymphoma symptoms, with the most substantial improvements seen in global health status/QoL, lymphoma symptoms, fatigue, role, emotional, and social functioning. GI symptoms (diarrhea, constipation, nausea, and vomiting) were generally similar between treatment arms and returned to baseline levels after treatment completion. These HRQoL data underscore the complementarity of PROs, as an adjunct to clinician-reported AEs, in evaluating the efficacy and tolerability of new treatments, including Pola-R-CHP, which may represent a new benchmark for patient-reported HRQoL in previously untreated DLBCL. This trial was registered at www.clinicaltrials.gov as NCT03274492.

Functional high-risk (FHR) multiple myeloma (MM) is defined as an unexpected, early relapse (ER) of disease in the absence of baseline molecular or clinical risk factors (RF), making FHR MM inherently dependent on which RFs were assessed at diagnosis, and what treatment patients received. To establish the true incidence of FHR, we analyzed uniformly treated, transplant-eligible patients from the Myeloma-XI (MyXI) trial that had been profiled for the International Myeloma Society and Working Group (IMS/IMWG) defined high-risk cytogenetic aberrations (HRCA), and the SKY92 gene expression HR signature (GEP-HR). A total of 135 MyXI patients were studied, with a median follow-up of 88 months; 25 (18.5%) experienced ER, defined as relapse <18 months from maintenance randomization post-autologous stem-cell transplantation. Hereof, 15 (60%) were IMS/IMWG-HR at diagnosis, of whom 8 were also GEP-HR. Another 6 patients were GEP-HR only and would have been missed by IMS/IMWG-HR. Among 4 patients with IMS/IMWG- and GEP-standard risk, 2 had isolated HR markers at diagnosis, leaving only 2 patients (8% of ER; 1.5% of all) truly meeting all FHR-criteria. Combined IMS/IMWG-HR and GEP-HR profiling identified 84% of ER, and differentiated long-term outcome across all 135 patients: co-occurring IMS/IMWG and GEP-HR was associated with very short overall survival compared to the absence of both (HR = 13.1; 95% CI, 6.5-26.1, P < .0001), followed by GEP-HR only (HR = 5.1; 95% CI, 2.4-11.1, P < .0001) and IMS/IMWG-HR only (HR = 3.2; 95% CI, 1.6-6.2, P = .0007). Our results support more comprehensive baseline diagnostic profiling to identify those at risk of ER upfront. The trials were registered at the ISRCTN Registry as ISRCTN49407852 and at clinicaltrials.gov as #NCT01554852.

T-cell engagers (TCEs) are transformative therapeutics in hematologic malignancies, including non-Hodgkin lymphoma. Initially approved for relapsed/refractory disease settings, TCEs are now explored in first-line and second-line settings, often combined with standard-of-care (SOC) treatments, including chemotherapy and antibody-drug conjugates. This study investigates glofitamab (CD20×CD3 TCE) combinations in preclinical humanized lymphoma models, addressing heterogeneity of tumor antigen expression, immune evasion, and T-cell exhaustion. Combining glofitamab with R-CHP-Pola (rituximab, cyclophosphamide, doxorubicin, prednisone, and polatuzumab vedotin) chemotherapy or Pola demonstrated strong synergistic antitumor efficacy with rapid tumor regression and reduced tumor cell proliferation. Glofitamab combination with gemcitabine/oxaliplatin also demonstrated strong efficacy, enhancing intratumor T-cell number, activation, and reduced exhaustion. These combinations were particularly advantageous in models with low and heterogeneous CD20 expression, facilitating rapid tumor debulking and elimination of CD20-low/CD20- cells. Translational studies with patient-derived peripheral blood mononuclear cells receiving glofitamab combination with chemotherapies demonstrated sustained T-cell functionality throughout extended treatment cycles. Novel chemotherapy-free combinations, including CD19-targeted 4-1BBL and CD19-CD28, amplified glofitamab activity, especially in CD20 high- and homogenous-expressing tumor models, with dual costimulatory approaches revealing synergy. In addition, the combination with checkpoint inhibitors (programmed cell death protein 1/Lag3-bispecific antibody) and regulatory T-cell depletion (α-CD25) emerged as promising approaches for enhanced efficacy and to sustain T-cell functionality. These findings highlight the versatility of glofitamab when integrated with SOC and innovative combinations, addressing resistance and improving patient outcomes. The preclinical investigations provide a strong foundation for ongoing and future clinical trials, emphasizing the need to tailor TCE-based combination therapies to maximize efficacy while minimizing toxicity in lymphoma treatment. These trials were registered at www.clinicaltrials.gov as #NCT04408638 and NCT03467373.

With up to 10 years of follow-up, we report results from the final analysis of RESONATE- 2, a phase 3 study of first-line ibrutinib vs chlorambucil for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients aged ≥65 years with previously untreated CLL/SLL without del(17p) were randomly assigned to receive either single-agent ibrutinib (420 mg/d; n = 136) or chlorambucil (0.5-0.8 mg/kg; ≤12 cycles; n = 133). With a median follow-up of 9.6 years in the ibrutinib arm, the median progression-free survival (PFS) was 8.9 years (95% confidence interval [CI], 7.0 to not estimable [NE]) vs 1.3 years (95% CI, 0.9-1.6) for the chlorambucil arm. Among patients with unmutated immunoglobulin heavy chain variable (uIGHV), del (11q), mutated TP53, or complex karyotype, the median PFS was 8.4 years (95% CI, 6.8 to NE) with ibrutinib and 0.7 years (95% CI, 0.4-1.2) with chlorambucil. Median overall survival (OS) with ibrutinib was not reached. The most common adverse events (AEs) of any grade included diarrhea (52%), fatigue (41%), cough (39%), nausea (32%), arthralgia (31%), peripheral edema (31%), and hypertension (30%). During the entire study period, 34 of 136 patients (25%) had an ibrutinib dose reduction due to AEs; these AEs improved in 30 of 34 patients (88%). At study completion, 27% of patients remained on first-line ibrutinib treatment. This landmark RESONATE-2 study defines median PFS and demonstrates continued OS benefit of first-line ibrutinib treatment for patients with CLL/SLL, including those with high-risk genomic features. Sustained efficacy and tolerability of ibrutinib reemphasize the favorable benefit-risk profile. This trial was registered at www.ClinicalTrials.gov as NCT01722487/NCT01724346.

Attempting to induce a complete remission before allogeneic hematopoietic cell transplant (alloHCT) is current practice in patients with acute myeloid leukemia (AML). However, benefit of remission induction strategy (RIST) before alloHCT has never been proven in a prospective trial. Potent conditioning regimens exist that allow for successful alloHCT in patients with active AML. Therefore, the ASAP trial was conducted to test RIST by salvage chemotherapy before alloHCT against immediate transplant after intensified conditioning. In total, 281 patients with AML with poor response after first induction or untreated first relapse were randomized 1:1 to RIST with high-dose cytarabine plus mitoxantrone vs immediate alloHCT with sequential conditioning after nonintensive disease control (DisC) measures, preferentially watchful waiting only. Overall survival at 5 years from randomization analyzed according to intention-to-treat was 46.1% for DisC vs 47.5% for RIST (P = .82). In multivariable Cox regression analysis, genetic AML risk according to European LeukemiaNet criteria (P < .0001), age (P = .001), and comorbidities (P = .046) predicted survival, but not treatment arm (hazard ratio, 1.08 for DisC vs RIST; P = .67). In conclusion, long-term follow-up of the ASAP trial showed no survival advantage for standard salvage chemotherapy before alloHCT as opposed to immediate alloHCT. The trial results question the general concept of RIST with intensive standard salvage therapy before alloHCT for all patients, because immediate alloHCT may reduce time in hospital and health care expenses. Novel bridging therapies that are well tolerated, and posttransplant maintenance with targeted drugs are urgently warranted, especially for adverse-risk AML, to improve outcomes after alloHCT. This trial was registered at www.ClinicalTrials.gov as #NCT02461537.

Modakafusp alfa is a first-in-class immunocytokine-directing interferon alfa to CD38+ cells. Our previous phase 1/2 trial identified 2 potential phase 2 doses of modakafusp alfa for patients with relapsed/refractory multiple myeloma (RRMM): 1.5 or 3 mg/kg every 4 weeks. The overall response rate (ORR) among 30 patients treated at 1.5 mg/kg was 43%. This phase 2 dose optimization study randomized 147 patients with triple-class refractory disease and ≥3 previous lines of therapy 1:1 to modakafusp alfa 120 mg (n = 71) or 240 mg (n = 75) every 4 weeks (fixed-dose equivalents of 1.5 and 3 mg/kg every 4 weeks). Patients had received a median of 6 previous lines of therapy; 66% were penta-exposed and 45% had previously been exposed to anti-B-cell maturation antigen (BCMA) therapy. Modakafusp alfa development was discontinued for strategic reasons by the sponsor and the study was terminated early. At median follow-up of 7.3 and 7.6 months in the 120- and 240-mg arms, ORRs were 32% and 41%, and median progression-free survival was 4.1 and 5.3 months, respectively. ORRs were higher in patients who had not received previous BCMA therapy (46% vs 29%). The most common treatment-related adverse events (TEAEs) in the 120- and 240-mg arms were thrombocytopenia (75% and 84%; grade ≥3, 55% and 61%; respectively) and neutropenia (68% and 73%; grade ≥3, 56% and 68%; respectively); 90% and 96% of patients, respectively, experienced grade ≥3 TEAEs; 39% and 44%, respectively, experienced serious TEAEs. Our results confirm the efficacy of single-agent modakafusp alfa for patients with RRMM. This trial was registered at www.clinicaltrials.gov as #NCT03215030.

Patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC) have limited treatment options. The phase 3 ENHANCE-3 study aimed to determine whether magrolimab (magrolimab arm) was superior to placebo (control arm) when either was combined with venetoclax and azacitidine. Adults with previously untreated AML who were ineligible for IC were randomized to receive magrolimab (1 mg/kg on days 1 and 4, 15 mg/kg on day 8, 30 mg/kg on days 11 and 15, then weekly for 5 weeks, and then every 2 weeks) or placebo, venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg daily thereafter), and azacitidine (75 mg/m2 days 1-7) in 28-day cycles. The primary end point was overall survival (OS); key secondary end points included complete remission (CR) rate and safety. After randomization of 378 patients, the trial was stopped at a prespecified interim analysis owing to futility. At final analysis, with median follow-up of 7.6 months (magrolimab arm) vs 7.4 months (control arm), median OS was 10.7 vs 14.1 months (hazard ratio, 1.178; 95% confidence interval, 0.848-1.637). The CR rate within 6 cycles was 41.3% vs 46.0%. Addition of magrolimab to venetoclax and azacitidine resulted in more fatal adverse events (19.0% vs 11.4%), primarily driven by grade 5 infections (11.1% vs 6.5%) and respiratory events (2.6% vs 0%). There were similar incidences of any-grade infections, febrile neutropenia, and neutropenia between arms. These results highlight the difficulty in improving outcomes for patients with AML who were ineligible for IC. This trial was registered at www.clinicaltrials.gov as #NCT05079230.

Acalabrutinib is a Bruton tyrosine kinase inhibitor approved for the treatment of chronic lymphocytic leukemia. We present results from ELEVATE-TN after a median follow-up of 74.5 months. Overall, 535 patients were randomized (acalabrutinib-obinutuzumab, n = 179; acalabrutinib, n = 179; chlorambucil-obinutuzumab, n = 177). Median age was 70 years, 63.0% had unmutated immunoglobulin heavy chain variable region gene (uIGHV), 13.6% had del(17p) and/or mutated TP53, and 17% had complex karyotype (CK; ≥3 chromosomal abnormalities). Median progression-free survival (PFS) was not reached (NR) for acalabrutinib-obinutuzumab and acalabrutinib vs 27.8 months for chlorambucil-obinutuzumab (both P < .0001); estimated 72-month overall PFS rates were 78.0%, 61.5%, and 17.2%, respectively. Acalabrutinib-obinutuzumab resulted in improved PFS vs acalabrutinib monotherapy (hazard ratio [HR], 0.58; P = .0229). Patients with uIGHV, del(17p) and/or mutated TP53, or CK had significantly improved PFS with acalabrutinib ± obinutuzumab vs chlorambucil-obinutuzumab (P < .0001, P ≤ .0009, and P < .0001 for both acalabrutinib-containing arms, respectively). Median overall survival (OS) was NR for all treatments, with significantly longer OS for acalabrutinib-obinutuzumab than chlorambucil-obinutuzumab (HR, 0.62; P = .0349). Estimated 72-month OS rates were 83.9%, 75.5%, and 74.7% for acalabrutinib-obinutuzumab, acalabrutinib, and chlorambucil-obinutuzumab, respectively. Adverse events (AEs) occurring after >4 years were mostly grade 1 to 2. Rates of AEs, serious AEs, and events of clinical interest were similar between acalabrutinib-containing arms and consistent with the known safety profiles of acalabrutinib and obinutuzumab. Efficacy and safety of acalabrutinib-containing arms were maintained, with longer PFS in both acalabrutinib arms than chlorambucil-obinutuzumab including in patients with high-risk features. This trial was registered at www.ClinicalTrials.gov as #NCT02475681.

Rilzabrutinib is a covalent, reversible Bruton tyrosine kinase inhibitor targeting multiple immune thrombocytopenia (ITP)-related mechanisms. The phase 3 LUNA3 study in previously treated adults with persistent/chronic ITP evaluated oral rilzabrutinib 400 mg twice daily (n = 133) vs placebo (n = 69) for 24 weeks. At baseline overall, median age was 47 years, 63% female, 7.7 year median ITP duration, and 28% prior splenectomy. Overall (N = 202), 85 (64%) rilzabrutinib and 22 (32%) placebo patients achieved platelet response (≥50 × 109/L or 30 × 109/L to <50 × 109/L and doubled from baseline) during the first 12 weeks and were eligible to continue. The primary end point, durable platelet response (platelet count ≥50 × 109/L for ≥two-thirds of ≥8 of the last 12 of 24 weeks without rescue therapy), was observed in 31 (23%) rilzabrutinib vs 0 placebo patients (P < .0001). All secondary efficacy end points were significantly superior for rilzabrutinib (P < .05). Median time to first platelet response was 15 days in rilzabrutinib responders. Rilzabrutinib significantly reduced rescue therapy use by 52% (P = .0007) and improved week 25 bleeding scores (P = .0006). Improved physical fatigue was sustained from week 13 (P = .01) through 25 (P = .0003). Treatment-related adverse events were mainly grade 1/2. One rilzabrutinib patient with multiple risk factors had serious treatment-related grade 3 peripheral embolism (lower left leg), and another died from unrelated pneumonia. Rilzabrutinib in patients who failed multiple previous ITP therapies showed rapid and durable platelet response, reduced rescue medication and bleeding, improved physical fatigue, and favorable safety. Trial registration: www.clinicaltrials.gov (#NCT04562766) and www.clinicaltrialsregister.eu (#2020-002063-60).

Patients with TP53-mutated acute myeloid leukemia (AML) have an extremely poor prognosis, necessitating new treatments. The global, randomized, phase 3 ENHANCE-2 trial evaluated the anti-CD47 monoclonal antibody magrolimab plus azacitidine (Magro/Aza) for previously untreated TP53-mutated AML. Patients determined ineligible for intensive therapy were randomized to receive Magro/Aza or venetoclax plus Aza (Ven/Aza); those eligible for intensive therapy were randomized to receive Magro/Aza or 7+3 induction chemotherapy. The primary end point was overall survival (OS) in the nonintensive arm. At interim analysis, nonintensive-arm OS hazard ratio (HR) between treatment groups was 1.191 (95% confidence interval [CI], 0.744-1.906), meeting the study's definition for futility and resulting in study termination. At final analysis, median OS was 4.4 vs 6.6 months (HR, 1.132; 95% CI, 0.783-1.637; P = .5070) in the nonintensive arm (n = 205) and 7.3 vs 11.1 months (HR, 1.434; 95% CI, 0.635-3.239; P = .3798) in the intensive arm (n = 52) between Magro/Aza and control groups, respectively. Incidences of grade ≥3 adverse events were similar across Magro/Aza and control groups (nonintensive, n = 194: 96.9% and 95.9%; intensive, n = 50: 92.6% and 95.7%), including grade ≥3 anemia (nonintensive: 27.1% and 23.5%; intensive: 25.9% and 21.7%). Grade ≥3 infections were observed in 50.0% and 53.1% of patients in the nonintensive arm and 44.4% and 65.2% of intensive-arm patients. ENHANCE-2 did not meet its primary end point of OS in TP53-mutated AML but provides important data informing future studies in this challenging population. This trial was registered at www.clinicaltrials.gov as #NCT04778397.

Fixed-duration venetoclax-rituximab (VenR) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) in the phase 3 MURANO trial resulted in superior progression-free survival (PFS) and overall survival (OS) vs bendamustine-rituximab (BR). We report the final analyses of MURANO (median follow-up, 7 years). Patients were randomized to VenR (venetoclax 400 mg daily for 2 years plus monthly rituximab for 6 months; n = 194) or BR (6 months; n = 195). In a substudy, patients with progressive disease (PD) received VenR as retreatment or crossover from BR. At the final data cut (3 August 2022), the median PFS with VenR was 54.7 months vs 17.0 months with BR. The 7-year PFS with VenR was 23.0%. The 7-year OS was 69.6% and 51.0%, respectively. Among VenR-treated patients with undetectable minimal residual disease (MRD; uMRD) and no PD at end of treatment (EOT; n = 83), the median PFS from EOT was 52.5 vs 18.0 months in patients with MRD at EOT (n = 35; P < .0001). Fourteen patients had enduring uMRD. Three distinct mutations in BCL2 in 4 patients were identified. In the substudy, 25 patients were retreated with VenR, and 9 patients crossed over to VenR; the median PFS was 23 and 27 months, and the best overall response rate was 72% and 89%, respectively. At the end of combination treatment (EOCT), after retreatment or crossover, 8 and 6 patients achieved uMRD, respectively. No new safety findings were observed. Overall, these final MURANO analyses support consideration of fixed-duration VenR therapy for patients with relapsed/refractory CLL. This trial was registered at www.clinicaltrials.gov as #NCT02005471.

The multicenter, phase 3 German-Speaking Myeloma Multicenter Group (GMMG) ReLApsE trial randomized patients with relapsed and/or refractory multiple myeloma (RRMM) equally to lenalidomide/dexamethasone (LEN/DEX; 25 mg days 1-21, DEX 40 mg weekly, in 4-week cycles) reinduction, salvage high-dose chemotherapy (sHDCT; melphalan 200 mg/m2), autologous stem cell transplantation (ASCT), and LEN maintenance (10 mg/d; transplant arm, n = 139) vs continuous LEN/DEX (control arm, n = 138). Ninety-four percent of patients had received frontline HDCT/ASCT. We report an updated analysis of survival end points with a median follow-up of 99 months. Median progression-free survival (PFS) was 20.5 and 19.3 months in the transplant and control arm, respectively (hazard ratio [HR], 0.98; P = .9). Median overall survival (OS) was 67.1 and 62.7 months, respectively, (HR 0.89; P = .44). Landmark analyses from sHDCT and the contemporaneous LEN/DEX cycle 5 were performed because of 29% dropout of patients before sHDCT/ASCT in the transplant arm but did not reveal significant differences in PFS/OS. Time to progression after frontline HDCT/ASCT was a prognostic factor but did not predict benefit from sHDCT/ASCT. The GMMG ReLApsE trial does not support use of sHDCT/ASCT in RRMM after frontline HDCT/ASCT. This trial was registered at www.clinicaltrialsregister.eu as #EudraCT2009-013856-61.

BMT CTN (Blood and Marrow Transplant Clinical Trials Network) 1506 ("MORPHO") was a randomized study of gilteritinib compared with placebo as maintenance therapy after hematopoietic cell transplantation (HCT) for patients with FLT3-ITD-mutated acute myeloid leukemia (AML). A key secondary end point was to determine the impact on survival of before and/or after HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD. We conducted a post hoc analysis of the data and found that the level of MRD detected with this approach correlated remarkably with RFS and relapse risk, and that MRD detectable at any level negatively affected RFS. In the placebo arm, 42.2% of participants with detectable FLT3-ITD MRD relapsed compared with 13.4% of those without detectable MRD. We found that 14.8% of participants had multiple FLT3-ITD clones detected as MRD and had worse survival irrespective of treatment arm. Finally, we examined the kinetics of FLT3-ITD clonal relapse or eradication and found that participants on the placebo arm with detectable MRD relapsed rapidly after HCT, often within a few weeks. MRD-positive participants on the gilteritinib arm relapsed either with FLT3 wild-type clones (assessed by capillary electrophoresis), after cessation of gilteritinib with persistent MRD, or on progression of multiclonal disease. These data demonstrate the potential of FLT3-ITD MRD to guide therapy with gilteritinib for this subtype of AML. This trial was registered at www.clinicaltrials.gov as #NCT02997202.

Complement C5 inhibitor treatment with ravulizumab or eculizumab for paroxysmal nocturnal hemoglobinuria (PNH) improves outcomes and survival. Some patients remain anemic due to clinically significant extravascular hemolysis (cs-EVH; hemoglobin [Hb] ≤9.5 g/dL and absolute reticulocyte count [ARC] ≥120 × 109/L). In the phase 3 ALPHA trial, participants received oral factor D inhibitor danicopan (150 mg 3 times daily) or placebo plus ravulizumab or eculizumab during the 12-week, double-blind treatment period 1 (TP1); those receiving placebo switched to danicopan during the subsequent 12-week, open-label TP2 and continued during the 2-year long-term extension (LTE). There were 86 participants randomized in the study, of whom 82 entered TP2, and 80 entered LTE. The primary end point was met, with Hb improvements from baseline at week 12 (least squares mean change, 2.8 g/dL) with danicopan. For participants switching from placebo to danicopan at week 12, improvements in mean Hb were observed at week 24. Similar trends were observed for the proportion of participants with ≥2 g/dL Hb increase, ARC, proportion of participants achieving transfusion avoidance, and Functional Assessment of Chronic Illness Therapy-Fatigue scale scores. Improvements were maintained up to week 72. No new safety signals were observed. The breakthrough hemolysis rate was 6 events per 100 patient-years. These long-term data demonstrate sustained efficacy and safety of danicopan plus ravulizumab/eculizumab for continued control of terminal complement activity, intravascular hemolysis, and cs-EVH in PNH. This trial was registered at www.clinicaltrials.gov as #NCT04469465.

Interferon alfa has activity against multiple myeloma (MM). Modakafusp alfa is an immunocytokine comprising 2 attenuated interferon alfa-2b molecules and an anti-CD38 immunoglobulin G4 antibody, targeting delivery of interferon alfa to CD38-expressing (CD38+) immune and myeloma cells. This phase 1/2 trial enrolled patients with relapsed/refractory multiple myeloma with ≥3 prior lines of treatment and refractory to, or intolerant of, ≥1 proteasome inhibitor and ≥1 immunomodulatory drug. During dose escalation, modakafusp alfa was administered at 10 doses in 4 schedules across 13 cohorts. The primary end point was safety for dose escalation, and overall response rate (ORR) for dose expansion. We enrolled 106 patients who had received a median of 6.5 lines of prior therapy; 84% of patients had myeloma previously refractory to an anti-CD38 antibody. The most feasible dosing schedule was every 4 weeks (Q4W), at which the maximum tolerated dose was 3 mg/kg. Among 30 patients treated at 1.5 mg/kg Q4W, the ORR was 43.3%, with a median duration of response of 15.1 months (95% confidence interval [CI], 7.1-26.1); median progression-free survival was 5.7 months (95% CI, 1.2-14). Grade ≥3 adverse events (AEs) occurred in 28 (93.3%) patients, the most common were neutropenia (66.7%) and thrombocytopenia (46.7%); infections were reported in 8 (26.7%) patients (including grade 3 in 4 [16.7%]). Modakafusp alfa therapy induced upregulation of the type 1 interferon gene signature score, increased CD38 receptor density in CD38+ cells, and innate and adaptive immune cell activation. Modakafusp alfa resulted in antitumor activity and immune activation in patients with MM. AEs were primarily hematologic. This trial was registered at www.clinicaltrials.gov as #NCT03215030.

Cold agglutinin disease (CAD) and warm antibody autoimmune hemolytic anemia (wAIHA) are rare autoimmune hemolytic anemias characterized by red blood cell destruction, largely attributable to complement activation resulting in intravascular and extravascular hemolysis. Pegcetacoplan is a subcutaneously administered C3-targeted therapy, which may be suitable for treating CAD and wAIHA. In this open-label phase 2 study, analyses were conducted in 2 cohorts, 1 for patients with CAD and the other for those with wAIHA. In each cohort, patients were randomly assigned to receive pegcetacoplan 270 mg/d or 360 mg/d for up to 48 weeks. Safety end points included the incidence and severity of treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESI). Efficacy end points included change from baseline in hemoglobin (Hb), lactate dehydrogenase, absolute reticulocyte count, haptoglobin, indirect bilirubin, and functional assessment of chronic illness therapy (FACIT)-fatigue scale. Thirteen of 13 (100%) and 10 of 11 (91%) patients with CAD and wAIHA, respectively, experienced at least 1 TEAE. Ten patients had at least 1 serious AE; none were considered related to pegcetacoplan. The only treatment-related AESIs were injection site reactions. Pegcetacoplan increased Hb levels, reduced hemolysis, and increased FACIT-fatigue scale scores in the first weeks; at week 48 the median (interquartile range) change from baseline Hb for the CAD and wAIHA total groups was 2.4 (0.90-3.00) and 1.7 g/dL (-1.40 to 2.90), respectively, and improvements in hemolysis and FACIT-fatigue scale scores were maintained. This study demonstrated that pegcetacoplan is generally well tolerated and suggests it can be effective for patients with CAD and wAIHA. This trial was registered at www.ClinicalTrials.gov as #NCT03226678.

Despite several approved therapies, multiple myeloma (MM) remains an incurable disease with high unmet medical need. "Off-the-shelf" T-cell bispecific antibodies (TCBs) targeting B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GPRC5D) have demonstrated high objective response rates in heavily pretreated patients with MM; however, primary resistance, short duration of response, and relapse driven by antigen shift frequently occur. Although GPRC5D represents the most selective target in MM, recent findings indicate antigen loss occurs more frequently than with BCMA. Thus, anti-GPRC5D immunotherapies must hit hard during a short period of time. Here, we characterize forimtamig, a novel GPRC5D-targeting TCB with 2+1 format. Bivalent binding of forimtamig to GPRC5D confers higher affinity than classical 1+1 TCB formats correlating with formation of more stable immunological synapses and higher potency in tumor cell killing and T-cell activation. Using an orthotopic mouse model of MM, forimtamig recruited T effector cells to the bone marrow and induced rapid tumor killing even after the introduction of step-up dosing to mitigate cytokine release. Combination of forimtamig with standard-of-care agents including anti-CD38 antibodies, immunomodulatory drugs, and proteasome inhibitors improved depth and duration of response. The combination of forimtamig with novel therapeutic agents including BCMA TCB and cereblon E3 ligase modulatory drugs was potent and prevented occurrence of GPRC5D -negative tumor relapse. Forimtamig is currently being evaluated in phase 1 clinical trials in patients with relapsed and refractory MM for monotherapy and in combination treatments. This trial was registered at www.ClinicalTrials.gov as #NCT04557150.