IACH NEWS OF THE WEEK

June 26, 2026
Prepared by Dr Edwin Uriel Suárez

Highlights - European Hematology Association Congress 
(EHA 2026; June 11 to 14, Stockholm, Sweden)

Talquetamab–Daratumumab in Relapsed or Refractory Myeloma (Phase 3 clinical trial) 

Takeaways:

-        Talquetamab, a bispecific antibody targeting GPRC5D (G protein-coupled receptor class C group 5 member D) and CD3, has led to durable responses in patients with heavily pretreated relapsed or refractory multiple myeloma (RRMM) in phase 1–2 trials, with a limited effect on normal B cells.

-        The MonumenTAL-3 study demonstrated that among patients with RRMM who had previously received at least one line of therapy, both talquetamab plus daratumumab and pomalidomide (Tal-DP) and talquetamab plus daratumumab (Tal-D) led to significantly longer progression-free survival (PFS), measurable residual disease (MRD)-negative complete response and overall survival (OS) than daratumumab plus pomalidomide and dexamethasone (DPd).

In a phase 3 trial, patients with RRMM were randomly assigned to receive Tal-DP (n=287), Tal-D (n=287), or DPd (n=290). At the interim analysis (median follow-up, 24.6 months), PFS (primary endpoint) was significantly longer with Tal-DP and Tal-D than with DPd (24-month estimate, 81.3% and 77.6% vs. 51.2%; hazard ratio [HR] for death, Tal-DP vs. DPd, 0.28 [95% confidence interval [CI], 0.20 to 0.40], and Tal-D vs. DPd, 0.33 [95% CI, 0.24 to 0.46]; P<0.001 for both comparisons). The overall response was higher with Tal-DP and Tal-D than with DPd, as was complete response or better and MRD–negative complete response (52.3% and 46.3% vs. 15.9%) (P<0.001 for all comparisons). Overall survival at 24 months was 89.2% with Tal-DP, 87.9% with Tal-D, and 79.1% with DPd (HR, Tal-DP vs. DPd, 0.47 [95% CI, 0.30 to 0.73], and Tal-D vs. DPd, 0.51 [95% CI, 0.33 to 0.78]). Serious adverse events occurred in 63.0%, 52.6%, and 53.7% of the patients in the Tal-DP, Tal-D, and DPd groups, respectively; fatal adverse events occurred in 1.8%, 4.0%, and 4.6%.

Mezigdomide, carfilzomib, and dexamethasone versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma (SUCCESSOR-2): a phase 3, open-label, randomised controlled trial

Takeaways:

-        Mezigdomide, an oral potent cereblon E3 ligase modulator, induces maximal, rapid Ikaros and Aiolos degradation, resulting in enhanced myeloma cell cytotoxicity and immune stimulation versus immunomodulatory drugs.

-        The results of SUCCESSOR-2 showed that mezigdomide–carfilzomib–dexamethasone substantially improves outcomes (progression free survival [PFS]) versus carfilzomib–dexamethasone in patients with relapsed or refractory multiple myeloma (MM) who are predominantly triple-class exposed, refractory to anti-CD38 antibodies and to lenalidomide.

-        The safety profile of mezigdomide–carfilzomib–dexamethasone was consistent with previous mezigdomide studies, with infections and neutropenia being the most common grade 3 or 4 adverse event.

This trial is active but not recruiting. Eligible adult patients had measurable MM, had received at least one previous regimen (including anti-CD38 antibodies and lenalidomide) on which they had achieved minimal response or better, and documented disease progression during or after their most recent treatment. Of 762 patients assessed for eligibility, 606 patients were enrolled, and 479 were included in the analyses (288 patients in the mezigdomide–carfilzomib–dexamethasone group and 191 patients in the carfilzomib–dexamethasone group). At 10.6 months median follow-up, mezigdomide–carfilzomib–dexamethasone significantly improved PFS (primary endpoint) compared with carfilzomib–dexamethasone (median 18.0 months vs 8.3 months; hazard ratio 0.48 [95% confidence interval 0.36–0.63]; P<0.0001). Grade 3 or 4 adverse events were observed in 241 (84%) patients receiving mezigdomide–carfilzomib–dexamethasone versus 105 (56%) patients receiving carfilzomib–dexamethasone, including neutropenia (176 [61%] vs 17 [9%]) and infections (98 [34%] vs 29 [16%]). Deaths occurred in 62 (22%) patients in the mezigdomide–carfilzomib–dexamethasone group and 51 (27%) patients in the carfilzomib–dexamethasone group, mainly due to disease progression.

Tafasitamab plus lenalidomide and R-CHOP versus R-CHOP for first-line treatment of patients with high-risk diffuse large B-cell lymphoma (frontMIND): a global, phase 3, randomised, double-blind, placebo-controlled trial

This study was also presented at ASCO 2026, and we summarized it in a previous newsletter (June 5, 2026).

Takeaways:

-        Approximately 40% of patients with high-risk diffuse large B-cell lymphoma (DLBCL) are not cured with first-line R-CHOP.

-        Progression-free survival (PFS) was significantly improved with addition of tafasitamab (a humanized monoclonal antibody targeting CD19) + lenalidomide to R-CHOP (tafa-len-R-CHOP) versus R-CHOP.

-        The reduction in the risk of disease progression or death in these patients with tafa-len-R-CHOP, and the possibility of PFS benefit in specific subgroups with needs not met by current first-line treatment regimens, including patients younger than 65 years, those with germinal center B-like molecular subtype, and those with bulky disease, could expand the first-line armamentarium for these patients with high-risk disease.

In the phase 3 frontMIND study, patients (n=899) aged 18–80 years with previously untreated high-intermediate or high-risk DLBCL or high-grade B-cell lymphoma were randomly assigned (1:1), stratified by International Prognostic Index (IPI) or age-adjusted IPI and geographical region, to receive six 21-day cycles of standard R-CHOP or tafa-len-R-CHOP. The primary endpoint was investigator-assessed PFS analyzed in the intention-to-treat population. At the time of the primary analysis, the median follow-up was 35.2 months (95% confidence interval [CI], 35.0–35.4). PFS improved in the tafa-len-R-CHOP group compared to the R-CHOP group (hazard ratio [HR], 0.75; 95% CI, 0.59–0.96; P=0.0194). The 2-year PFS rates were 71.1% (66.3–75.4) and 62.9% (57.9–67.5), respectively. The interim HR for overall survival was 0.85 (0.63–1.14). The overall rate of grade 3 or higher treatment-emergent adverse events (TEAEs) was higher with tafa-len-R-CHOP (87% of 443 patients) than with R-CHOP (76% of 447 patients). Additionally, a higher rate of fatal TEAEs was observed with tafa-len-R-CHOP (6%) than with R-CHOP (4%). However, there were fewer overall deaths in the tafa-len-R-CHOP group than in the R-CHOP group (82 [19%] vs. 97 [22%]). 

Efficacy and safety of mitapivat in sickle cell disease: results from the global, randomized, phase 3 RISE UP trial 

Takeaways:

-        Mitapivat, an oral activator of pyruvate kinase (PK), including the red blood cell–specific (PKR) and PKM2 isoforms, increases adenosine triphosphate (ATP) and decreases 2,3-diphosphoglycerate (2,3-DPG), with the potential to improve hemolytic anemia and reduce sickling.

-        In the RISE UP study, a placebo (PBO)-controlled trial, Mitapivat treatment led to a statistically significant hemoglobin (Hb) response and improved markers of hemolysis in patients with sickle cell disease (SCD).

-        Among those who achieved Hb response, additional clinical benefits (reductions in sickle cell pain crises [SCPC], associated hospitalizations, and fatigue) were observed.

-        Mitapivat was generally well-tolerated with a low discontinuation rate.

In the RISE UP study, a PBO-controlled trial, patients (n=207) with SCD were randomized 2:1 to mitapivat 100 mg (n=138) or PBO (n=69) twice daily. Primary endpoints were Hb response (≥1.0 g/dL increase in average Hb concentration from week 24 through week 52 compared with baseline) and annualized rate of SCPC. The median (Quartile 1, Quartile 3) age was 25.0 years (21.0, 37.0). Baseline Hb (mean [±standard deviation]) was 8.62 (±1.10) g/dL in the mitapivat group and 8.54 (±1.20) g/dL in the PBO group. In the mitapivat group, 40.6% of patients (56/138) achieved Hb response compared with 2.9% (2/69) in PBO (2-sided P<0.0001). The annualized rate of SCPC was 2.62 (95% confidence interval [CI], 2.29-3.01) in the mitapivat group compared with 3.05 (2.57-3.64) in PBO (2-sided P=0.1213). Annualized rates of hospitalizations for SCPC were 1.16 (95% CI, 0.87-1.55) for responders and 1.76 (1.41-2.20) for nonresponders. The average change from baseline, least-squares mean in PROMIS Fatigue 13a T-scores (patient-reported fatigue), was clinically meaningful. Serious adverse events were reported in 20.3% (n=28) and 29.0% (n=20) of patients receiving mitapivat and PBO, respectively.  No new safety signals were observed.

Gilteritinib versus midostaurin in patients with newly diagnosed FLT3-mutated acute myeloid leukemia eligible for intensive therapy: Results from the Phase 3 HOVON156/AMLSG28-18/PASHA Trial 

Takeaways:

-        Intensive chemotherapy (chemo) + midostaurin (MIDO), a 1st generation FLT3 inhibitor (FLT3i), is the standard of care (SoC) for newly diagnosed (ND) FLT3-mutated (FLT3^mut+) acute myeloid leukemia (AML; internal tandem duplication [ITD] or tyrosine kinase domain [TKD]).

-        Gilteritinib (GILT), a highly potent selective 2nd generation FLT3i active against both FLT3 mutations, is the SoC for relapsed/refractory FLT3^mut+ AML.

-        Survival outcomes for GILT were not significantly different from MIDO in ND FLT3^mut+ AML.

In the HOVON156/AMLSG28-18/PASHA  open-label trial, 768 patients were randomized to induction chemo (cycle 1: standard 7+3 [cytarabine + anthracycline]; cycle 2: daunorubicin + intermediate-dose cytarabine) + either oral GILT (n=384) or MIDO (n=384) on days 8–21. Consolidation for patients in complete remission (CR), CR with incomplete hematologic recovery (CRi) or morphologic leukemia free state (MLFS) consisted of chemo (intermediate-dose cytarabine or mitoxantrone/etoposide) + GILT or MIDO; or autologous/allogeneic hematopoietic stem cell transplantation (auto/alloHSCT) with GILT or MIDO maintenance for 1 year.

Median (range) age was 59 (18–78) years; 37% had intermediate ELN2017 risk; 48% had FLT3-ITD allelic ratio ≥0.5; 21% had FLT3-TKD; and 58% had NPM1 comutations. 255 patients completed total treatment (GILT, n=144; MIDO, n=101). The most frequent reason for premature discontinuation was relapse after initial CR/CRi/MLFS (GILT, (13%); MIDO, (25%). On-protocol alloHSCT rates were 38% (GILT) vs 37% (MIDO). At data cutoff (15 Oct 2025), median follow-up was 43.2 months. Median overall survival (primary endpoint) was not reached (NR) in both arms and survival outcomes were not significantly different (hazard ratio [HR] 1.02 [95% confidence interval [CI]: 0.81–1.28]; P=0.864).  Median (95% CI) event free-survival was 51.1 (24.7–NR) months for GILT vs 19.9 (14.3–35.7) months for MIDO (HR 0.83 [95% CI: 0.68–1.02], P=0.052). Treatment-related adverse events (AE) due to GILT or MIDO were 40% in both arms; corresponding grade ≥3 rates were 23% for GILT and 19% for MIDO. Serious AE rate was 68% in GILT vs 59% in MIDO. 

High-Dose Methotrexate as CNS Prophylaxis in Ultra High-Risk Large B-Cell Lymphoma: An International Multicenter Analysis

Takeaways:

-        In large B-cell lymphoma (LBCL), use of high-dose methotrexate (HD-MTX) to prevent central nervous system (CNS) relapse (so-called CNS prophylaxis) remains controversial. International guidelines continue to recommend HD-MTX in patients deemed ultra high risk (UHR) because of a lack of robust data specific to these subgroups.

-        This largest of international comparative data set of patients with LBCL with UHR features showed no significant reduction in CNS relapse with HD-MTX in all UHR or in any individual subgroup; strongly supporting previous studies in suggesting HD-MTX prophylaxis has no meaningful benefit for most patients.

Analyses were performed on 1,923 patients meeting UHR criteria (≥1 of the following: CNS international prognostic index score 5-6; testicular, renal/adrenal, or breast involvement; ≥3 extranodal sites). No significant difference in 3-year CNS relapse rate was observed between no HD-MTX (n=1,051) versus HD-MTX patients (n=872), including in multivariable analyses adjusting for baseline characteristics (3-year rate, 9.3% vs 8.1%; adjusted hazard ratio [HR], 1.13 [95% confidence interval [CI], 0.82 to 1.57]). Analyses restricted to isolated CNS relapse also confirmed no difference (5.9% vs 5.7%; adjusted HR, 1.03 [95% CI, 0.69 to 1.53]). In the landmark analysis (no HD-MTX n=782, HD-MTX n=773), no difference in 3-year CNS relapse was observed (6.7% vs 6.6%, adjusted HR, 0.95 [95% CI, 0.62 to 1.44]).

EHA Guidelines on management of chronic lymphocytic leukemia and Richter transformation

Keypoints:

-        Determine somatic hypermutation (SHM) status of immunoglobulin heavy variable (IGHV) genes following ERIC (European Research Initiative on Chronic lymphocytic leukemia [CLL]) recommendations in all patients before first‐line treatment.

-        Determine TP53 aberrations [del(17p) and TP53 gene mutations] by fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) following ERIC recommendations in all patients with CLL before each treatment line.

-        Due to limited reproducibility, assessment of complex karyotype is not recommended before treatment initiation outside clinical trials.

-        Treatment should only be initiated when iwCLL (International Workshop on CLL) criteria are met.

-        Vaccination against pneumococcus, varicella zoster, and hepatitis B viruses and seasonal repetitive vaccination against influenza and SARS‐CoV‐2/COVID-19 in all patients under surveillance, even with expected impaired response to vaccination. No live vaccines should be given.

-        Antimicrobial prophylaxis is not generally recommended.

-        Immunoglobulin (Ig) replacement is only advised with recurrent symptomatic or active infections needing hospitalization, in addition to laboratory‐confirmed hypogammaglobulinemia (total IgG <4 g/L).

-        Patients with an established diagnosis of autoimmune cytopenias and requirement of treatment for CLL should receive CLL treatment as recommended for all other CLL. In case of unsatisfactory response, the anti-CD20 antibody rituximab may be used, or CLL treatment should be started.

-        Chemoimmunotherapies (CIT) are no longer recommended, because they are either inferior (bendamustine+rituximab, chlorambucil + obinutuzumab) to targeted agents or associated with a higher risk for adverse events, including secondary neoplasia such as myeloid malignancies (fludarabine + cyclophosphamide + rituximab).

-        Time‐limited targeted therapies should be preferred over continuous therapy in patients with CLL without TP53 aberrations (See Figure 1 in original paper).

-        The selection of combination therapy should take into consideration the biological profile of the CLL and the adverse event profile of the agents, as well as the patient's comorbidities, co‐medications, history of infections, and ease of treatment (See Figure 2 in original paper). In particular, in patients with CLL and mutated IGHV status, continuous therapy should be avoided.

-        Acalabrutinib and zanubrutinib should be preferred over ibrutinib for continuous treatment of all new patients on the basis of their favorable toxicity profiles.

-        Patients who are well controlled on ibrutinib without notable adverse events should not be switched to second-generation Bruton tyrosine kinase (BTK) inhibitors.

-        Time‐limited treatment with venetoclax + CD20 antibody or continuous treatment with a second‐generation covalent BTK inhibitor are preferred treatments for most patients with relapsed/refractory CLL (See Figure 3 in original paper).

-        Patients with intolerance to acalabrutinib or zanubrutinib may switch to another second‐generation covalent BTK inhibitor.

-        Patients with disease progression on covalent BTK inhibitor therapy should switch to venetoclax‐based regimens or be treated with a non‐covalent BTK inhibitor.

-        After time‐limited treatment with venetoclax (either in combination with a BTK inhibitor or a CD20 antibody), a covalent BTK inhibitor or re‐treatment with venetoclax may be considered, depending on prior response and time since discontinuation (re‐treatment is more effective when the prior treatment‐free interval exceeds 2 years, whereas early relapse warrants switching drug class).

-        Patients with double‐refractory CLL should receive the non‐covalent BTK inhibitor pirtobrutinib, or, if not available, idelalisib + rituximab; these agents should also be considered as a bridge to allogeneic stem cell transplantation (alloSCT) in eligible patients.

-        Outside of clinical trials, CIT is the standard regimen for Richter transformation-diffuse large B-cell lymphoma (RT-DLBCL).

-        Patients with RT-DLBC should be offered participation in clinical trials whenever possible

-        De novo DLBCL (non-clonal related RT-DLBCL) should be treated according to DLBCL guidelines.

-        Patients with clonal RT‐DLBCL in remission, and being fit enough, should be offered alloSCT for consolidation (when a suitable donor is available).