CLL, AML, Lymphoma, and Myeloma Updates Poised to Impact Clinical Practice

Valentina Ardila Avila, MD University of Miami Sylvester Comprehensive Cancer Center

Key Points

• The phase 3 CLL17 trial demonstrated that fixed-duration venetoclax-based regimens are noninferior to continuous ibrutinib, with comparable 3-year progression-free survival (PFS) of about 80%, supporting time-limited therapy as an effective frontline option in untreated chronic lymphocytic leukemia (CLL).

• In relapsed/refractory follicular lymphoma, the phase 3 EPCORE FL-1 trial showed that epcoritamab plus R2 significantly improved overall response rate (ORR) and PFS, positioning bispecific antibodies as potentially practice-changing in this setting.

• The phase 2 PARADIGM study demonstrated that azacitidine plus venetoclax outperformed intensive 7+3 chemotherapy in fit patients with adverse-risk acute myeloid leukemia (AML), with higher response rates and superior event-free survival, suggesting a paradigm shift in frontline therapy for high-risk disease.

• MajesTEC-3 showed that teclistamab plus daratumumab dramatically improved PFS compared with standard daratumumab-based regimens in relapsed/refractory myeloma.

The 2025 ASH Annual Meeting showcased several practice-changing studies across hematologic malignancies, with a growing emphasis on time-limited therapy, targeted combinations, and bispecific antibodies.

CLL: Evolving Treatment Strategies

The CLL17 trial presented important phase 3 data comparing continuous versus fixed-duration therapy in previously untreated CLL. Continuous ibrutinib was evaluated against two fixed-duration regimens: venetoclax plus obinutuzumab (VO) and venetoclax plus ibrutinib (VI). At 3 years, PFS was similar across all arms—81.1% for VO, 81% for ibrutinib (HR 0.87; CI 0.54–1.41), and 79.4% for VI (HR vs I: 0.84; CI 0.53–1.32)—demonstrating noninferiority of fixed-duration therapy.¹

Panelists emphasized that treatment choice should be individualized, taking into account patient-related factors (age, comorbidities), disease characteristics, and regimen-specific toxicities. They noted that time-limited therapy may reduce the risk of resistance-associated mutations and preserve the option to rechallenge with the same agents upon progression.

Dr. Coombs underscored that there’s not a standard role for minimal residual disease (MRD) in CLL. While MRD status remains a useful prognostic marker—patients achieving MRD negativity typically experience longer PFS—she advised against extending therapy solely based on MRD positivity after a fixed-duration regimen.

Updates Across the Lymphoma Landscape

For diffuse large B-cell lymphoma (DLBCL), panelists emphasized that Pola-R-CHP should be considered first-line therapy, especially for patients with the non-germinal center subtype, which demonstrated the greatest benefit in clinical studies. In relapsed/refractory disease, CAR-T cell therapy remains central, while bispecific antibodies—such as epcoritamab and glofitimab—are emerging as strong alternatives.

In follicular lymphoma (FL), bendamustine-rituximab continues to be the standard first-line regimen for patients requiring treatment. Among relapsed/refractory FL studies presented, the EPCORE FL-1 trial was a major highlight. This phase 3 study compared epcoritamab plus rituximab and lenalidomide (E plus R2) with R2 alone. E plus R2 produced a significantly higher ORR (95.7% vs 81%; P<.0001) and markedly improved PFS (HR 0.21; 95% CI 0.13–0.33), underscoring its potential to redefine treatment in this setting.²

Key Advances in AML

Panelists highlighted the practice-changing results of the PARADIGM study, a phase 2 trial comparing azacitidine plus venetoclax (aza-ven) with conventional 7+3 induction chemotherapy in newly diagnosed, fit adults with poor- or adverse-risk AML. The aza-ven regimen demonstrated significantly higher ORRs (88% vs 62%; P<0.001) and composite complete response rates (81% vs 55%; P<0.001). Event-free survival was also superior with aza-ven (HR 0.61; P=0.017), supporting its role as an effective alternative to intensive chemotherapy in this high-risk population.³

For patients with favorable- or intermediate-risk disease, panelists discussed incorporating quizartinib for those with FLT3-ITD mutations, citing its greater potency and improved tolerability, while reserving gilteritinib for the relapsed/refractory setting. They noted that triplet therapy with aza-ven plus isocitrate dehydrogenase (IDH) inhibitors is not yet standard of care and IDH inhibitors should generally be reserved for relapse.

Finally, addressing treatment-related cytopenias with aza-ven, Dr. Borate emphasized that growth factor support is appropriate when bone marrow blasts are below 5%.

Multiple Myeloma

The myeloma panel highlighted that 3 years of daratumumab should now be considered standard of care for patients with high-risk smoldering multiple myeloma. The panel also emphasized that CD38-directed antibodies—daratumumab and isatuximab—are clinically equivalent. Despite the availability of new proteasome inhibitors, bortezomib remains the preferred first-line option, given its established efficacy, tolerability, and lower cost compared with carfilzomib.

With respect to MRD-guided treatment escalation or de-escalation, the panel concluded that there is currently insufficient evidence to support routine clinical decision-making.

A major focus of the discussion was the phase 3 MajesTEC-3 trial, which compared teclistamab (a B-cell maturation antigen and CD3 bispecific antibody) plus daratumumab with standard regimens of daratumumab combined with dexamethasone and pomalidomide (DPd) or bortezomib (DVd) in relapsed or refractory multiple myeloma. At 36 months, PFS was 83.4% with teclistamab–daratumumab versus 29.7% with DPd or DVd (HR 0.17; P<0.001).⁴ While these results highlight a promising new therapeutic option, Dr. Orlowski noted important limitations, including the predominance of daratumumab-naïve patients in the trial. 

Collectively, these data reflect a continued shift toward targeted, antibody-based, and time-limited strategies across hematologic malignancies, with multiple studies poised to influence near-term clinical practice.

References

1. Al-Sawaf O, Stumpf J, Zhang C,  et al. Fixed-duration versus continuous treatment for chronic lymphocytic leukemia. N Engl J Med. 2025. Epub 20251206. doi:10.1056/NEJMoa2515458

2. Falchi L, Nijland M, Huang PH, et al. Epcoritamab, lenalidomide, and rituximab versus lenalidomide and rituximab for relapsed or refractory follicular lymphoma (EPCORE FL-1): a global, open-label, randomised, phase 3 trial. Lancet. 2025. Epub 20251207. doi:10.1016/S0140-6736(25)02360-8

3 . Fathi A, Perl A, Fell G, et al. Results from paradigm – a phase 2 randomized multi-center study comparing azacitidine and venetoclax to conventional induction chemotherapy for newly diagnosed fit adults with acute myeloid leukemia. Blood. 2025;146(Supplement 1):6-6. doi:10.1182/blood-2025-6

4. Costa LJ, Bahlis NJ, Perrot A, et al. Teclistamab plus daratumumab in relapsed or refractory multiple myeloma. N Engl J Med. 2025. Epub 20251209. doi:10.1056/NEJMoa2514663