TP53 mutation + Chr del(17p)

In the phase 3 randomized SEQUOIA study (NCT03336333), zanubrutinib (arm A) demonstrated superior progression-free survival (PFS) compared with bendamustine-rituximab (BR; arm B) in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) without del(17p). In the phase 3 AMPLIFY study (NCT03836261), acalabrutinib-venetoclax with or without obinutuzumab demonstrated prolonged PFS vs chemoimmunotherapy (investigator's choice of fludarabine, cyclophosphamide, and rituximab [FCR] or BR) in patients with treatment-naive CLL without del(17p) or TP53 mutations...Zanubrutinib also demonstrated longer PFS whether adjusted for age (PFS-INV hazard ratio &lsqb;HR], 0.26; 95% CI, 0.13-0.54; P<.0003) or unadjusted (PFS-INV HR, 0.45; 95% CI, 0.23-0.88; P=.0197). These results highlight zanubrutinib monotherapy as an effective treatment option for all patients with treatment-naive CLL/SLL, including patients who might otherwise be considered for more intensive fixed-duration combination regimens.

P1, N=7, Completed, Iovance Biotherapeutics, Inc. | Phase classification: P1/2 --> P1

P=N/A, N=500, Recruiting, AbbVie | Active, not recruiting --> Recruiting | N=350 --> 500 | Trial completion date: Dec 2025 --> Dec 2030 | Trial primary completion date: Dec 2025 --> Dec 2030

Considering that TP53 alterations accumulate during MM progression and are associated with drug resistance even in the context of novel therapies, our study further emphasizes the need for routine evaluation of both del(17p) and TP53 mutations. Patients with multi-hit TP53 should be prioritized for inclusion in trials of novel therapeutic strategies.

This new strategy, along with the improved tolerability of these agents, offers particular benefit to older and frail patients, with dosing tailored to comorbidities and concomitant therapies.Given the heterogeneity in older patients' health status, geriatric assessments (e.g., CIRS, FRAIL score) are additional key for individualized therapy decisions and adverse events influence therapy choice (e.g. cardiovascular risk with BTK inhibitors. Beyond clinical factors, patient preferences-such as opting for continuous (e.g., BTK inhibitor monotherapy) versus time-limited therapy (e.g., venetoclax plus obinutuzumab or ibrutinib plus venetoclax)-and treatment tolerability are decisive.

P1/2, N=144, Recruiting, AVM Biotechnology Inc | Trial completion date: Jun 2025 --> Dec 2026 | Trial primary completion date: Apr 2025 --> Apr 2026

Recent advancements in Bruton's tyrosine kinase (BTK) inhibitors like acalabrutinib and zanubrutinib offer improved efficacy and safety profiles, impacting treatment choice for all patients namely elderly patients with comorbidities. Targeted therapy is preferred for most patients, with geriatric assessment pivotal for treatment decisions. Second-generation drugs aim to improve outcomes both in efficacy and safety, advocating for a patient-centered approach in clinical studies.

Among SR patients according to the genomic definition with normal creatinine, median PFS of those with high beta2-microglobulin was not significantly different from patients with normal beta2-microglobulin level. This study validates the IMS/IMWG genomic definition of high-risk myeloma in a large cohort of patients diagnosed from 2019.

Moreover, treatment paradigms are shifting toward earlier integration of immunotherapy, and therapeutic strategies are individualized based on refined molecular risk profiles and clone dynamics. Therefore, a correct definition of HRMM could help in significantly improving both clinical and therapeutic management of a subgroup of patients with an extremely aggressive disease.

Zanubrutinib + venetoclax demonstrated impressive efficacy and a favorable safety profile in patients with TN CLL/SLL, regardless of the presence of TP53-aberrant disease.

P1/2, N=7, Completed, Iovance Biotherapeutics, Inc. | N=70 --> 7 | Trial completion date: Sep 2025 --> Dec 2024 | Trial primary completion date: Sep 2025 --> Nov 2024 | Active, not recruiting --> Completed

These consensus statements provide practical recommendations for the current manage-ment of TN CLL patients in Singapore and similar healthcare systems based on up-to-date evidence. Regular updates to treatment guidelines are important to ensure responsiveness to emerging evidence and evolving clinical practices and to improve patient outcomes and quality of life.