Multiple myeloma (MM) remains incurable despite advances in treatment, driving interest in novel therapies for relapsed/refractory cases. This large retrospective study evaluated venetoclax-based regimens in 232 heavily pretreated patients with MM, most of whom were triple-class refractory. Patients with the t(11;14) translocation—linked to BCL-2 dependence—had significantly better response rates (64%) and longer median progression-free survival (11.8 months) compared to patients who were non-t(11;14). Among non-t(11;14) patients, BCL-2 expression by immunohistochemistry (IHC) did not reliably predict benefit. Importantly, high-risk cytogenetic abnormalities such as del(17p) and 1q gain/amplification reduced the efficacy of venetoclax even in patients who were t(11;14)-positive.

The best outcomes were observed with venetoclax-daratumumab combinations, supporting their synergistic potential. Overall, venetoclax was well tolerated, with low discontinuation due to adverse events, though infection risks remained notable. These findings reinforce venetoclax’s role in t(11;14)-positive MM, particularly in combination regimens, and suggest limited benefit in non-t(11;14) cases despite BCL-2 IHC positivity. Future research should focus on earlier-line use and refined biomarker-based patient selection to optimize outcomes.

Reference: Bolarinwa A, Nagaraj M, Zanwar S, et al. Venetoclax-based treatment combinations in relapsed/refractory multiple myeloma: practice patterns and impact of secondary cytogenetic abnormalities on outcomes. Blood Cancer J. 2025;15(1):57. doi: 10.1038/s41408-025-01264-2

In multiple myeloma (MM), bone disease is a major source of morbidity, making bone-protective agents like zoledronic acid (ZOL) and denosumab essential to care. ZOL has shown strong efficacy in reducing skeletal-related events (SREs), including in patients without evident bone lesions. Denosumab is non-inferior to ZOL and preferred in patients with renal impairment. Long-term ZOL treatment beyond two years continues to reduce SRE risk with minimal added toxicity. After one year of monthly ZOL, extending dosing to every 12 weeks has proven effective in multiple studies. Although denosumab interval extension is promising in other diseases, data in MM are limited, and discontinuation carries a risk of rebound bone loss, particularly vertebral fractures.

Evidence supports reinitiating bone protection at relapse, even without symptoms, though lifetime bisphosphonate exposure should be considered. Bone markers, like urinary N-telopeptide, have been explored for treatment individualization, but clinical utility remains unproven. Importantly, even patients in deep remission (very good partial response or complete response) remain at risk for SREs, suggesting ongoing treatment may still be needed. A practical approach is monthly ZOL for at least a year, followed by dosing every 12 weeks up to four years if VGPR or better is achieved. Bone-protective therapy should resume at relapse or new SREs, with adjustments based on disease status, imaging, and individual risk factors.

Reference: Gundesen MT, Schjesvold F, Lund T. Treatment of myeloma bone disease: When, how often, and for how long? J Bone Oncol. 2025;52:100680. doi: 10.1016/j.jbo.2025.100680. 

The FDA’s recent acceptance of minimal residual disease (MRD) negativity as a surrogate endpoint for accelerated approval in multiple myeloma (MM) represents a major advancement in clinical trial design and drug development. MRD negativity—defined as no detectable malignant plasma cells at a sensitivity of at least 10⁻⁵—has shown strong individual-level associations with improved progression-free and overall survival in both newly diagnosed and relapsed/refractory MM. Two major meta-analyses, EVIDENCE and I2TEAMM, provided robust data confirming that MRD-negative complete response at 9 or 12 months reliably predicts long-term outcomes. With FDA endorsement, MRD offers a more sensitive and timely endpoint than overall response rate or progression-free survival, significantly shortening trial timelines.

Unanimously supported by the FDA’s Oncologic Drugs Advisory Committee, this decision paves the way for more efficient clinical trials and faster access to new therapies—potentially reducing development timelines by years. Future trials may now combine early MRD readouts with long-term endpoints in a single study, streamlining approval pathways. The collaborative effort between industry, academia, and regulators sets a precedent for other areas in oncology to establish early surrogate endpoints. As additional trial data emerge, MRD's role may further expand, both in MM and beyond, helping optimize drug development and accelerate patient access worldwide.

Reference: Landgren O, Devlin SM. Minimal Residual Disease as an Early Endpoint for Accelerated Drug Approval in Myeloma: A Roadmap. Blood Cancer Discov. 2025;6(1):13-22. doi: 10.1158/2643-3230.BCD-24-0292.