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MULTIPLE MYELOMA, GAMMOPATHIES

Phase III randomized trial of Thal+ZLD versus ZLD in patients with asymptomatic multiple myeloma – updated results after 18-year follow-up

Leukemia (2024)Cite this article

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Smoldering multiple myeloma (SMM) is an asymptomatic phase of multiple myeloma (MM) first described in 1980 [1]. It is associated with a yearly risk of progression to MM of approximately 10% in the first 5 years, 3% in the following 5 years, and 1% thereafter [2]. While a watch-and-wait strategy has traditionally been the standard approach for SMM, the notion of early intervention has been under investigation for over three decades [3, 4]. The earliest studies using melphalan in combination with steroids did not demonstrate benefit in terms of response or overall survival (OS) [3, 4]. Subsequently, the use of bisphosphonates was associated with reduction in skeletal-related events without improvement in progression-free survival (PFS) or OS [5]. Upon emergence of evidence for thalidomide activity in MM [6], our group conducted a phase II study of thalidomide in SMM, showing activity in this setting [7]. This was the basis of a phase III randomized trial in 2003, which compared thalidomide (Thal) plus zoledronic acid (ZLD) to ZLD in patients with SMM. In 2013, initial results were published after 6 years of follow-up: patients in the Thal+ZLD arm had longer time-to-progression (TTP) (2.4 vs. 1.2 years, P = 0.02) and 1-year PFS (86% vs. 55%, P = 0.005) compared to the ZLD arm, with progression defined according to the International Myeloma Working Group (IMWG) response criteria [8]. Thal+ZLD was also associated with longer TTP and PFS when progression was defined as “CRAB” features, but these results were not statistically significant [9]. The approval of lenalidomide, which is associated with lower neurotoxicity compared to thalidomide, and emergence of SMM risk stratification systems [10,11,12], shaped the design of subsequent studies, which used lenalidomide-based interventions targeting intermediate- and high-risk SMM patients. In the QuiRedex trial, lenalidomide plus dexamethasone combination was associated with longer TTP and OS compared to active surveillance in high-risk SMM [13]. In the ECOG-ACRIN trial, lenalidomide was associated with improvement in PFS, but not OS, in intermediate- or high-risk patients after a follow-up of 35 months [14]. Given the short follow-up, it remains unclear whether early intervention offers a survival advantage. Thus, we performed an updated analysis of the Thal+ZLD vs. ZLD trial to evaluate OS after approximately 18 years of follow-up. We also evaluated TTP to MM and myeloma-free survival among all patients and in the different risk groups.

This was a randomized phase III clinical trial (NCT00432458) which enrolled patients ≥ 18 years with a new diagnosis of SMM who had measurable disease. The study design has been previously described [9]. Patients with small asymptomatic lytic lesions on plain skeletal survey radiographs were eligible. Based on the initial protocol, ZLD 4 mg was administered every 28 days; the dosing was later changed to every 3 months for the first year, then yearly, to mitigate the risk of osteonecrosis of the jaw. Patients in the Thal+ZLD arm also received Thal 200 mg/day. There was no crossover between the arms. The study enrolled patients at Mayo Clinic and Memorial Sloan Kettering, but this analysis only included Mayo Clinic patients.

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Fig. 1: PFS and OS in the overall cohort.

Data availability

The data generated in this study is available upon request from the corresponding author.

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Acknowledgements

This study was supported by R01CA100080 from the National Cancer Institute; the Predolin Foundation.

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Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    Nadine Abdallah, Thomas E. Witzig, Shaji K. Kumar, Martha Q. Lacy, Suzanne R. Hayman, Angela Dispenzieri, Morie A. Gertz & S. Vincent Rajkumar

  2. Division of Hematology, Department of Medicine, Mayo Clinic, Jacksonville, FL, USA

    Vivek Roy

  3. Division of Hematology/Oncology, Department of Medicine, Mayo Clinic Arizona, Phoenix, AZ, USA

    P. Leif Bergsagel

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  1. Nadine Abdallah
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Contributions

NA and SVR analyzed the data and wrote the first draft of the manuscript. TEW, SKK, MQL, SRH, AD, VR, MAG, and PLB. provided critical revision and final approval of the manuscript version for publication.

Corresponding author

Correspondence to S. Vincent Rajkumar.

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Competing interests

The study drugs thalidomide and Zometa (zoledronic acid) were provided by Celgene Pharmaceuticals and Novartis Oncology, respectively. S.V.R. has received grants from NIH and research funding from Celgene for clinical trials. T.E.W. has received research funding from Celgene and Novartis for clinical trials. A.D. has received research funding from Celgene, Millennium Pharmaceuticals, Pfizer, and Janssen and received a travel grant from Pfizer. M.A.G. served as a consultant for Millennium Pharmaceuticals and received honoraria from Celgene, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Novartis, GlaxoSmithKline, Prothena, Ionis Pharmaceuticals, and Amgen. M.Q.L. received research funding from Celgene. S.K.K. served as a consultant for Celgene, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Janssen, and Bristol-Myers Squibb and received research funding from Celgene, Millennium Pharmaceuticals, Novartis, Onyx Pharmaceuticals, AbbVie, Janssen, and Bristol-Myers Squibb. The remaining authors declare no competing financial interests.

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Abdallah, N., Witzig, T.E., Kumar, S.K. et al. Phase III randomized trial of Thal+ZLD versus ZLD in patients with asymptomatic multiple myeloma – updated results after 18-year follow-up. Leukemia (2024). https://doi.org/10.1038/s41375-024-02192-z

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