Bone disease in multiple myeloma (MM) causes significant morbidity and mortality. Many patients with myeloma present with bone disease at diagnosis, which may progress throughout the course of their disease.
Charlotte Pawlyn, Clinical Lecturer, The Institute of Cancer Research, The Royal Marsden Hospital, London, UK, and Evangelos Terpos, Associate Professor of Hematology, University of Athens, GR, discussed the use of personalized therapy using bone-targeting agents, during Debate 1: Bone Disease, at the 2nd How to Diagnose and Treat Multiple Myeloma in Berlin, DE. Results were drawn from the MRC Myeloma IX1 study (ISRCTN68454111) and the Amgen-482 (NCT01345019) study.
MRC Myeloma IX
This randomized study assigned patients to bisphosphonate (either clodronic acid or zoledronic acid) and induction therapies, and then assigned to thalidomide maintenance therapy or no maintenance at second randomization.
- N = 1,970
- Arm 1: Intravenous zoledronic acid (ZOL): n = 981, 4 mga (adose adjusted for patients with impaired renal function)
- Arm 2: Oral clodronate (CLO): n = 979, 1,600 mg/day
The primary end-points of the study were overall survival (OS), progression-free survival (PFS) and response. Secondary end-points were skeletal-related events (SREs) and safety.
There was no requirement at baseline for bone disease. Bisphosphonate treatment continued at least until disease progression.
Results showed patients receiving ZOL had reduced SREs and increased OS and PFS, even after results were adjusted using SREs. A significantly improved 10 month OS was achieved in patients given ZOL compared with patients receiving CLO. Benefits in the reduction of SREs using ZOL over CLO persisted for more than three years.
The Amgen-482 study was an international, randomized, double-blind, multicenter study comparing ZOL with denosumab in the prevention of fractures and other SREs in adult patients with newly diagnosed MM and bone disease. The primary end-point of the study was non-inferiority for the time to first on-study SRE, other end-points were OS and PFS.
- N = 1,718
- Arm 1: intravenous ZOL, n = 859, 4mga
- Arm 2: subcutaneous denosumab (DEN), n = 859, 120mg
- Patients received either subcutaneous DEN and intravenous placebo, or intravenous ZOL and subcutaneous placebo
Patients receiving DEN long-term showed fewer SREs than those receiving ZOL long-term. Exploratory analysis showed that DEN improved PFS compared with ZOL (DEN 46.09 months, ZOL 35.38 months).
Dr Pawlyn stressed that there is no evidence of cumulative toxicity after 2—3 years of ZOL use. With an increase in the occurrence of SREs at relapse, Dr Pawlyn argued that it made sense to continue with bone disease therapy, rather than stopping and starting, thus ensuring treatment as early as possible to prevent further skeletal damage.
Dr Pawlyn also discussed the increased risk of fractures when stopping DEN, as it is not incorporated in the bone matrix and, in certain osteoporosis patients, leads to reduced bone mineral density. In her opinion, results from both the Myeloma IX and the Amgen-482 studies support the argument for continuous bone-targeted therapy, with OS and PFS even suggesting anti-myeloma activity.
Dr Pawlyn recognized toxicities of bone-targeted therapy, mentioning that if toxicity had already occurred, there may be no benefit in stopping the treatment. She suggested that there is no increase in toxic effects after a plateau is reached between 2—3 years of bone-targeted treatment. She concluded by stating that the studies do not clearly indicate how to personalize bone-targeted therapy.
Professor Terpos indicated how the results of the MRC Myeloma IX study showed that ZOL reduced SREs more effectively than CLO in the overall population.1
Prof Terpos mentioned how this meant that if the disease can be managed, the bone-targeted agents may not be needed. He again highlighted the toxic effect of bone-targeted therapy, concentrating on renal failure and osteonecrosis of the jaw, and how guidance suggests that the bone-targeted therapy should be discontinued for patients achieving CR or VGPR after 12—24 months. Caution was given for patients with renal impairment, with neither CLO nor ZOL being recommended for patients with creatinine clearance below 30ml per minute.
Prof Terpos outlined a typical treatment consisting of stopping bone-targeting therapy after 12 months, providing CR has been achieved, and giving the treatment once every three months. Dr Pawlyn suggested that ZOL should be used to treat newly diagnosed patients, and DEN for those with renal failure. This should be continued indefinitely, given every two months, and should only stop for those in long-term remission who have a very low risk of relapse.
The consensus in the audience was almost entirely on the side of more personalized treatment, supporting Prof Terpos’ suggestions.
- Morgan, G.J., et al. Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial. The Lancet Oncology, 2011 Aug 12(8), pp.743-752. DOI: 1016/S1470-2045(11)70157-7
- Pawlyn C. Debate 1: Bone Disease. 2019 Apr 5. 2nd How to Diagnose and Treat Multiple Myeloma, ESH 2019, Berlin, Germany.
- Terpos E. Debate 1: Bone Disease. 2019 Apr 5. 2nd How to Diagnose and Treat Multiple Myeloma, ESH 2019, Berlin, Germany.