In her second talk in Amgen One’s Multiple Myeloma stream, Professor Noopur Raje from Harvard Medical School discussed the evolution in our understanding of multiple myeloma (MM) bone disease and challenged her Australian colleagues to engage in regular open discussions where collective experience can be pooled to keep driving improvements in understanding and management.
“A lot of time and energy has been spent on understanding the tumour cell in MM. Now there’s a lot of work to be done to understand the bone microenvironment in as much detail. It’s a complex landscape that plays just as important a role as the cancer itself,” began Prof. Raje.
Bones are one of the systems hard hit by MM
“Arising from the bones, MM also has a significant impact on them as well. Bone lesions are still one of the defining diagnostic criterions.1-4 As imaging techniques and observation of the bone get better, we’re understanding more. But I think we’re still likely to be underestimating the burden of disease on bone at the moment,” remarked Prof. Raje. She touched upon the various imaging techniques that help to visualise the extent of disease across the spectrum of MM. “Whole body low-dose computed tomography (CT) scans are more sensitive than conventional X-ray and even MRI is now enabling us to look at active MM and osteoporosis versus monoclonal gammopathy of undetermined significance (MGUS) and osteoporosis.5 We’re getting down to that level of detail now,” she added.
Management of MM is as much about management of bone disease as the cancer itself
Professor Raje then discussed the latest data on the treatments for bone disease in multiple myeloma, specifically bisphosphonates, surgical procedures (such as vertebroplasty and balloon kyphoplasty), radiotherapy and the effects on bone disease seen with MM-specific treatments themselves.6
There is a plethora of data on bisphosphonates reducing skeletal-related events in MM through their inhibition of bone resorption.7,8 A key trial for Prof. Raje was MRC Myeloma IX, which showed that, regardless of the presence of bone lesions at the start, it is still worth treating the symptomatic MM patients with a bone agent as well. “There is a protective effect when it comes to skeletal-related events,”9 she explained. “But we still hear concerns about osteonecrosis of the jaw (ONJ) and occasionally stress fractures with bisphosphonates.10,11 It’s more a case of keeping it on the radar rather than forgoing treatment. Studies we’ve done to look at frequency of dosing have showed us it’s possible to dose less frequently based on serum N-telopeptide (NTX) and when you do the rate of skeletal-related events and risk of ONJ is low.”10
As she went on to discuss the evidence for denosumab versus zoledronic acid in MM patients, Prof. Raje said the findings of Study 244, which investigated the use of denosumab versus zoledronic acid in patients with bone metastases from solid tumours (excluding breast and prostate) or multiple myeloma were unexpected. 12 “In that study we couldn’t understand why there was a survival disadvantage in patients in the denosumab arm, until we went back and looked at the set up. We had no control over renal function, transplant or nontransplant, stage of disease or performance status. It was then we knew we needed to find out the answer and thankfully Amgen pulled together one of the biggest studies of the decade,”13 she remarked. This new double-blind trial comparing denosumab with zoledronic acid has shown non-inferiority of denosumab for time to first on-study skeletal-related event (HR 0.98; 95% CI, 0.85-1.14; p=0.01) and confirmed non-inferiority of the secondary endpoint, overall survival (HR 0.90; 95% CI, 0.70-1.16; p=0.41).13 “We also saw from a safety perspective that zoledronic acid worsened renal function, while denosumab had a protective effect,”13 she added.
The interaction between MM treatments and the bone microenvironment should also be considered
Finally, as she re-iterated the complex, interdependent nature of the bone microenvironment and tumour cell on the pathogenesis of MM, Prof. Raje touched briefly on what we know about MM-specific treatments and their individual impact on markers of bone formation and remodelling.14 “We’re still not sure if resorption is what’s keeping the tumour dormant. When we look at treatments like bortezomib in animal models, we see that it definitely affects markers of bone formation and other osteoblast stimulators.14 However, I think a lot more research is needed to understand the bone niche more before we can claim to have a handle on this,” she concluded.
This article was sponsored by Amgen, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Amgen.
- Multiple Myeloma Research Foundation. 2014. https://www.themmrf.org/wp-content/uploads/MMRF_Disease_Overview.pdf. Accessed August 30, 2017.
- Durie BGM. https://www.myeloma.org/sites/default/files/images/publications/UnderstandingPDF/concisereview.pdf. Accessed August 16, 2017.
- Snowden JA, et al. Br J Haematol. 2011;154:76-103.
- Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.
- Terpos E, et al. ASCO Educational Book 2016.
- Roodman GD. Hematology Am Soc HematolEduc Program. 2008:313-319.
- Rosen LS et al. Cancer J .2001;7(5):377-387.
- Flanagan AM, Chambers TJ. Calcif Tissue Int 1991;49(6):407-415.
- Morgan GJ, et al. Clin Cancer Res 2013;19(21):6030-6038.
- Raje N, et al. Clin Can Res 2008;14(8):2387-2395.
- Grasko JM, J Oral Maxillofacial Surg 2009;67(3):645-649.
- Henry DH, et al. J Clin Oncol 2011;29(9):1125-1132.
- Raje N, et al. Lancet Oncol 2018;19(3):370-381.
- Terpos E, et al. Br J Haematol2006;135:688-692.