Introduction
Bone involvement is present in >80% of patients with multiple myeloma [ 1 ]. This can cause lytic lesions in the bone leading to pathological fractures and significant pain. Prophylactic orthopaedic surgery e.g. vertebroplasty, kyphoplasty and stabilisation for spinal lesions and nailing for long bone stabilisation [ 2 ], is indicated to prevent pathological fractures if the lesion is graded ≥9/12 on Mirels’ score [ 3 ]. Although successful, these surgeries have risks and lengthy recovery periods. Recent advances in the non-surgical management of multiple myeloma, including targeted chemotherapy, have been shown to be effective at preventing the osteoclastogenic processes occurring within the microenvironment of the myeloma deposits, thus inhibiting their growth [ 4 ]. We present a case indicating that myeloma chemotherapy may obviate prophylactic femoral nailing for high Mirels’ score lesions in the femoral head with impending pathological hip fracture.
This article was previously presented as a poster at the 6th World Congress on Spine and Spinal Disorders on December 6, 2020.
Case presentation
A 72-year-old woman presented to the hospital in December 2017 with back pain. A plain X-ray of the patient’s lumbar spine indicated an advanced generalised loss of bone density and degenerative anterolisthesis in the lumbosacral region of her spine (L5-S1). Her primary care physician performed routine investigations for her back pain, which found her to be anaemic. Subsequent serum analysis indicated elevated levels of total protein - 81g/L (60 - 80g/L), globulin - 52g/L (20 - 40g/L) and alkaline phosphatase - 199U/L (30 - 130U/L) and decreased albumin levels - 29g/L (35 - 50g/L). Protein electrophoresis and serum immunofixation revealed an immunoglobulin A (IgA) kappa paraprotein of 18g/L (0.8 - 4.0g/L) and raised kappa serum free light chains of 2000mg/L (3.30 - 19.40mg/L). Whole-body CT scans showed widespread lytic bone lesions and a bone marrow biopsy confirmed infiltration by plasma cells with normal FISH (fluorescent in-situ hybridisation). She was hence diagnosed with International Staging System (ISS) stage 3 multiple myeloma [ 5 ] in March 2018. This was successfully treated that year with bortezomib, thalidomide and dexamethasone in addition to regular bisphosphonates (zoledronic acid). According to the International Myeloma Working Group (IMWG) criteria, she achieved a stringent complete response to this initial induction therapy [ 6 ], which was subsequently discontinued, however, she was deemed unsuitable for stem cell transplant due to recurrent diverticulitis. As such, she was placed on active surveillance.
The patient presented again to the hospital in June 2020 with rapid onset severe bone pain in her back and pelvis. Her paraprotein had increased from 0g/L at her previous clinic appointment to 9g/L while her serum-free light chains had also increased from 14mg/L to 103mg/L, indicating serological progression. Whole-body MRI scans indicated a very aggressive relapse of the myeloma with deposits in her spine and right femur with significant involvement of the bony cortex as seen in Figure 1 and Figure 2 . The deposit in her femoral head was graded 10/12 on Mirels’ score indicating prophylactic femoral nailing. However, it was thought that surgery would provide a limited cytoreductive effect and prevent chemotherapy from occurring for six weeks post-surgery, potentiating pathological hip fracture and allowing for disease progression at other bony sites. As early, rapid treatment is vital, the patient was instead treated with daratumumab, bortezomib and dexamethasone with an escalation of zoledronic acid to monthly infusions. The patient was also kept ambulatory with protected weight-bearing, crutches, physiotherapy and fall-prevention education.
These interventions alone resulted in a complete response according to the IMWG uniform criteria [ 6 ] as well as the resolution of all focal active bone marrow lesions on whole-body diffusion-weighted MRI scans. Furthermore, the myeloma deposits were significantly reduced such that the femoral lesion was graded <8 on Mirels’ score. Overall, these non-surgical interventions led to a significant reduction in the patient’s night and rest pain in her lumbosacral spine and pelvis. Prior to treatment, the patient was unable to traverse the stairs, however, within three months of beginning treatment, she was able to do so. She remains in a complete response as of December 2022 with ongoing daratumumab and denosumab (120mg) maintenance treatment (once every four weeks) with surveillance blood tests performed concurrently. She is fully ambulatory and reports no symptoms relating to her femoral lesion.
Discussion
Multiple myeloma makes up 1% of all cancers diagnosed worldwide [ 7 ]. Its incidence increases with age and is positively associated with the male sex and black ethnicity [ 8 ]. In newly diagnosed myeloma, current treatment algorithms distinguish patients based on their eligibility for autologous stem cell transplant (ASCT) [ 9 ]. For those who are eligible, initial treatment involves four to six cycles of induction therapy with a combination of bortezomib (Velcade), dexamethasone and either lenalidomide (VRd), thalidomide (VTd) or cyclophosphamide (VCd) [ 10 ]. These medical treatments have resulted in drastic improvements in survival rates, life expectancy and quality of life for multiple myeloma patients. Overall response rates are over 80% with progression-free survival of around 50 months [ 11 - 12 ]. Furthermore, the integration of anti-osteoclastogenic therapies, such as bisphosphonates (zoledronic acid), and RANK-ligand inhibitors (denosumab) has approximately halved the risk of fractures [ 13 ].
The pathogenesis of multiple myeloma results from an imbalance of osteoblastic and osteoclastic bone activity with the latter dominating [ 14 ]. Consequently, over 80% of patients with multiple myeloma will suffer from destructive lesions of the bone at the point of diagnosis; These tend to be lytic in nature and <20mm in diameter [ 15 ]. Lesions occur in “the vertebrae (66% of patients), ribs (45%), skull (40%) and pelvis (30%)” [ 16 ] and require whole-body MRI, positron emission tomography-computed tomography (PET-CT) or low-dose whole-body CT ideally to diagnose. Recent studies have found MRI to have similar bony lesion detection rates when compared with CT/PET in all aforementioned areas except the ribs and skull where additional X-rays are recommended [ 17 ]. MRI is further indicated to rule out spinal cord compression and guide surgical intervention in those with spinal lesions [ 18 ].
The lytic lesions result in painful bones (73%) and impending pathological fractures (>50%) during the course of the disease [ 19 ]. This bone pain is usually managed with analgesia, chemotherapy and bisphosphonates; however, the risk of pathological fracture remains high. For those impending pathological fractures of the long bones, surgical intervention via intramedullary nailing provides a solution associated with reduced blood loss and morbidity [ 20 ]. Furthermore, prophylactic nailing was found to result in increased survival and ambulation rates six months post-surgery [ 21 ]. In 1989, Hilton Mirels proposed a system to "quantify the risk of sustaining a pathological fracture through a metastatic lesion in a long bone". This system was based on the site, nature, size and pain associated with the lesion, as seen in Table 1 . High-risk lesions (scoring ≥9/12 on Mirels' scale) indicated prophylactic nailing prior to irradiation as seen in Table 2 [ 22 ]. Mirels’ system was found to be “reproducible, valid and more sensitive than clinical judgement across all experience levels” [ 23 ]. A 2003 report, however, found a lack of objectivity and reproducibility in the system [ 24 ]. Additionally, it was devised during an era in which myeloma therapies were limited. Furthermore, there are complications associated with nailing including wound dehiscence and infections, which further prolong recovery [ 25 ]. For these reasons, there has recently been a shift from managing myeloma patients, especially elderly patients experiencing their first relapse, with osteolytic lesions via instrumented surgical intervention to the aforementioned combination of steroids and chemotherapy as well as the use of minimally invasive surgery such as kyphoplasty and bracing to manage pain [ 26 ]. Thus, it is vital to take a patient-by-patient approach when considering whether medical therapy is preferable to prophylactic surgical intervention in high-risk lesions.
Table 1
Mirels' scoring system for lytic lesions of long bones Adapted from [ 27 ]
| Score | Site | Nature | Size | Pain |
| 1 | Upper extremity | Blastic | <1/3 | Mild |
| 2 | Lower extremity | Mixed lytic and blastic | 1/3 – 2/3 | Moderate |
| 3 | Peritrochanteric | Lytic | >2/3 | Functional |
Table 2
Clinical recommendations for the management of lytic lesions of long bones based upon Mirels' scoring system Adapted from [ 27 ]
| Risk of Pathological Fracture | Mirels’ scale point total | Mirels’ treatment recommendations |
| Impending | ≥9 | Prophylactic stabilisation |
| Borderline | 8 | Consider stabilisation |
| Not impending | ≤7 | Non-operative care |
Conclusions
Multiple myeloma often warrants surgery in order to treat impending pathological fractures of long bones such as the femur; This is more so the case in those lesions graded ≥9/12 on Mirels’ score. Our case, however, shows that lytic lesions, even those indicating prophylactic nailing as per Mirels’ score, may be managed and treated effectively through the use of targeted chemotherapy and bisphosphonates thus obviating intramedullary nailing and the complications and risks associated with this. Furthermore, our case is in keeping with current literature describing the limitations of Mirels’ classification system and the potential need for an updated system. Further research should be conducted into the safety and efficacy of a purely medical treatment regimen in patients with high Mirels’ score lesions, similar to our cognizant decrease in instrumented spinal surgery. If this research shows significant benefits to purely medical management over surgical management, consideration could be taken as to whether prophylactic femoral nailing is necessary despite indications.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
References
1. Multiple myeloma associated bone disease. Rasch S, Lund T, Asmussen JT, Lerberg Nielsen A, Faebo Larsen R, Østerheden Andersen M, Abildgaard N. Cancers (Basel) 2020;12:2113. doi: 10.3390/cancers12082113.
2. Bone disease in multiple myeloma: pathophysiology and management. Hameed A, Brady JJ, Dowling P, Clynes M, O'Gorman P. Cancer Growth Metastasis. 2014;7:33–42. doi: 10.4137/CGM.S16817.
3. Management of skeletal metastases: an orthopaedic surgeon's guide. Agarwal MG, Nayak P. Indian J Orthop. 2015;49:83–100. doi: 10.4103/0019-5413.143915.
4. Optimizing the management of patients with spinal myeloma disease. Molloy S, Lai M, Pratt G, et al. Br J Haematol. 2015;171:332–343. doi: 10.1111/bjh.13577.
5. International staging system for multiple myeloma. Greipp PR, San Miguel J, Durie BG, et al. J Clin Oncol. 2005;23:3412–3420. doi: 10.1200/JCO.2005.04.242.
6. International uniform response criteria for multiple myeloma. Durie BG, Harousseau JL, Miguel JS, et al. Leukemia. 2006;20:1467–1473. doi: 10.1038/sj.leu.2404284.
7. Multiple myeloma. Palumbo A, Anderson K. N Engl J Med. 2011;364:1046–1060. doi: 10.1056/NEJMra1011442.
8. MGUS and smoldering multiple myeloma: diagnosis and epidemiology. Mateos MV, Landgren O. Cancer Treat Res. 2016;169:3–12. doi: 10.1007/978-3-319-40320-5_1.
9. Multiple myeloma current treatment algorithms. Rajkumar SV, Kumar S. Blood Cancer J. 2020;10:94. doi: 10.1038/s41408-020-00359-2.
10. Multiple myeloma: every year a new standard? Rajkumar SV. Hematol Oncol. 2019;37 Suppl 1:62–65. doi: 10.1002/hon.2586.
11. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Rosiñol L, Oriol A, Teruel AI, et al. Blood. 2012;120:1589–1596. doi: 10.1182/blood-2012-02-408922.
12. Superior complete response rate and progression-free survival after autologous transplantation with up-front velcade-thalidomide- dexamethasone compared with thalidomide-dexamethasone in newly diagnosed multiple myeloma. Cavo M, Tacchetti P, Patriarca F, et al. Blood. 2008;112:158.
13. The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network. Terpos E, Sezer O, Croucher PI, et al. Ann Oncol. 2009;20:1303–1317. doi: 10.1093/annonc/mdn796.
14. Treatment for myeloma bone disease. Yeh HS, Berenson JR. Clin Cancer Res. 2006;12:6279–6284. doi: 10.1158/1078-0432.CCR-06-0681.
15. Role of radiography, MRI and FDG-PET/CT in diagnosing, staging and therapeutical evaluation of patients with multiple myeloma. Lütje S, de Rooy JW, Croockewit S, Koedam E, Oyen WJ, Raymakers RA. Ann Hematol. 2009;88:1161–1168. doi: 10.1007/s00277-009-0829-0.
16. Multiple myeloma. Collins CD. Cancer Imaging. 2004;4 Spec No A:0–53. doi: 10.1102/1470-7330.2004.0010.
17. Comparison of modern and conventional imaging techniques in establishing multiple myeloma-related bone disease: a systematic review. Regelink JC, Minnema MC, Terpos E, et al. Br J Haematol. 2013;162:50–61. doi: 10.1111/bjh.12346.
18. Multiple myeloma: diagnosis and treatment. Rajkumar SV, Kumar S. Mayo Clin Proc. 2016;91:101–119. doi: 10.1016/j.mayocp.2015.11.007.
19. Consensus on surgical management of myeloma bone disease. The Surgeon's Committee of the Chinese Myeloma Working Group of the International Myeloma Foundation. Orthop Surg. 2016;8:263–269. doi: 10.1111/os.12267.
20. Centromedullary nailing of the femur for bone metastasis: clinical and radiological evaluation using the Tokuhashi score in 24 patients [Article in French] Obert L, Jarry A, Lepage D, Jeunet L, Tropet Y, Vichard P, Garbuio P. Rev Chir Orthop Reparatrice Appar Mot. 2005;91:737–745. doi: 10.1016/s0035-1040(05)84485-x.
21. Benefits of early intramedullary nailing in femoral metastases. Arvinius C, Parra JL, Mateo LS, Maroto RG, Borrego AF, Stern LL. Int Orthop. 2014;38:129–132. doi: 10.1007/s00264-013-2108-x.
22. Metastatic disease in long bones: a proposed scoring system for diagnosing impending pathologic fractures. 1989. Mirels H. Clin Orthop Relat Res. 2003:0–13. doi: 10.1097/01.blo.0000093045.56370.dd.
23. Critical evaluation of Mirels' rating system for impending pathologic fractures. Damron TA, Morgan H, Prakash D, Grant W, Aronowitz J, Heiner J. Clin Orthop Relat Res. 2003;415:0–7. doi: 10.1097/01.blo.0000093842.72468.73.
24. The validity of the Mirels score for predicting impending pathological fractures of the lower limb. Howard EL, Shepherd KL, Cribb G, Cool P. Bone Joint J. 2018;100-B:1100–1105. doi: 10.1302/0301-620X.100B8.BJJ-2018-0300.R1.
25. Treatment of pathologic fractures of the proximal femur. Angelini A, Trovarelli G, Berizzi A, Pala E, Breda A, Maraldi M, Ruggieri P. Injury. 2018;49 Suppl 3:0–83. doi: 10.1016/j.injury.2018.09.044.
26. Multiple myeloma. van de Donk NWCJ, Pawlyn C, Yong KL. Lancet. 2021;397:410–427. doi: 10.1016/S0140-6736(21)00135-5.
27. In brief: classifications in brief: Mirels' classification: metastatic disease in long bones and impending pathologic fracture. Jawad MU, Scully SP. Clin Orthop Relat Res. 2010;468:2825–2827. doi: 10.1007/s11999-010-1326-4.