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Q46. A 68-year-old patient is undergoing workup for suspected Multiple Myeloma (MM). Imaging studies are being considered to evaluate potential bone involvement. Which of the following statements regarding MM bone disease and its imaging is least accurate?

  • (A) In patients with suspected smoldering myeloma or solitary plasmacytoma of bone, finding additional bone lesions via advanced imaging will upstage them to active MM, directly impacting treatment approaches.
  • (B) MM-associated bone disease is characterized by an uncoupling of osteoclastic and osteoblastic activity, with an observed increase in new osteoclast generation even in early MM and Monoclonal Gammopathy of Undetermined Significance (MGUS).
  • (C) FDG-PET/CT is a valuable tool for assessing bone damage in MM, offering high sensitivity and specificity. However, it’s inability to detect very small lesions (<1 cm) and can yield false-negative results in a subset of patients with extensive disease.
  • (D) Whole-body low-dose CT skeletal surveys are generally preferred over conventional radiographs for detecting myelomatous bone lesions and are capable of identifying lesions missed by conventional radiography.
  • (E) While Magnetic Resonance Imaging (MRI) is superior to conventional radiographs for detecting lesions in the pelvis and spine, its overall sensitivity for detecting bone involvement in MM is also superior to that of conventional radiographs.
點此顯示正解

(B) MM-associated bone disease is characterized by an uncoupling of osteoclastic and osteoblastic activity, with an observed increase in new osteoclast generation even in early MM and Monoclonal Gammopathy of Undetermined Significance (MGUS).

詳解

1. Why (B) is the LEAST ACCURATE statement

Option (B) is inaccurate because it overstates the presence of increased osteoclast generation in MGUS. While the statement correctly identifies the uncoupling of osteoclastic and osteoblastic activity in MM bone disease, the critical error lies in asserting that "an observed increase in new osteoclast generation" occurs "even in early MM and MGUS."

The pathophysiologic critique:

The bone phenotype in MGUS is subtle and heterogeneous, not characterized by uniformly increased osteoclast generation. Recent evidence demonstrates that:

  • MGUS patients show variable skeletal changes: While some MGUS patients have increased fracture risk and reduced bone mineral density, "ubiquitous changes to bone parameters throughout the skeleton are nevertheless uncommon in MGUS," with local changes often attributed to plasma cell proximity2
  • Increased osteoclastic activity is associated with progression, not stable MGUS: Histomorphometric analyses reveal "a distinct bone resorption phenotype in patients with progressing MGUS and SMM compared with those who remain stable, supporting the concept that increased osteoclastic activity precedes disease progression"2
  • Bone marrow glutamate levels distinguish MGUS from MM: Studies show that "bone marrow mononuclear cells from MM patients release higher levels of Glu compared to those from patients with monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM)," and this increased glutamate production "correlates with elevated bone resorption activity"5

The more accurate characterization of MM bone disease emphasizes: 1. Dual mechanism: Both increased osteoclast activation AND suppressed osteoblast differentiation/function14 2. The imbalance is the hallmark: The uncoupling creates net bone loss through RANKL/osteoprotegerin dysregulation, MIP-1α, and Wnt inhibitors (DKK-1, sFRP-2)16 3. MGUS is not uniformly characterized by increased osteoclastogenesis: Only progressing MGUS shows this phenotype, and it is not a defining feature of stable MGUS2

The statement conflates the well-established pathophysiology of active MM with the precursor state of MGUS, where increased osteoclast generation is neither universal nor characteristic of the disease stage.

2. Why the other options are ACCURATE

(A) is accurate: The IMWG criteria define active MM requiring treatment based on myeloma-defining events, which include >1 focal lesion ≥5mm on MRI7. Finding additional bone lesions via advanced imaging (CT, MRI, or PET/CT) in patients with suspected smoldering myeloma or solitary plasmacytoma directly upstages them to active MM and changes management from observation to treatment7[^10].

(C) is accurate: FDG-PET/CT offers high sensitivity and specificity for MM bone disease and is recommended by IMWG for baseline assessment in clinical trials and response evaluation78. However, PET/CT has recognized limitations: it can yield false-negative results in a subset of patients, and small lesions (<1 cm) may not be detected due to spatial resolution constraints[^9]. The IMWG acknowledges these limitations while still recommending PET/CT as a valuable tool7.

(D) is accurate: Whole-body low-dose CT is the IMWG's first-choice imaging technique and minimal requirement for detecting osteolytic lesions, replacing conventional radiography78. CT detects lesions missed by conventional radiographs, which require 30-50% cortical erosion before lesions become visible. In one study, CT identified lytic lesions in 20% of patients who had negative plain radiographic surveys[10][11].

(E) is accurate: MRI demonstrates superior sensitivity compared to conventional radiographs for detecting bone marrow involvement in MM, particularly in the pelvis and spine7[^10]. The IMWG recommends whole-body MRI (or spine and pelvis MRI if whole-body is unavailable) when CT is negative, specifically because of MRI's high sensitivity for detecting focal lesions that constitute myeloma-defining events78.

詳解 · 中文翻譯

1. 為什麼 (B) 是最不準確的敘述

選項 (B) 是不準確的因為它誇大了MGUS 中增加破骨細胞生成的存在。雖然敘述正確地識別了 MM 骨病中破骨細胞和成骨細胞活動的不耦合，關鍵錯誤在於聲稱「觀察到的新破骨細胞生成增加」發生於「甚至在早期 MM 和 MGUS 中」。

病理生理學批評：

MGUS 中的骨表型是微妙和異質性的，而不是以均勻增加的破骨細胞生成特徵化。最近證據證示：

  • MGUS 患者顯示可變骨骼變化：雖然一些 MGUS 患者有增加的骨折風險和減少的骨礦物質密度，「整個骨骼的普遍骨參數變化尤未在 MGUS 中不常見」，局部變化通常歸因於漿細胞鄰近2
  • 增加的破骨細胞活動與進展相關，而不是穩定 MGUS：組織形態計量分析顯示「在進展 MGUS 和 SMM 患者中與保持穩定患者相比明顯骨吸收表型，支持增加的破骨細胞活動先於疾病進展的概念」2
  • 骨髓谷氨酸水平區分 MGUS 與 MM：研究顯示「來自 MM 患者的骨髓單核細胞與來自單克隆免疫球蛋白不確定意義（MGUS）或惰性多發性骨髓瘤（SMM）患者相比釋放更高水平的 Glu」，此增加的谷氨酸產生「與升高的骨吸收活動相關」5。

MM 骨病的更準確特徵化強調： 1. 雙重機制：升高的破骨細胞激活和被抑制的成骨細胞分化/功能14 2. 不平衡是標誌：不耦合通過 RANKL/osteoprotegerin 失調、MIP-1α 和 Wnt 抑制劑（DKK-1、sFRP-2）造成凈骨喪失16 3. MGUS 不是統一地以升高的破骨細胞生成特徵化：僅進展 MGUS 顯示此表型，並且它不是疾病階段的定義特徵2。

敘述混淆了活躍 MM 的眾所周知的病理生理學與 MGUS 的前驅狀態，其中升高的破骨細胞生成既不是通用的也不是疾病階段的特徵。

2. 為什麼其他選項是準確的

(A) 是準確的：IMWG 標準定義需要治療的活躍 MM 基於骨髓瘤定義事件，包括 MRI 上 >1 個病灶 ≥5mm7。在懷疑的惰性骨髓瘤或單發漿細胞瘤患者中通過高級影像（CT、MRI 或 PET/CT）發現額外骨病變直接將其升級為活躍 MM 並改變管理從觀察到治療7[^10]。

(C) 是準確的：FDG-PET/CT 提供高敏感性和特異性用於 MM 骨病並由 IMWG 推薦用於臨床試驗基線評估和反應評估78。但是，PET/CT 有已識別限制：它可在患者亞群中產生假陰性結果，小病變（<1 cm）可能由於空間分辨率限制而不被檢測到[^9]。IMWG 承認這些限制同時仍推薦 PET/CT 作為有價值的工具7。

(D) 是準確的：全身低劑量 CT 是 IMWG 的第一選擇影像技術和檢測溶骨性病變的最少要求，替換常規放射線攝影78。CT 檢測常規放射線攝影錯過的病變，其需要 30-50% 皮質侵蝕在病變變得可見前。在一項研究中，CT 在 20% 的患者中識別溶骨病變，其有陰性普通放射線攝影調查[10][11]。

(E) 是準確的：MRI 相比常規放射線攝影為 MM 中檢測骨髓受累證示優越敏感性，特別是在骨盆和脊椎中7[^10]。IMWG 推薦全身 MRI（或如果全身不可用，脊椎和骨盆 MRI）當 CT 陰性時，特別是因為 MRI 的高敏感性檢測構成骨髓瘤定義事件的病灶78。

參考文獻 (AMA)

  1. Cantley MD, Trainor LJ, Cheney EA, Watt SM, Vandyke K. Skeletal Health in the Precursor Stages of Multiple Myeloma: Fracture Risk and Bone Phenotypes in Monoclonal Gammopathy of Undetermined Significance and Smouldering Myeloma. Pathology. 2025;:S0031-3025(25)00348-4. doi:10.1016/j.pathol.2025.11.002. PMID:41565487. ↩↩↩↩

  2. Toscani D, Lungu O, Chiu M, et al. High Glutamate Levels in the Bone Marrow of Multiple Myeloma Patients Promote Osteoclast Formation: A Novel Target for Osteolytic Bone Disease. Leukemia. 2025;:10.1038/s41375-025-02715-2. doi:10.1038/s41375-025-02715-2. PMID:40721650. ↩↩↩↩↩↩

  3. Heider U, Hofbauer LC, Zavrski I, et al. Novel Aspects of Osteoclast Activation and Osteoblast Inhibition in Myeloma Bone Disease. Biochemical and Biophysical Research Communications. 2005;338(2):687-93. doi:10.1016/j.bbrc.2005.09.146. PMID:16216218. ↩

  4. Nador G, Vijjhalwar R, Javaid MK, Edwards CM, Ramasamy K. Biochemical Bone Biomarkers in Plasma Cell Dyscrasias. British Journal of Haematology. 2026;. doi:10.1111/bjh.70467. PMID:41948808. ↩↩

  5. Oranger A, Carbone C, Izzo M, Grano M. Cellular Mechanisms of Multiple Myeloma Bone Disease. Clinical & Developmental Immunology. 2013;2013:289458. doi:10.1155/2013/289458. PMID:23818912. ↩↩

  6. Hillengass J, Usmani S, Rajkumar SV, et al. International Myeloma Working Group Consensus Recommendations on Imaging in Monoclonal Plasma Cell Disorders. The Lancet. Oncology. 2019;20(6):e302-e312. doi:10.1016/S1470-2045(19)30309-2. PMID:31162104. ↩↩

  7. Cowan AJ, Green DJ, Kwok M, et al. Diagnosis and Management of Multiple Myeloma: A Review. Jama. 2022;327(5):464-477. doi:10.1001/jama.2022.0003. PMID:35103762. ↩↩↩↩↩↩↩↩↩↩↩↩↩↩

  8. Wu F, Bernard S, Fayad LM, et al. Updates and Ongoing Challenges in Imaging of Multiple Myeloma: Expert Panel Narrative Review. AJR. American Journal of Roentgenology. 2021;217(4):775-785. doi:10.2214/AJR.21.25878. PMID:33978464. ↩↩↩↩↩↩

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