Rare case of recurrent refractory multiple myeloma with lipid deposition in the vertebral body: a case description

Introduction

Multiple myeloma (MM) is a malignant tumor caused by clonal proliferation of plasma cells in the bone marrow. Although drugs and therapies have been introduced to the market to significantly improve the prognosis of patients with MM, relapse and refractory disease remain challenges in the treatment of MM.

Part of the reason for the poor efficacy of MM treatments is that tumor cells are protected by the “domesticated” microenvironment, which provides a natural shelter for abnormal plasma cells to resist the killing effect of chemotherapy drugs, providing a basis for relapse and resistance. Previous research suggests that bone marrow adipocytes (BMAds) are involved in the development, recurrence, and drug resistance of MM (1). However, there is a lack of studies on bone fat deposition on magnetic resonance imaging (MRI) related to the recurrence of MM.

In this report, we describe a patient with recurrent refractory MM occurring in a short period. The manifestations were tumor infiltration of plasma cells in the vertebral body and nearby soft tissue, with a paratumor vertebral body that exhibited lipid deposition on MRI. This case suggests the influence of bone marrow adipose tissue (BMAT) on the recurrence of MM and further confirms the correlation between the adipose differentiation of the tumor microenvironment and recurrence. We hope this report can alert hematologists to the relationship between bone lipid deposition and MM recurrence and aid in the development of novel predictive risk factors for this condition.

Case presentation

A 66-year-old female was admitted to the Affiliated Hospital of Guizhou Medical University for recurring fever for more than 1 month. Physical examination at presentation demonstrated no obvious abnormalities. Tests of hemoglobin, creatinine, calcium serum, serum albumin, serum globulin, urine protein, serum IgA, M-spike quantification, etc., were conducted (Table 1). The serum protein immunofixation assay was positive for IgA λ, and the serum protein electrophoresis results demonstrated the presence of M protein. Whole-body bone scan revealed no abnormalities.

In the routine bone marrow analysis, we noted abnormal hyperplasia of plasma cells, mainly primitive and naïve plasma cells (17%). The size and shape of the abnormal plasma cells differed from those of normal cells in that they were large and mostly circular or oval. The cells also had abundant cytoplasm (which stained dark blue or red) along with vacuoles and a few foam-like particles. They were binucleated or multinucleated, with the nuclei being almost round but often skewed, with coarse, granular chromatin. They also exhibited a nucleolus. In the immunoassay, plasma cells (R7) accounted for 6.67% of all nucleated cells. The MM-related fluorescence in situ hybridization (FISH) test was negative. Moreover, gene rearrangement analysis demonstrated positivity for IGH tube A (FR1-JH) and tube B (FR2-JH).

After a comprehensive query of the patient’s medical history and auxiliary examination, the patient was diagnosed with standard-risk MM and treated with a BRD (bortezomib, lenalidomide, and dexamethasone) chemotherapy regimen. After four courses of chemotherapy, the patient was assessed as a complete response. Because the patient declined undergoing autologous hematopoietic stem cell transplantation, she received four courses of consolidation therapy consisting of IRD (ixazomib, lenalidomide, and dexamethasone), followed by lenalidomide maintenance therapy.

During maintenance treatment, the patient developed neck pain accompanied by weakness in both lower limbs. However, her blood lipid and cholesterol levels remained normal, and her blood was weakly positive for M protein. No abnormal plasma cells were found in the bone marrow-related tests. However, cervical MRI demonstrated multiple vertebral lipid deposits and a solid mass in the vertebral body and near the soft tissue (Figure 1A). Cervical computed tomography (CT) demonstrated bone destruction and a local soft tissue mass in the C2 vertebra and the accessory atlantoaxial ligament, as well as uneven bone density loss in the C4 and C5 vertebrae (Figure 1B). Postoperative neck X-ray demonstrated no obvious lesion in the C2–4 adnexa (Figure 1C,1D). The lesion biopsy results were follows: CD5, negative; CD56, highly positive; CD38, mostly positive; CD138, mostly positive; κ, weakly positive; λ, highly positive; CD43, highly positive; MUM1, mostly positive; and Ki-67 score, 80% (Figure 2). Consequently, the resected tumor was a plasma cell tumor. Ultimately, tumor resection alleviated the weakness in both lower limbs. After tumor resection, the patient underwent second-line treatment for reinduction. The treatment timeline is provided in Figure 3.

Figure 1 Relevant imaging test results. (A) MRI of the cervical spine. (B) CT of the cervical spine. (C) X-ray in the cervical lateral position. (D) X-ray in the cervical frontal position. CT, computed tomography; MRI, magnetic resonance imaging.

Figure 2 HE staining and immunohistochemistry results for the resected lesion (200×). (A) HE staining showed abnormal plasma cells (as indicated by the arrows); (B) CD5–; (C) CD38+; (D) CD56+; (E) CD138+; (F) Ki-67 score of 80%; (G) λ+. HE, hematoxylin and eosin.

Figure 3 Timeline of patient treatment. BRD, bortezomib, lenalidomide, and dexamethasone; CR, complete response; D-KPD, daratumumab-carfilzomib, pomalidomide, and dexamethasone; IRD, ixazomib, lenalidomide, and dexamethasone.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

MM is the second most common hematological malignancy worldwide. Effective risk stratification, incorporating both patient-specific factors (e.g., performance status) and disease-specific markers (e.g., high-risk cytogenetic abnormalities), is essential for prognostic assessment and guiding optimal therapeutic decision-making (2). Our case was a 66-year-old female; the MM-related FISH test was negative, and she was subsequently diagnosed with standard-risk MM. The patient achieved remission after chemotherapy of BRD and IRD, with maintenance therapy consisting of lenalidomide.

During the maintenance therapy, however, the patient experienced space-occupying lesions that developed in the cervical vertebrae and near the soft tissue; these lesions were confirmed to be plasma cell tumors through biopsy. Through immunohistochemistry, the resected lesion was confirmed to be positive for CD56, CD38, CD138, and λ. Moreover, the patient’s blood was weakly positive for M protein, although the bone marrow was devoid of any abnormal plasma cell tests. As a result, extramedullary recurrence of the resected lesion was suspected. Extramedullary MM (EMM) is an aggressive subtype of myeloma and is defined by the emergence of subclones capable of self-sustained expansion, apoptotic avoidance, and therapeutic resistance. These adaptations entail a high-risk condition, which is associated with inferior survival even amid broader advances in myeloma management (3).

Additionally, this patient did not have a poor prognosis except that EMM was accompanied by obvious lipid deposition on MRI (Figure 1A). However, the MM recurred in a short period; moreover, the resected vertebral lesion had a Ki-67 score of 80%. In 2024, Liu et al. reported that normalized peri-prostatic adipose tissue (PPAT) could serve as a predictor for osseous metastatic spread in treatment-naïve prostate cancer (4). Another in vivo study found that BMAds promote myeloma cell migration and contribute to myeloma cells having a propensity to metastasize to bone. The study employed a murine model of myeloma and further discovered that BMAd-derived factors elevate tumor cell migration, sustain cell viability, and confer apoptotic resistance. These findings collectively suggest that excessive adipogenesis within the marrow compartment facilitates the progression of myeloma within the bone microenvironment (1). Therefore, vertebral lipid deposition in our patient might have been related to short-term EMM recurrence and an increase in the tumor proliferation index in our patient.

A lipid deposit is a fatty tissue mass wrapped in a thin membrane, formed by local lipid deposition caused by abnormal lipid metabolism. Various diagnostic modalities, including CT, sonography, and MRI, have been employed to quantify lipid tissue accrual. Acoustic energy becomes attenuated upon traversing biological tissues, yielding suboptimal sonographic visualization. Meanwhile, CT may overlook subcentimeter adipose regions. In contrast, MRI provides superior soft-tissue contrast and delineation of adipose-tissue boundaries, consequently achieving optimal spatial resolution for identifying adiposity. In clinical practice, conventional MRI is typically used to determine lipid contents in tissues and is presently the most accurate, noninvasive method for quantifying body fat and bone marrow fat (5). Moreover, in patients with normal blood lipid and cholesterol levels, MRI can be a beneficial supplement for lipid deposit detection. Therefore, in our case, despite the patient having normal blood lipid and cholesterol levels, MRI examination demonstrated recurrent lipid deposition in the cervical vertebrae adjacent to the tumor and significantly higher sensitivity for detecting her lipid deposition levels than did CT (Figure 1A,1B). Over the past decades, research has been conducted on MRI techniques in detecting MM and its precursors. MRI is helpful in the diagnosis, staging, and follow-up of plasma cell dyscrasias. However, there is a lack of studies on the relationship between the detection of bone fat deposition by MRI and the recurrence of MM.

Due to local endocrine, paracrine, or metabolic factors, the pathophysiological links between BMAT and MM are that BMAds harvested from patients with MM exhibit an in vitro capacity to enhance malignant plasma cell proliferation and confer cytoprotection against chemotherapy-induced apoptosis. They also excrete free fatty acids (FFAs) and produce adipokines, so numerous signaling molecules originating from BMAT possess myelomagenesis-promoting properties and stimulate MM expansion. Research has attested to the expression of leptin receptors on MM cells concurrent with leptin secretion by marrow adipocytes. This adipokine is correlated with accelerated proliferation of myeloma cells in experimental culture systems (6). Peroxisome proliferator-activated receptor (PPAR) is strongly associated with lipid deposition, and high PPAR expression can promote lipogenesis. One study reported the PGI2-PPARδ axis to be responsible for neovascularization in MM. Notably, PPARδ activity was found to be modulated by extracellular prostaglandin I2 (PGI2) concentrations within the bone marrow stromal microenvironment. PGI2, principally synthesized as a proinflammatory mediator, participates directly in vasculogenesis and angiogenic processes. Expression levels of this receptor exhibit robust correlation with markers of advanced disease and adverse clinical indicators. PPARδ expression and consequent activation signify a proangiogenic cellular phenotype and have a strong association with advanced tumor stage and an elevated risk of disease recurrence or metastatic dissemination (7). We hope that productive clinical research focused on the lipid deposit of bone in MM will be conducted in the future, including the assessment of changes in bone lipid contents on MRI, to improve the sensitivity and efficacy of recurrent MM detection. Bone lipid deposition may prove to be a clinical risk factor among patients with MM.

Conclusions

Our observations may increase the role of bone lipid deposition in MM recurrence. We believe that patients with MM with lipid deposition may require intensive induction and maintenance therapy to reduce recurrence risk. Future clinical trials should focus on assessing the utility of PPARα inhibitors for not only the management of MM but also for the prevention and treatment of MM recurrence. We also suggest including the assessment of changes in lipid contents in the routine lipid profile and MRI tests to improve their detection sensitivity and efficacy for MM recurrence. Moreover, methods based on mass spectrometry may be widely applied clinically to detect minor changes in the metabolism of fatty acids and other molecules and thus predict changes in the tumor microenvironment. In general, changes in tumor microenvironment lipids may serve as a novel target for the prevention and alleviation of drug resistance and recurrence or as a clinical risk factor among those with MM.

Acknowledgments

We would like to thank the patient for her authorization to publish this case, all the staff at Hospital for their contribution to this work, and the native English-speaking scientists of Elixigen (Huntington Beach, CA, USA) for editing our manuscript.

Footnote

Funding: This work was supported by the Subject Excellent Reserve Talent Project (grant number gyfyxkrc-2023-14) and the Science and Technology Department of Sichuan Province (grant number 2020YJ0438).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2207/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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