Multiple myeloma (MM) is a clonal plasma cell malignancy often confined to the bone marrow, although extramedullary disease (EMD) can develop, especially in advanced or relapsed cases. Leptomeningeal EMD is a rare and aggressive manifestation associated with a dismal prognosis. This case report highlights the critical role of 18F-FDG PET/CT in managing such complex presentations.

A 73-year-old man with relapsed multiple myeloma and new lumbar pain was re-staged with 18F-FDG PET/CT, which showed metabolically active osteolytic lesions and possible leptomeningeal involvement. Subsequent MRI confirmed pathological intradural lesions, corroborated by histopathology as plasma cell neoplasms. PET/CT’s ability to detect hypermetabolic activity in atypical and non-enhancing lesions provided essential insights into disease progression, which guided effective treatment with radiotherapy and carfilzomib/dexamethasone-based therapy, resulting in sustained complete response.

This case underscores the advantages of PET/CT, including early detection of subtle extramedullary lesions, superior sensitivity compared to conventional imaging, and precise monitoring of therapeutic response. Through the integration of advanced imaging and multidisciplinary care, this patient achieved 15 months of progression-free survival post-EMD detection, emphasizing the transformative impact of PET/CT in personalized myeloma management.

18F-FDG, extramedullary disease, leptomeningeal, MRI, multiple myeloma, PET/CT

Multiple myeloma (MM) is an incurable lymphoprolife- rative disorder of malignant clonal plasma cells originating from the bone marrow. It is the second most common hematological malignancy in adults, with over 35,750 new cases reported worldwide in 2024, accounting for over 2% of overall cancer mortality. The estimated overall survival after disease diagnosis for the period 2014-2020 is approximately 61.1%.^[1] Extramedullary disease (EMD), where malignant plasma cells proliferate outside the bone marrow, can be detected at MM diagnosis but is more commonly found at relapse (15% at diagnosis versus 28% at relapse).^[2] At diagnosis, extramedullary lesions are typically located in the skin and soft tissues, often affecting a single area.^[3] As multiple myeloma progresses and under the influence of various therapeutic stressors, plasma cells can dedifferentiate, acquiring a more plasmablastic and immature morphology, and spread to more atypical or unusual sites. In relapsed or refractory myeloma, affected areas include the kidneys, lymph nodes, central nervous system, respiratory tract, gastrointestinal tract, liver, pleura, and pericardium.^{[3, 4]}

The use of 18F-FDG PET/CT in patients with relapsed multiple myeloma and extramedullary disease is critical for disease evaluation and management. This imaging modality helps detect metabolically active disease sites, including extramedullary lesions that are often missed by conventional imaging methods. PET/CT provides detailed insights into the extent of disease progression and metabolic activity, enabling a better understanding of the aggressive nature of EMD and facilitating tailored therapeutic strategies. Additionally, it is valuable for monitoring response to therapy and detecting early recurrence or progression.

A 73-year-old man diagnosed with IgG kappa MM, III ISS stage in 2016 initially exhibited significant plasma cell infiltration (50%) with reduced erythropoiesis during his myelogram examination. After receiving six cycles of targeted therapy using the VCD protocol (bortezomib, cyclophosphamide, dexamethasone), he achieved a complete response. This led to an autologous hematopoietic stem cell transplantation a year later, followed by maintenance therapy with bortezomib. During a routine disease reassessment, he showed a sustained complete response, with no paraprotein detected in the serum.

However, seven years after his initial diagnosis and successful treatment, the patient was admitted to St Marina University Hospital in Varna because of newly developed lumbar pain. An immunoelectrophoresis test indicated elevated serum paraprotein levels of 2.2 g/L. This finding necessitated further investigation via a restaging 18F-FDG PET/CT scan, performed on a Philips Vereos hybrid scanner 70 minutes after the injection of 407 MBq 18F-FDG, which revealed metabolically active osteolytic lesions in the left sacrum, right scapula, and existing compression fractures of the lumbar vertebrae (L1 and L3) with maximum standardized uptake value (SUVmax) up to 5.1/ evaluation on a five-point visual scale (FPS) 5. Importantly, the 18F-FDG PET/CT scan identified unexpected metabolically active lesions in the medullary canal at the Th11/12 levels (Fig. 1) and the right sacral neuroforamen at S2/S3 (Fig. 2) , with a SUVmax of 6.8/ FPS 5. These findings raised suspicion for extramedullary involvement of the disease.

Figure 1.

Fusion 18F-FDG PET/CT of metabolically active lesions in the medullary canal at the level of Th11/12 suspected of leptomeningeal extramedullary disease.

Figure 2.

Fusion 18F-FDG PET/CT of metabolically active lesions in the medullary canal at the level of S2/3 suspected of leptomeningeal extramedullary disease.

The follow-up MRI of the lumbar spine confirmed the presence of pathological intradural extramedullary lesions, which appeared iso-intense on T1 and T2-weighted images compared to the spinal cord, with moderate post-contrast enhancement. These lesions were located in the spinal canal at the Th11/12 level, compressing the conus medullaris and cauda equina, and at the S2/S3 level, indicating a rare manifestation of extramedullary dissemination.

In response to these findings, the patient underwent spinal stabilization and a biopsy of the tumor formation, which histologically confirmed soft tissue involvement by plasma cell neoplasm. The patient also received radiation therapy targeting the sacrum and thoracolumbar spine from Th11 to L4. Following six courses of targeted therapy using the Car/Dex protocol (carfilzomib/dexamethasone), the patient achieved a complete response, with no paraprotein detectable in the serum.

To date, he continues to receive targeted therapy and maintains a complete response. This case demonstrates the importance of being vigilant for extramedullary disease in multiple myeloma, as well as the potential for extended overall survival and progression-free survival, with extramedullary involvement detected 15 months later using comprehensive treatment strategies.

The presence of extramedullary disease (EMD) represents an aggressive form of MM, which can be detected at staging or relapse. Significant changes in biological processes enable myeloma cells to thrive outside of the supporting environment of the bone marrow in EMD, including leptomeningeal myeloma. Mutations and chromosomal abnormalities including TP53 deletions and MYC dysregulation are important alterations that are linked to increased extramedullary spread rates and especially aggressive di-sease behavior. Due to these changes, myeloma cells are more invasive and can migrate to locations such as the leptomeningeal space.‌^[5] The pathophysiology of EMD depends on specific cell surface proteins, including as CD44 and CD56, which aid tumor cells in adhering to distant organs, including CNS structures, and in separating from the bone marrow. These markers and their participation in signaling pathways that support life outside of the marrow are partially responsible for the cells’ loss of bone marrow dependency, which raises the risk of CNS and leptomeningeal involvement. Despite being uncommon, leptomeningeal involvement in MM has a dismal prognosis because to the disease’s quick progression and ineffective treatment.^[6]

In recent years, an increase in the incidence of extramedullary disease has been reported. A registry study of 3,744 patients found that the incidence of EMD increased from 6.5% in 2005 to 23.7% in 2014.^[3] The etiology of this observation may be multifactorial. To date, few published cases report the rare extramedullary manifestation of multiple myeloma as leptomeningeal involvement. CNS involvement is rare but has an even worse prognosis than EMD at other sites, especially if there is leptomeningeal involvement. PET/CT with 18F-FDG and other radiopharmaceuticals^[7] and MRI are significantly more sensitive in detecting these lesions, leading to the identification of more cases that would otherwise be missed. The use of 18F-FDG PET/CT is pivotal in evaluating leptomeningeal extramedullary disease in multiple myeloma, a rare and aggressive manifestation with a poor prognosis. This imaging modality offers several advantages over traditional diagnostic techniques by providing metabolic, rather than solely anatomical, information. Leptomeningeal involvement in MM often eludes detection by conventional imaging such as MRI, especially when lesions are diffuse or non-enhancing.‌^[8] However, 18F-FDG PET/CT can detect hypermetabolic activity even in subtle disease presentations, thus playing a key role in identifying active leptomeningeal disease. Studies have highlighted its superior sensitivity in capturing metabolically active extramedullary sites, facilitating early diagnosis and better disease staging. In the context of therapy monitoring, PET/CT is invaluable for assessing treatment response. The high uptake of FDG in active disease sites correlates with aggressive myeloma behavior, including central nervous system (CNS) involvement.^[9] By quantifying metabolic activity, PET/CT helps distinguish between active disease and post-treatment changes, offering a precise tool for guiding therapy modifications and predicting outcomes. Moreover, PET/CT is instrumental in detecting disease progression or relapse. Leptomeningeal EMD is particularly challenging to manage due to its resistance to standard therapies, and early identification through advanced imaging can enable timely interventions, potentially improving patient survival.

In a large retrospective, multi-institutional study (N=172), the median overall survival (OS) after the onset of CNS involvement was 6.7 months. The median OS was 2 months for untreated patients and 8 months for those who received CNS disease treatment.^[10] Another study involving 16 patients treated with various combinations of systemic therapy, intrathecal targeted therapy, and radiation therapy highlighted the poor outcomes in patients with leptomeningeal involvement, with a median OS of 82 days.^[11]

As the treatment landscape evolves, options such as targeted therapies and intrathecal delivery methods are being explored to improve outcomes for these patients. However, despite these advances, the intrinsic challenges of the disease and its late-stage diagnosis continue to impede significant improvements in survival.^[12]

This case demonstrates the pivotal role of 18F-FDG PET/CT in detecting and managing leptomeningeal EMD in MM, a rare but aggressive form of the disease. PET/CT was instrumental in identifying hypermetabolic intradural lesions that MRI later confirmed, guiding timely and targeted therapy. Its ability to detect subtle extramedullary sites and monitor metabolic responses makes it indispensable in relapsed MM. The patient’s remarkable progression-free survival underscores the potential of combining advanced imaging with comprehensive treatment strategies. This case highlights PET/CT as a cornerstone for personalized care, bridging the gap between early detection and effective therapy in complex myeloma presentations.