Current and Potential Applications of Positron Emission Tomography for Multiple Myeloma and Plasma Cell Disorders

Abstract

Fluorine-18 (18F)-fluorodeoxyglucose (FDG) positron emission tomography (PET) allows evaluation of elevated glucose metabolism in malignancies. There has been increasing interest in FDG PET/CT for plasma cell disorders since the International Myeloma Working Group outlined multiple applications of this imaging modality, including distinguishing smoldering myeloma from active multiple myeloma, confirmation of solitary plasmacytoma, and multiple indications in patients with known multiple myeloma, including determining extent of initial disease, monitoring therapy response, and detection of residual disease following therapy. The field of molecular imaging is now shifting focus from evaluation of metabolism to targeted evaluation of specific tumor markers. Targeted PET imaging targeted of CXCR4 and CD38 has advanced into translational clinical trials, bringing us closer to powerful imaging options for myeloma. In this review we discuss the current applications of FDG PET/CT in plasma cell disorders, as well as advances in targeted PET imaging.

Summary

FDG PET/CT has been proven to provide clinical value for multiple scenarios of plasma cell disorders, including distinguishing smoldering myeloma from active multiple myeloma, confirmation of solitary plasmacytoma, and multiple indications in patients with known multiple myeloma, including determining extent of initial disease, monitoring therapy response, and detection of residual disease following therapy. However, FDG PET/CT has limitations, including not all individual plasma cell disorders are FDG-avid and false positive FDG-avidity must be carefully excluded. Newer PET tracers targeted to specific molecules on multiple myeloma cells present a tremendous opportunity to improve detection and treatment of plasma cell disorders.

Clinical value and limitations of FDG PET/CT in multiple myeloma and plasma cell disorders

Fluorine-18 (18F)-fluorodeoxyglucose (FDG) positron emission tomography (PET) allows evaluation of glucose metabolism, which is often elevated in malignancies. There has been increasing interest and use of FDG PET/CT in patients with multiple myeloma and other plasma cell disorders since the consensus statements from the International Myeloma Working Group (IMWG) on the role of FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders [1] and recommendations for imaging of monoclonal plasma cell disorders [2]. These consensus statements raised awareness of the compelling and growing evidence that FDG PET/CT provides valuable imaging of bone lesions and extra-medullary disease in patients with plasma cell disorders, with multiple applications during the course of disease [1, 2].

In earlier stages of disease, patients with smoldering multiple myeloma and FDG-avid lesions on FDG PET/CT have a higher risk of progression to active multiple myeloma and a shorter time to progression [3]. It has been proposed that FDG PET/CT may be utilized in smoldering multiple myeloma to select patients for clinical trials of early therapy to prevent or delay progression to active disease [4, 5]. The stage of solitary plasmacytoma has traditionally been defined by biopsy-proven clonal plasma cells at a single site. However, in patients defined with solitary plasmacytoma by traditional imaging methods, FDG PET/CT may detect lytic osseous lesions and/or soft tissue masses which lead to a diagnosis of multiple myeloma [6–8]. And the presence of FDG-avid lesions on FDG PET/CT in patients with solitary plasmacytoma defined by traditional imaging methods have a greater risk of developing active multiple myeloma [9]. The IMWG recommends FDG PET/CT as an imaging modality as part of the initial evaluation on patients with suspected solitary plasmacytoma to confirm solitary disease versus detection of unsuspected additional sites of disease involvement [1].

For disease which has advanced to active multiple myeloma, FDG PET/CT has demonstrated multiple clinically valuable applications. A meta-analysis demonstrated FDG PET/CT was the imaging modality with the highest sensitivity and specificity for the detection of disease (Figure 1), particularly extra-medullary disease [10]. MRI is more accurate for the detection of diffuse bone marrow involvement [11], but otherwise FDG PET/CT and MRI have demonstrated similar sensitivity and specificity for osseous lesions [12]. Thus, while some guidelines suggest whole-body low-dose CT as the favored method for detection of osseous disease in multiple myeloma [13, 14], the IMWG suggests FDG PET/CT should be considered for assessment of disease burden, given the dual metabolic and anatomic information provided and the increased ability to detect extramedullary disease [1]. FDG PET/CT has also been suggested as a predictive marker for patients at initial diagnosis of multiple myeloma [15, 16]. Both the number of FDG-avid lesions and increased Standardized Uptake Values (SUVs) of lesions predict shorter progression free and overall survival [16]. Follow therapy of multiple myeloma, there are multiple prospective studies demonstrating the power of FDG PET/CT to monitor therapy response (reviewed in [1]). Abrogation of FDG-avidity following chemotherapy prior to stem cell transplant is a predictive marker for progression free and overall survival [17]. Likewise, the lack of FDG-avid lesions following stem cell transplant is associated with longer disease control [16, 18]. Residual FDG-avidity following transplant may represent minimal residual disease (MRD). The IMWG recommends FDG PET/CT as the preferred imaging technique to evaluate response to therapy in multiple myeloma [1].

Figure 1.

Sensitive detection of multiple myeloma tumor burden by FDG PET/CT. Trans-axial FDG PET, CT, and fused FDG PET/CT images in a 79-year-old man with multiple myeloma demonstrate an FDG-avid osseous lesion in the left scapula (long arrow). Dedicated review of the CT images given FDG PET findings identified a lytic osseous lesion that went undetected by CT alone. This demonstrates the ability of FDG PET to supplement CT in the detection of multiple myeloma disease burden.

Thus, FDG PET/CT has demonstrated clinical value at multiple points of the plasma cell disorder disease spectrum, including smoldering multiple myeloma, solitary plasmacytoma, and active myeloma myeloma, and the IMWG has made multiple recommendations for the use of FDG PET/CT in these patients, as summarized in the following practice points.

• For patients with smoldering myeloma and solitary plasmacytoma, FDG PET/CT provides clinical value by excluding unsuspected sites of disease that may define active multiple myeloma.

• For patients with active multiple myeloma, FDG PET/CT provides clinical value as part of initial evaluation to assess disease burden and provide a prediction of prognosis, as well as following therapy as the preferred method of therapy response evaluation and as part of minimal residual disease assessment.

While FDG PET/CT has demonstrated substantial impact in patients with plasma cell disorders, it is important to recognize that important limitations exist. 10–30% of patients with established multiple myeloma bone disease lack FDG-avid malignancy [15, 16] (Figure 2) and there are false positivity due to bone marrow repopulation following therapy, inflammation, and degeneration [19]. In earlier stages of disease, detection by FDG PET may be even more difficult. More sensitive methods of detecting, localizing, and measuring tumor burden would improve staging and treatment selection of patients with plasma cell disorders. This has generated substantial interest in novel molecular imaging agents for plasma cell disorders.

Figure 2.

Non-FDG-avid multiple myeloma as a false negative on FDG PET. (A) Trans-axial CT and fused FDG PET/CT in a 55-year-old man with smoldering multiple myeloma demonstrate no FDG-avid or osseous lytic lesions. (B) Trans-axial CT and fused FDG PET/CT on a 2-month follow-up scan demonstrate new non-FDG-avid osseous lytic lesions (arrows), consistent with active multiple myeloma. This demonstrates the potential for false negative FDG PET findings as well as the need to evaluate the CT images of a FDG PET/CT scan to detect non-FDG-avid disease.

Metabolic tracers other than FDG utilized in plasma cell disorders

Several metabolic tracers other than FDG have been investigated in plasma cell disorders; however, data for these tracers is much more limited and there are no consensus recommendations for utilizing them in current clinical care. These tracers evaluate cell membrane, amino acid, or DNA metabolism, rather than glucose metabolism which is evaluated with FDG. Choline is a component of cell membranes and choline uptake is increased in cells with increased metabolism. Carbon-11 (11C)-choline [20] and 18F-fluorocholine [21] have both demonstrated avidity in multiple myeloma. Methionine is an amino acid and marker of amino acid metabolism. 11C-methionine has been utilized to visualize osseous myeloma [22]. Thymidine is a pyrimidine deoxynucleoside and marker of DNA synthesis and cell proliferation. 18F-fluorothymidine [23] and 11C-4-thiothymidine [24] have both been utilized in pilot trials of multiple myeloma.

Targeted PET imaging as a paradigm for the future molecular imaging

While metabolic PET tracers, most notable FDG, have demonstrated substantial clinical value, the next generation of PET tracers will likely be targeted to specific molecules on different tumor types. This paradigm has recently been utilized to detect and treat neuroendocrine (NET) tumors by targeting somatostatin receptors found on many NET malignancies [25, 26]. Gallium-68 (68Ga)-DOTATATE is a positron emitting PET radiotracer with higher sensitivity for well and moderately differentiated neuroendocrine tumors [25]. By replacing 68Ga with the beta-emitting 177Lu, a molecule capable of radiation-induced tumor suppression is created. NETs with 68Ga-DOTATATE uptake have shown excellent response to 177Lu-DOTATATE. In a phase 3 trial of 177Lu-DOTATATE for midgut NETs, the 116 patients receiving 177Lu-DOTATATE had a 65% progression-free survival (95% confidence interval 50 to 77%) at 20 months, compared with a 11% progression free-survival (95% confidence interval 4 to 23%) in the control group receiving a standard treatment agent, octreotide [26]. The concept of targeted imaging and therapy is being expanded to multiple malignances, with imaging and therapy targeting prostate-specific membrane antigen (PSMA) in prostate cancer demonstrating great promise [27–29].

Targeted imaging in plasma cell disorders: CXCR4, CD38, and BCMA

Biomarker targets in plasma cell disorders that have recently been exploited for imaging and therapy include the chemokine receptor 4 (CXCR4), cluster of differentiation 38 (CD38), and B-cell maturation antigen (BCMA). While still early in clinical development, targeted molecular imaging and therapy agents have already shown success in early clinical trials.

The activation of CXCR4 by binding of stromal cell-derived factor 1 triggers tumor growth in multiple malignancies [30] and is overexpressed in multiple myeloma cells [31]. A 68Ga-labeled ligand of CXCR4, 68Ga-pentixafor, has been synthesized and has demonstrated avidity in patients with myeloma, often at higher rates than FDG [32–35]. Conjugation of CXCR4 ligands with beta emitting isotopes has produced therapy agents for early clinical trials [36, 37].

A developing field of molecular imaging are antibody-based PET radiotracers, known as immunoPET tracers. The ability to radiolabel different antibodies with positron emitting isotopes had allowed the field of immunoPET to develop for multiple malignancies. For multiple myeloma, nearly all multiple myeloma cells express CD38, making it an excellent focus for targeted imaging and therapy. CD38 is a transmembrane glycoprotein that is expressed on nearly all multiple myeloma cells, as well as expressed at lower levels on normal lymphoid and myeloid [38]. Daratumumab is an already FDA-approved monoclonal antibody therapy for multiple myeloma that targets CD38. Conjugating daratumumab with the positron emitting radio-isotopes Copper-64 (64Cu) and Zirconium-89 (89Zr) has allowed the creation of immunoPET tracers for myeloma imaging. 64Cu-daratumumab has demonstrated the ability to image multiple myeloma cells in a murine model [39]. 89Zr-daratumumab has been utilized in both preclinical [40, 41] and early clinical trials [41], with 89Zr-daratumumab detecting multiple myeloma in human patients which was overlooked by FDG PET/CT and other clinically standard imaging methods (Figure 3). Full antibodies utilized for immunoPET require long systemic circulation times, in the range of 5–8 days, for optimal target localization and background clearance in humans [42, 43], thus the longer 78 hour half-life of 89Zr will likely be more favorable for delayed imaging of this immunoPET tracers than 68Ga. More advanced clinical trials for these immunoPET agents are planned.

Figure 3.

Visualization of multiple myeloma by 89Z-daratumumab immunoPET in an 80-year-old male. (A) MIP image from a 89Z-daratumumab PET/CT demonstrates multiple foci of osseous avidity, including a left scapular focus (arrow). (B) Axial CT and (C) fused PET/CT images from the 89Z-daratumumab PET/CT demonstrate the left scapular focus localizes to a lytic osseous lesion on CT (arrows). (D) MIP image from an FDG PET 1-week prior fails to identify the lesions seen on 89Z-daratumumab PET/CT.

BCMA plays an important role in plasma cell transformation and progression of plasma cell disorders [44] and is highly expressed and nearly exclusively present on B-cells [45]. Using ultra-small gadolinium containing nanoparticles targeted to BCMA targeting antibodies, investigators have improved signal-to-noise for multiple myeloma detection by MRI in a mouse model [46]. This demonstrates both the potential for BCMA as a plasma cell disorder target and fact that molecular imaging with be pursued with multiple imaging modalities, beyond the scope of this review.

Practice points.

• For patients with smoldering myeloma and solitary plasmacytoma, FDG PET/CT provides clinical value by excluding unsuspected sites of disease that may define active multiple myeloma.

• For patients with active multiple myeloma, FDG PET/CT provides clinical value as part of initial evaluation to assess disease burden and provide a prediction of prognosis, as well as following therapy as the preferred method of therapy response evaluation and as part of minimal residual disease assessment.

Research Agenda.

• While metabolic PET tracers, most notable FDG, have demonstrated substantial clinical value in plasma cell disorders, the next generation of PET tracers will likely be targeted to specific molecules on different tumor types.

• For plasma cell disorders, CXCR4 and CD38 targeted PET tracers have already demonstrated initial success in early clinical trials. More advanced clinical trials for these novel PET agents are planned.