Pseudoprogression of extramedullary lesions during elranatamab therapy in relapsed or refractory multiple myeloma

Abstract

Pseudoprogression comprises a transient increase in tumor burden caused by immune cell infiltration or inflammatory responses after immunotherapy, including chimeric antigen receptor T-cell therapy and the use of bispecific antibodies. Although pseudoprogression has been reported following several immunotherapy types, cases of pseudoprogression associated with elranatamab remain rare. Herein, we describe the case of a 67-year-old woman with relapsed/refractory multiple myeloma who developed pseudoprogression of extramedullary lesions following treatment with elranatamab. On day 4 of therapy, the patient presented with left periorbital swelling and lagophthalmos. Computed tomography (CT) revealed the enlargement of multiple extramedullary lesions in this patient. Dexamethasone administration improved the ocular symptoms. Lagophthalmos recurred after administration of the second dose of elranatamab but responded to dexamethasone. On day 13, a CT-guided biopsy of the chest wall lesion revealed dense T cell infiltration within the tumor tissue, consistent with pseudoprogression rather than true progression. The patient’s serum M-protein levels decreased within 2 weeks of treatment initiation. At 2 months, follow-up CT demonstrated a reduction in the extramedullary lesions, and the patient achieved a very good partial response. This case highlights that pseudoprogression may occur during elranatamab therapy, similar to that which may occur with other T-cell-redirecting immunotherapies. Differentiating pseudoprogression from true progression is clinically important, as misinterpretation may lead to premature discontinuation of effective therapy. Careful clinical evaluation, integration of imaging findings, and histopathological confirmation (whenever feasible) are essential for the appropriate management of such cases.

INTRODUCTION

Elranatamab is a humanized bispecific antibody that concurrently targets the B-cell maturation antigen (BCMA) expressed on malignant plasma cells and CD3 on T cells, thereby facilitating T-cell-mediated cytotoxicity against multiple myeloma (MM) cells. In a previous clinical study, elranatamab demonstrated significant and durable antitumor activity in patients with triple-class refractory, relapsed, and refractory MM.¹

Pseudoprogression, characterized by transient tumor enlargement due to immune cell infiltration rather than true tumor growth, has been increasingly recognized in the context of immunotherapies such as chimeric antigen receptor T-cell (CAR-T) and bispecific antibody therapies.^2,3 Although this phenomenon has been well documented in solid tumors, reports of pseudoprogression in extramedullary MM remain limited.^4–6 Tumor enlargement due to pseudoprogression can exert mass effects on adjacent organs and potentially cause significant clinical complications. Localized inflammatory responses in anatomically constrained regions, such as the cervical or mediastinal regions, have been associated with life-threatening respiratory or circulatory complications in patients treated with bispecific antibody therapies for lymphoid malignancies.^7,8

Given that pseudoprogression reflects the immune-mediated antitumor activity of therapeutic agents, accurate differentiation from true disease progression is essential for appropriate clinical management. Herein, we describe a case of pseudoprogression involving an orbital extramedullary lesion following elranatamab administration that required additional dexamethasone intervention.

CASE REPORT

A 64-year-old woman was referred to our hospital for further evaluation of hypergammaglobulinemia. Bone marrow aspiration revealed increased malignant plasma cells, leading to a diagnosis of immunoglobulin G (IgG) lambda-type MM. Conventional G-banding showed a normal female karyotype, and fluorescence in situ hybridization (FISH) analysis revealed a gain of 1q21 and a t(4; 14) translocation. According to the International Staging System, the disease was classified as stage II. Computed tomography (CT) revealed multiple lytic bone lesions distributed throughout the body and extramedullary disease. The extramedullary lesions were located adjacent to the cranium, costae, and vertebral column. No apparent orbital lesions were reported, and the patient did not present with any orbital symptoms; however, she had been previously diagnosed with Fuchs endothelial corneal dystrophy, which can lead to progressive vision loss.

The patient initially received combination therapy with daratumumab, bortezomib, and dexamethasone (DBd) to achieve a partial response (PR). However, she was unable to tolerate DBd or a subsequent regimen of daratumumab, carfilzomib, and dexamethasone because she developed peripheral neuropathy—although PR was achieved. She was then treated with five courses of isatuximab, pomalidomide, and dexamethasone (IsaPD), resulting in a very good PR (VGPR). To enhance the clinical response, the patient underwent high-dose chemotherapy followed by autologous stem cell transplantation (ASCT).

Despite the initial response, the patient’s disease relapsed 6 months after ASCT. Additional chemotherapy regimens were attempted but failed to achieve a satisfactory response. BCMA-targeting CAR-T cell therapy was initiated using idecabtagene vicleucel. Although the patient developed grade 1 cytokine release syndrome (CRS) and pseudoprogression of the extramedullary lesions throughout her body, this achieved a significant reduction in the tumor burden. Nevertheless, the patient experienced a relapse 8 months after CAR-T cell therapy. Retreatment with the IsaPD regimen was unable to control the disease, and CT imaging confirmed the progression of extramedullary lesions—including those involving the left orbital cavity, chest wall, and regions adjacent to the thoracolumbar vertebrae (Fig. 1). Bone marrow aspiration again demonstrated increased malignant plasma cells with a normal karyotype (46,XX [20/20]), and FISH analysis revealed no deletion of 17p. Given the patient’s underlying Fuchs endothelial corneal dystrophy, radiotherapy for the orbital lesions was contraindicated.

Fig. 1.

CT images acquired at different time points before and after elranatamab treatment. Extramedullary lesions are identified in the left orbital cavity (A), anterior chest wall (B), surfaces of the vertebrae (C), pancreas (D), and right renal hilum (E). CT: Computed tomography

The patient was then administered elranatamab monotherapy according to the recommended dose escalation schedule. The patient developed grade 1 CRS on day 3 of treatment, which was successfully managed with tocilizumab. On day 4, the patient developed left periorbital swelling and lagophthalmos, which improved with dexamethasone administration. CT imaging on day 4 revealed enlargement of extramedullary lesions across multiple sites (Fig. 1). After the second dose of elranatamab, lagophthalmos in the left eye recurred and responded to treatment with dexamethasone. On day 13, a biopsy of the chest wall lesion revealed T cell infiltration within the tumor tissue, consistent with pseudoprogression (Fig. 2). Based on these findings, we decided to continue elranatamab treatment. Two months after treatment initiation, CT revealed complete remission of the extramedullary lesions and decreased serum M-protein levels, indicating a VGPR (Fig. 3).

Fig. 2.

Histopathological examination of the resected chest wall tumor demonstrated diffuse proliferation of atypical plasma cells (A). Immunohistochemical analysis reveals infiltration of CD3-, CD4-, and CD8-positive T cells (B–D) within the tumor, which consisted of CD138-positive myeloma cells (E).

Fig. 3.

Clinical course of the patient. Serum-free light chain (FLC) and total IgG levels decreases within 2 weeks of elranatamab treatment initiation. The timing of elranatamab administration, CT, and biopsy is indicated.

DISCUSSION

We recently treated a case of pseudoprogression of extramedullary lesions, including those in the orbital cavity, in a patient with MM. Before receiving elranatamab, the patient had previously received BCMA-targeting CAR-T therapy, which caused both CRS and pseudoprogression. To the best of our knowledge, no reports have demonstrated pseudoprogression occurring both after CAR-T therapy and subsequent bispecific antibody treatment in the same patient.

Pseudoprogression after T-cell–redirecting therapies has been increasingly recognized in multiple myeloma and lymphoma, although biopsy-proven cases remain rare.^3,4,6,9,10 Thus, the underlying mechanisms of pseudoprogression remain largely unknown. Previous reports have described transient tumor enlargement following both BCMA-directed CAR-T cell therapy and bispecific antibodies, supporting a shared immune-mediated mechanism.^2–4,6,9,10 In these settings, rapid T-cell activation and cytokine release can trigger local inflammation, endothelial activation, and increased vascular permeability, leading to tissue edema and temporary lesion swelling before subsequent tumor reduction occurs. Cytokines such as IL-6, IL-1, and TNF-α, which are elevated during CRS, are known to enhance vascular permeability and may therefore contribute to the development of pseudoprogression.^11,12 Taken together with our present findings showing dense CD8-positive T-cell infiltration, these observations suggest that immune-cell infiltration–induced inflammation and cytokine-driven vascular leakage collectively play a major role in this phenomenon.³ Although pseudoprogression indicates active antitumor immunity, careful differentiation from true progression remains essential to avoid premature discontinuation of effective therapy.

Pseudoprogression has also been reported with GPRC5D×CD3 bispecific antibodies such as talquetamab.⁴ In a recent case report, pseudoprogression occurred during talquetamab therapy, whereas true progression was noted with teclistamab in the same patient.⁴ Because GPRC5D is expressed in normal keratinized tissues, including the skin and tongue, differences in antigen distribution might influence the occurrence of pseudoprogression among various T-cell redirecting antibodies. This observation suggests that antigen biology and tissue expression may modulate the local immune response underlying pseudoprogression.

Distinguishing pseudoprogression from true disease progression remains a major challenge in clinical practice, as it directly influences subsequent therapeutic decisions. Histopathological confirmation via biopsy is the gold standard. In the current case, a CT-guided biopsy of the anterior chest wall mass suggested that the increase in lesion size reflected immune-mediated tumor infiltration rather than true progression, as indicated by the abundance of CD8-positive T cells within the lesions (Fig. 2). However, tissue sampling is often not feasible due to anatomical constraints. Alternative assessments using serial imaging and laboratory biomarkers can assist in differentiating these two entities in such cases. In the current case, the patient’s serum-free light chain and IgG levels declined within 2 weeks of therapy initiation, suggesting that the enlargement of the lesion represented treatment-induced inflammation rather than actual worsening of the disease (Fig. 3). Subsequent CT imaging confirmed a significant tumor reduction 2 months after the initiation of elranatamab therapy (Fig. 1). This case underscores the utility of serial M-protein monitoring, in addition to pre- and post-treatment imaging, when assessing treatment responses in cases of MM with extramedullary involvement. The availability of serological markers for monitoring therapeutic responses is a distinctive advantage of MM over lymphoma or solid tumors.

Although pseudoprogression indicates favorable antitumor activity, clinical intervention may be required when it results in the compression of certain organs (e.g., the spinal cord) or life‑threatening respiratory or circulatory obstruction.^2,6,13 Prophylactic local radiotherapy has been proposed as an effective strategy to prevent fatal airway compromise caused by bispecific antibodies, particularly in cases with cervical lymphoma masses.⁶ Although local radiotherapy can be beneficial for tumor control, it was not feasible in this case due to the patient’s comorbid Fuchs endothelial corneal dystrophy. This condition increases the risk of cataract surgery and may render the cornea more vulnerable to radiation-induced damage. Single doses of dexamethasone, delivered as needed, effectively alleviated the patient’s ocular symptoms and contributed to the induction of systemic tumor remission—as confirmed by CT performed 2 months later. Although long-term, high-dose corticosteroid use can suppress T cell proliferation and potentially interfere with the efficacy of immunotherapy, previous studies have reported that corticosteroid administration does not adversely affect the long-term outcomes of BCMA-targeted CAR-T therapy for MM.^14,15 Based on this evidence, we opted for short-term corticosteroid administration to manage any complications related to tumor pseudoprogression during elranatamab therapy.

Our experience highlights the importance of recognizing pseudoprogression in patients with MM who receive bispecific antibody therapy. Short-term administration of corticosteroids as needed may represent an effective strategy for managing complications related to pseudoprogression, and continuous monitoring of M-protein levels may assist in distinguishing between pseudoprogression and true disease progression.