Targeting BCMA in Plasmablastic Lymphoma With Teclistamab: A Case Study of Three Patients

Abstract

Plasmablastic lymphoma (PBL) is a rare subtype of non-Hodgkin lymphoma (NHL) with limited standard therapeutic options and poor outcomes. PBL typically lacks expression of the B-cell antigens CD20 or CD19 and, accordingly, has not benefited from the incorporation of B-cell–targeted antibodies. However, recent reports demonstrate that B-cell maturation antigen (BCMA) is expressed in most patients with PBL. BCMA is an established therapeutic target in multiple myeloma. Herein, we describe the clinical course of 3 patients with PBL found to express BCMA by immunohistochemistry who were treated with the BCMA×CD3 bispecific antibody teclistamab after developing disease refractory to at least 2 lines of standard therapy. A complete response was observed in 2 patients: 1 patient remains in remission after 2 years of teclistamab treatment, while the second achieved a complete response after 1 cycle of teclistamab, subsequently underwent allogeneic stem cell transplantation, and developed relapsed PBL 3 months post-transplant. The third patient developed a small bowel obstruction and transitioned to hospice care after 1 cycle of teclistamab. This case series adds to the growing evidence that BCMA is expressed in a considerable subset of patients with PBL and suggests that BCMA may serve as a potential molecular biomarker in PBL for further investigation of available BCMA-directed therapies.

Plasmablastic lymphoma (PBL) is a rare, aggressive subtype of non-Hodgkin lymphoma (NHL) associated with HIV infection, Epstein-Barr virus (EBV) infection, and immunocompromised states, and for which therapeutic options remain limited.¹ PBL is thought to originate from a post–germinal center B cell that lacks expression of mature B-cell markers, including CD20, CD19, and PAX5, while expressing classic plasma cell markers such as CD38, CD138, and MUM-1/IRF-4.² Importantly, B-cell maturation antigen (BCMA) is expressed on a majority of PBL specimens, regardless of stage or other features at diagnosis.^2,3 Frontline therapy for PBL typically involves anthracycline-based chemotherapy, such as cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) or dose-adjusted etoposide/prednisone/vincristine/cyclophosphamide/doxorubicin (DA-EPOCH). Survival outcomes remain poor relative to other aggressive NHLs. Unlike NHLs that express B-cell antigens, there is limited evidence supporting the clinical efficacy of antigen-targeted immunotherapies or antibody–drug conjugates in PBL. Thus, unlike B-cell NHL, outcomes for PBL have not improved with the incorporation of antigen-directed therapies into standard treatment regimens. In a cohort of 344 American patients with PBL, the 2-year overall survival (OS) was 59%.⁴ Neither treatment with DA-EPOCH nor consolidation with stem cell transplant (SCT) was associated with improved survival.⁴ A separate analysis of 281 patients reported a 5-year OS of 36%, highlighting the dismal prognosis of this disease.⁵ Despite a lack of prospective clinical trials, an initial case report and a small retrospective cohort of 8 patients treated with DA-EPOCH combined with bortezomib (DA-EPOCH-V) demonstrated a complete response in 100% of patients and a 2-year OS of 50%, with a favorable safety profile.^6,7 However, more robust prospective clinical data are needed, and no clear biomarkers predicting response were identified in this study. A subsequent multicenter retrospective review of DA-EPOCH-V outcomes reported a complete response in 15 of 16 patients, with a 2-year OS of 81% and a 5-year OS of 63%.⁸

As PBL lacks the typical antigen expression pattern of other mature NHLs, the integration of antigen-targeting therapies has been limited.^9–11 Additionally, the rarity of PBL has constrained the feasibility of prospective clinical trials. BCMA was first identified as a therapeutic target in multiple myeloma, leading to the development of BCMA-targeting bispecific antibodies and CAR-T cells.^12,13 Teclistamab is a BCMA-targeting bispecific antibody approved for relapsed multiple myeloma. BCMA is also expressed in PBL, making it a rational therapeutic target in this disease.³ This case series presents 3 patients with PBL who were treated with teclistamab. All patients provided written consent for the off-label use of commercial teclistamab, administered outside of an Institutional Review Board–approved protocol, after experiencing disease progression on ≥2 lines of therapy due to the lack of standard treatment options.

Case Series

Patient 1

A 33-year-old male with no history of immunodeficiency presented with a chest wall mass. Biopsy revealed an EBV-indeterminate, monotonous lymphoid population infiltrating adipose tissue, comprised of a lambda-restricted cell population positive for CD138, MUM1, and c-Myc, with a Ki-67 proliferative index of >95%, consistent with PBL. PET/CT imaging confirmed stage IIE disease, and bone marrow biopsy demonstrated no evidence of PBL involvement. Fluorescence in situ hybridization (FISH) studies showed no rearrangements in MYC, BCL-2, and BCL6 or fusions in MYC or IGH. The patient had no history of HIV or immunocompromising conditions and was not taking any medications at diagnosis. International Prognostic Index (IPI) score at diagnosis was low (0 points).

The patient received 6 cycles of DA-EPOCH-V. Although he showed an initial response after 3 cycles, posttreatment PET/CT revealed recurrent hypermetabolic disease in the anterior mediastinum, prompting consolidative radiation therapy (40 Gy). Subsequent PET/CT imaging showed a complete metabolic response (CMR), and he subsequently underwent an autologous SCT with carmustine/etoposide/cytarabine/melphalan (BEAM) conditioning. On day 100 post-transplant, PET/CT demonstrated new multifocal osseous lesions, and subsequent biopsy confirmed recurrent PBL. Treatment with 4 cycles of ifosfamide/carboplatin/etoposide with daratumumab (Dara-ICE) resulted in resolution of the osseous disease, although new perilymphatic lung nodules were seen (Figure 1A). Biopsy of a lung lesion confirmed PBL, and immunohistochemistry (IHC) demonstrated BCMA expression in 90% of malignant cells (Figure 2A, B). IHC staining was performed using a rabbit monoclonal antibody (ab315340; Abcam) for all patients. After discussion with the patient, treatment with teclistamab was initiated, resulting in a CMR by PET/CT after 1 cycle. The course was complicated by grade 1 cytokine-release syndrome (Figure 1B). The patient underwent consolidative allogeneic SCT using a matched unrelated donor. On day +30 post-transplant, PET/CT demonstrated a CMR, and his chimerism was 100% in all compartments. However, day 100 PET/CT revealed new osseous lesions, with biopsy confirming relapsed PBL; repeat BCMA staining was not performed due to technical issues. Teclistamab was resumed in combination with donor lymphocyte infusions (DLIs), producing a mixed response, but the disease progressed after 5 cycles of teclistamab and 2 DLIs (Figure 1B). The patient’s disease was subsequently refractory to the GPRC5D-targeting bispecific antibody talquetamab, as well as carfilzomib, lenalidomide, and dexamethasone, and he ultimately died from progressive disease. He survived 2 years and 8.5 months.

Figure 1.

Radiographic and metabolic responses to teclistamab. Perilymphatic PBL lesion (arrows) in Patient 1 on (A) CT and (B) PET/CT following 1 cycle of teclistamab. PET/CT showing splenic hypermetabolic PBL lesions in Patient 2 (C) prior to teclistamab (arrows), (D) following 2 cycles, and (E) following 18 cycles.

Abbreviation: PBL, plasmablastic lymphoma.

Figure 2.

Biopsy specimens with H&E and BCMA IHC staining for (A, B) Patient 1, (C, D) Patient 2, and (E, F) Patient 3. BCMA IHC was performed for all patients using a rabbit monoclonal antibody (ab315340; Abcam) (original magnification, ×40 for all).

Abbreviations: BCMA, B-cell maturation antigen; H&E, hematoxylin-eosin; IHC, immunohistochemistry.

Patient 2

A 60-year-old male with a medical history of stage IV chronic kidney disease presented with abdominal pain and CT imaging demonstrating mass-like thickening of the descending colon. Pathology from his subsequent partial colectomy revealed kappa-restricted lymphoid cells expressing CD38, CD138, and MUM-1, negative for EBV and HHV8, involving the pericolonic fat and submucosa. The Ki-67 proliferative index was 80% to 90%. BCMA staining noted 2+ staining in 5% of plasma cells in his colectomy specimen (Figure 2C, D). Postcolectomy PET/CT scan revealed osseous, splenic, and hepatic lesions, consistent with stage IV PBL. He had no history of HIV, immunocompromising condition, or relevant medication exposures. IPI at diagnosis was high-intermediate (3 points). FISH studies were not obtained at the time of diagnosis, and additional tissue was not available for retrospective analysis.

The patient was treated with DA-EPOCH for 6 cycles with intrathecal methotrexate for central nervous system (CNS) prophylaxis. PET/CT imaging following 3 and 6 cycles of therapy confirmed a complete response. His disease relapsed 4 months later, and he was treated with gemcitabine/oxaliplatin/daratumumab. Due to his chronic kidney disease and other comorbidities, he was not considered a candidate for transplantation. Despite initial clinical improvement, his PBL progressed after 8 cycles of treatment. PET/CT demonstrated worsening hypermetabolic abdominal and perisplenic masses (Figure 1C), and biopsy confirmed recurrent PBL. He was then started on teclistamab. Although he did not experience cytokine-release syndrome or immune effector cell–associated neurotoxicity syndrome, his treatment course was complicated by viral pneumonia, which was managed with intravenous immunoglobulin and supportive measures. A repeat PET/CT scan after 2 cycles of therapy showed a partial response (Figure 1D), which deepened after 4 cycles, with PET/CT demonstrating a CMR (Figure 1E). Following confirmation of a sustained CMR after 7 cycles of teclistamab, therapy was transitioned to every-2-week dosing and ultimately discontinued after 24 cycles. The patient remains on active surveillance without evidence of relapsed PBL, 3 years and 9 months after his initial diagnosis.

Patient 3

A 71-year-old female presented with nausea and vomiting. CT imaging revealed peritoneal nodules, and PET/CT demonstrated widespread lymph node avidity and hypermetabolic skeletal lesions. Biopsy of a peritoneal nodule was concerning for PBL and demonstrated features overlapping with myeloma, including IgA gammaglobulinemia (2,193 mg/dL). Bone marrow biopsy demonstrated involvement by an EBV-negative, HHV8-negative neoplasm most consistent with PBL. IHC for BCMA showed diffuse 2+ staining in 100% of plasma cells (Figure 2E, F). The patient was otherwise healthy, with no history of HIV, immunodeficiency, or other comorbidities at diagnosis. The patient’s IPI at diagnosis was high risk (5 points). FISH analysis revealed MYC amplification without rearrangement, an IGH translocation, and gains of 2 copies of BCL2, BCL6, and TP53. Additional cytogenetic findings included tetrasomy of chromosomes 3 and 7 and trisomy of chromosomes 9 and 13.

The patient completed 6 cycles of CHOP. Post-treatment PET/CT showed disease progression, with new lesions involving a cardiophrenic lymph node, a peritoneal nodule, and a small bowel lesion. The patient concurrently developed diplopia, and cerebrospinal fluid analysis showed malignant cells consistent with CNS involvement. She began treatment with intrathecal methotrexate followed by systemic therapy with lenalidomide/bortezomib/dexamethasone. Her CNS symptoms resolved with intrathecal therapy; however, her systemic disease progressed, with PET/CT revealing new subcutaneous skin nodules. She was started on teclistamab, but experienced disease progression during the first cycle associated with a malignant small bowel obstruction. She was subsequently transitioned to hospice care 11 months after initial diagnosis.

Discussion

To our knowledge, this is the first case series to document objective clinical responses to teclistamab in patients with refractory PBL. Consistent with prior reports, each patient demonstrated BCMA expression via IHC.³ Despite patients 1 and 2 experiencing treatment failure with standard first- and second-line therapies, both achieved a CMR to teclistamab. Patient 1 further illustrates the potential role of teclistamab as a salvage therapy prior to allogeneic SCT. Furthermore, this series highlights the use of teclistamab in patients harboring significant comorbidities, such as in patient 2, where teclistamab was well tolerated and associated with minimal treatment-related adverse events.

These cases are consistent with a previous report describing a durable remission in an adolescent patient with PBL arising from B-cell acute lymphoblastic leukemia who was treated with BCMA-targeting CAR-T cells.¹⁴ Collectively, these reports suggest that BCMA is a potential therapeutic target in PBL. In our case series, the most robust response was observed in patient 2 with low BCMA expression, suggesting that the prognostic relevance of BCMA as a therapeutic biomarker merits further characterization. The generalizability of our findings may be limited, however, as none of these 3 patients had HIV or apparent immunodeficiencies, which are commonly observed in PBL. Prospective clinical trials are needed to further explore the safety and clinical efficacy of teclistamab and other BCMA-directed therapies in PBL, a disease historically associated with dismal outcomes.