Page 354 - Haematologica Vol. 109 - July 2024

CASE REPORT
Phenomenon of tumor flare with talquetamab in a patient with extramedullary myeloma
Multiple myeloma (MM) is the second most common he- matological malignancy; it is incurable, leading to a disease course with multiple relapses.1 There have been significant improvements in survival over the past two decades, driven by the development of novel targeted agents and combina- tion therapies. Bispecific T-cell engagers (BiTE) are the latest addition to the therapeutic armamentarium with response rates in triple-class refractory approximately double that of other treatments (apart from chimeric antigen receptor [CAR] T-cell therapy). The development of BiTE has been one of the most novel and promising developments in MM in the last 2 years.2
Recently, talquetamab, a humanized antibody that targets CD3, a receptor present in T cells and the G protein-cou- pled receptor class 5 member D (GPRC5D), an orphan re- ceptor on malignant plasma cells3 has received Food and Drug Administration approval for relapsed MM after four prior lines of therapy. This first-in-class BITE was studied in a phase I clinical trial for R/R MM that showed response rates of 64% to 75% and a duration of response of 7.8 to 10.2 months based on the dose given.3 The response rate for extramedullary disease (EMD) was lower at 40% to 45%. While exceptionally promising, the full efficacy and treatment course of this drug is still being explored in larger studies. In the past two decades, a new phenomenon of rapid tem- porary onset, or pseudo-disease progression before disease response was identified as a side effect of immunotherapy.4 First identified in chronic lymphocytic leukemia (CLL) this phenomenon now known as tumor flare reaction (TFR)4 has also been seen in MM and has even been reported in solid tumors treated with checkpoint inhibitors.5 It has been identified as a low-level (4%) adverse event of BITE use in lymphoma.6 Despite its identification, this phenomenon remains poorly understood, and its incidence is likely un- derreported. TFR has been associated with morbidity and mortality. In this case, we report an episode of TFR asso- ciated with talquetamab in a patient with MM presenting with extramedullary manifestations.
We present a 75-year-old male patient with a medical history of end-stage renal disease requiring hemodialysis (secondary to his myeloma). He also had a history of atrial fibrillation, and a prior stroke with no residual deficits. He was diagnosed in May 2020. Initial diagnosis revealed 70% plasma cells in the bone marrow and a high-risk 1q21 gain in cytogenetics. The patient had received multiple prior lines of therapy including two prior immunomodulatory agents (lenalidomide and pomalidomide), two proteasome inhibitors (bortezomib and carfilzomib), daratumumab, alkylating agents (cyclophosphamide, melphalan). He pro-
gressed quickly through multiple therapies and developed extramedullary skin lesions that were biopsy proven to be involved with myeloma. The patient also developed plas- macytomas in the form of ulcerated lesions in his stomach (biopsy proven) that led to melena that was stabilized with local interventions on endoscopy. In May 2023, the patient was admitted for a teclistamab step-up cycle. Initial doses of teclistamab were accompanied by worsening pain in the skin lesions as well as the development of new skin lesions. In the setting of new skin lesions, it was not clear whether the patient was responding to teclistamab. However, light chains were improving, and therapy was continued with palliative radiotherapy (RT) to the painful skin lesions. After three full doses of teclistamab, the patient presented with melena due to a plasmacytoma eroding into the gastric mucosa. This was accompanied by progression of disease as seen by the continued development of numerous skin lesions and a rise in involved light chains. The patient was given palliative RT to his stomach and taken off teclistamab. The patient was then given hyperfractionated cyclophospha- mide over 2 days. There were neither significant changes in skin lesions nor in light chain levels. He was subsequently treated with talquetamab with ramp-up dosing on days 1, 3 and 5 and full-dose administration on day 7. On the sec- ond day of talquetamab treatment, the patient reported an increase in the growth of fungating lesion behind the left knee. On physical exam the patient had a 6 cm by 4 cm fungating mottled gray mass independent of bone on the popliteal fossa. He had enumerable smaller 1-3 cm mass- es over the surface of his body. No other physical exam findings such as tenderness, or other rashes were noted on exam. By the third day, these lesions appeared more erythematous. The patient also reported pain in these le- sions. The pain was managed with supportive medications such as gabapentin and opioids.
On 6 day of treatment, the patient developed a high-grade fever and chills, suspected to be symptoms of cytokine release syndrome (CRS). Administration of tocilizumab led to symptom resolution. A full dose of talquetamab was administered on day 7 without complications, and by that time, the patient’s pain had improved. On day 8 since initiating talquetamab, the patient was discharged with re- duced pain in the lesions. Follow-up investigations showed resolved skin lesions (Figure 1), a significant drop in κ/λ ratios, and decreased lactate dehydrogenase (LDH) levels (Table 1) suggesting complete response (CR). Inflammatory markers a month prior to talquetamab ferritin was 1,564 ng/mL and C-reactive protein (CRP) was 1.9 mg/dL both normalized 3 months after therapy.
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