Phenomenon of tumor flare with talquetamab in a patient with extramedullary myeloma

Multiple myeloma (MM) is the second most common hematological 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 combination 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-coupled receptor class 5 member D (GPRC5D), an orphan receptor 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 temporary 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 underreported. TFR has been associated with morbidity and mortality. In this case, we report an episode of TFR associated 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 progressed quickly through multiple therapies and developed extramedullary skin lesions that were biopsy proven to be involved with myeloma. The patient also developed plasmacytomas 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 cyclophosphamide 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 second 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 masses 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 lesions. 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 reduced 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.

The initial increase in size, erythema around these skin lesions and worsening pain followed by resolution of these lesions was concluded to be an example of TFR secondary to talquetamab. The patient was only on prophylactic antimicrobials and there was no discharge from these fungating lesions and clinically we did not suspect cellulitis. The patient’s lesions were consistent with prior biopsy proven EMD. Most significantly there was a clear temporal relationship to treatment, and a correspondence with serological myeloma markers. The rise in LDH (a frequent surrogate for disease activity and tumor lysis) and even a slight rise in the κ light chains corresponded with the expansion of skin lesions. The skin lesions resolved completely as the light chain ratio normalized, LDH fell and patient achieved a biochemical CR. The CR in this penta-refractory, unfavorable cytogenetics patient continues to affirm the effectiveness of novel BiTE but this rare and poorly understood phenomenon is important as it could impact patient outcomes in several ways. Initially, when the patient was given teclistamab, the patient had worsening skin lesions and pain. Given the possibility of TFR, we continued treatment for four full doses with palliative measures such as local RT. However, with a clear increase in light chains on progressive assessments and development of melena, we decided to discontinue teclistamab. We were certain at that point that the patient had progression of disease. When the patient was given talquetamab, pain as well as worsening erythema at the site of skin lesions occurred. This was short-lived (a few days) as compared to progression of disease on teclistamab. With the first outpatient visit for the patient about a week after the first full dose of talquetamab, it was clear that the patient was responding both in terms of skin lesions as well as involved light chains. We confirmed his response with positron emission tomography/computed tomography (Figure 2) To our knowledge only one other case of TFR has been reported with talquetamab though more cases in the setting of anti-BCMA directed therapies have been reported.^8,9 None of these cases involved dermatological progression, and the other case of talquetamab induced TFR was noted on positron emission tomography scan only. Furthermore, the flare in tumor markers corresponding with our patient’s flare in skin lesions provides a biochemical timeline not documented previously. In these other cases, patients were also managed symptomatically and monitored with resolution of TFR at 6 weeks. As such awareness of the timing and nature of the phenomenon appears to be key to preventing adverse outcomes.

Figure 1.Serial images of patient’s extramedullary fungating skin lesions.

Table 1.Laboratory trends for the patient.

Figure 2.Timeline comparing positron emission tomography scans from April 2023 and August 8, 2023. Scan show interval improvement in left proximal thigh mass and left subcutaneous nodularity, alongside treatment dates.

While poorly understood, the phenomenon of TFR has been linked to an immune response and T-cell infiltration leading to inflammation and disease activity.⁷ This is important to consider for EMD patients as they have traditionally been considered to have a higher risk disease and a lower response rate to the BiTE. Given the intrinsic immunomodulatory and T-cell engaging nature of BiTE, TFR may prove to be a greater adverse event in BITE therapies than prior therapies and will remain an ongoing challenge to differentiate from a true progression. It is for these reasons that improving the identification, management, and the decision of therapy continuation in patients with TFR is a matter of clinical importance. Importantly, both talquetamab and teclistamab were safely given to this patient with end-stage renal disease on hemodialysis, a patient population that was excluded in the pivotal clinical trials.

Finally, our case shows that patients resistant to one T-cell redirecting therapy may respond to a second agent with a different target. The effectiveness of talquetamab in this teclistamab-refractory patient provides further data for BiTE sequencing.

As further immunotherapies are introduced for myeloma patients, the development of guidelines for BiTE sequencing, and TFR monitoring will be beneficial to develop a uniform approach for the management of patients with EMD that are treated with BiTE.

Footnotes

• Received October 20, 2023
• Accepted February 13, 2024

Correspondence

N. SHAH - nisshah@montefiore.org

Disclosures

No conflicts of interest to disclose.

Contributions

NS, DC, MG were responsible for patient care and finalized the manuscript. DK was responsible for the radiology images. MF and SB wrote the manuscript. MJ, MG and AM supervised the study.