SUMMARY

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with the rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• Chari et al (2024)¹ published the clinical management of TFR and tumor pseudoprogression as adverse events (AEs) in patients with RRMM treated with TALVEY.
• Three case reports describe the occurrence of tumor flare or pseudoprogression using radiographic imaging, following treatment with TALVEY.^2-5
  • Forsberg et al (2024)² reported a case of tumor flare reaction (TFR) associated with TALVEY in a 75-year-old patient with multiple myeloma (MM) presenting with extramedullary manifestations.
  • Leipold et al (2022 and 2023)^3,4 reported 2 events of pseudoprogression in a 61year-old male patient with relapsed and refractory MM (RRMM); 1 event was transient and self-limiting after receiving TALVEY.
  • Jamet et al (2023)⁵ reported the case of a flare-up phenomenon in a 61-year-old female patient receiving TALVEY for the treatment of relapsed MM.

BACKGROUND

• TFR or tumor pseudoprogression is an increase in the size of the primary tumor, or the appearance of a new lesion followed by tumor regression. It is not true tumor progression that has been proven by histopathological biopsies that found infiltration and recruitment of various immune cells, such as T or B lymphocytes, in the tumor.^6,7
• The specific mechanism of TFR is unknown but may be correlated with the activation and infiltration of natural killer cells and T-cells in cancer foci and changes in the tumor microenvironment.^8,9
• Notable clinical features of TFR include fever, leukocytosis, tumor pain, hypercalcemia, diffuse bone pain, lymphocytosis, fever, splenomegaly, rash/pruritus, electrolyte imbalance, and radiological imaging showing pseudoprogression.^7,10,11

CLINICAL ManagEment

Chari et al (2024)¹ published the clinical management of TFR and tumor pseudoprogression as AEs in patients with RRMM treated with TALVEY.

• Pain management of TFRs should involve analgesics, including opioids, and corticosteroids to control MM- and inflammation-related symptoms.
• To ensure patients continue receiving effective therapy, TFRs should be confirmed before adjusting the treatment regimen.
• Worsening of pain with TALVEY step-up or early doses should prompt repeat disease assessment.
• Decreased serum free light-chain ratio, worsening pain, or increased tumor size in imaging results indicate response to treatment. The associated pain or imaging changes are likely due to robust T-cell infiltration at focal disease sites.

CLINICAL DATA - Case Reports

Forsberg et al (2024)² reported a case of TFR associated with TALVEY in a 75-year-old patient with MM presenting with extramedullary manifestations.

• The patient had end-stage renal disease requiring hemodialysis secondary to his myeloma, had a history of atrial fibrillation, and had suffered a prior stroke with no residual deficits.
• The patient was initially diagnosed with myeloma in May 2020, with 70% of plasma cells in the bone marrow and a high-risk 1q21 gain.
• After receiving multiple prior lines of therapy, the patient developed extramedullary skin lesions that had biopsy-proven involvement with myeloma.
• The patient was treated with TALVEY step-up dosing on days 1, 3, and 5, and received the first full treatment dose on day 7.
  • On day 2 of TALVEY treatment, an increase in the growth of fungating lesion behind the left knee was reported.
    • Physical examination revealed a 6x4 cm fungating mottled gray mass independent of bone on the popliteal fossa and numerous smaller masses measuring 1-3 cm over the body surface.
    • Tenderness and rashes were not observed on examination.
  • On day 3 of TALVEY treatment, the lesions appeared more erythematous and the patient reported pain in the lesions; supportive medications such as gabapentin and opioids were used to manage the pain.
    • Initial increase in lesion size along with erythema and worsening pain followed by resolution were determined to be an example of TFR secondary to TALVEY treatment.
    • The patient received only prophylactic antimicrobials; there was no discharge from the fungating lesions and no clinical suspicion of cellulitis.
    • These lesions were consistent with prior biopsy-proven extramedullary disease (EMD).
    • There was a clear temporal relationship to treatment and correspondence with serological myeloma markers. The expansion of skin lesions corresponded to the increase in lactate dehydrogenase (LDH) and kappa light chains. As the light chain ratio normalized, the skin lesions resolved completely.
  • On day 6 of TALVEY treatment, the patient developed high-grade fever and chills, suspected to be symptomatic of cytokine release syndrome; symptoms resolved with tocilizumab treatment.
  • On day 7, a full dose of TALVEY was administered without complications; at this time, the patient's pain had improved.
  • On day 8 after starting TALVEY treatment, the patient was discharged with reduced pain in the lesions.
• About 1 week after the first full dose of TALVEY, it was determined that the patient was responding (in terms of skin lesions and involved light chains); response was confirmed with positron emission tomography (PET)-computed tomography (CT).
• Follow-up investigations showed resolution of skin lesions, a significant decrease in kappa/lambda ratios (365.24 prior to TALVEY step-up; 331.86 during TALVEY step-up; 9.6 at 28 day follow up; 0.46 at 50 day follow-up), and decrease in LDH levels, suggesting complete remission (CR).
• Levels of inflammatory markers, including ferritin and C-reactive protein, normalized 3 months after TALVEY therapy.

Leipold et al (2022 and 2023)^3,4 reported the case of a 61-year-old Caucasian male with high-risk cytogenetics, who was diagnosed with immunoglobulin A (IgA) kappa MM with EMD and developed pseudoprogression after receiving TALVEY.

• The patient had high-risk cytogenetics, including t(14;20), amp(1q), and del(1p); biopsy-proven EMD in both lungs, anemia, osteolytic bone disease, and 80% bone marrow infiltration by malignant plasma cells.⁴
• The patient received B-cell maturation antigen (BCMA) targeting chimeric antigen receptor T-cell (CAR-T) therapy as the fourth line of treatment and experienced violent coughing 10 days later.³
• An ¹⁸F-fluorodeoxyglucose (FDG)-PET scan revealed full resolution of focal bone lesions but disseminated FDG uptake at the lung and mediastinal lymph nodes similar to sarcoidosis.³
• Noncaseating granuloma formation without evidence of residual MM cells was revealed in an endobronchial ultrasound-guided biopsy along with bronchoalveolar lavage (BAL).³
• Single-cell ribonucleic acid sequencing (RNA-seq) on the BAL sample revealed cluster of differentiation 4 (CD4+) Tcells exhibiting simultaneous expression of genes associated with Type 1 helper (Th1) T-cells (TBX21, CXCR3, IFNG, TNF) and Th17 T-cells (RORC, IL23R, CCR6, CCL20, KLRB1), indicative of a Th1-polarized Th17 phenotype.³
  • Furthermore, these cells expressed IL4I1, ABCB1, and CSF210-12, while IL17A, IL17B, IL17E (IL25), and/or IL17F was not expressed, highlighting the presence of proinflammatory Th17.1 cells. This suggested that the patient suffered from noninfectious, Th17.1 T-cell driven sarcoidosis-like auto-immune phenomenon located in the lungs following anti-BCMA CAR T-cell therapy. The patient received high-dose inhaled steroids, which resolved his respiratory symptoms.
• The patient subsequently relapsed from CR. The FDG-PET scan showed known sarcoidosis-like pulmonary changes in addition to a number of new softtissue lesions, which were CXCR4 positive and suspicious for extramedullary relapse.³
• The patient was enrolled in a trial investigating TALVEY. After 1 week of dosing, he experienced severe pain crisis, and a diffusion-weighted magnetic resonance imaging (MRI) revealed an increase in the size of multiple extramedullary lesions but no new lesions.³
  • M-protein levels decreased simultaneously, suggesting either mixed response or pseudoprogression.³
• The patient received painkillers, and all lesions disappeared on a follow-up scan 6 weeks later, confirming pseudoprogression. He was in ongoing CR for 6 months at the time of reporting.³

Jamet et al (2023)⁵ reported the case of a flare-up phenomenon in a 61-year-old female patient receiving TALVEY for the treatment of relapsed MM, diagnosed via 2deoxy-2 18FFDG (2-[¹⁸F]FDG)-PET-CT scan.

• The patient participated in the MonumenTAL-2 trial (clinicaltrials.gov identifier: NCT05050097) in June 2022 and received 28-day cycles of TALVEY. The patient had lambda light chain-only MM and had received 8 prior lines of therapy, including PIs, immunomodulatory drugs, and anti-CD38 antibody.
• At baseline, 2-[¹⁸F]FDG-PET-CT showed 1 osteolytic hypermetabolic focal bone lesions of the right femur's upper extremity (maximum standardized uptake value [SUV_max], 4.12; metabolic tumor volume [MTV], 9.35 cm³). This lesion was starting to erode the cortical bone in axial CT-alone slice.
• At the end of cycle 1 (day 28), biochemical and metabolic responses were evaluated, wherein the 2-[¹⁸F]FDG-PET-CT scan showed several new focal bone lesions in the ribs, an increase in the intensity of 2-[¹⁸F]FDG uptake (SUV_max, 6.61), and MTV of 29.97 cm³ of the right femur's osteolytic lesion.
  • The cortical bone was completely destructed, and osteolysis extended to adjacent soft tissues.
  • Monoclonal component evaluation confirmed a very good partial response (VGPR), with a 97% decrease in involved light chains.
• At the end of cycle 3, the 2-[¹⁸F]FDG-PET-CT scan showed an aspect of complete metabolic response.
  • All previously detected focal bone lesions in the ribs had disappeared, and the intensity of 2[¹⁸F]FDG uptake and MTV of the right femur's focal bone lesions had significantly decreased, with an uptake equal to the liver background, which was a level 3 on the Deauville scale.
  • Axial CT-alone slice depicted the rebuilding of the cortical bone. Simultaneously, serum lambda free-light chain evaluation and bone marrow aspiration confirmed CR.

literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 24 July 2024.