A Heavily Treated Relapsed/Refractory Multiple Myeloma Patient on Talquetamab

Presentation

The patient is a 75-year-old female with a history of IgA, kappa light chain myeloma, ISS stage I with noted t(11;14), initially diagnosed in 2011. She completed induction therapy of lenalidomide, bortezomib, and dexamethasone (RVd), followed by an autologous stem cell transplant conditioned with melphalan 200 mg/m². She achieved a stringent complete response (sCR) at day 100 restaging and was started on lenalidomide maintenance. She did well for 5 years, at which time she progressed with a rise in her IgA paraprotein and noted anemia. In 2016, she went on the M13-367 clinical trial with venetoclax and dexamethasone. In 2018, her disease progressed with a new compression fracture; after leaving the trial her treatment was changed to pomalidomide, daratumumab, and dexamethasone. Restaging at that time did note 17p deletion and a BRAF mutation. She had noted progression in 2021 with chin numbness, clinically corresponding with a mass on her clivus bone. She received radiation and then started carfilzomib, cyclophosphamide, and dexamethasone.

In September 2021, the patient again showed progression with a rise in her paraprotein and PET-positive disease. She then was started on the EA-GSK-213304 clinical trial with belantamab mafodotin. She left the trial after she experienced progression with extramedullary disease, and she was started on carfilzomib and elotuzumab. Her disease continued to progress, and she was admitted for salvage chemotherapy with bortezomib in combination with dexamethasone, cyclophosphamide, etoposide, and cisplatin (V-DCEP) x2 cycles.

The patient’s disease responded to the two cycles of chemotherapy, with the plan to move forward to B-cell maturation antigen (BCMA) chimeric antigen receptor therapy (CAR-T) with idecabtagene vicleucel. She received bridging therapy with carfilzomib, selinexor, and dexamethasone, followed by lymphodepleting chemo and CAR-T, having developed grade 1 cytokine release syndrome (CRS). She achieved sCR, with minimal residual disease negative status, at day 30, though progression was seen with extramedullary disease by day 100. At that time, she was started on a clinical trial of radiation plus pembrolizumab. In August 2023, the patient’s disease again progressed, and she was started on another BCMA agent, teclistamab, with initial response and then progression with new plasmacytomas and ongoing cytopenias. In August 2023, she was given additional salvage chemotherapy to gain disease control. 

As of September 2023, the patient was non-secretory with extramedullary disease and being followed by PET/CTs. She had multiple areas of activity on PET and several palpable plasmacytomas to her scalp, mouth, and upper extremities. She had no changes in genetics on bone marrow. Other comorbidities at that time included thrombocytopenia, anemia, fatigue, and mild pain related to plasmacytomas. She remained as active as possible and had a good oral intake.

Treatment

We see cases like this in long-term myeloma patients with multiple relapses and treatment changes with less duration of response. For this particular patient, her performance status remained remarkably high, and at no point did she want to stop therapy. There is no consensus for treating relapse, especially multiply relapsed myeloma; the National Comprehensive Cancer Network (NCCN) guidelines list a variety of treatments.¹

There were many potential approaches to treatment for this patient, and we also considered and enrolled her on clinical trials when possible. At the point of this relapse in September 2023, there were really few options, and a clinical trial could not be considered due to the non-secretory status of her disease and count issues. We reviewed the case and felt that a different target was needed; talquetamab, a bispecific GPRC5D-directed CD3 T-cell engager, had been FDA-approved the month before and was now available.

The patient started talquetamab with standard ramp-up dosing in the hospital and then weekly dosing in the outpatient setting. She did well with step-up dosing, though she experienced grade 1 CRS that was managed by one dose of tocilizumab. She developed worsening pancytopenia, though her main issues had been weight loss with decreased appetite, xerostomia, dysgeusia, and dysphagia consistent with adverse events (AEs) seen on the MonumenTAL-1 clinical trial.² She also started experiencing dry, brittle, and peeling nails at around month 4 of therapy. From a disease standpoint, she has responded with improvement in PET-positive areas and no new plasmacytomas.

Patient education and collaboration with our clinical pharmacist and registered dietician has been essential. Ongoing management of side effects and frequent assessments has been another important part of the patient’s care. We have also added filgrastim for neutropenia and romiplostim for thrombocytopenia, with noted improvement in both. Our patient was also started on monthly IV immunoglobulin for infection prophylaxis.

Discussion

Talquetamab is a bispecific G protein-coupled receptor, family C, group 5, member D (GPRC5D)-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody for 28 days. The receptor is primarily expressed in plasma cells and hard keratinized tissues.^2-4 The MonumenTAL-1 trial was a phase 1/2   study performed in two parts. Safety was the major focus in part 1 and effectiveness and ongoing side effect management in part 2. The phase 1 dose escalation gave two dose options of subcutaneous (SC) talquetamab at 0.4 mg/kg weekly or 0.8 mg/kg biweekly. The overall response rate was 70% for patients receiving the drug at 0.4 mg/kg weekly, and 64% for those receiving it at 0.8 mg/kg biweekly.^3,5,6 This data was for a heavily pretreated population; about 70% of patients were penta-drug refractory, which is similar to our patient.

The phase 2 portion of the MonumenTAL-1 trial had weekly or biweekly dosing of talquetamab, with a weekly step-up dosing schedule. Step-up weekly dosing is given day 1 at 0.06 mg/kg, day 4 at 0.3 mg/kg, day 7 at full dose 0.4 mg/kg, and weekly after that. Patients receive premedication with a corticosteroid, an antihistamine, and an antipyretic for step-up dosing. The 0.8 mg/kg SC every-other-week dosing has the same step-up, with day 10 dosing at 0.8 mg/kg.^2,4

Common adverse events included CRS, which occurred in 77% and 80% of patients who received the agent 0.4 mg/kg weekly and 0.8 mg/kg biweekly, respectively. Skin-related changes and dysgeusia also occurred. All but one case of CRS was grade 1 or 2, and there was one dose-limiting grade 3 rash.

Speaking more to the safety profile, the risk of CRS was about 76%, with 57% grade 1 events. The median time to CRS onset was 27 hours, with a median duration of 17 hours. Neurotoxicity risk was 55%, with grade 3 or 4 in only about 6% of cases. The most common neurologic toxicity was headache (20%), followed by encephalopathy (15%), sensory neuropathy (14%), and motor dysfunction (10%). The most common hematologic AEs present in ≥20% of patients were anemia, neutropenia, lymphopenia, and thrombocytopenia. Skin-related events were seen in about 50-60% and nail-related events in about 50% of patients. Taste disturbances were seen in about 50% of patients.^4-6

At this point, the patient experienced grade 1 CRS, which resolved with no further issues after she received a dose of tocilizumab. She had onset of taste issues in the first month of talquetamab, with increased symptoms of dysgeusia, dysphagia, xerostomia, and diminished appetite as treatment continued. While responding to therapy, she had a 15-pound weight loss although her weight stabilized by month 4 of therapy. We have taken a multi-team approach to assessment and management of her treatment-related issues. Our registered dietician continues to work with her and her spouse on her caloric intake, with ideas on how to add supplements. She has increased her caloric intake, although her appetite remains an issue. Using an immersion blender has made it easier to eat, although she can taste little. For her dry mouth, she is trying coconut oil prior to eating, which has been helpful. She also added oil to foods. She has not had a rash, although she does now have nail issues with peeling and dry, brittle nails. She remains very fatigued, resting as needed, and otherwise remains active.  

This case is an example of a multiply relapsed myeloma patient who has had a combination of standard-of-care and clinical trial approaches. Side-effect management is essential to successfully treating patients through so many lines of therapy. The APP, clinical pharmacist, and other care team members play an essential role in mitigating and managing treatment-related toxicities.  

References

1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Multiple Myeloma. Version 2.2024, 11/01/23 © 2023. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf
2. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022;387(24):2232-2244.
3. Chari A, Askari E, Caers J, et al. Plain language summary of the MonumenTAL-1 study of talquetamab in people with relapsed or refractory multiple myeloma. Future Oncol. 2023;19(27):1823-1840.
4. Janssen Biotech, Inc. (2023). Talvey (teclistamab-cqyv) package insert. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/TALVEY-pi.pdf
5. Chari A, Touzeau C, Schinke C, et al. Talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): Phase 1/2 results from MonumenTAL-1. Blood 2022; 140 (Suppl 1):384-387. 
6. Keam SJ. Talquetamab: First approval. Drugs. 2023;83(15):1439-1445.