Non-BCMA-Targeting Bispecifics in the Treatment of R/R Multiple Myeloma - Episode 2

MonumenTAL-1 and Bispecifics Under Development for The Treatment of R/R Multiple Myeloma

Dr Peter Voorhees reviews bispecifics under development and updated outcomes data from the MonumenTAL-1 trial, evaluating talquetamab in patients with R/R multiple myeloma.

Case: A 63-Year-Old Man with R/R Multiple Myeloma

Clinical Presentation:

Patient AG is a 63 y/o man.

  • PMH: Diabetes, Hypertension
  • SMH: Does not smoke or drink alcohol
  • In October 2018, AG was admitted from clinic with hypercalcemia (Ca 13.7) and anemia (Hb 10.6) after a right pathologic hip fracture.

Clinical Workup and Diagnosis:

  • Calcium: 11.7 mg/dL
  • M-protein, 2.1 g/dL
  • Hemoglobin: 11.2 g/dL
  • Elevated LDH
  • Albumin, 2.7 g/dL
  • SCr, 1.3 mg/dL
  • Bone marrow biopsy confirms 25% clonal plasma cells, FISH del(17p)
  • PET-CT confirms osteolytic bone lesions in both hips; SF diagnosed with IgG kappa multiple myeloma

Disease Relapse and Treatments:

  • AG was initiated on VRd (bortezomib, lenalidomide, and low-dose dexamethasone) in frontline setting
  • He subsequently relapsed and progressed on 3 lines of therapy including belantamab mafodotin
  • He was then enrolled in a clinical trial and started on treatment with the bispecific antibody, talquetamab following four prior lines of therapy
  • Talquetamab was started at a dose of 0.4 mg/kg every week SC

Peter Voorhees, MD: With regard to novel bispecific antibodies with new targets, there are several being evaluated in clinical trials. We know there are a lot of BCMA-targeted bispecific antibodies being evaluated. Teclistamab is the first agent to undergo accelerated approval by the FDA here in the United States. But there is a significant need for other targets beyond BCMA, and GPRC5D is one of those targets, and talquetamab is a bispecific antibody that is directed against GPRC5D. There’s also another agent that’s a bit behind in development that is a bispecific antibody directed against GPRC5D as well.

The interesting thing about GPRC5D, again, it’s a relatively plasma cell-specific marker, but it does appear to be expressed at higher levels in malignant plasma cells vs nonmalignant plasma cells, suggesting that it could potentially be somewhat more targeted against the malignant plasma cells vs the nonmalignant plasma cells. Whereas BCMA is expressed at high levels on both nonmalignant and malignant plasma cells. The other thing to recognize is that GPRC5D is expressed in hair follicles, which can explain some of the adverse effects of talquetamab that we’ll discuss later. It is also expressed in certain structures in the tongue, which may relate to some of the on-target, off-tumor adverse effects that we’ll talk about in more detail.

FCRH5 is another target that is plasma cell-specific, and there is a bispecific antibody by the name of cevostamab that is in clinical trials for patients with relapsed/refractory multiple myeloma. This is a target that seems to be preferentially expressed in plasma cells, but it is also expressed in nonmalignant plasma cells as well.

MonumenTAL-1 was a first in human phase 1 study looking at both intravenous and subcutaneous talquetamab in patients with relapsed/refractory multiple myeloma. It also had phase 2 expansion cohorts, specifically patients receiving the recommended phase 2 doses of 0.4 mg/kg subcutaneously on a weekly basis, and there was also a dosing schedule of 0.8 mg/kg subcutaneously given every other week. So, this was a study that treated very heavily pretreated patients; the median number of prior lines of therapy for patients receiving the 0.4 mg/kg weekly dose was 5. Thirty one percent of these patients had high-risk cytogenetics. Nearly a quarter of patients had extramedullary disease, and importantly, close to 75% were triple-class refractory, and 30% were penta-refractory.

The median follow-up of this study was 11 months, and importantly, in the 143 patients who were treated at the 0.4 mg/kg weekly dose, the overall response rate was 73%. The majority of these were deep responses, so very good partial responses and better were seen in 58% of patients, and complete responses and better were seen in 29% of patients. These responses occurred fairly quickly. The median time to first response was 1.2 months, and the median time to complete response was 2.1 months. The responses were durable; the median duration of response was 9.3 months, and median progression-free survival was 7.5 months, which I think is quite respectable.

The data from the 0.8 mg/kg every other week dosing schedule were also presented at the ASH [American Society of Hematology] annual meeting, demonstrating very similar overall response, depth of response, progression-free survival, duration of response. The pharmacokinetic parameters between the 2 dosing schedules were virtually superimposable, so while the follow-up in the 0.8 mg/kg every other week cohort are not quite as mature, I think early data would suggest that this is an agent that could potentially be given on an every-other-week schedule, which would be nice for patients.

Transcript edited for clarity.