In the first article of a 2-part series, Amrita Krishnan, MD, discusses the two recent trials that show talquetamab’s promise for the treatment of patients with advanced multiple myeloma.
A 74-year-old woman was diagnosed with stage II IgG-λ multiple myeloma in 2017 and initially underwent triplet therapy of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone as induction therapy then had an autologous stem cell transplant. The patient achieved a very good partial response (VGPR) for 2 years. The patient first relapsed in 2019 and came back to her physician with complaints of mid back pain, constipation, and intermittent episodes of paresthesia in her upper extremities. She underwent 28-day treatment of daratumumab (Darzalex), carfilzomib (Kyprolis), and dexamethasone (DKd) and saw a decrease in her platelet count to 140 x 109/L from 160 x 109/L seen in 2017.
Eight months later in May of 2020, she relapsed again and reported more pain. Fluorescence in situ hybridization was positive for MYC translocation and she was given a third-line therapy of primary ciliary dyskinesia and had a partial response with minor reductions in her hemoglobin levels and platelet count. However, she experienced a third relapse in June 2021 and further uptake noted at L1-L3 and new soft tissue lesions on left seventh and eighth ribs was found in another fluorodeoxyglucose PET/CT scan. Along with radiotherapy, she was given 4 cycles of selinexor (Xpovio), bortezomib, and dexamethasone (SVd), but still relapsed with high B-cell maturation antigen levels at 67%. Chrimeic antigen receptor (CAR) T-cell therapy was declined due to deteriorating renal cell function.
Talquetamab (Talvey) was initiated after the fourth relapse and step-up dosing was initiated every 3 days and 0.8 mg/kg given every 2 weeks until disease progression or unacceptable toxicity. She achieved a VGPR on therapy and had a mild rash. At a 12-month follow-up, she maintained her response without progressive disease or a reduction in CD19 B-cells. She is continuing the full dose of talquetamab every 2 weeks.
Targeted OncologyTM: What was the design and responses of the phase 1 MonumenTAL trial (NCT03399799) looking at talquetamab in patients with relapsed/refractory multiple myeloma?
Krishnan: This was the phase 1 study with step-up dosing, which is a little confusing, because there's a weekly and then there's and every 2 weeks [treatment] scheduling and the step-up dosing is a little bit different for every 2 weeks vs the weekly dosing.1 Prior use of BCMA therapy was allowed, [but these patients were intolerant to other therapies].
The most active dose either weekly or every other week had 68% and 72% overall response rates, [respectively], with over 50 patients in each group having a VGPR or better.1 Initially, they started out with [giving it intravenously (IV)] in the trial, and then they got rid of the IV. Most of these bispecific antibody therapies all had an IV formulation that they abandoned.
What were the adverse events (AEs) seen on this trial?
Hematology toxicity is common with [talquetamab and] most of these kinds of drugs. You tend to get self-limited neutropenia and we tend to use a lot of growth factor support to keep people on [the treatment]. About 76% experienced cytokine release syndrome [CRS] at grade 1 in the weekly group [and about 79% experienced it in the twice weekly group], but only 3% of patients got grade 3 CRS...so most people are getting mild CRS.1
In the every 2 week [dosing] group, CRS most mostly grade 1 with about 10% to 20% [of patients] with grade 2 CRS. Tocilizumab [Actemra] was given to patients on this study, with 63% patients [in the 405 μg/kg twice weekly group] getting tocilizumab. We tend to use it at even grade 1 CRS...someone could argue we overreact [when needing to use this], but we'd rather do it early and not progress to higher grade CRS.1
What data suggest combining talquetamab with daratumumab could be effective?
The phase 1 TRiMM-2 study [NCT04108195] allowed [patients who had a] prior CD38 antibody if it was given over 90 days [before trial enrollment]. Patients could also be refractory to prior daratumumab, which was the key part because they also had a lot of patients [on the trial] who had prior different bispecifics. For example, we had many patients on TRiMM who had prior teclistamab-cqyv [Tecvayli], but this [trial] was the only way they could get talquetamab at that point. The talquetamab dosing was either weekly or biweekly.2
[At first], I was a skeptic of this combination approach, but the ORR [in the step-up dosing bi-weekly group] was about 85%, so it was a pretty robust response. Some of these patients had prior CAR T-cell therapy, and the ORR in patients with prior T- cell redirection therapy was about 65% [in the weekly group], even going up to about 80% with every 2-week dosing [group]. This trial had a small number of patients, but it was promising and suggested that if even if the patient had a prior bispecific antibody therapy, this [combination] could be an option for them.2
1. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-Cell-Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma. N Engl J Med. 2022 Dec 15;387(24):2232-2244. doi: 10.1056/NEJMoa2204591
2. Dholaria BR, Weisel K, Manteos MV, et al. Talquetamab (tal) + daratumumab (dara) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Updated TRIMM-2 results. J Clin Oncol. 2023;41(suppl 16):8003. doi:10.1200/JCO.2023.41.16_suppl.8003