As of July 19, 2021, 95 patients have received SC talquetamab. The RP2D was originally identified as a weekly SC dose of 405 µg/kg talquetamab with step-up doses. However, alternative dosing schedules that require less frequent administration continue to be investigated. A biweekly RP2D was also identified as an SC dose of 800 µg/kg talquetamab with step-up doses.

30 patients received the 405 µg/kg weekly dosing schedule (median age: 61.5 years [range 46–80]; 63% male; 100% triple-class exposed; 80% penta-drug exposed; 77% triple-class refractory, 20% penta-drug refractory; 30% prior BCMA-directed therapy; median follow-up: 7.5 mo [range 0.9–15.2]). 23 patients received the 800 µg/kg biweekly dosing schedule (median age: 60.0 years [range 47–84]; 48% male; 96% triple-class exposed; 70% penta-drug exposed; 65% triple-class refractory, 22% penta-drug refractory; 17% prior BCMA-directed therapy; median follow-up 3.7 mo [range 0.0–12.0]).

There were no treatment discontinuations due to AEs at either of the RP2Ds. The most common AEs at the 405 µg/kg weekly dose were CRS (73%; 1 patient had grade 3 CRS), neutropenia (67%; grade 3/4: 60%), and dysgeusia (60%; grade 2: 29%); skin-related AEs occurred in 77% (all grade 1/2; nail disorders: 30%) of patients, and infections occurred in 37% of patients (1 patient had grade 3 COVID-19 pneumonia). The most common AEs at the 800 µg/kg biweekly dose were CRS (78%; all grade 1/2), dry mouth (44%; all grade 1/2), and neutropenia (44%; grade 3/4: 35%); skin-related AEs occurred in 65% of patients (grade 3: 13%; nail disorders: 17%) and infections occurred in 13% of patients (1 patient had grade 3 pneumococcal sepsis).

In 30 response-evaluable patients treated with the 405 µg/kg weekly dose, the overall response rate (ORR) was 70% (very good partial response or better [≥VGPR] rate: 57%). In 17 response-evaluable patients treated with the 800 µg/kg biweekly dose, the ORR was 71% (≥VGPR rate: 53%). Responses were durable and deepened over time in both cohorts (Figure). Median duration of response (DOR) was not reached at either RP2D; the 6-month DOR rate for patients who received the 405 µg/kg weekly dose was 67% [95% CI: 41–84]. Serum trough levels of talquetamab were comparable at both RP2Ds. Consistent with the mechanism of action for talquetamab, pharmacodynamic data from cohorts treated at both dose levels showed peripheral T-cell activation and induction of cytokines.

• As of Feb 8, 2021, 174 pts received talquetamab, 102 by IV and 72 by SC; in parts 1 and 2, 28 pts were treated at the RP2D, identified as weekly SC 405 µg/kg, with 10.0 and 60.0 µg/kg step-up doses.
• Patients treated at the RP2D had a median age of 61.5 y (range 46–80) and a median of 5.5 prior lines of therapy (range 2–14; 100%/79% triple-class/penta-drug exposed; 71%/18% triple-class/penta-drug refractory; 86% refractory to last line of therapy; 21% with prior B-cell maturation antigen–directed therapy).
• No dose-limiting toxicities occurred at the RP2D in part 1.
• Most common AEs at the RP2D were:
  • CRS (79%; grade 3 4%; median time to onset: day after SC injection),
  • neutropenia (64%; grade 3/4 54%),
  • anemia (57%; grade 3/4 29%) and
  • dysgeusia (57%; all grade 1/2);
  • infections were reported in 32% of patients (grade 3/4 4%) and neurotoxicity in 7% (grade 3/4 0).
• In all, 75% of pts dosed at the RP2D had skin-related AEs (grade 3/4 0), including 18% with nail disorders.
• The overall response rate at the RP2D in response-evaluable pts (n = 24) was 63%, with 50% reaching very good partial response or better; 9/17 (53%) evaluable triple-class refractory pts and 3/3 (100%) penta-drug refractory pts had a response.
• Median time to first confirmed response at the RP2D was 1.0 mo (range 0.2–3.8); responses were durable and deepened over time (median follow-up 6.2 mo [range 2.7–9.7+] for responders at the RP2D).
• At the RP2D, exposure was maintained over the maximum EC₉₀ target level from an ex vivo cytotoxicity assay, and consistent T cell activation was seen.

As of 20 Jul 2020, 137 pts had received talquetamab; 102 by IV (0.5 – 180 µg/kg) and 35 by SC (5 – 800 µg/kg) dosing. Median age was 64 years (33 – 80; 31% were ≥70) and 22% had ISS stage III disease at study entry. Median number of prior therapies was 6 (2 – 20) over a median of 6.5 years (0.9 – 27) since diagnosis, 85% were refractory to last line of therapy, 79% triple-class refractory, 73% penta-drug exposed, and 31% penta-drug refractory. 13 (10%) pts had received selinexor and 21 (15%) had prior BCMA-directed therapy.

Most frequently reported all grade AEs were anemia (50%), CRS (47%), neutropenia (45%), and lymphopenia (40%). Most common grade 3 – 4 AEs were lymphopenia (37%), anemia (27%), and neutropenia (25%). CRS was mostly grade 1 – 2 except for 5 pts with grade 3 CRS (˂8% of pts with CRS) that occurred with IV dosing; only grade 1 – 2 CRS was seen with SC dosing. CRS was generally confined to the first cycle with median time to onset of 1 day (1 – 3) for IV and 2 days (1 – 5) for SC dosing. Treatment-related neurotoxicity was reported in 7 (5%) pts (all resolved/resolving; median duration of 2 days [1 – 9]): 4 had grade 1 – 2 events and 3 had grade 3 events of delirium (n=1), decreased level of consciousness (n=1), or confusion (n=1). Six of 7 pts had neurotoxicity that occurred in the context of CRS, including all 3 grade 3 events. Infections were reported in 37% of pts (8% grade 3 – 4). Infusion related reactions (IV; 15%) and injection site reactions (SC; 14%) were grade 1 – 2 and generally occurred in cycle 1. Two dose-limiting toxicities were observed: clinically asymptomatic grade 4 increased lipase in the setting of a pancreatic plasmacytoma (7.5 µg/kg IV) and grade 3 maculopapular rash (135 µg/kg SC). The maximum tolerated dose (MTD) has not been defined.

Overall response rate (ORR) for IV doses of 20 – 180 µg/kg was 78% (14/18; 2 pending confirmation); 6/6 responded at the 60 µg/kg IV dose. ORR for SC doses of 135 – 405 µg/kg was 67% (8/12); 3/4 responded at the 405 µg/kg SC dose. Responses were noted starting at 1.0 µg/kg, were rapid at a median of 1 month (0.2 – 3), and durable with median not reached in 36/46 (4 pts with response 15+ months; longest at 23+ months). Data at higher doses are immature, and results will be updated at the meeting.