Recommended Phase II Doses of Talquetamab in Patients With Relapsed/Refractory Multiple Myeloma From MonumenTAL‐1: Clinical Pharmacology Results

Abstract

Talquetamab is the first and only GPRC5D × CD3 bispecific antibody approved for relapsed/refractory multiple myeloma (RRMM). In the phase I/II MonumenTAL‐1 study, overall response rates (ORRs) were > 66% in patients with RRMM treated with subcutaneous talquetamab at the recommended phase II doses (RP2Ds): 0.4 mg/kg weekly and 0.8 mg/kg every other week. We characterized the pharmacokinetics (PK), pharmacodynamics, immunogenicity, and exposure‐response relationships for efficacy and safety following talquetamab administration in phase I and II. In phase I, talquetamab exposure increased in an approximately dose‐proportional manner across intravenous and subcutaneous doses and was maintained around or above the 90% maximum effective concentration identified in an ex vivo cytotoxic assay at the RP2Ds. Higher levels of T‐cell activation and cytokine induction were observed at the RP2Ds compared with lower doses. Talquetamab demonstrated time‐dependent clearance with a half‐life of 7.56 days at initial treatment and 12.2 days at steady state. Patients with immunoglobulin G multiple myeloma and International Staging System (ISS) stage II/III exhibited higher clearance of talquetamab, which resulted in lower exposure. Dose adjustment based on myeloma subtype and ISS stage was not required. In exposure‐response analyses, a near‐flat relationship was demonstrated for ORR, duration of response, and progression‐free survival at the exposure range of the RP2Ds. In safety exposure‐response analyses, rates of grade 1/2 dysgeusia increased with higher exposures. The incidence of anti‐talquetamab antibodies had no apparent impact on the PK, efficacy, or safety of talquetamab. These clinical pharmacology results support the selection of the talquetamab RP2Ds.

Study Highlights.

WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Talquetamab is a novel bispecific antibody targeting GPRC5D and CD3. In MonumenTAL‐1, overall response rates (ORRs) of >66% and clinically manageable safety were observed in patients with relapsed/refractory multiple myeloma who received the recommended phase II doses (RP2D) of talquetamab: 0.4 mg/kg weekly or 0.8 mg/kg every other week (Q2W).

WHAT QUESTION DID THIS STUDY ADDRESS?

What are the clinical pharmacology results of talquetamab in MonumenTAL‐1, and do these data quantitatively support RP2D selection and proposed change in step‐up dose schedule for the Q2W RP2D?

WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

In phase I, pharmacokinetics, pharmacodynamics, immunogenicity, and exposure‐response data supported initial selection of the talquetamab RP2Ds. The target concentration for talquetamab was maintained at both RP2Ds. Changes in pharmacodynamic markers following talquetamab were consistent with its mechanism of action. Immunogenicity had no apparent impact on the PK, efficacy, or safety of talquetamab. Exposure‐response analyses showed ORR increased with dose, plateauing at or above the RP2Ds. Across phase I and II, clinical pharmacology results confirmed selection of the RP2Ds and supported a change in step‐up dose schedule for the Q2W RP2D. Population pharmacokinetics data showed no clinically meaningful differences in talquetamab exposure based on differences in patient body weight, supporting mg/kg‐based talquetamab dosing. A near‐flat exposure‐response relationship was demonstrated for ORR at the RP2Ds. While dose was not associated with increased risk of grade ≥ 3 cytopenias or infections, increased rates of grade 1/2 dysgeusia were observed with increasing exposures.

HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Future studies providing clinical pharmacology analyses will continue to support clinical data and guide efficient drug development.

Advances in the treatment of multiple myeloma (MM) include the now‐standard options of immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti‐CD38 monoclonal antibodies (mAbs), which have notably improved patient survival. ¹ , ² However, even with these developments, patients typically relapse. ² , ³ , ⁴ , ⁵ Thus, there remains an unmet need for novel therapies that can be used following exposure to these standard therapies. The development of targeted immunotherapies for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who are triple‐class exposed (to an IMiD, PI, and anti‐CD38 mAb) has yielded B‐cell maturation antigen (BCMA)‐targeting therapies, including antibody‐drug conjugates, chimeric antigen receptor T‐cell (CAR‐T) therapies, and bispecific antibodies (BsAbs), ⁶ , ⁷ , ⁸ and more recently, a non‐BCMA targeting therapy, talquetamab. ⁹ , ¹⁰ , ¹¹ , ¹²

Talquetamab is a first‐in‐class, off‐the‐shelf, T‐cell redirecting BsAb that targets G protein‐coupled receptor family C group 5 member D (GPRC5D) on tumor cells and CD3 on T cells. ¹³ The binding of talquetamab to GPRC5D, an orphan receptor highly expressed on malignant plasma cells but with limited expression in healthy tissues, in conjunction with CD3, mediates T‐cell‐induced killing of GPRC5D‐expressing myeloma cells. ¹³ , ¹⁴ The maximum concentration associated with the 90% maximum drug effect (maximum EC₉₀) for talquetamab was identified as 353 ng/mL from an ex vivo cytotoxicity assay ¹⁵ ; this maximum EC₉₀ represents the target concentration for talquetamab now used in clinical exposure.

In the phase I/II MonumenTAL‐1 study (NCT03399799/NCT04634552), two subcutaneous (SC) recommended phase II doses (RP2Ds) were identified in phase I: 0.4 mg/kg weekly (QW) or 0.8 mg/kg every other week (Q2W), preceded by two or three step‐up doses, respectively. ⁹ , ¹⁰ Results from phase I (data cutoff January 17, 2022) showed overall response rates (ORRs) of 70% and 64% at the QW and Q2W RP2Ds, respectively. ⁹ In phase I/II (data cutoff October 11, 2023), ORRs were 74% and 69% in patients without prior exposure to T‐cell redirection (TCR) therapies (CAR‐T therapies or BsAbs) at the QW and Q2W RP2Ds, respectively. ¹⁰ In a separate phase II cohort of patients with prior exposure to TCR therapies and who received either QW or Q2W dosing, the ORR was 67%. ¹⁰ Talquetamab had a manageable safety profile, with relatively low rates of high‐grade neutropenia and severe infections, and humoral immune function was preserved. ¹⁰ , ¹⁶ The most common adverse event was cytokine release syndrome (CRS), ¹⁰ a systemic inflammatory response characterized by increased levels of inflammatory cytokines, including interleukin (IL)‐6 and interferon‐γ, consistent with CAR‐T and other TCR therapies. ⁷ , ¹⁷ , ¹⁸ , ¹⁹ Based on these data, talquetamab at 0.4 mg/kg QW and 0.8 mg/kg Q2W was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for treatment of patients with RRMM who received ≥ 4 and ≥ 3 prior lines of therapy, respectively; under both approvals, prior therapies must include an IMiD, PI, and anti‐CD38 mAb. ¹¹ , ¹²

We report the integrated analysis of pharmacokinetics (PK), pharmacodynamics, exposure‐response analyses for efficacy and safety, and immunogenicity for talquetamab across phase I and II of MonumenTAL‐1 to support the selection and registration of the RP2Ds.

METHODS

Study design

The MonumenTAL‐1 study design has been described previously ⁹ , ¹⁰ and is shown in Figure 1 . Eligible patients were aged ≥ 18 years and had measurable RRMM per International Myeloma Working Group (IMWG) criteria. ²⁰ , ²¹ In phase I, patients were required to be intolerant to or progressed on established therapies. In phase I dose escalation, designed to identify the putative RP2Ds, patients were treated with intravenous (IV) talquetamab (0.0015–0.18 mg/kg QW and 0.0005–0.00338 mg/kg Q2W) or SC talquetamab (0.005–0.8 mg/kg QW, 0.8 and 1.2 mg/kg Q2W, and 1.6 mg/kg monthly). In phase I dose expansion, designed to evaluate preliminary antitumor activity and characterize safety and tolerability at the identified RP2Ds, patients received SC talquetamab at the putative RP2Ds: 0.405 mg/kg QW (first full treatment dose preceded by step‐up doses of 0.01 and 0.06 mg/kg) on days 1, 8, and 15 of a 21‐day cycle or 0.8 mg/kg Q2W (step‐up doses of 0.01, 0.06, and 0.3 mg/kg) on days 1 and 15 of a 28‐day cycle. For operational convenience, the 0.405 mg/kg QW dose was later modified to 0.4 mg/kg QW in phase II.

Figure 1.

MonumenTAL‐1 study design. ^aFull treatment dose was preceded by a different step‐up dosing regimen. ^bThe QW SC RP2D in phase I was 0.405 mg/kg; this changed to 0.4 mg/kg in phase II for operational convenience, with similar exposure. BCMA, B‐cell maturation antigen; C _avg,4weeks, estimated average concentration during the dosing period of the first 4 weeks of full treatment doses; C _max,4weeks, estimated maximum concentration during the dosing period of the first 4 weeks of full treatment dose; E–R, exposure‐response; IV, intravenous; ORR, overall response rate; PD, pharmacodynamic; PK, pharmacokinetics; popPK, population pharmacokinetics; Q2W, every other week; Q4W, every 4 weeks; QW, weekly; RP2D, recommended phase II dose; sBCMA, soluble B‐cell maturation antigen; SC, subcutaneous; TCR, T‐cell redirection; TEAE, treatment‐emergent adverse event.

In phase II, patients without prior exposure to TCR therapies (cohort A [0.4 mg/kg QW] and cohort C [0.8 mg/kg Q2W]) or with prior exposure (cohort B [either RP2D]) were required to have received ≥ 3 prior lines of therapy that included an IMiD, PI, and anti‐CD38 mAb. Patients in phase II were also required to have an Eastern Cooperative Oncology Group performance status of 0 to 2.

Pharmacokinetics

In phase I, intensive blood samples were collected for PK analyses during talquetamab step‐up doses and cycles 1 and 3 of the first full dose; in phase II, PK sampling was sparse (Table S1 ). Talquetamab serum concentrations were measured using an internally validated electrochemiluminescence immunoassay on the MSD® platform.

PK parameters were estimated via noncompartmental analysis (NCA) using the validated computer program Phoenix™ WinNonlin® (version 8.1, Certara LP, USA). The NCA was conducted based on data from patients in phase I.

Talquetamab concentrations were also analyzed using a population PK analysis approach based on both intensive and sparse samples from phase I and II. All patients (with or without prior exposure to TCR therapies) who received ≥ 1 dose of IV or SC talquetamab and had ≥ 1 measurable talquetamab concentration were included in the population PK analysis. The PK data cutoff was April 22, 2022.

The population PK base model was selected following comparisons between several structural models, including one‐ and two‐compartment linear models, nonlinear models (Michaelis–Menten clearance alone or parallel linear and Michaelis–Menten clearances), parallel time‐independent linear clearance and time‐dependent linear clearance, and parallel time‐independent linear clearance and time‐dependent nonlinear clearances. Zero‐order or first‐order models were tested as absorption models for SC dosing. Interindividual random effects on the selected parameters modeled as log‐normal distribution were introduced and retained if their values were not close to zero and if their inclusion did not disrupt model stability. The final population PK model was evaluated with goodness‐of‐fit diagnostics and estimation‐corrected visual estimate plots.

Covariate relationships were prescreened using generalized additive modeling based on Akaike information criteria, ²² followed by univariable testing (P < 0.01), and were then tested using a stepwise covariate modeling approach ²³ with the statistical criteria of P < 0.01 for the forward addition step and P < 0.001 for the backward elimination step. All continuous covariates were included in the population PK model using a scaled structure based on either a standard value or the median value of the covariate within the population. All categorical covariates were included in the population PK model using a proportional structure with either a level specific to the categorical covariate or the most common level of the covariate as the reference level. Graphical analyses of covariate effects on key PK parameters were performed to determine if there was a remaining trend. Covariates assessed are shown in Table S2 . Body weight was included a priori in the model as a covariate for central volume and clearance because body weight has a significant effect on PK parameters for several immunoglobulin G (IgG)‐based antibodies. ²⁴ , ²⁵ , ²⁶ Covariate effects on exposure metrics at the RP2Ds were determined in subgroup analyses by simulation using the final population PK model and individual post hoc PK parameters.

A slightly different step‐up dosing schedule was included in the US FDA and EMA approval labels for talquetamab for the 0.8 mg/kg Q2W schedule ¹¹ , ¹² to ensure better consistency with the 0.4 mg/kg QW schedule. PK simulations were performed using the final population PK model and individual post hoc PK parameters to compare talquetamab exposure following the studied (0.01, 0.06, and 0.3 mg/kg) and proposed (0.01, 0.06, and 0.4 mg/kg) step‐up dosing for the 0.8 mg/kg Q2W schedule.

Pharmacodynamics

In phase I, whole blood and serum samples were collected for immunophenotyping and cytokine analyses. Immunophenotyping analysis included the evaluation of T‐cell activation and quantification of absolute counts of CD3+ and CD8+ T cells and CD19+ B cells. T‐cell activation was assessed by the proportions of CD3+ and CD8+ T cells expressing programmed cell death protein 1 (PD‐1) and CD38, respectively. Serum IL‐6, IL‐10, and IL‐2Rα concentrations were assessed at baseline (before the first step‐up dose), after step‐up doses, and after full treatment doses. Maximum fold change relative to baseline (and up to cycle 2) was evaluated for T‐cell activation and each cytokine.

Serum concentrations of soluble B‐cell maturation antigen (sBCMA), a marker of tumor burden, were measured at baseline and after treatment, for example, pre dose of cycle 2 day 1, by a validated electrochemiluminescence immunoassay on the MSD® platform. The percent change of sBCMA concentration relative to baseline was evaluated at cycle 2 day 1.

Exposure‐response analysis for efficacy and safety

Efficacy exposure‐response analyses of ORR (assessed by investigator per IMWG 2011 criteria ²¹ ) were conducted in patients who received SC talquetamab in phase I to support the selection of the RP2Ds. The exposure‐response relationship for efficacy (ORR, duration of response [DOR], and progression‐free survival [PFS]) was then examined in a pooled population of patients treated at the RP2Ds from phase I and II to confirm the RP2Ds. The combined phase I/II analyses, which excluded cohort B patients who had prior exposure to TCR therapies, were conducted in patients who either terminated early or had ≥ 3 months of follow‐up to ensure maturity of efficacy data in the ongoing study. The data cutoff was May 16, 2022. The relationship between talquetamab and ORR was evaluated by univariable and multivariable logistic regressions and graphical exploration. The logistic models assumed that the logit of the probability of an outcome/event depends on explanatory variables of interest, as follows:

$$\text{logit}\left(P_{\text{event}}\right)=\log \left(\frac{P_{\text{event}}}{1-P_{\text{event}}}\right)={\beta }_0+{\beta }_1\times X_1+{\beta }_2\times X_2+\dots {\beta }_n\times X_n$$

where P _event is the probability of a certain outcome/event (response), β ₀ is the intercept parameter, X _1…n is the explanatory variable that may be categorical or continuous, and β ₁ … _n is the estimated parameter for the impact of the ith level of the categorical covariate or the impact of the continuous covariate.

In the phase I ORR logistic regression analysis, an E _max model instead of a linear model was used. The Kaplan–Meier method was used for DOR and PFS and stratified by quartiles of estimated PK exposure metrics.

In the combined phase I/II safety exposure‐response analyses, selected endpoints included grade ≥ 3 cytopenias (anemia, leukopenia, neutropenia, lymphopenia, and thrombocytopenia), grade ≥ 3 infections, grade ≥ 2 weight loss, grade 1/2 dysgeusia, and any‐grade and grade ≥ 2 CRS, and were examined in patients who received SC talquetamab, excluding cohort B patients who had prior exposure to TCR therapies, and regardless of follow‐up duration. The data cutoff was May 16, 2022. Exposure‐response analyses for all endpoints were evaluated graphically.

Exposure metrics were derived using the individual post hoc PK parameter estimates based on the final population PK model and the actual individual dosing information. Due to the time‐varying clearance of talquetamab and potential bias to exposure‐response relationships from interactions between posttreatment effects and drug exposure, first treatment dose and first‐cycle exposure metrics were used in the analyses, including estimated average concentration during the first 4 weeks of full treatment dosing (C _avg,4weeks) and estimated trough concentration after the first full treatment dose (C _{trough,1stdose}) for efficacy, and estimated maximum concentration during the first 4 weeks of full treatment dosing (C _max,4weeks) for safety. All exposure metrics showed a high degree of correlation (correlation coefficient > 0.85). As the majority of CRS events occurred during step‐up dosing, ¹⁰ estimated maximum concentration (C _max) over the first, second, and third step‐up doses was used to assess exposure‐response relationships between talquetamab and CRS.

Immunogenicity

Baseline and selected predose serum samples were assessed for immunogenicity (Table S1 ). Anti‐talquetamab antibodies (antidrug antibodies [ADAs]) were measured using an internally validated electrochemiluminescence immunoassay on the MSD® platform to screen, titer, and confirm talquetamab specificity of antibodies in patients who received one or more doses of talquetamab and had appropriate samples for detection (i.e., patients with at least one sample obtained after the first full dose of talquetamab). The influence of immunogenicity on talquetamab exposure was evaluated by comparing PK profiles of ADA‐positive and ADA‐negative patients. The influence of immunogenicity on talquetamab efficacy (ORR) and safety (CRS, systemic administration‐related reaction, and injection‐site reaction), stratified by ADA status, was assessed.

Software

Population PK analysis was performed using nonlinear mixed‐effects modeling with the first‐order conditional estimation with interaction method using NONMEM (version 7.4.3, ICON, Hanover, Maryland, USA), facilitated within the environment of Perl‐speaks‐NONMEM (version 4.8.1). PK simulations and exposure‐response analyses for efficacy and safety were performed using R software (version 4.0.3 or higher, R Core Team, Vienna, Austria).

Ethics statement

The MonumenTAL‐1 study protocol and amendments were approved by each site's Institutional Review Board. MonumenTAL‐1 was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with the Good Clinical Practice guidelines of the International Council for Harmonization. All patients provided informed written consent.

RESULTS

Initial RP2D selection

In phase I, talquetamab exposure increased in an approximately dose‐proportional manner across the escalating range of first and repeated talquetamab doses (Figure S1 ). The target concentration for talquetamab (the maximum EC₉₀, 353 ng/mL) was achieved at both RP2Ds (Figure S2 ); lower doses failed to maintain concentrations above the maximum EC₉₀ and showed lower ORRs compared with the RP2Ds. Detailed PK parameters at each RP2D are summarized in Table S3 . A positive exposure‐response relationship between ORR and C _avg,4weeks was observed, with ORR increasing with higher talquetamab exposure across SC doses below the RP2Ds and reaching a plateau at or above the RP2Ds (Figure 2 ). Changes in pharmacodynamic markers following talquetamab were consistent with its mechanism of action; higher induction of T‐cell activation markers (CD38 and PD‐1) at both RP2Ds was observed compared to cohorts receiving lower talquetamab doses (Figure S3 ). Patients with deeper responses to talquetamab showed greater reduction in sBCMA levels than patients with minimal responses (Figure S4 ). These data supported initial RP2D selection.

Figure 2.

Exposure‐response relationship between ORR and estimated C _avg,4weeks, in patients who received SC talquetamab in phase I. Error bars represent the 95% CI of ORR in the respective exposure quartile groups. Vertical lines represent quartiles. Shaded areas of the logistic regression plots represent the 95% CIs of the estimated ORR. Doses below the RP2Ds (< RP2D) are: 0.005, 0.015, 0.045, and 0.135 mg/kg QW. Doses above the RP2Ds (> RP2D) are: 0.8 mg/kg QW, 1.2 mg/kg Q2W, and 1.6 mg/kg Q4W. Observed probability of ORR in each quartile is as follows: quartile 1 (mainly composed of < RP2D doses, with a median concentration of 310 ng/mL, < 353 ng/mL of maximum EC₉₀), 30.3%; quartile 2 (median concentration of 1,327 ng/mL), 78.1%; quartile 3 (median concentration of 1,940 ng/mL), 69.7%; quartile 4 (median concentration of 3,421 ng/mL), 60.6%. In total, of 134 patients in phase I, 131 were included in the exposure‐response analysis (3 patients had missing exposure metrics and/or nonevaluable efficacy response). C _avg,4weeks, estimated average concentration during the dosing period of the first 4 weeks of full treatment doses; ORR, overall response rate; Q2W, every other week; Q4W, every 4 weeks; QW, weekly; RP2D, recommended phase II dose; SC, subcutaneous.

Population PK analyses and covariate effects

The final population PK dataset included 5,354 records of measurable serum talquetamab concentrations from 492 patients (100 patients received IV talquetamab and 392 patients received SC talquetamab); baseline characteristics of these patients are shown in Table S4 .

The final population PK model was a two‐compartment model with sequential zero‐ and first‐order absorption and parallel linear time‐independent clearance and linear time‐dependent clearance (Figure S5 ). Covariates and parameter estimates are shown in Tables S2 and S5 , respectively. Estimation‐corrected visual checks confirmed that the final model adequately described talquetamab PK (Figure S6 ).

Simulations at the RP2Ds were performed to assess talquetamab concentration‐time profiles. Steady state (defined as 90% of steady‐state concentration) was reached at week 16 for both RP2Ds (data not shown). The median terminal‐phase half‐life was 7.56 days at initial treatment and 12.2 days at steady state. The decline of time‐dependent clearance with time is likely due to the decrease in tumor burden or target level, disease severity, or improvement of cancer‐related cachexia as a result of talquetamab treatment, similar to what has been shown with nivolumab, ²⁷ teclistamab, ²⁸ and daratumumab. ²⁹ Both RP2Ds maintained a C _trough around or above the maximum EC₉₀ of 353 ng/mL (Figure 3 a ), consistent with the observed data (Figure S2 ). The overlapping concentration‐time profiles and maintenance of C _trough around or above the maximum EC₉₀ may explain the similar ORRs observed for the two RP2Ds.

Figure 3.

Simulated talquetamab serum concentration‐time profiles at (a) RP2Ds and (b) following two step‐up schedules for 0.8 mg/kg Q2W SC talquetamab. The solid line represents the median, and the shaded region represents the 90% estimation interval. EC₉₀, concentration associated with the 90% maximum drug effect; max, maximum; QW, weekly; Q2W, every other week; RP2D, recommended phase II dose; SC, subcutaneous.

The model‐estimated individual C _avg,4weeks across key clinical patient subgroups are shown in Figure 4 for the 0.8 mg/kg Q2W RP2D. The observed trend was similar for the exposure metrics tested (C _avg,4weeks, C _{trough,1stdose}, and C _max,4weeks) for each RP2D, as well as between the RP2Ds. No clinically meaningful differences (< 20%) in exposure to talquetamab were observed based on body weight. C _avg,4weeks values were approximately 100% higher (two‐fold) in patients with non‐IgG vs. IgG MM and approximately 30% lower in patients with International Staging System (ISS) stage II or III vs. I. Mild or moderate renal or hepatic impairment had no clinically meaningful effect on PK ¹¹ , ¹² ; all other covariates tested, encompassing demographic characteristics (e.g., sex), intrinsic factors (e.g., baseline creatinine clearance), biomarkers (e.g., baseline total T cells), prior treatment status (e.g., prior use of daratumumab), and others (e.g., ADAs) (Table S2 ), also had no clinically meaningful effect on talquetamab exposure.

Figure 4.

Subgroup analysis of the estimated average concentration during the dosing period of the first 4 weeks of treatment full doses (C _avg,4weeks) at 0.8 mg/kg Q2W SC RP2D. Solid red circle represents geometric mean ratio, and error bar represents 95% CI. Dashed black line represents reference value of 1, and associated numeric values are shown in the right‐hand column. The shaded gray area spans ratios of 0.8 and 1.25. Analyses assumed that all patients who were included in the PK analyses received talquetamab SC dosed at RP2D 0.8 mg/kg Q2W SC preceded by three step‐up doses of 0.01, 0.06, and 0.3 mg/kg on days –6, –4, and –2, before the first full treatment dose on day 0. ^a Other (for race), Asian and other races. ^b Hepatic impaired, hepatic mild, and moderate functions. ^c Immune response refers to patients with at least one positive ADA measurement; all others refer to patients with all negative ADAs or missing ADA data. ADA, antidrug antibody; Afr Am, African American; C _avg,4weeks, estimated average concentration during the dosing period of the first 4 weeks of full dose treatment; CRCL, creatinine clearance; CRS, cytokine release syndrome; C _avg, estimated average concentration; ECOG PS, Eastern Cooperative Oncology Group performance status; IgG, immunoglobulin G; ISS, International Staging System; MDRD, modification of diet in renal disease; PK, pharmacokinetics; Q2W, every other week; RP2D, recommended phase II dose; SC, subcutaneous.

Dose confirmation based on exposure‐response analysis for efficacy at the RP2Ds

The exposure‐response relationship was examined for ORR at the RP2Ds in patients who had not previously received TCR therapy and who had ≥ 3 months of follow‐up (n = 254). The results showed a near‐flat exposure‐response relationship between ORR and talquetamab exposure for both RP2Ds (Figure 5 a ). Multivariable analyses identified only MM subtype and extramedullary plasmacytomas (but not PK exposures) as having the potential to impact ORR (Table S6 ); further analyses showed that exposures were not related to ORR within each category of MM subtype (Figure S7 ) or extramedullary plasmacytoma group. No dose adjustment was required based on IgG vs. non‐IgG subtype.

Figure 5.

Exposure‐response relationship for (a) RP2D ORR vs. estimated C _avg,4weeks and (b) DOR and (c) PFS stratified by estimated C _avg,4weeks and C _{trough,1stdose} quartiles in patients treated with RP2Ds with ≥ 3 months of follow‐up. Error bars represent the 95% CI of ORR in the respective exposure quartile groups. Shaded areas of the logistic regression plots represent the 95% CI of the estimated ORR; n = 254 total RP2Ds with 3‐month follow‐up; n = 242 included in exposure‐response analysis; and n = 12 patients with missing exposure metrics and/or were not evaluable for the efficacy‐response relationship. CAR‐T, chimeric antigen receptor T‐cell; C _avg,4weeks, estimated average concentration during the dosing period of the first 4 weeks of full dose treatment; C _TAUFD1, estimated trough concentration after the first full treatment doses (C _{trough,1stdose}); DOR, duration of response; IgG, immunoglobulin G; IRC, independent review committee; ORR, overall response rate; PFS, progression‐free survival; Q2W, every other week; QW, weekly; RP2D, recommended phase II dose.

Kaplan–Meier curves for DOR and PFS with C _avg,4weeks and C _{trough,1stdose} showed overlapping CIs and a plateaued relationship between talquetamab exposure and DOR and PFS at the RP2Ds (Figure 5 b,c ).

Exposure‐response analysis for safety

Across phase I and II (n = 365 patients), no significant safety exposure‐response trends were observed for grade ≥ 3 cytopenias, grade ≥ 3 infection, or grade ≥ 2 weight loss (Figure 6 a ). A trend of increased incidence with increasing exposure was observed for grades 1 and 2 dysgeusia (Figure 6 b ); dysgeusia incidence rates were comparable between the RP2Ds (0.4 mg/kg QW, 66.7% [n = 14/21]; 0.8 mg/kg Q2W, 58.3% [n = 21/36]). The exposure‐response relationships between CRS events (any‐grade CRS and grade ≥ 2 CRS) and talquetamab C _max at each step‐up dose were not significant in the quartile analysis (Figure S8 ). Talquetamab exposure at each step‐up dose was comparable in patients with or without CRS events, consistent with the quartile analysis and indicating no exposure‐response relationships.

Figure 6.

Exposure‐response relationship for (a) selected safety endpoints and (b) dysgeusia by estimated C _max,4weeks exposure quartiles. Error bars show 95% CIs of adverse event occurrence rates in the respective exposure quartile groups. C _max,4weeks, estimated maximum concentration during the first 4 weeks of full treatment doses.

Immunogenicity at the RP2Ds

In phase I, ADA‐positive and ADA‐negative patients had comparable talquetamab exposures (Figure S9 ). Across phase I and II analyses, the presence of ADAs generally had no apparent impact on the efficacy or safety of talquetamab at the RP2Ds (Table 1 ).

Table 1.

Summary of immunogenicity vs. efficacy and safety in patients who received talquetamab at the RP2Ds

		Phase I and phase II RP2Ds
		0.4 mg/kg QW		0.8 mg/kg Q2W
		ADA‐negative	ADA‐positive	ADA‐negative	ADA‐positive
	All treated patients, n	98	40	98	24
Efficacya	ORRb n (%)	70 (71.4)	34 (85.0)	62 (63.3)	18 (75.0)
Safetyc	CRS, n (%)	81 (82.7)	29 (72.5)	74 (75.5)	18 (75.0)
	sARR, n (%)	2 (2.0)	2 (5.0)	4 (4.1)	0
	ISR, n (%)	13 (13.3)	6 (15.0)	8 (8.2)	5 (20.8)

Percentages are calculated with the number of all treated patients in the immunogenicity analysis set as the denominator.

ADA, treatment‐emergent antidrug antibody; CRS, cytokine release syndrome; IMWG, International Myeloma Working Group; IRC, independent review committee; ISR, injection‐site reaction; ORR, overall response rate; RP2D, recommended phase II dose; sARR, systemic administration‐related reaction; SC, subcutaneous.

^a Efficacy was assessed in patients who had received at least one dose of talquetamab, had undergone at least one postbaseline disease assessment, and had a response that could be evaluated.

^b Response and progression were assessed by IRC based on IMWG consensus criteria (2016) in patients who received the RP2Ds in phase I and II.

^c Safety was assessed in patients who had received at least one dose of talquetamab.

Simulations to support the change of step‐up dose schedule

Simulations were also conducted to compare talquetamab exposure at the studied step‐up dose schedule (0.01, 0.06, and 0.3 mg/kg) with the proposed step‐up dose schedule (0.01, 0.06, and 0.4 mg/kg) for the 0.8 mg/kg Q2W RP2D, as included in the US FDA and EMA approval labels for talquetamab. ¹¹ , ¹² The studied and proposed step‐up dose schedules demonstrated comparable talquetamab exposure (Figure 3 b ), supporting the change in the third step‐up dose for the 0.8 mg/kg Q2W RP2D from 0.3 to 0.4 mg/kg to ensure better consistency with the 0.4 mg/kg QW dosing schedule.

DISCUSSION

We described the PK, including population PK, pharmacodynamics, and immunogenicity of talquetamab and exposure‐response relationships for efficacy and safety in patients with RRMM enrolled in the phase I/II MonumenTAL‐1 study. Population PK and exposure‐response analyses are often used to guide drug development and support dose schedule selection. ³⁰ , ³¹ , ³² The talquetamab 0.4 mg/kg QW SC dose was initially identified as the RP2D based on PK, pharmacodynamics, safety, and efficacy data in the phase I dose escalation portion of MonumenTAL‐1, and the 0.8 mg/kg Q2W SC dose was then also chosen based on comparable PK and clinical outcomes as the 0.4 mg/kg QW RP2D and a more convenient dosing schedule. The data reported here supported the selection of both RP2Ds. The change in the step‐up dosing schedule for talquetamab 0.8 mg/kg Q2W to 0.01, 0.06, and 0.4 mg/kg prior to the first full treatment dose was supported by the comparable exposure and lack of an exposure‐response relationship for CRS. More importantly, based on clinical data from MonumenTAL‐1, the rate of CRS at the first treatment dose (0.4 mg/kg) in the 0.4 mg/kg QW cohort (27%) was lower than that at the third step‐up dose (0.3 mg/kg) in the 0.8 mg/kg Q2W cohort (36%). ¹⁰ Together, these data supported the approval of the talquetamab RP2Ds for use in patients with triple‐class exposed RRMM. ¹¹ , ¹²

The population PK model included body weight, MM subtype (IgG vs. non‐IgG) and ISS stage (I vs. II or III) as important covariates with the potential to affect talquetamab PK. Body weight can significantly affect the PK of mAbs and BsAbs, including teclistamab ²⁴ , ²⁵ , ²⁶ (another T‐cell redirecting BsAb approved for the treatment of RRMM, which targets BCMA). ³³ , ³⁴ As such, the final population PK model included the effect of body weight on total clearance at time 0 (CL₀) and volume of distribution of the central compartment. However, as the data described here show, no clinically meaningful differences (i.e., < 20%) in talquetamab exposure were observed based on differences in body weight. Due to conservative considerations of variability of body weight on safety aspects of T‐cell redirecting BsAbs, including talquetamab, mg/kg‐based talquetamab dosing was selected as the better benefit–risk option over flat dosing. The disease state variables, MM subtype (IgG vs. non‐IgG) and ISS stage (I vs. II or III), were also included in the final model for CL₀. Similar to talquetamab, higher elimination rates (or lower PK exposures) have been observed in IgG MM vs. non‐IgG MM patients receiving teclistamab, ²⁸ isatuximab, ³⁵ and daratumumab. ³⁶ Patients with ISS stage II or III had higher CL₀ than patients with ISS stage I, indicating that disease severity and health status could affect talquetamab PK, consistent with the time‐varying PK. The final exposure‐response model for efficacy included only MM subtype and extramedullary plasmacytoma as significant covariates, but not PK metrics. IgG MM had lower talquetamab exposure and lower ORR than non‐IgG MM. However, similar to non‐IgG MM, there was no apparent exposure‐response relationship for ORR at the RP2Ds for IgG MM. No dose adjustment was required.

In phase I, the target talquetamab concentration of 353 ng/mL (the maximum EC₉₀ identified in an ex vivo cytotoxic assay) ¹⁵ was achieved at both RP2Ds, but not at lower SC doses, which also showed lower ORRs than the RP2Ds. A similar approach was used to support the identification of the RP2D for teclistamab, indicating that this target concentration based on the maximum EC₉₀ has the potential to guide RP2D selection for T‐cell redirecting therapies in hematologic malignancies. ³⁷ A positive exposure‐response relationship was observed between ORR and talquetamab exposure, and the ORR reached a plateau at or above the RP2Ds. The exposure‐response relationship for ORR was relatively flat at the RP2Ds, indicating that patients were at an optimal exposure for ORR. Previously published results utilizing a mechanism‐based quantitative systems pharmacology (QSP) approach support the exposure‐response analysis above, demonstrating that the RP2D reached or was close to the maximum ORR observed with talquetamab, but was not too high to limit trimer formation. ³⁸ DOR and PFS showed similar trends as the ORR data, indicating that there was no obvious exposure‐response relationship among the quartiles. The simulations confirmed that talquetamab concentrations at both RP2Ds were maintained around or above the maximum EC₉₀. Together with the near‐flat exposure‐response relationships for efficacy, these data suggest that the talquetamab RP2Ds provide sufficient exposures for efficacy.

Exposure‐response analyses for selected safety endpoints in phase I and II showed that the talquetamab RP2Ds were not associated with an increased risk of grade ≥ 3 cytopenia or infection or grade ≥ 2 weight loss. A positive exposure‐response relationship was observed for grade 1/2 dysgeusia; incidence rates were similar at both RP2Ds, as expected from comparable talquetamab exposures. Dysgeusia, a taste disorder, is a commonly reported adverse event associated with GPRC5D‐targeting therapies. ⁹ , ¹⁰ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² In MonumenTAL‐1, while the majority of patients reported dysgeusia, events were manageable with supportive care and dose modifications. ⁹ , ¹⁰ , ⁴¹ , ⁴² , ⁴³ The underlying mechanism for taste changes is not yet fully understood, although GPRC5D is expressed in the filiform papillae of the tongue, which are keratinized structures that lack taste receptors. ⁹ , ¹⁴ In addition, high rates of CRS are commonly observed following administration of CAR‐T and other TCR therapies, including talquetamab. ⁷ , ⁹ , ¹⁰ , ¹⁸ , ¹⁹ However, the exposure‐response analysis showed no correlation of any‐grade CRS or grade ≥ 2 CRS with talquetamab exposure in MonumenTAL‐1. Neither the probability of a patient experiencing a CRS event nor CRS severity was associated with peak talquetamab exposure at any step‐up or full treatment dose. Overall, the exposure‐response analyses of selected safety endpoints did not identify any safety concerns with either talquetamab RP2D.

By binding to GPRC5D on MM cells and to CD3 on T cells, talquetamab induces T‐cell activation and killing of GPRC5D‐expressing MM cells. ⁹ , ¹⁰ , ¹³ The observed changes in pharmacodynamic markers following talquetamab treatment in phase I were consistent with this mechanism of action. Higher induction of T‐cell activation markers (CD38 and PD‐1) at both RP2Ds was observed when compared with cohorts receiving lower doses of talquetamab. In preclinical studies, induction of pro‐inflammatory cytokines was indicative of talquetamab‐mediated T‐cell activation. ¹³ , ¹⁵ Induction of cytokines, such as IL‐6, is in line with the preclinical data and the proposed mechanism of action of talquetamab.

Patients with deeper responses to talquetamab showed a more marked decrease in sBCMA levels than patients with minimal responses. These findings are aligned with a previous report in which baseline sBCMA levels correlated with tumor burden, and changes in sBCMA levels correlated with clinical activity in patients with RRMM. ⁴⁴ Taken together, these observations may support the use of sBCMA as a potential marker of response following talquetamab treatment.

In the current analysis, the presence of ADAs had no apparent impact on the PK, efficacy, or safety of talquetamab. However, as only small numbers of ADA‐positive patients were included, immunogenicity data are being collected in all clinical studies of talquetamab to further evaluate these findings.

In conclusion, clinical pharmacology results from MonumenTAL‐1 support the selection of the two talquetamab RP2Ds and eventual approved doses of 0.4 mg/kg QW (preceded by step‐up doses of 0.01 and 0.06 mg/kg) and 0.8 mg/kg Q2W (preceded by step‐up doses of 0.01, 0.06, and 0.4 mg/kg) for the treatment of patients with RRMM.

Funding

Johnson & Johnson.

Conflicts of interest

J.G., J.Z., D.V., B.H., T.J.M., T.R., C.H., C.K., N.H.‐B., and D.O. are employed by Johnson & Johnson and have stock/other ownership interests in Johnson & Johnson. D.Y. is employed by Johnson & Johnson, has stock and other ownership interests in AstraZeneca, Johnson & Johnson, and Moderna Therapeutics, and reports intellectual property of biological agent‐exosome compositions and uses thereof. X.M. was employed by Johnson & Johnson at the time of the analysis and has stock/other ownership interests in Johnson & Johnson. J.T. is employed by Johnson & Johnson, has stock/other ownership interests in Johnson & Johnson, and has received research funding from Johnson & Johnson. M.N.S. is employed by Johnson & Johnson, has stock and other ownership interests in Johnson & Johnson, has received research funding from Johnson & Johnson, and has patents, royalties, or other intellectual property with Johnson & Johnson. S.G. was employed by Johnson & Johnson at the time of the analysis, has stock/other ownership interests in Johnson & Johnson, and has patents with Johnson & Johnson. J.B. has received research funding from 2 Seventy Bio, AbbVie, Amgen, Bristol Myers Squibb, C4 Therapeutics, Caribou Biosciences, CARsgen, Cartesian Therapeutics, Celularity, CRISPR Therapeutics, Fate Therapeutics, Genentech, GSK, Ichnos Sciences, Incyte, Johnson & Johnson, Juno Therapeutics, K36 Therapeutics, Karyopharm, Lilly, Novartis, Poseida, Roche, Sanofi, and Takeda, is a consultant for AstraZeneca, Bristol Myers Squibb, Caribou Biosciences, Galapagos, Johnson & Johnson, K36 Therapeutics, Kite Pharma, Legend Biotech, Pfizer, Roche, Sanofi, Sebia, and Takeda, and has received honoraria from Johnson & Johnson. A.K. reports a consulting/advisory role for Celgene, GlaxoSmithKline, Johnson & Johnson, Oncopeptides, Pfizer, and Regeneron; has served in a leadership role for Sutro Biopharma; has served on speakers' bureaus for Amgen, Celgene, and Takeda; has stock/other ownership interests in BMS; and has received research funding from Johnson & Johnson.

Author contributions

J.G., J.Z., D.Y., X.M., D.V., B.H., T.J.M., J.T., T.R., C.H., C.K., M.N.S., S.G., N.H.‐B., J.B., A.K., and D.O. wrote the manuscript; J.G., J.Z., D.Y., X.M., D.V., B.H., T.J.M., J.T., T.R., C.H., C.K., M.N.S., N.H.‐B., J.B., A.K., and D.O. designed the research; J.G., J.Z., D.Y., X.M., D.V., B.H., T.J.M., J.T., T.R., C.H., C.K., M.N.S., N.H.‐B., J.B., A.K., and D.O. analyzed the data; J.G., J.Z., D.Y., X.M., M.N.S., and S.G. contributed analytical tools.

Supporting information

Data S1