CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurses: 1.00 Nursing contact hour
Physicians: maximum of 1.00 AMA PRA Category 1 Credit™
Pharmacists: 1.00 contact hour (0.1 CEUs)
Released: March 07, 2024
Expiration: March 06, 2025
MonumenTAL-1 Modified Dosing: Safety and Efficacy of Talquetamab in R/R MM
Sagar Lonial, MD, FACP:
Now we will switch gears and discuss current data with the use of bispecific antibodies for patients with R/R multiple myeloma. This next section will examine updated data on a modified dosing schedule in the MonumenTAL-1 study for talquetamab, a first-in-class bispecific IgG4 antibody that binds to GPRC5D and CD3 receptors, currently approved for patients with R/R multiple myeloma.10
MonumenTAL-1 was a multicenter, phase I/II trial of talquetamab with a dose-escalation phase (part 1) and a dose-expansion phase (part 2). Phase I of this study enrolled patients who had experienced progression or intolerance to all established therapies. Phase II enrolled patients with 3 or more previous lines of therapy, including a PI, an IMiD, and an anti-CD38 antibody.
Treatment cohorts included those who received talquetamab 0.4 mg/kg subcutaneously once weekly, those who received talquetamab 0.8 mg/kg subcutaneously once every 2 weeks, and those who received prior T-cell redirection therapy and then talquetamab at either 0.4 mg/kg once weekly or 0.8 mg/kg once every 2 weeks.
The primary endpoint was ORR. Secondary endpoints included duration of response (DoR), rate of very good partial response or better, rate of CR or better, rate of stringent CR or better, time to response, PFS, OS, MRD, and safety.10 This analysis, however, focuses on the exploratory endpoint of efficacy and safety in modified dosing cohorts.
MonumenTAL-1 Modified Dosing: Prospective Cohorts Assignment
Sagar Lonial, MD, FACP:
This trial included a responsive dose reduction cohort and 2 prospective dose-reduction cohorts. The 2 prospectively designed dose-reduction cohorts permitted dose reduction following a confirmed response of PR or better and included switching from 0.8 mg/kg Q2W dosing to 0.4 mg/kg Q2W dosing or switching from 0.8 mg/kg Q2W dosing to less frequent dosing Q4W.
The responsive dose reduction cohort consisted of 50 patients who reduced their dose after a partial response or better, to mitigate AEs, or both.10 These cohorts included patients who had not received prior T-cell redirection therapy and received weekly (n = 25) or every other week dosing (n = 15) of talquetamab, as well as patients who had received prior T-cell redirection therapy (n = 10).
At the time these data were presented at ASH 2023, 24 patients were included in the prospective cohorts.10 Nineteen of those patients modified their dose after achieving a partial response or better. Nine patients reduced their dose intensity from 0.8 mg/kg to 0.4 mg/kg Q2W. Ten patients reduced the frequency of their doses from 0.8 mg/kg Q2W to 0.8 mg/kg Q4W.
MonumenTAL-1 Modified Dosing: Efficacy in TAL-Responsive, Dose-Reduction Cohorts
Sagar Lonial, MD, FACP:
In the responsive dose reduction cohort, talquetamab dose reduction typically occurred for patients who had already achieved a response, rather than solely to mitigate AEs.10 This indicates patients responded relatively quickly.
The median time to dose reduction for patients on the weekly dosing schedule was 3.2 months, and patients receiving every other week dosing had a median time to dose reduction of 4.5 months. Similarly, the median time to dose reduction for patients with prior T-cell redirection therapy was 4.7 months.
The median time to dose reduction is important because it suggests that for all the T-cell redirection therapies, whether targeting GPRC5D or BCMA, the current FDA-labeled dose may be higher than needed to elicit a response. Thus, reducing the dose and allowing T-cells to recover could be important for maintaining T-cell health, which likely will relate to long-term disease control.
Most patients who underwent a dose reduction maintained a response.10 The 12-month DoR rate for patients on weekly dosing was 78%, and 85% for patients on every other week dosing schedule. Patients with prior T-cell redirection therapy maintained a 100% 12-month DoR rate.
Despite the small numbers, these data suggest that HCPs should feel comfortable making changes in dose or schedule based on tolerability or even empirically based on individual patient responses.
MonumenTAL-1 Modified Dosing: Efficacy in Prospective Dose-Reduction Cohorts
Sagar Lonial, MD, FACP:
Overall, the efficacy demonstrated in the prospective dose reduction cohort affirms the results observed in the responsive dose reduction cohort.10 The median time to dose reduction following response was 3.1 months (range: 2.3-4.2). Responses were maintained following the dose reduction, with an ORR of 79%. At a median follow-up of 13 months, the median PFS was 13.2 months (95% CI: 8.8-not estimable) and the median DoR has not yet been reached.
These data suggest that if patients respond to treatment, they are likely to do well in the long-term and these dose reductions or modifications did not diminish the efficacy of talquetamab overall.
Now, the outstanding question is for those patients in the lower range of PFS, who are likely early progressors or nonresponders, how can we augment their response? There are a number of trials in progress with the goal of addressing this issue.
MonumenTAL-1 Modified Dosing: Safety in Prospective Dose-Reduction Cohorts
Sagar Lonial, MD, FACP:
With regards to safety in the prospective dose reduction cohorts, approximately half of skin toxicities resolved over time.10 A number of patients experienced no changes. Overall, the skin, nail, and oral toxicities all appeared to improve with dose reduction.
Many HCPs are comfortable making dose reductions among responders in order to keep patients on therapy.
LINKER-MM1 Update: Linvoseltamab in R/R MM
Sagar Lonial, MD, FACP:
Linvoseltamab is a BCMA-targeted bispecific antibody that is currently under review by the FDA and EMA for treatment of R/R multiple myeloma after 3 or more previous therapies. The open-label phase I/II LINKER-MM1 study evaluated dose reduction and modification, with the goal of maximizing the overall benefit of this approach.11
In this study, patients with active multiple myeloma received step-up dosing early on during Weeks 1 to 2, then escalated their doses to 200 mg weekly for Weeks 3 to 14.11 Frequency of dosing was then reduced to 200 mg every other week from Week 16 to Week 23. Beyond 6 months, patients who achieved a very good partial response or better reduced their dose frequency to 200 mg once a month, while patients with less than a very good partial response continued on the every other week dosing schedule.
The primary endpoint of this study was the ORR determined by blinded independent review, while the secondary endpoints were ORR per the investigators, DoR, MRD, PFS, and OS.11
LINKER-MM1 Update: Response
Sagar Lonial, MD, FACP:
For the primary outcome, the ORR per independent review was almost 70%, not dissimilar from studies of many of the other BCMA-directed bispecific antibodies.11,12 The median time to response was quick, approximately 7 months for complete remission or greater.
In the 10 patients who received prior belantamab mafodotin, the ORR was maintained at about 70%, which suggests that prior BCMA-directed antibody–drug conjugate therapy does not necessarily limit the efficacy of this drug overall.
Finally, in the 37 patients who had CR or stringent CR, approximately 50% were MRD negative at a cutoff of 10-5.
LINKER-MM1 Update: DoR and PFS
Sagar Lonial, MD, FACP:
The median PFS has not yet been reached.11 The probability of PFS at 9 months was approximately 73%, and PFS at 12 months is approximately 66%. Although the exact median has not yet been reached, these data indicate that it will be well beyond a year.
Considering the DoR, an estimated 87% of patients were still in ongoing remission at 12 months. This was impressive and suggests that linvoseltamab may be as good, if not better than many of the other BCMA-targeting bispecific antibodies.12
We need longer follow-up in the LINKER trial to understand whether these data hold up or not. However, this current analysis presents very impressive PFS benefits from treatment with linvoseltamab overall.
LINKER-MM1 Update: Adverse Events
Sagar Lonial, MD, FACP:
CRS was the most frequent AE, though the incidence of grade 3 or grade 4 CRS was very low.11 This suggests the CRS rates may be slightly lower for linvoseltamab than with other bispecific antibodies.12 However, more data, longer follow-up, and larger patient numbers are needed to confirm this conclusively.
Across the board, there was a low incidence of grade 3 or 4 AEs, which were primarily neutropenia, anemia, lymphopenia and thrombocytopenia.11 The rate of immune effector cell–associated neurotoxicity syndrome (ICANS) of any grade was approximately 7.7% and often co-occurred with CRS. Grade 3 ICANS was only observed in 3 patients.
Thirteen deaths were due to treatment-emergent AEs that occurred 30 days after the last dose.11 Ten of them were associated with infections and were deemed treatment-related, including Pneumocystis jirovecii pneumonia (PJP), and pseudomonal sepsis, highlighting that infection prophylaxis continues to be important during treatment with BCMA-bispecific antibody treatment.12
Linker-MM1 Update: Infectious Adverse Events
Sagar Lonial, MD, FACP:
Broken down here in a little bit more detail, COVID-19, pneumonia, and upper respiratory tract infections were common infectious complications.11 All cases of PJP occurred before the study protocol instituted mandatory prophylaxis.
LINKER-MM1 Update: CRS Onset, Severity, and Management With Tocilizumab
Sagar Lonial, MD, FACP:
Most CRS was categorized as grade 1 or 2, and was seen during step-up dosing.11 No grade 3 or higher CRS was seen after step-up dosing. Cases of CRS typically resolved within 1 day.
Tocilizumab was administered to 21% of patients for CRS, and recurrence was relatively uncommon. This is notable, considering that CRS was observed in 72.1% of patients receiving teclistamab, with approximately one third requiring tocilizumab (36.4%).13
At my center, to facilitate outpatient administration, every patient receives a dose of tocilizumab as preemptive therapy to reduce the incidence of complications and allow patients to receive this treatment without necessarily having to be in the hospital.
Bispecific Antibodies in R/R Multiple Myeloma: Clinical Implications
Sagar Lonial, MD, FACP:
Patients with R/R multiple myeloma who progress after multiple lines of treatment—particularly those whose disease is refractory to IMiDs, PIs, and anti-CD38 therapies—had limited treatment options prior to the approval of various immune-modifying therapy. Now, BCMA-directed CAR T-cell therapy (idecabtagene vicleucel or ciltacabtagene autoleucel), BCMA-directed bispecific therapy (teclistamab and elranatamab), and the GPRC5D-targeted bispecific antibody (talquetamab) have continued to demonstrate promising efficacy for patients with R/R multiple myeloma. They are approved for patients with R/R multiple myeloma after 4 or more prior lines of therapy, including a PI, an IMiD, and a CD38 mAb.
With the availability of these agents, we have been learning more about the optimal use of this class of drugs in clinical practice. Understanding optimal dosing with bispecific antibodies can help patients remain on therapy for improved long-term outcomes. The data on dose modifications in the MonumenTAL-1 trial are reassuring and suggest that patients who have responded well to talquetamab are likely to do well in the long term, and dose reductions or modifications do not diminish the efficacy of talquetamab overall.
As we continue to see new advances and novel agents performing well in clinical trials, such as the encouraging efficacy and safety data with linvoseltamab in LINKER-MM1, it will give patients more options for therapy and continue to provide an expanded armamentarium for combating R/R multiple myeloma.
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