Shaji Kumar, MD:
Venetoclax is a targeted small-molecule BCL2 inhibitor that has been studied in several hematological malignancies. In R/R MM, the combination of venetoclax and dexamethasone resulted in a response in approximately one half of patients with translocation (11;14). Preclinical work and phase I trials suggested a synergistic effect with the addition of bortezomib, which could increase the efficacy of venetoclax. Based on these data, the BELLINI trial was initiated.

BELLINI was a randomized phase III trial that enrolled patients with R/R MM after 1-3 previous lines of therapy, which was not refractory to PI therapy (N = 291). Patients enrolled in this trial received bortezomib 1.3 mg/m² and dexamethasone 20 mg with or without venetoclax 800 mg.^20,21 The initial results of this study demonstrated that venetoclax plus Vd provided a significant improvement in PFS vs Vd alone, but it also was associated with more early deaths in the unselected patient population. A subset analysis in patients with translocation (11;14) or high BCL2 expression showed improved PFS without an increase in mortality, suggesting that this may be an effective therapy for this subset of patients.²⁰

The final OS analysis of the BELLINI trial was reported at ASH 2021, with almost 4 years of follow-up data, in a variety of different subgroups.²¹

Shaji Kumar, MD:
Patients in the 2 arms were fairly balanced in terms of age, sex, disease stage, cytogenetic profile, prior exposure to PIs and IMiDs and prior lines of therapy. This trial enrolled patients with 1-3 previous lines of therapy, and approximately 45% of the patients had only 1 previous line of therapy. The current analysis focused on the high-risk patients with translocation (11;14) and high BCL2 expression (using quantitative polymerase chain reaction).

Shaji Kumar, MD:
Results after the longer median follow-up of 45.6 months, support the earlier findings. PFS was significantly improved with the addition of venetoclax to Vd (median PFS: 23.4 months) vs placebo plus Vd (median PFS: 11.4 months), with HR of 0.58 (95% CI: 0.43-0.78; P = .0003). The median OS has not yet been reached for either arm, but there was a decrease in OS early with the addition of venetoclax to Vd. This seems to level out with longer follow-up, and OS appears similar at approximately 40 months.

Shaji Kumar, MD:
Two subgroups that might benefit most from venetoclax have been identified as patients with t(11;14) and high BCL2 expression. For patients with t(11;14), there was significant improvement in PFS with the addition of venetoclax (median PFS: 36.8 months) compared with placebo (median PFS: 9.3 months), with HR of 0.12 (95% CI: 0.03-0.44; P = .0014). Although this subgroup had only 35 patients, the HR was noteworthy. The addition of venetoclax had no significant impact on OS in this subgroup; however, there were only 4 events in the venetoclax arm and 5 in the placebo arm. The HR for OS was 0.61 (95% CI: 0.16-2.32; P = .4654) for patients with t(11;14).

Shaji Kumar, MD:
A similar finding was reported in patients with high BCL2 expression (about 30% of all patients in the study). The analysis revealed improved PFS with the addition of venetoclax (median: 30.1 months) compared with placebo (median: 9.9 months), with HR of 0.37 (95% CI: 0.21-0.64; P = .0005) and OS that trended in favor of venetoclax (HR: 0.70; 95% CI: 0.32-1.51; P = .3624).

Shaji Kumar, MD:
Comparing patients with either t(11;14) or high BCL2 subgroups by cytogenetic risk level showed improved PFS with the venetoclax treatment for patients with either standard-risk or high-risk cytogenetics. In patients with t(11;14) or high BCL2 subgroups and standard-risk cytogenetics, the median PFS was 34.3 months with the addition of venetoclax vs 9.9 months with Vd alone (HR: 0.33; 95% CI: 0.19-0.58; P = .0001). In patients with t(11;14) or high BCL2 subgroups and high-risk cytogenetics, the median PFS was 22.4 months with the addition of venetoclax vs 9.5 months with Vd alone (HR: 0.23; 95% CI: 0.04-1.21; P = .0819). This is important because patients with t(11;14) and high BCL2 expression often have multiple high‑risk cytogenetic features like 1q amplification or 17p deletion. Despite the smaller numbers in this analysis, these results suggest that venetoclax maybe an option for this subgroup of patients.

Shaji Kumar, MD:
The depth of response was significantly improved with the addition of venetoclax to Vd, particularly for patients with t(11;14) and those with high BCL2 expression. The rate of those patients achieving a very good partial response or better with the addition of venetoclax to Vd vs placebo plus Vd were improved in the overall population (63% vs 40%; P = .0004), in patients with t(11;14) (80% vs 27%; P = .0050), and in patients with high BCL2 expression (77% vs 31%; P < .0001). Similar trends were also seen with the rate of CR or better and the rate of MRD negativity.

Shaji Kumar, MD:
The overall rate of AEs was similar with or without the addition of venetoclax, with the exception of a slight increase in gastrointestinal toxicities, primarily diarrhea and nausea. When looking more closely at the incidence of infections, there were no additional treatment-emergent deaths with this longer follow-up period. Overall, there were 7 treatment-emergent deaths with the addition of venetoclax vs 2 treatment-emergent deaths with Vd alone, and 5 of those 7 deaths in the venetoclax arm were due to infection. Most of the early deaths were limited to patients who did not have a t(11;14), had low BCL2 expression, and also often had high‑risk cytogenetics.

Shaji Kumar, MD:
With the understanding that the combination of venetoclax plus Vd may not be the best approach for venetoclax-based therapy, additional studies have explored other combination approaches.

An ongoing phase I/II study has explored various combinations of venetoclax with daratumumab and dexamethasone, with or without bortezomib. In part 3 of this study, presented at ASH 2021, the safety and efficacy of 2 doses of venetoclax in combination with daratumumab and dexamethasone (Dd) were compared with bortezomib plus daratumumab and dexamethasone (DVd) in patients with R/R MM and t(11;14).²³

In this analysis, preliminary results were reported on safety and efficacy for venetoclax 400 mg QD plus Dd (n = 15), venetoclax 800 mg QD plus Dd (n = 7), and DVd (n = 19). All patients had received ≥1 prior therapy, including an IMiD, and none were refractory to PIs or CD38 antibodies.

Shaji Kumar, MD:
Patients were randomized 4:2:5 and the small sample size prevented further stratification, but the underlying characteristics of patients at the study entry were not appreciably different in age, disease stage, cytogenetic profile, prior exposure to PIs and IMiDs, and prior lines of therapy, as expected in a relapsed patient population.

Shaji Kumar, MD:
The results indicated a tolerable safety profile with safety signals consistent with what has been seen with these drugs in other studies. No treatment-emergent deaths were reported in any arm.

Shaji Kumar, MD:
There was a higher rate of any-grade TEAEs with DVd vs either dose of venetoclax plus Dd. Peripheral edema and peripheral neuropathy were more common with DVd, although gastrointestinal-related AEs were more common with venetoclax plus Dd.

Infection is a major risk factor in these studies; however, the 3 arms showed no significant difference in the rate of infections across the 3 arms. The overall number of patients was small, which may make it more difficult to see differences in AEs.

Shaji Kumar, MD:
The ORR with either 400 mg or 800 mg of venetoclax plus Dd was higher than with DVd (87% and 86% vs 63%, respectively) in this population of patients with t(11;14). It is noteworthy that some of these patients were able to experience deep responses, even a few achieving MRD negativity at 10^-6.

Shaji Kumar, MD:
Although the sample size was small and the follow-up time was limited, many of these responses appear to be durable in the relapsed setting. The median number of months on treatment appeared to be longer with venetoclax plus Dd (median 6.0 months with 400 mg and 8.5 months with 800 mg) compared with DVd (median 3.9 months).

Sagar Lonial, MD:
The next trial is a phase Ib/IIa dose expansion study assessing treatment with iberdomide plus dexamethasone. This was part of a larger phase I study of different treatment combinations with iberdomide in multiple cohorts (NCT02773030). At ASH 2021, I reported phase II results on the efficacy and safety of the combination iberdomide 1.6 mg plus dexamethasone 40/20 mg in heavily treated, triple-class exposed patients with R/R MM.²⁴ Cohort D enrolled 107 patients who had not received BCMA therapy, and cohort I enrolled 26 patients who had progressed on prior BCMA therapy.

Sagar Lonial, MD:
The baseline characteristics for both Cohort D and Cohort I were as expected for this patient population. The median age was approximately 65 years and median time from diagnosis was between 7 and 8 years. In Cohort D, 97% of patients were triple‑class refractory (refractory to ≥1 IMiD, ≥1 PI, and 1 CD38 monoclonal antibody), and 80% were triple‑class refractory in cohort I. The median number of lines of prior therapy was 6 in cohort D and 7 in cohort I. In cohort I, with all patients having progressed on prior BCMA therapy, 50% received an anti-BCMA antibody drug conjugate, 23% received a CAR T-cell therapy, and 31% received a T-cell engager. Overall, this was a heavily pretreated group of patients.

Sagar Lonial, MD:
In terms of patient disposition and exposure, a very small percentage of patients required iberdomide dose reduction (18% in cohort D and 15% in cohort I). Relative dose intensity of iberdomide was high (92% in cohort D and 89% in cohort I). At follow-up, the percentage of patients in ongoing treatment was 12% (cohort D) and 50% (cohort I), with progressive disease (PD) being the most common reason for discontinuation, 69% and 42%, respectively.

Sagar Lonial, MD:
Despite the fact that the patients enrolled in this study were triple-class refractory, the ORR was 26% in cohort D and 25% in cohort I, and most of the responses were PRs (18% vs 17%, respectively), but 7.5% of patients in cohort D and 4.2% of patients in cohort I achieved VGPR, and 1 patient in each cohort achieved either sCR or CR.

In addition, cohorts D and I showed similar clinical benefit rates (36.4% and 41.7%, respectively) and disease control rate (79% and 75%, respectively).

Sagar Lonial, MD:
The median duration of response for cohort D was 30.3 weeks, and the median PFS was 13.1 weeks. Median OS for all patients in cohort D was 46 weeks, but median OS was not reached for patients who responded to this treatment regimen.

Of interest, iberdomide was able to induce and stimulate NK cell and T‑cell responses even in these patients with late‑line, triple‑class refractory disease, and iberdomide significantly reduced Aiolos levels (a marker of anti-MM activity of immunomodulatory agents) during treatment as well.

Sagar Lonial, MD:
The predominant TEAEs with iberdomide and dexamethasone were hematologic toxicities, which was not a surprise for this class of drugs, along with infections. Neutropenia, anemia, and thrombocytopenia were the most common hematologic AEs, but very little febrile neutropenia was noted.

Of most importance, in both cohorts, there were very few nonhematologic AEs, particularly grade 3/grade 4 AEs, which speaks to the safety profile of iberdomide. Anecdotally, I had a patient who had been on approximately 8 prior lines of therapy who reported feeling best on iberdomide plus dexamethasone compared with his other treatments because the IMiD‑related AEs were absent. I think this is seen in the safety profile here, as well.

Shaji Kumar, MD:
The CAR T-cell trials continue to demonstrate high rates of efficacy for patients with R/R MM, and we have been looking forward to longer-term data. We now have 2 CAR T-cell therapies approved for MM: idecabtagene vicleucel and ciltacabtagene autoleucel. Both are approved for adult patients with R/R MM after ≥4 previous lines of therapy, including a PI, an IMiD, and a CD38 monoclonal antibody.

Updated results from the CARTITUDE-1 phase Ib/II study of ciltacabtagene autoleucel in heavily pretreated patients with R/R MM were presented at ASH 2021.²⁵ An earlier analysis showed favorable response and safety results after 12.4 months,²⁶ and this analysis revisited that trial after approximately 2 years. This single-arm trial enrolled 113 patients with R/R MM who had received ≥3 prior lines of therapy, including with a PI, an IMiD, and an anti-CD38 antibody or who were double-refractory to a PI and an IMiD. After undergoing apheresis, 97 patients went on to receive the ciltacabtagene autoleucel infusion.²⁵

Shaji Kumar, MD:
Patients in this study had advanced disease and a median age of 61 years, and almost 60% were male. The median number of prior lines of therapy was 6, and 90% of the patients had undergone ASCT. Almost 90% of these patients were triple‑class refractory, and 42.3% were penta-class refractory.

Shaji Kumar, MD:
Response rates from previous reports on this trial have held true, with an ORR of 97.9% with ciltacabtagene autoleucel, and more impressively, 82.5% of patients achieving an sCR, and almost 95% reaching VGPR or better.

We know the CAR T-cell modality is highly effective in eradicating MM cells but has lacked consistent durability of response for patients with R/R MM. In the updated results of the KarMMa trial with idecabtagene vicleucel, the median DoR was 10.9 months with a median PFS of 8.6 months.²⁷ The results from CARTITUDE‑1 were rather refreshing. In fact, at a similar median follow-up (21.7 months for CARTITUDE-1), the median DoR was not reached after ciltacabtagene autoleucel infusion, and 60% of patients were free of progression at 2 years.

Shaji Kumar, MD:
At 2 years, 60.5% of all patients maintained PFS and the 2-year PFS rate of 71% was particularly striking among those patients who reached sCR after ciltacabtagene autoleucel infusion. These are some of the best results we have seen with a BCMA‑directed CAR‑T in this heavily pretreated patient population. The median OS has not yet been reached, and the 2-year OS rate was 74%.

Shaji Kumar, MD:
Of 61 patients who were evaluable, 92% were MRD negative (10^-5) after infusion of ciltacabtagene autoleucel. For patients who were MRD negative for more than 12 months, the PFS was outstanding with a 2-year PFS rate of 100% and approximately 90% of patients remaining progression free beyond 33 months. The 2-year OS rate was also 100% for patients who were MRD negative for more than 6 months or more than 12 months.

Being a single‑arm study, we can only speculate about how this patient population may have fared on other therapy. However, a real‑world evidence study called LocoMMotion assessed the current efficacy of standard-of-care therapies in patients with R/R MM after triple-class exposure. That study showed an expected median PFS of approximately 4‑5 months for this group of patients.²⁸

Sagar Lonial, MD:
The single-arm MajesTEC‑1 study is a first-in-human, dose escalation/expansion phase I/II study of the BCMA‑directed bispecific agent teclistamab. In total, 165 patients with R/R MM who had undergone ≥3 prior lines of treatment, including an IMiD, a PI, and an anti-CD38 monoclonal antibody, and who had no prior BCMA therapy were enrolled.³³

The primary endpoint for MajesTEC-1 was ORR at the recommended phase II dose (RP2D). In the phase I portion of the trial, the RP2D was identified as teclistamab step-up doses of 0.06 and 0.30 mg/kg during Week 1 followed by 1.5 mg/kg weekly, using subcutaneous dosing. The data presented at ASH 2021 included patients from the phase I and phase II portion of the trial at the RP2D.

Sagar Lonial, MD:
In phase I portion, 40 patients started dose escalation and 20 discontinued treatment, most due to PD. In the phase II portion, an additional 125 patients were treated and 50 discontinued, most due to PD (n = 20) and death (n = 9). The median duration of treatment in the primary safety analysis was 5.9 months, and there were no dose reductions for safety reasons at that point.

Sagar Lonial, MD:
The baseline characteristics for this heavily pretreated group of patients was consistent with what we expected. The median age of patients was 64 years, and patients received a median of 5 prior lines of therapy, with 82% having had prior SCT. All patients enrolled in this trial were triple-class exposed, and 78% were triple-class refractory. In addition, 70% of patients had penta-drug exposure (≥2 PI, ≥2 IMiD, and ≥1 anti-CD38 monoclonal antibody), and 30% were penta-drug refractory.

Sagar Lonial, MD:
After treatment with teclistamab, 58% of patients achieved ≥VGPR, with 28.7% ≥CR, and 21.3% achieving sCR. The ORR was 62.0% (95% CI: 53.7-69.8).

The percentage of patients who reached MRD negativity was 24.7% at 10^-6 and 16.7% at 10^‑5. Among patients who achieved ≥CR, 41.9% also reached MRD negativity. The median DoR has not been reached yet, with a median follow-up of 7.8 months. The rate of PFS at 6 months was 64.4%, and the rate of PFS at 9 months was 58.5%. The median OS has not been reached. It appears that the median PFS is going to be approximately 1 year in this high-risk patient population.

Sagar Lonial, MD:
At data cutoff, 88% of patients were alive without subsequent treatment or progressive disease. I think the response durability from this analysis is exciting, especially the top one third of this graph where deep and durable responses can be seen. There are patients who are 18 months out and remain in ongoing CR or sCR. Many of these are likely the MRD‑negative patients as well.

Sagar Lonial, MD:
No new safety signals were identified in this study, and no patients required dose reduction. Although 9 deaths were reported, 7 were due to COVID-19, and neither of the remaining 2 deaths was related to teclistamab. The COVID virus and its vaccine are a concern for patients with MM overall, and our group has seen much lower vaccine responses in patients receiving BCMA or CD38-directed therapy, requiring vigilance, prophylaxis, and prevention.

Infections are an issue with BCMA-targeted therapy, and infection of any grade was observed in 63% of patients (grade 3/4: 35%). Injection site reactions also occurred with teclistamab subcutaneous injections (35.2% of patients), but all were grade 1/2.

Sagar Lonial, MD:
As with any bispecific T-cell–targeted agent or CAR T-cell therapy, cytokine-release syndrome (CRS) was seen with teclistamab in 71.5% of patients (49.7% at grade 1, 21.2% at grade 2). One transient grade 3 CRS was reported. Of these CRS events, 97% occurred during step-up and cycle 1.

Supportive measures were employed for 66% of patients, and all events resolved without treatment discontinuation.

Sagar Lonial, MD:
Neurotoxicity is also a potential AE experienced with bispecific T-cell–targeted agents and CAR T-cell therapies. In the MajesTEC-1 trial, 12.7% of patients experienced some form of neurotoxicity, but all were grade 1 or 2. Five patients who received the recommended dose of teclistamab experienced immune effector cell-associated neurotoxicity syndrome (ICANS), but all were grade 1 or 2, and all resolved.

Shaji Kumar, MD:
The next study we will discuss is the phase I/II trial of the bispecific antibody that targets BCMA x CD3, REGN5458, in heavily pretreated patients with R/R MM.³⁴ The study enrolled patients with R/R MM after ≥3 previous lines of therapy, including an IMiD, a PI, and a CD38 monoclonal antibody or those who were double refractory to an IMiD and a PI with PD on or after CD38 monoclonal antibody.

This study used a slightly different dosing strategy with step‑up dosing in Week 1 and Week 2 to limit AEs, particularly CRS, followed by full dose weekly administration in Weeks 3-16 and transitioning to dosing every 2 weeks beyond 16 weeks. REGN5458 was administered in an IV formulation.

The primary endpoint of this study was safety, tolerability, and determining the RP2D. These data as presented at ASH 2021 include updated results from the phase I portion.

Shaji Kumar, MD:
The median age of patients was 64 years, and the median number of prior lines of therapy was 5. The majority of patients (≥95%) were refractory to the standard therapies, including IMiDs, PIs, and anti‑CD38. In this trial, 90% of patients were refractory to their last line of therapy, 38% were penta refractory, 32% were quad refractory, and 19% were triple refractory.

Shaji Kumar, MD:
In this trial, all patients experienced hematologic TEAEs with REGN5458 with 42% of patients experiencing grade 3 events and 33% experiencing grade 4 events. These events included anemia, lymphopenia, neutropenia, and thrombocytopenia.

Among nonhematological TEAEs, fatigue (45%) and CRS (38%) were most common, but infections also were a concern, particularly pneumonia which was observed in 23% of patients. Although 38% of patients experienced CRS, none was grade ≥3. Additionally, 3 patients experienced grade 2 ICANS, and 2 patients reached dose-limiting toxicity. Five deaths were reported but were unrelated to treatment.

Shaji Kumar, MD:
In the REGN5458 study, the overall rate of CRS was 38% compared with the 60%‑80% range for the other bispecific studies reported at ASH 2021. It is hard to say how much of this lower rate is related to the step‑up dosing, but it might have played a major role in mitigating this AE. In this study, all but 3 of the 28 cases were grade 1 CRS, and there was no correlation between CRS and dose level or response. Of the total number of patients experiencing CRS, 18 received supportive measures, including 43% who received tocilizumab.

Shaji Kumar, MD:
In this trial, the ORR with REGN5458 was 51% among all enrolled patients. Of the responders, 86% achieved VGPR or better, and 43% reached CR or better. At the highest dose levels (200-800 mg), 75% of patients experienced a response compared with 48% of patients receiving 24-96 mg and 29% for patients receiving 3-13 mg.

The median time to response was less than 1 month, and 70% responded within the first 2 months. The estimated median DoR had not been reached, and some patients showed deep responses with MRD negativity.

Shaji Kumar, MD:
The next study we will discuss explores therapy with the BCMA x CD3 T-cell engaging bispecific antibody, ABBV-383 (previously known as TNB-383). This phase I dose-escalation and expansion study of ABBV-383 enrolled patients with R/R MM who had received ≥3 lines of prior treatment including a PI, IMiD, and anti-CD38 monoclonal antibody with no previous BCMA-targeted therapy allowed.²²

In this study, patients received ABBV-383 IV once every 3 weeks using a 3+3 design and backfilling for dose. The 60-mg dose level was selected for dose expansion based on the AE profile and efficacy.

Shaji Kumar, MD:
In total, 118 patients were enrolled on the study, but this update focused on the 75 patients who received ABBV-383 at the ≥40-mg dose levels in the escalation and expansion cohorts. Baseline characteristics of patients enrolled on this study were comparable to those on other relapse studies in the immunotherapy space. The majority of patients were at least triple‑class refractory (61%), and the median prior lines of therapy was 5.

Shaji Kumar, MD:
There were very few TEAEs that led to dose interruptions or reductions. Dose discontinuation was seen in only 4% of the 75 patients receiving ABBV-383 ≥40 mg and in 6% of patients overall. Dose interruptions were seen in 26% of patients, and dose reductions were seen in 5% of patients. In the cohort of patients receiving ABBV-383 ≥40 mg, 4 experienced dose-limiting toxicity, including platelet count decrease and CRS. Treatment-emergent deaths occurred in 6 patients, including COVID-19 (n = 3), liver injury (n = 1), and sepsis (n = 1), but all deaths were considered unrelated to ABBV-383.

Shaji Kumar, MD:
There is some dose‑dependent impact on TEAEs with ABBV-383, with higher rates of some AEs in the higher dose group. Overall, serious AEs occurred in 46% of patients, with 49% experiencing serious AEs at doses ≥40 mg.

Hematologic AEs included neutropenia (27%), anemia (25%), thrombocytopenia (22%), and lymphopenia (15%). CRS was reported in 69% of patients (only 3 patients ≥grade 3). AEs related to infections occurred in 32% of patients, similar to other bispecific antibody studies. Serious neurotoxicity was infrequent, but 2 patients experienced confusion, and 2 patients who received ABBV-383 60 mg developed ICANS.

Shaji Kumar, MD:
Any grade of CRS was observed in 69% of patients receiving ABBV-383 with ≥40 mg dose, and there is clearly a dose‑dependent impact. Most of the grade ≥2 CRS was observed at the highest dose levels (90 mg and 120 mg), which led to the decision to use the 60-mg dose for the phase II setting. All CRS events resolved quickly with tocilizumab or standard care.

Shaji Kumar, MD:
In the 26 patients in the ≥40-mg dose-escalation cohort, the ORR was 81%, and 69% reached VGPR or better, with a median follow-up period of 8 months. In the dose-expansion and dose-escalation cohort (n = 60) who all received ≥40 mg doses, the ORR was 60%, and 40% reached VGPR or better with a median follow-up of 4.3 months. Many of these patients remain on therapy, and ORR may continue to increase and be more in line with the dose-expansion cohort of 80% at longer follow-up.

Sagar Lonial, MD:
In addition to the various BCMA-directed bispecific therapies that are in clinical trial, other novel targets also are under investigation for R/R MM. The next agent we will discuss is cevostamab, a bispecific antibody that targets FcRH5. Like BCMA, FcRH5 is expressed on almost all plasma cells and has been shown to be a promising target for MM cells.

This multicenter, phase I dose-finding study assessed cevostamab in patients with R/R MM who have no available or appropriate treatment options, and previous therapy with CAR T-cells and bispecific antibodies were allowed.³⁵ At ASH 2021, the presented data included updated safety and efficacy findings from a large cohort of patients divided into single and double step-up dosing to reduce and mitigate the incidence of CRS. Cevostamab was administered by IV every 3 weeks in 21-day cycles.

In the single step-up cohorts, the step-up dose of 0.05-3.6 mg was administered on Day 1 of cycle 1, and the target dose of 0.15-198 mg was administered on Day 8 of cycle 1. In the dose expansion for single step-up dosing, 3.6 mg was administered on Day 1 of cycle 1, and 90 mg was administered on Day 8, followed by dosing of 90 mg on Day 1 of each additional cycle for up to 17 cycles.

In the double step-up cohorts, the first step-up dose of 0.3-1.2 mg was given on Day 1 of cycle 1, the second step-up dose of 3.6 mg was given on Day 8 of cycle 1, and the target dose of 60-160 mg was given on Day 15 of cycle 1. These were followed by the target dose of 60-160 mg on Day 1 of each additional cycle. In the dose expansion for double step-up dosing, 0.3 mg was administered on Day 1 of cycle 1, 3.6 mg was administered on Day 8 of cycle 1, and 160 mg was administered on Day 15, followed by dosing of 160 mg on Day 1 of each additional cycle for up to 17 cycles.

Sagar Lonial, MD:
In total, 161 patients were enrolled to receive cevostamab. The median age of enrolled patients was 64 years, and the median number of prior therapies was 6. Like the BCMA-directed bispecific studies discussed above, this population was heavily pretreated with 84.5% being triple-class refractory and 68.3% being penta-drug refractory.

Sagar Lonial, MD:
In this study, all but 1 patient had ≥1 AE with cevostamab, and 59.6% reported at least 1 serious adverse event with 13% of patients discontinuing cevostamab due to an AE (4.3% were deemed cevostamab-related).

Common hematologic AEs included neutropenia, anemia, thrombocytopenia, and lymphopenia. CRS was reported in about 80% of patients; however, all but 2 patients were grade ≤2. Infections were reported in approximately 50% of patients, with one half of those being grade ≥3. Most other AEs were relatively common among this patient population and were mostly low grade.

Sagar Lonial, MD:
CRS was observed predominantly in cycle 1 with 70% of the cases reported within 24 hours of the first dose of cevostamab, and only 1 case leading to discontinuation. CRS was reported in about 80% of patients, but only 1.2% were grade 3.

ICANS was associated with CRS in 23 patients (14%), and symptoms were resolved in all but 1 patient, who discontinued treatment. Four patients experienced confusion, and 2 patients had aphasia with ICANS. Almost all patients with both ICANS and CRS reported only grade 1/2 AEs, and most responded to tocilizumab and/or corticosteroids.

Sagar Lonial, MD:
This study explored the relationship of single or double step-up dosing and CRS. The treatment-related CRS profile was improved with double step‑up dosing: 88.4% of patients experienced CRS in the single step-up cohort vs 79.5% in the double step-up cohort. In the double step-up cohort, a larger proportion of patients who did have CRS experienced grade 1 CRS with fever only and no other symptoms. Virtually all patients with CRS experienced grade <3 events, and in the first cycle, there was no target dose–dependent increase in CRS.

Sagar Lonial, MD:
The ORR for patients who received the double step-up expansion regimen (0.3 mg/3.6 mg/160 mg) was 54.8%. The ORR for patients who received the single step-up expansion regimen (3.6 mg/90 mg) was 29%. ORR improvement increased with dosage levels, 57% (≥132 mg) vs 36% (20-90 mg). In addition, some patients with ≥VGPR achieved MRD negativity at 10^‑5.

The median time to response was 1 month, and time to best response was 2.1 months.

Sagar Lonial, MD:
The median DoR among responders in the C1 single step-up cohort was 11.5 months (95% CI: 6.0-18.4), with a median follow-up of 14.3 months. The median follow-up for the C1 double step-up responders was 6.5 months, and additional data on the DoR in this cohort are highly anticipated.

Sagar Lonial, MD:
Another target of interest is GPRC5D, which is expressed on plasma cells, including MM clones. The MonumenTAL‑1 study assessed talquetamab, a first-in-class bispecific IgG4 antibody that binds to GPRC5D and CD3 receptors, to treat patients with R/R MM that is refractory or intolerant to established anti-MM therapy.³⁶

The study used 2 step-up dosing schedules, and all patients were premedicated with a glucocorticoid, antihistamine, and antipyretic before step-up doses and first full dose. Thirty patients received the 405 μg/kg dose weekly on 21-day cycles with 2-3 step-up doses given prior to first full dose, and 25 patients received the 800-μg/kg dose every 2 weeks on 28-day cycles with 2-3 step-up doses given prior to first full dose. Primary objectives were safety, tolerability, and efficacy.

Sagar Lonial, MD:
Baseline characteristics in the 2 groups were similar; however, patients treated with the 405-μg/kg dose compared with those treated with the 800-μg/kg dose were more likely to be younger (median 61.5 years vs 64 years) and male (63% vs 44%), and have bone marrow plasma cells ≥60 (21% vs 8%). The 405-μg/kg dose group also had 6 (vs 5) median prior lines of therapy, and their prior treatment exposure was slightly higher for BCMA therapy (27% vs 16%), triple-class exposure (100% vs 92%), and penta-drug exposures (80% vs 68%).

Triple-class refractory status was similar for both groups (77% for 405-μg/kg dose and 76% for 800-μg/kg dose).

Sagar Lonial, MD:
Hematologic toxicity with talquetamab was manageable, and most cytopenias occurred during step-up and cycle 1 or 2. Neutropenia was the most common hematologic AE in 67% of patients in the 405-μg/kg weekly cohort and 44% in the 800-μg/kg every 2-weeks cohort, and many of these patients experienced grade 3/4 neutropenia. 

Sagar Lonial, MD:
GPRC5D may not be as uniquely expressed on plasma cells, and this study revealed a few new AEs for the bispecific antibody class with talquetamab. Dysgeusia, dysphasia, skin exfoliation, and nail disorders were all reported. Although these AEs were not grade 3/4, they were reported at higher rates in the 405-μg/kg weekly cohort, with dysgeusia and dysphagia being reported about twice as often compared with the 800-μg/kg every 2-week dosing. Skin and taste issues are somewhat new for a bispecific therapy and are likely on‑target effects of targeting GPRC5D.

Sagar Lonial, MD:
The step-up dose strategy in this study sought to reduce and mitigate cases of CRS, but 77% of patients in the 405-μg/kg weekly cohort and 72% in the 800-μg/kg every 2-week cohort experienced CRS. Of these patients, all but 1 patient had a grade 1 or grade 2 event. The median times to the onset of CRS and duration were 2 days, and all patients received and responded to supportive measures. Most patients required only tocilizumab and/or steroids for CRS, but 1 patient did briefly require a vasopressor for management of CRS.

Sagar Lonial, MD:
The ORR was 70% for patients receiving talquetamab 405-μg/kg weekly and 66% for patients receiving talquetamab 800-μg/kg every 2 weeks. In both cohorts, more than 50% achieved ≥VGPR and almost 10% reached sCR. Likewise, ORR for patients with triple-class refractory disease was 65% (405-μg/kg) and 67% (800 μg/kg), and for patients with penta-drug refractory disease, it was 83% for both cohorts. Response rates were very similar between the 2 dosing cohorts, and I think AEs will likely drive which of these schedules is used more frequently.

Shaji Kumar, MD:
Taking the lead from the novel bispecific therapies, CAR T-cell therapies also are being developed against other MM targets. This last study that we will discuss provided early data on a CAR T-cell therapy, MCARH109, that targets the GPRC5D protein. This 3+3 phase I dose escalation study assessed the safety and efficacy of MCARH109 in patients with R/R MM after ≥3 lines of therapy, including a PI, an IMiD, and a CD38 monoclonal antibody.³⁸ Patients who relapsed after BCMA-targeted treatment and/or CAR T-cell therapy were allowed.

Patients underwent leukapheresis followed by lymphodepletion for 3 days and then infusion with MCARH109 (25-450 x 10⁶ CAR T-cells). Patients were assigned to 1 of 4 cohorts based on dose level: 25 x 10⁶ (n = 3), 50 x 10⁶ (n = 3), 150 x 10⁶ (n = 6), and 450 x 10⁶ (n = 5).

Shaji Kumar, MD:
The patients enrolled in the phase I study with MCARH109 were a unique population: All but 4 patients had high-risk cytogenetics, and the median age of patients enrolled ranged from 50-65, depending on the dosing cohort. The median number of prior lines of therapy was 6 in the 25 x 10⁶ and 450 x 10⁶ cohorts and 7 in the 50 x 10⁶ and the 150 x 10⁶ cohorts. Of importance, 10 of these patients had prior treatment with other BCMA-targeted therapies, and 8 patients had received CAR T-cell therapy in the past.

Shaji Kumar, MD:
The safety profile for MCARH109 was similar to those in other CAR‑T studies in R/R MM. All but 1 patient experienced CRS, but only 1 CRS event ≥3 grade was reported. Patients in the highest dose level (450 x 10⁶) appeared to have more serious AEs, including at least 1 patient with CRS ≥3 grade, neurologic toxicity ≥3 grade, and macrophage activation syndrome.

As in the study with talquetamab mentioned above, low-grade skin and taste changes were reported with MCARH109. Of note, nail changes were reported in each cohort.

Shaji Kumar, MD:
There were no dose-limiting toxicities reported in this study. As mentioned, CRS was seen in all but 2 patients, and 1 patient experienced ≥3 grade. The duration of the CRS was fairly short (median of 3 days), and only 1 patient experienced ICANS. Based on these data, a dose level between 150 x 10⁶ and 450 x 10⁶ might produce good efficacy without the significant toxicity, particularly the neurological toxicity, seen at the 450 x 10⁶ dose.

Shaji Kumar, MD:
The median follow-up period ranged from 11.9 weeks in the 25 x 10⁶ and 450 x 10⁶ cohorts to 34.6 weeks in the 50 x 10⁶ cohort and 21.4 weeks for the 150 x 10⁶ cohort. At least 2 patients in each cohort (60-100%) achieved minimal response or better. Importantly, ≥VGR was achieved in 33% of patients who received 25 x 10⁶ CAR T-cells, 67% of patients who received 50 x 10⁶ CAR T-cells, and 80% of patients who received 450 x 10⁶ CAR T-cells (but no patients who received 150 x 10⁶ CAR T-cells). It is also important to note that bone marrow MRD negativity was reached by 2 patients (40% to 67%) in each dose level.

Of the 10 patients who had prior BCMA-targeted treatment, 8 achieved ≥PR, 3 achieved ≥CR, and 5 achieved bone marrow MRD negativity. Of the 8 patients who had prior CAR T-cell treatment, 6 achieved PR, 3 achieved CR, and 2 achieved bone marrow MRD negativity. This study tells us 2 things: A CAR T-cell therapy can work after a CAR T-cell therapy with a different target, and 1 CAR T-cell therapy after a different target may be particularly relevant in that setting.