Several abstracts presented at this year’s American Society of Clinical Oncology (ASCO) annual meeting highlighted advances in treating newly diagnosed multiple myeloma (NDMM) and relapsed/refractory MM (RRMM). Included were several reports on bispecific antibodies (bsAbs) and combinations, as well as new data on chimeric antigen receptor (CAR) T-cell therapies—particularly its use in earlier lines of treatment for RRMM.
Researchers in Germany and Austria investigated the role of the anti-SLAMF-7 monoclonal antibody (mAb) elotuzumab in patients with NDMM in a randomized phase 3 study. Elotuzumab has demonstrated efficacy and is approved for RRMM, but its role in NDMM is unknown. Transplant-eligible NDMM patients (N=579) were randomized in a 1-to-1 ratio to receive six cycles of carfilzomib (K), lenalidomide (R) and dexamethasone (KRd) followed by four consolidation cycles of KRd and lenalidomide maintenance, all of which were given either with or without elotuzumab. Among the 574 patients who received treatment and were included in the intent-to-treat analysis, about one fourth had high-risk genetics. The coprimary outcomes of minimal residual disease (MRD) negativity and very good partial response (VGPR) or better were achieved in 49.8% of patients receiving elotuzumab plus KRd vs 35.4% of patients receiving only KRd, a significant difference (P=0.0005). Treatment-emergent adverse events (TEAEs) grade 3 or higher were slightly higher with elotuzumab (72.9% vs 62.5% in the KRd-only group). The most common adverse events (AEs) in both groups were febrile neutropenia, grade 3/4 thrombocytopenia, pneumonia, and grade 3/4 cardiac events. The researchers concluded that the addition of elotuzumab significantly improved the rate of early, deep MRD-negative remission in the frontline setting.
Investigators at Emory University found that carfilzomib, pomalidomide, dexamethasone (KPd) deepened responses in patients with high-risk NDMM (ie, presence of t[4;14], t[14;16], del17p, circulating plasma cells, or double-hit myeloma) who had achieved a partial response or better after initial treatment with autologous stem cell transplant. Patients (N=29) were treated with KPd; at study entry, 24.1% of patients had achieved a complete response (CR) or better, and 68.9% had a VGPR or better. By the end of the study, these values reached 79.3% and 100%, respectively. Of the 15 patients evaluable for MRD, MRD (10-5) and (10-6) was achieved in 80% and 53.3%, respectively. After a median follow-up of more than 2 years, the 36-month PFS was 63.2% and 36-month overall survival (OS) was 72.4%. Of the six patients who died while on the study, five died from progressive disease. TEAEs occurring in 20% or more of patients were fever (37.9%), fatigue (34.5%), grade 3/4 diarrhea (27.6%), nausea (24.1%), cough (20.7%), muscle cramps (20.1%), and acneiform rash (20.1%). About 10% of patients experienced grade 3/4 cardiac AEs, and 17.2% experienced grade 3/4 cataracts. Although responses were deepened in this high-risk population, progression-free survival (PFS) and OS remained poor, indicating that strategies for sustaining remission warrant further study.
In the RRMM setting, several studies evaluated the role of bsAbs both alone and in combination with other therapies.
In October 2022, the FDA approved teclistamab, the first bsAb (BCMA×CD3), for patients with RRMM who have received at least four prior lines of therapy including the three main classes of myeloma therapy (proteasome inhibitor [PI], immunomodulatory drug [IMiD], and anti-CD38 mAb) based on the results of the MajesTEC-1 study. Previously published results after 14 months of follow-up showed that teclistamab achieved an overall response rate (ORR) of 63%, with 39% of patients achieving a CR or better, as well as a median duration of response (DOR) of 18.4 months and a median PFS of 11.3 months.
Presented at this year’s ASCO was extended follow-up data (median follow-up: 22 months) from MajesTEC-1. Of 165 patients receiving teclistamab at the recommended phase 2 dose (RP2D; 1.5 mg/kg every week), 43% achieved a CR or better; median DOR was 24 months, with a median PFS of 12.5 months, and a median OS of 21.9 months. Hematologic AEs (any grade) included neutropenia (72%), anemia (54%), thrombocytopenia (42%), and lymphopenia (35%). Infections occurred in 78% of patients (52% grade 3/4), and nine immune effector cell-associated neurotoxicity syndrome (ICANS) events (all grade 1/2) were reported in five patients. Of the 49 patients continuing on the study, about 90% continue to receive dosing every 2 weeks. The authors suggest that the responses are deep, durable, and independent of refractory status, supporting teclistamab as a “safe and effective off-the-shelf BCMA bispecific therapy for patients with RRMM.”
Results from the phase 1/2 LINKER-MM1A study of the bsAb linvoseltamab (BCMA×CD3) in patients with RRMM were also reported at ASCO. Patients had progressed on at least three lines of therapy, including a PI, IMiD, and an anti-CD38 antibody, or were at least triple class (IMiD/PI/anti-CD38 Ab) refractory. Data published in advance of the meeting suggested that higher efficacy was observed with the 200-mg compared with the 50-mg dose, including in patients with high disease burden. The ORR for the 200-mg group (n=58) was 64% vs 50% with the 50 mg cohort (n=104). Median DOR was not reached for either cohort after median follow-up of 2.3 months for the 200-mg dose group and 4.7 months for the 50-mg dose group. A response at 6 months was seen in 89% of patients in the 200-mg group and 85% in the 50-mg group. The most common TEAEs were CRS, fatigue, and anemia. Grade ≥3 ICANS occurred in two patients in the 200-mg cohort and one patient in the 50-mg cohort. About 8% of patients in both groups discontinued treatment due to AEs. Infections occurred in 43% (Grade 3/4: 26%) in the 200-mg cohort and 59% (Grade 3/4: 31%) in the 50-mg cohort.
Another investigational bsAb, elranatamab (BCMA×CD3), is under FDA Priority Review for the treatment of patients with RRMM. A pooled analysis of 86 patients with RRMM previously treated with BCMA-directed approaches from the MagnetisMM clinical trials program found that elranatamab is safe and effective in this population. Previous BCMA-directed treatment included an antibody-drug conjugate (ADC; 67.4%), CAR T cells (41.9%), or both (9.3%). After a median follow-up of 10.3 months, ORR was 45.3% (41.4% with prior ADC and 52.8% with prior CAR T) and CR or better was achieved in 17.4% of patients. Median PFS was 4.8 months, and median OS was not reached by 10 months, with an OS rate of 60.1% at 9 months. Most common TEAEs were cytokine release syndrome (CRS; 65.1%), anemia (59.3%), neutropenia (44.2%), and thrombocytopenia (40.7%). ICANS was reported in 5.8% of patients. According to the researchers, these results support the use of elranatamab in RRMM and who have had prior exposure to BCMA-directed therapies.
A combination of two novel bsAbs, teclistamab and talquetamab, has shown promise with respect to both response rate and safety profile in RRMM. Teclistamab is the first BCMA-directed bsAb approved for the treatment of triple-class–exposed RRMM, and talquetamab is an experimental bsAb targeting the myeloma antigen G protein–coupled receptor 5D (GPRC5D×CD3). The multinational team of researchers behind the phase 1b RedirecTT-1 trial combining teclistamab and talquetamab proposed that targeting both antigens simultaneously might help overcome resistance mechanisms, such as antigen escape. The trial included 63 patients with RRMM and sought to identify the recommended phase 2 regimen (RP2R) for the combination. This was a heavily pretreated group, with patients having received a median 5 (1–11) prior treatments. Common TEAEs included CRS (81%), neutropenia (76%), and anemia (60%). One case of ICANS was reported. The ORR at the RP2R was 92% (12/13) among all evaluable patients. Of the 43% of patients who had extramedullary disease (EMD), the ORR was 83%. The researchers determined that, based on the results, this combination warrants further study in patients with high-risk EMD, for whom treatment options are currently limited.
Another study involving talquetamab (GPRC5D×CD3) evaluated this bsAb in combination with the anti-CD38 mAb daratumumab in patients previously treated with at least three lines of therapy. Preliminary results from the TRIMM-2 study showed promising efficacy for this combination, with the potential for a synergistic effect between the two agents. Updated results from 65 patients over a median follow-up of 11.5 months showed an ORR in about three fourths of the patients, with responses deepening over time. ORRs in patients exposed/refractory to prior therapy were 75%/76% for anti-CD38, 74%/64% for anti-BCMA, and 75%/75% for bsAb. At 12 months, 86% of responders, and 89% of patients with a CR or better, continued to show responses. Common AEs included CRS (78%; all grade 1/2), dysgeusia (75%), dry mouth (55%), anemia (52%), fatigue (45%), and skin exfoliation (45%). At data cutoff, 84% of responders remained on therapy, and the median PFS was 19.4 months, with 12-month PFS and OS rates of 76% and 93%, respectively. According to the researchers, the results from this steroid-sparing combination showed manageable safety and promising results in this heavily pretreated patient population, including patients refractory to anti-CD38/BCMA and T-cell redirecting therapies.
Risk of Infection With Bispecific Antibodies
Targeting BCMA and GPRC5D in RRMM with bsAbs has been associated with an increased infection risk, but this association requires further clarification. To investigate this issue, researchers followed 80 patients treated with 86 courses of bsAb therapy in early-phase clinical trials conducted between 2019 and 2022. Of the patients, 56 received BCMA bsAb,15 received GPRC5D bsAb combined with CD38 mAb with or without IMiDs, and 15 received GPRC5D bsAb monotherapy. A total of 117 infections were reported, 89 in the BCMA group, 24 in the GPRC5D combination group, and 4 in the GPRC5D monotherapy group. The infection rates were similar among patients receiving BCMA bsAb and GPRC5D bsAb, but the incidence of high-grade infections (grade ≥3) was higher with BCMA bsAb treatment (P=0.01). Grade 5 events were observed in 8% (n=7) of patients treated with BCMA bsAb compared to none treated with GPRC5D bsAb. According to the researchers, the findings suggest that the risk of infection with bsAb therapy is high in RRMM, and the risk is higher for BCMA bsAb compared to GPRC5D bsAb, with higher cumulative incidence of infection, higher-grade infection, and more infections that require hospitalization.
Another study investigated infections associated with talquetamab. In the phase 1/2 MonumenTAL-1 study, a total of 339 patients with RRMM received subcutaneous talquetamab, either once a week (n=143) or every 2 weeks (n=145); in addition, 51 had prior T-cell redirection therapy. The researchers found that new-onset infections were most likely to occur during the first two cycles of treatment. Grade 3/4 infections observed in more than two patients included pneumonia (3.5%) and urinary tract infection (2.1%) with the once weekly dose; and pneumonia (2.1%) and COVID-19 (2.1%) with the every-2-weeks dose. Among patients receiving prior T-cell redirection therapy, 6% developed pneumonia. According to the researchers, the rate of opportunistic infections was low with talquetamab, as were rates of discontinuation and deaths. Although not directly compared in this study, infection rates, particularly rates of fatal infections, appear lower with talquetamab than with BCMA-targeted T-cell–based therapies, the authors concluded.
Based on results from the CARTITUDE-1 trial, the FDA in February 2022 approved ciltacabtagene autoleucel (cilta-cel) for the treatment of adult patients with RRMM who had received at least four lines of therapy, including a PI, an IMiD, and an anti-CD38 mAb. Final results from CARTITUDE-1 were presented at this year’s ASCO. A total of 97 patients received cilta-cel over a median follow-up of 33.4 months (range, 1.5–45.2). Median DOR was 33.9 months; median PFS was 34.9 months, with an estimated 47.5% of patients maintaining response at 36 months. According to the researchers, the typical median OS in the heavily pretreated RRMM setting is only about 12 months, highlighting a substantial improvement with cilta-cel in this trial. Out of 49 patients evaluable for MRD, 26 remained MRD-negative for 12 months or more. Of those patients, 20 sustained an MRD-negative CR or better. In addition, 18 patients were MRD negative with a CR or better 24 months after infusion. Safety of cilta-cel was as expected. Overall, six new cases of second primary malignancy were reported, including two cases of basal cell carcinoma and one case each of myelodysplastic syndrome, B-cell lymphoma, melanoma, and prostate cancer. According to the researchers, the median PFS with a single infusion of cilta-cel is longer than that observed with any previously reported therapy in this setting. The ongoing CARTINUE study will follow the course of these patients over a 15-year period.
A retrospective study of data also indicated favorable outcomes for cilta-cel as standard-of-care (SOC) therapy in patients with RRMM. Overall, 177 patients from 12 US academic medical centers were leukapheresed and 139 received cilta-cel. Many patients (55%) in this analysis would have been considered ineligible to enroll in CARTITUDE-1. Of the patients, 83% received bridging chemotherapy, with an ORR of 28%. CRS (grade ≥3: 7%) developed in 81% and ICANS (grade ≥3: 8%) developed in 22% of patients. Infections were seen in 32% of patients. Best response rates, recorded in 118 patients, were partial response (PR) or better (80%); VGPR or better (62%); and CR or better (40%). The authors concluded that intended SOC with cilta-cel has a favorable ORR despite the fact that a larger proportion of patients in this analysis had high-risk features relative to CARTITUDE-1 trial patients; for example, more patients in the current study had EMD (35%) compared with the CARTITUDE-1 study (~14%).
A late-breaking abstract presenting data from the CARTITUDE-4 phase 3 trial reported that compared with SOC (pomalidomide, bortezomib, and dexamethasone [PVd] or daratumumab, pomalidomide, and dexamethasone [DPd]), a single infusion of the dual-binding BCMA-targeting CAR T-cell therapy cilta-cel was associated with a significant improvement in PFS in patients with lenalidomide-refractory MM after first relapse. CARTITUDE-4 represents the first phase 3 study designed to evaluate the efficacy and safety of CAR T-cell therapy in patients with lenalidomide-refractory MM after first relapse, including patients earlier in the course of disease and treatment than were included in previous CARTITUDE trials.
CARTITUDE-4 included 419 patients with lenalidomide-refractory MM who had received between one and three lines of therapy, including a PI and IMiD. In the cilta-cel arm (n=208), patients received bridging therapy with physician’s choice of either PVd or DPd followed by a single cilta-cel infusion 5 to 7 days after lymphodepletion. No manufacturing failures were reported. In the SOC arm, patients received either PVd (n=28) or DPd (n=183) until disease progression. During a median follow-up period of 16 months, the 12-month PFS rates were 76% versus 49% for cilta-cel and SOC, respectively (HR 0.26; P<0.0001). Cilta-cel was associated with a significantly improved ORR (P<0.0001) and an improved number of CR or greater responses (P<0.0001) compared with SOC. MRD negativity rate was also improved with cilta-cel (P<0.0001). In addition, there was a positive trend toward improved OS in the cilta-cel arm (HR=0.78). Grade 3/4 AEs occurred in 97% and 94% of patients treated in the cilta-cel or SOC arms, respectively (including infections [27% vs 25%] and cytopenias [94% vs 86%]). In the cilta-cel arm, 76% had CRS (1% grade 3; no grade 4/5), 5% had ICANS (all grade 1/2) and one patient had a grade 1 movement/neurocognitive AE.
Researchers from the Dana-Farber Cancer Institute and others presented results from a phase 1 study of PHE885, a T-charge–manufactured BCMA-directed CAR T-cell therapy in patients with RRMM. BCMA-directed CAR T-cell therapies have been approved for RRMM, though implementation in clinical practice is subject to lengthy manufacturing times and strong demand for access. According to the researchers, T-charge manufacturing can shorten manufacturing time to less than 2 days and preserve T cell stemness, resulting in rapid expansion and prolonged CAR T-cell persistence.
In the current study, PHE885 produced high response rates with no unexpected safety findings in heavily pretreated patients with RRMM. A total of 46 patients were evaluated with a range of doses of PHE885. Patients had a median of 4 (2–10) prior lines of treatment, 37% had EMD, and 96% were triple-class refractory. Although these patients had aggressive disease, only 28% required bridging therapy due to the quick production time of PHE885. CRS of any grade was noted in 96% of patients and ICANS occurred in 22% (7% grade 3). Other common treatment-related grade 3/4 AEs included anemia (54%), neutropenia (50%), and thrombocytopenia (37%). In the 43% of patients evaluable for efficacy, ORR was 98%. Of 10 evaluable patients, 6 were MRD negative at 10-5 (by next-generation sequencing).
Data from a phase 1 study of another rapid CAR T-cell therapy, GC012F, was presented by several research groups based in China. GC012F is a BCMA/CD19 dual-targeting fast CAR T-cell therapy. According to the researchers, the novel FasT CAR-T platform enables manufacturing of the treatment in 22 to 36 hours. In data previously reported by the group, GC012F led to deep and durable responses in 29 patients with RRMM. The latest data presented at ASCO included 12 months of efficacy follow-up for these patients, 90% of whom had high-risk disease (by Stratification for Myeloma and Risk-Adapted Therapy [mSMART]). ORR was 93.1% (27/29), stringent CR was 82.8% (24/29), and 89.7% achieved a VGPR or better. GC012F was still detectable in 23 patients at 6 months and in 16 patients at 12 months after infusion, with a median time of persistence of 410 days. All 29 patients achieved MRD negativity by flow cytometry (sensitivity 10-4 to 10-6). The median DOR was 37.0 months, and the median PFS was 38.0 months. Of the 29 patients, 25 had CRS of any grade, but no cases of ICANS were observed. The researchers noted that these updated results show that GC012F provides deep and durable responses along with a very high MRD negativity rate, suggesting that GC012F warrants further investigation in this setting.
Belantamab mafodotin (belamaf) is an antibody-drug conjugate that targets BCMA. In November 2022, the manufacturer of belamaf (GSK) initiated the process for withdrawing belamaf from the US market based on findings from DREAMM-3, which did not meet the requirements of the FDA Accelerated Approval regulations. Patients included in DREAMM-3 had RRMM at second relapse and were receiving third-line or later treatment. New results from the DREAMM-3 phase 3 trial in RRMM suggest that belamaf produced more durable and deeper responses compared to the comparator of pomalidomide plus low-dose dexamethasone (Pd); however, no difference was observed in PFS between the two groups. A total of 325 patients were randomized in a 2:1 ratio to receive belamaf or Pd. Over a median duration of follow-up of 11.5 months, median PFS was longer with belamaf (11.2 months vs 7.0 months), but the PFS was similar between the treatment groups (P=0.558). Belamaf appeared to induce deeper responses compared with Pd and showed a longer DOR: at 12 months, the probability of maintaining response was 0.768 with belamaf vs 0.484 with Pd. The safety profile was consistent with previous reports for belamaf and Pd. Current research efforts with respect to belamaf are focusing on its role in combination with established and novel agents.
Another study of belamaf, DREAMM-9, evaluated this agent in combination with bortezomib, lenalidomide, and dexamethasone (VRd) in a phase 1 study in patients with transplant-ineligible NDMM. Data from the updated interim analysis suggested that belamaf plus VRd had no new safety signals and provided early and deep antimyeloma responses in this setting. Patients were separated into seven different cohorts including 12 to 14 patients each. Grade ≥3 AEs occurred in 35% of patients and led to belamaf dose reductions in 7% and dose delays in 63% of all treated patients. The most commonly reported nonocular AEs across all cohorts were thrombocytopenia (46%), constipation (36%), diarrhea (34%), and peripheral sensory neuropathy (31%). Of the patients, 100% of patients in two cohorts, both at the highest dose of 1.9 mg/kg responded. Median time to VGPR or better ranged from 2.1 to 3.1 months (months) across cohorts.
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Jointly provided by the MMRF and RedMedEd.
This educational activity is supported by educational grants from Bristol Myers Squibb and GSK.
