News & Events

Updates in MM From ASH 2023 for Health Care Professionals—Part 3

Several oral presentations at this year’s American Society of Hematology (ASH) Annual Meeting & Exposition highlighted encouraging outcomes in the treatment of smoldering multiple myeloma (SMM), newly diagnosed MM (NDMM), and relapsed/refractory MM (RRMM). Presentations included updated data on bispecific antibodies (bsAbs) and chimeric antigen receptor T (CAR T)–cell therapy, as well as several novel agents in development.

CAR T-Cell Therapy

Updates to KarMMa-3 and CARTITUDE-2: CAR T Use in Earlier Lines of Therapy

Recent advancements in the treatment of RRMM have been highlighted in updates from two large CAR T-cell therapy trials: KarMMa-3 and CARTITUDE-2. The KarMMa-3 trial demonstrated the efficacy of idecabtagene vicleucel (ide-cel) in RRMM patients who received 2–4 prior regimens. With 386 patients randomized to receive either ide-cel or standard regimens, ide-cel demonstrated a median progression-free survival (PFS) of 13.8 months and a 51% reduction in the risk of disease progression or death, compared to 4.4 months in the control group. At 18 months, PFS rates were 41% for the ide-cel group versus 19% for standard treatments. The complete response (CR) rate was 44% in the ide-cel arm, with 22% of patients achieving both ≥CR and minimal residual disease (MRD) negativity. The findings indicate an improved response, as well as a longer median time to the next treatment and second PFS, suggesting sustained remission. There were no reported cases of Parkinsonism or Guillain–Barré syndrome.

Additional results from KarMMa-3 reported health-related quality of life (HRQoL) data. Patients receiving ide-cel demonstrated significant benefits in 18 out of 21 HRQoL domains and experienced quicker times to confirmed improvements and prolonged times to deterioration of symptoms, indicating not just clinical but also functional and well-being advantages.

Long-term data on ciltacabtagene autoleucel (cilta-cel) from the CARTITUDE-2 trial, with nearly 29 months of follow-up, showed that all MRD-evaluable patients in cohort A (1–3 prior lines of therapy and lenalidomide-refractory MM) achieved MRD negativity, with 40% maintaining MRD negativity for over 6 months. The overall response rate (ORR) was 95%, with a 24-month PFS and overall survival (OS) rates of 75%. Cohort B, which included patients with early relapse after first-line treatment, showed that 93% reached MRD negativity and an OS rate of 84%. These results suggest that cilta-cel can induce deep and durable responses even in high-risk groups with early relapse.

Wearable Devices for CAR T Therapy Monitoring

Findings regarding a wearable device for early cytokine release syndrome (CRS) detection in patients being treated with CAR T-cell therapy were presented. This study showed that the wearable device was superior for monitoring CRS compared with traditional methods. The device, which tracks vital signs such as temperature and heart rate, detected CRS events about 103 minutes earlier than standard care. The study also personalized CRS detection by adjusting temperature thresholds according to each patient’s baseline, leading to even earlier CRS identification. Of note, the device could also detect subclinical CRS events.

Bispecific Antibodies

Navigating Infection Risks With bsAbs

A study evaluated the incidence and characteristics of infections in patients treated with B-cell maturation antigen (BCMA)–targeted (teclistamab or elranatamab) and G protein–coupled receptor, class C, group 5, member D (GPRC5D)-targeted (talquetamab) bsAbs. The study included 229 patients across 13 tertiary centers and showed that infections requiring treatment, hospitalization, or treatment delays occurred in a significant portion of the cohort—62%. Notably, infections were more prevalent and severe among those receiving anti-BCMA therapies, with all grade ≥4 events occurring in this subgroup. Infections predominantly affected the pulmonary tract and presented as disseminated infections. Among these, bacterial infections were most common, followed by viral and fungal pathogens. Complications such as invasive pulmonary aspergillosis and progressive multifocal leukoencephalopathy were also reported. The hospitalization rate was 57%, and nearly half of the infectious events affected treatment administration. Of note, the study found that patients treated with anti-GPRC5D bsAbs had a lower risk of first infection compared to the anti-BCMA group, suggesting differential immunosuppressive profiles between these therapies. According to the researchers, dosing interval strategies and prophylaxis appear “necessary and effective” for improving morbidity and mortality rates with these agents.

Talquetamab Studies

An analysis from the MonumenTAL-1 trial suggested a benefit for reduced or less-frequent dosing of talquetamab in RRMM patients who achieved partial response (PR) or better, which may help mitigate treatment-emergent adverse events (TEAEs). Results from an analysis of 45 patients who switched to lower-intensity dosing showed that most patients achieved a deepened or maintained response after dose adjustment, with 88.9% sustaining their response 6 months post-switch. Importantly, GPRC5D-associated TEAEs, including oral, nail, and skin-related issues, improved or resolved over time for some patients in the adjusted-dosing cohorts. The authors suggest that “further analyses on the impact of reduced or less frequent talquetamab dosing on clinical outcomes are warranted.”

Another talquetamab study, the phase 1b MonumenTAL-2 study, indicates encouraging results with this agent in combination with pomalidomide. The study included 35 RRMM patients over a median follow-up of 7–11 months. Results indicated a high ORR in both weekly and biweekly dosing cohorts, with deep responses including CRs and very good partial response. In addition, the most common AEs were dysgeusia, CRS, and neutropenia, none of which led to significant treatment discontinuations.

MRD Negativity and Prognostic Value for RRMM Treated With CAR T and T-Cell Engagers (TCEs)

Evaluating prognostic utility of MRD in RRMM patients treated with either CAR T-cell therapy or TCEs, researchers found that sustained MRD negativity was associated with significantly improved survival outcomes. The study involved 269 RRMM patients, 125 treated with CAR T-cell therapy and 144 with TCEs. Out of 509 MRD assessments, patients achieving MRD negativity had a median PFS of 20 months compared to just 3 months in MRD-positive patients. OS was also substantially improved in MRD-negative patients. Notably, MRD negativity rates were higher in patients treated with CAR T-cell therapy compared to TCEs, though the impact of MRD negativity was similar for both CAR T and TCE. In addition, MRD status proved to be an independent prognostic factor for PFS and OS, irrespective of other clinical features, highlighting the importance of MRD negativity as a treatment end point.

Earlier Phase Studies With Novel Agents

Bcl-2 Inhibitors

Results from a phase 1/2 study highlighted the efficacy of venetoclax (Ven) in combination with daratumumab (D) and dexamethasone (d) in treating patients with t(11;14)-positive RRMM. Initial data showed a 96% ORR, with 67% of patients achieving CR or better. In addition, the combination therapy demonstrated a MRD negativity of 38%, compared to 8% with DVd. Notably, MRD negativity was more durable in the venetoclax group, with some patients maintaining this status for over 12 months.

The combination of sonrotoclax, a BCL2 inhibitor, and dexamethasone showed promising safety and efficacy in RRMM patients with t(11;14). The most common AEs with this combination were insomnia, fatigue, nausea, and arthralgia, none of which were severe. The ORR was 58%, including CRs and VGPRs. At time of data cutoff, 9 patients remained on treatment with the longest duration of response being 483 days (20 cycles). A dose of 640 mg daily in combination with dexamethasone has been recommended for the phase 2 dose.

New CAR T Cells in RRMM

The phase 2 FUMANBA-1 study evaluating equecabtagene autoleucel (eque-cel, CT103A) in adult RRMM patients after ≥3 prior lines of therapy showed that sustained MRD negativity correlated with improved PFS. Out of 88 patients who achieved MRD negativity, 74 had a follow-up of at least 6 months without progression, and 43 had a follow-up of at least 12 months. Sustained MRD negativity was observed in 78.4% of the patients at 6 months and 74.4% at 12 months. Patients with sustained MRD negativity demonstrated longer PFS than those who did not sustain MRD negativity beyond 6 months. Patients with lower baseline tumor burden and less prior triple-class exposure were more likely to achieve sustained MRD negativity. High-risk cytogenetics, extramedullary disease, performance status, and the number of prior lines of therapy did not differ significantly across MRD subgroups and were comparable to the overall study population.

A phase 1 study evaluated BMS-986393 (CC-95266), a GPRC5D-targeted CAR T-cell therapy, in 70 patients who had received ≥3 prior treatment regimens, including BCMA-directed and CAR T-cell therapies. At a median follow-up of 5.9 months, the ORR was 86% with a CR rate of 38%. In patients refractory to prior BCMA-directed therapies, the ORR was 85% and the CR rate was 46%. TEAEs were mostly hematologic in nature, with 84% of patients experiencing CRS, which was mostly low-grade. Neurotoxicity was observed, with some dose-related events, but were typically reversible. Further research is under way to define the recommended phase 2 dose.

GC012F, a dual-targeting BCMA and CD19 CAR T-cell therapy, has shown efficacy and tolerability in transplant-eligible patients with high-risk NDMM. The phase 1 study, which used the FasTCAR-T platform implementing next-day manufacturing of CAR-T cells, included 22 evaluable patients with high-risk features. The results demonstrated a 100% ORR with a stringent CR rate of 95.5%. Of note, all patients achieved MRD negativity at a sensitivity of 10-6, with sustained MRD negativity at 6 and 12 months. The median duration of response (DOR) and PFS were not reached. Of the patients, 27% experienced low-grade CRS, with no reports of high-grade CRS and no reports of immune effector cell-associated neurotoxicity syndrome (ICANS) or treatment-related deaths.

One-year follow-up from a phase 1 study shows encouraging results with CART-ddBCMA, an autologous CAR-T therapy targeting BCMA with a unique synthetic binding domain. RRMM patients who had received ≥3 prior therapies were treated with a single infusion of CART-ddBCMA following lymphodepletion. As of June 2023, 40 patients with a median age of 66 years were enrolled, and 38 received CART-ddBCMA. The study reported a 100% ORR, with 76% achieving CR or better. Of note, 86% of evaluable patients reached MRD negativity. Of the patients, 95% had CRS, nearly all of which were grade 2 or lower (1 had grade 3 CRS); ICANS was reported in 18% of patients, mostly grade 2 or lower. Median DOR, PFS, and OS were not reached, and the estimated 18-month PFS rate was 67%.

Use of a fractionated initial therapy and booster dose of ARI0002h, a CAR-T cell therapy consisting of a humanized single-chain variable fragment directed at BCMA, showed activity and safety in 60 RRMM patients. Among 60 patients receiving ARI0002h, the ORR in the first 3 months was 95%, with 77% achieving ≥VGPR. MRD-negativity rates on evaluable samples were 98% on day 28 and 96% on day 100. At a median follow-up of 23.1 months, the estimated median PFS was 15.8 months, with no differences based on high-risk cytogenetics or triple-refractoriness. CRS was observed in 90% of patients, with 5% experiencing grades ≥3. ICANS was mild and was reported in 2 patients. A total of 44 out of 55 eligible patients received a booster dose, resulting in 19 patients maintaining stringent CR and 11 improving their response. Median CAR T-cell persistence in peripheral blood was 5 months, with 65% and 52% having measurable CAR T cells at 3 and 6 months, respectively. The authors note that the “booster dose may be partially responsible for the improvement of responses over time and exhaustion may play a role in relapse.”

Mezigdomide in RRMM

Results from the phase 1/2 CC-92480-MM-002 trial indicate potential efficacy for mezigdomide (MEZI), a novel oral cereblon E3 ligase modulator. The study evaluated MEZI in combination with dexamethasone (d) and either daratumumab (D) or elotuzumab (E) in patients who had undergone 2–4 previous lines of therapy. In the MeziDd cohort, the ORR was 75%, with a significant portion achieving stringent CRs, CRs, and VGPRs. Similarly, the MeziEd cohort demonstrated good tolerability and promising response rates, especially in patients who had previously received anti-CD38 monoclonal antibody therapy. According to the researchers, these “results support further evaluation of MEZI plus antimyeloma mAbs in phase 1/2 and phase 3 studies.”

HPN217 in RRMM

HPN217, a BCMA-targeting trispecific T-cell engager, was evaluated in a phase 1 dose-escalation study. HPN217 is a small globular protein, designed to “increase the therapeutic window by minimizing off-target toxicities and CRS.” The study included 97 patients, with 94 treated across various dose levels. Participants had received a median of 6 prior lines of treatment, with a significant proportion being exposed to ≥5 drugs and having undergone transplantation. Most TEAEs were manageable, and the maximum tolerated dose was not reached. CRS was predominantly grade 1–2, and responses were observed at doses ≥2.15 mg, with 55% of efficacy-evaluable patients achieving a PR or better. Among patients with a response, 73% (16/22) have had a confirmed response of VGPR or better. The half-life of HPN217 was median 68 hours, indicating sustained presence in the body. The treatment showed linear and dose-proportional pharmacokinetics, with transient cytokine increases higher with the initial dose compared to subsequent dose.

Jointly provided by the MMRF and RedMedEd.

This educational activity is supported by educational grants from AbbVie Inc., Bristol Myers Squibb, and GSK and sponsorship from Genzyme Corporation and Legend Biotech USA Inc.