Data presented at the International Myeloma Society (IMS) annual meeting held September 27–30 in Athens, Greece, focused on 3 main topics: (1) the use of newer agents, (2) optimizing outcomes, and (3) the use of minimal residual disease (MRD) measurements to predict long-term outcome for patients or to potentially stop maintenance therapy.
CC-220-MM-001 is an ongoing phase 1/2 trial of iberdomide, used alone and in various combinations, in patients with both relapsed/refractory (RRMM) and newly diagnosed (NDMM) multiple myeloma. Iberdomide-dexamethasone in RRMM, as published here, showed clinical activity in heavily pretreated patients, including those with immunomodulatory-refractory disease.
The initial results of iberdomide, bortezomib, and dexamethasone (IberVd) in 18 transplant-ineligible NDMM patients demonstrated an 88.9% (95% CI, 65.3-98.6) overall response rate (ORR) in the intent-to-treat population, with 4 stringent complete responses (sCRs), 5 CRs, 5 very good partial responses (VGPR), and 2 partial responses; 2 patients were not evaluable. Overall, 9 (50.0%) patients achieved at least a CR and 14 (77.8%) patients achieved a VGPR or better. Grade 3/4 treatment-emergent adverse events (TEAEs) were noted in 70.6% of patients. Neutropenia and pneumonia were the most common AEs (17% each). No patients discontinued due to AEs, however. The researchers reported that the combination showed “high efficacy with deep, ongoing responses in this cohort of mostly older patients… supporting further assessment of iberdomide combinations in the frontline setting.” Iberdomide is currently being studied (versus lenalidomide) as maintenance therapy following autologous stem cell transplant (ASCT) in a phase 3 trial.
Mezigdomide was combined with either bortezomib and dexamethasone (MeziVd) or carfilzomib and dexamethasone (MeziKd) in RRMM patients who had received 2 to 4 prior regimens or MeziVd-1.0 mg in RRMM patients who had received 1 to 3 prior regimens in the phase 1/2 CC-92480-MM-002 trial. The most common grade 3/4 TEAEs were hematologic and included neutropenia and thrombocytopenia with MeziVd and neutropenia and infections with MeziKd or MeziVd-1.0 mg. Dose reductions of mezigdomide due to TEAEs were required in 25% to 40% of patients, depending on the dose and combination. The ORR was 75.0% with MeziVd (21/28); 84.2% with MeziVd-1.0 mg (32/38); and 85.2% with MeziKd (23/27). Median time to response (range) was 1.38 (0.7-3.3), 0.89 (0.7-2.4), and 0.95 (0.9-5.1) months in the MeziVd, MeziVd-1.0 mg, and MeziKd cohorts, respectively. Median duration of response was 10.4 and 11.9 months in the MeziVd and MeziKd cohorts and was not reached in the MeziVd-1.0 mg group. These data support further exploration of mezigdomide in phase 3 studies. Mezigdomide is currently being studied in the SUCCESSOR-1 and -2 phase 3 trials.
Venetoclax, a potent oral BCL-2 inhibitor, has the potential to be the first biomarker-directed therapy for patients with RRMM positive for the t(11;14) translocation, who tend to exhibit higher BCL-2 levels.
In an ongoing phase 2 study, venetoclax, carfilzomib, and dexamethasone (VenKd) was used to treat patients with t(11;14)-positive RRMM. Patients were randomized 5:3:5 to receive K (70 mg/m2 weekly) and d (40 mg) in combination with daily venetoclax (400 mg or 800 mg) or Kd alone. The current analysis included 56 patients. The most common TEAEs, occurring in at least half of patients, were diarrhea, nausea, fatigue, and vomiting and were more common in venetoclax-treated patients than in those treated with Kd alone. Grade ≥3 TEAEs occurring in at least 20% in any group were lymphopenia, neutropenia, and hypertension. Grade ≥3 infection rates were higher in the VenKd groups vs Kd alone (29% vs 20% vs 11%). After a median follow-up of approximately 1–2 years, ORRs (95% CI) were 94% (71-100), 95% (75-100), and 58% (34-80) in the venetoclax 400 mg, 800 mg, and Kd-alone groups, respectively. CR/sCR rates were 29, 50, and 11%, respectively. Median time to response was 1.0, 1.0, and 2.4 months, and 12-month progression-free survival (PFS) estimates were 67, 85, and 79%, with median PFS of 42.4 months. Overall survival (OS) data are not yet mature. Study enrollment is ongoing. According to the researchers, treatment with VenKd was well tolerated and produced favorable responses in at least 90% of patients.
The CANOVA study compared once-daily oral venetoclax and dexamethasone (Vd) versus pomalidomide and dexamethasone (Pd) in 263 patients 18 years and older who had t(11;14)-positive RRMM and had received ≥2 prior lines of therapy. Vd did not significantly improve PFS relative to Pd, the primary end point of the trial. Patients receiving Vd showed a median PFS of 9.9 months compared with 5.8 months with Pd (HR = 0.823, 95% CI: [0.596, 1.136]; P=0.237). The safety profile of Vd was generally consistent with the known safety profiles when used as single agents, and no new safety signals emerged. The most common AEs in the Vd group were infection (61%), diarrhea (41%), lymphopenia (24%), and nausea (22%). The most common AEs in the Pd group were neutropenia (63%), infection (57%), thrombocytopenia (39%) and anemia (35%).
Bispecific antibodies (bsAbs) that target B-cell maturation antigen (BCMA) may contribute to increased infection risk in RRMM patients and warrant preventive measures against infection.
To devise recommendations for clinical practice, researchers analyzed data from the phase 1/2 MajesTEC‑1 study of teclistamab, a BCMA×CD3 bsAb, involving 165 RRMM patients. After a median follow-up of 21.7 months, approximately 78% of patients (n=129) developed infections, with over half of the overall study participants developing grade 3/4 infections. Twenty patients (12.1%) died due to infections (17 had COVID-19). Median time to first onset of any grade infection was 1.7 months. Overall, 70.9% of patients had at least 1 IgG value <400 mg/dL and 45.5% received intravenous immunoglobulin (IVIG). Grade 3/4 neutropenia occurred in 65.5% of patients at a median of 2.3 months, and 53.3% of patients received granulocyte colony-stimulating factor (G-CSF).
Recommendations
At IMS, the findings of a systematic review of 9 studies evaluating whether bsAbs are effective in managing extramedullary disease (EMD) and high-risk cytogenetic abnormalities (HRCAs) in RRMM—including ORRs of the entire cohort (N=660)—were reported. The ORRs for EMD and HRCAs were reported in 3 (n=78) and 4 (n=100) studies, respectively. From the studies that reported ORR for EMD, talquetamab (GPRC5D×CD3) was shown to have the highest ORR (0.45 [0.17; 0.77]), followed by elranatamab (BCMA×CD3; 0.38 [0.23; 0.55]) and teclistamab (0.36 [0.19; 0.56]). There was no significant difference in ORR among the agents with respect to EMD status. In studies that reported ORR for HRCAs, talquetamab had an ORR of 0.67 (0.17; 0.77) followed by teclistamab (0.61 [0.43; 0.76]), and elranatamab 0.55 (0.36; 0.73). Similarly, there was no significant difference in the ORR among these agents with respect to HRCA status. According to the researchers, EMD responses are significantly lower than the full cohort ORR; however, it is encouraging that responses to high-risk MM closely approximate ORR of these agents. The authors note that the reporting of EMD responses “needs to be improved, and clinical trials should report EMD responses distinctly, as it directly informs clinical decisions.”
Teclistamab, a bsAb recently approved for RRMM patients who have undergone ≥4 lines of therapy, has shown promise in clinical settings. Researchers from the Dana-Farber Cancer Institute/Brigham and Women’s Hospital reported their experience with teclistamab in 34 patients (median age 65; median 6 prior lines of therapy). Notably, 62% of patients had HRCAs, and 38% had EMD. Observed hematologic toxicities included anemia, neutropenia, and thrombocytopenia, and cytokine release syndrome (CRS), primarily grade 1 or 2, occurred in 56% of patients. Neurological toxicity was minimal, affecting 3% of patients. Infectious complications were noted in 32% of cases, with 9% classified as grade 3 or higher and no treatment-related deaths recorded. At a median follow-up of 6 weeks, ORR was 44%, with 9% achieving CR and 29% reaching VGPR or better. Teclistamab also demonstrated efficacy in patients with renal dysfunction, EMD, and/or HRCAs. According to the researchers, “teclistamab treatment in a commercial setting generated comparable responses to the previously reported clinical trials without any new toxicity signals.”
Forimtamig, a GPRC5D×CD3 T cell–engaging bsAb, has demonstrated significant clinical efficacy across various high-risk subgroups of RRMM patients, according to findings from a phase 1a dose-escalation study. In this first-in-human study, which included patients who were heavily pretreated and refractory to both proteasome inhibitors and immunomodulatory drugs, forimtamig exhibited an ORR of 66.7%, with 54.2% of patients achieving a VGPR or better. Importantly, the median duration of response was 12.2 months, with a majority of responders maintaining their responses at the time of data cutoff. Researchers also saw promising results in specific high-risk subgroups, including patients aged ≥65, those with >4 prior lines of therapy, and individuals with HRCAs. Of note, patients with 1q21 gain, known to be a HRCA, exhibited an ORR of 86.7%. Forimtamig also demonstrated effectiveness in patients previously treated with BCMA-targeted therapies, including antibody-drug conjugates, bsAbs, and CAR T-cell therapy, suggesting its potential as a salvage therapy. The study’s authors emphasized the need for further optimization of forimtamig dosing and scheduling and ongoing evaluation of its long-term treatment benefits, particularly in patients with high-risk disease characteristics.
The CARTITUDE-4 trial is a global, open-label, randomized controlled trial comparing ciltacabtagene autoleucel (cilta-cel) with physician’s choice of standard of care (SOC): either pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd) in lenalidomide-refractory MM patients. As of November 1, 2022, median follow-up was 15.9 months (range, 0.1–27), and 208 patients were randomized to cilta-cel (of whom 176 received cilta-cel) and 211 to SOC. Cilta-cel significantly improved PFS compared to SOC (median not reached vs 11.8 months), with a hazard ratio (HR) of 0.26 (P< 0.0001). In prespecified subgroup analyses, cilta-cel consistently demonstrated improved PFS across various patient subgroups. This includes patients <65 and 65–75 years of age and those who have any of the following: HRCAs, ≥1 HRCAs, ISS stage III, soft tissue plasmacytomas, high bone marrow plasma cell counts, or triple-class–refractory disease. Cilta-cel also showed efficacy when compared to both PVd and DPd. According to the researchers, the benefit shown was “similar to that seen in the overall ITT population, confirming efficacy of a single cilta-cel infusion in a range of clinically relevant MM subgroups.”
Autologous GPRC5D CAR T-cell therapy shows promising results in RRMM patients who have previously undergone anti-BCMA CAR T-cell therapy, according to the latest findings from a phase 2 trial. In this single-arm study conducted in China, 11 patients with RRMM who had previously received anti-BCMA CAR T-cell therapy were enrolled and treated. At a median follow-up of 14.8 months, all 11 patients achieved a response, with 45% achieving a CR or better. Of note, 73% of patients were MRD negative in bone marrow. The median PFS was 6.4 months, and 45% of patients remained progression-free at the time of analysis. The safety profile of GPRC5D-targeted–CAR T-cell therapy was manageable, with grade 3 or higher hematological toxicities being the most common AEs. CRS occurred in 91% of patients, but all cases were grade 1 or 2, and CRS was effectively managed with tocilizumab and dexamethasone. No neurological toxic effects were reported. According to the researchers, “GPRC5D-targeted CAR T-cell therapy is clinically active with a favorable safety profile in patients who do not respond to or relapse after anti-BCMA CAR T-cell therapy.”
PHE885, a fully human CAR T-cell agent manufactured using the T-Charge platform, has demonstrated durably persistent CAR T expansion in a phase 1 study conducted at the Dana-Farber Cancer Institute. Though CAR T-cell therapy targeting BCMA has shown benefit in the RRMM setting, challenges such as lengthy manufacturing times and limited in vivo persistence still need to be resolved. PHE885 had previously demonstrated a 98% ORR across all dose levels, with a 100% ORR at doses exceeding 5×106 CAR T cells. The latest analysis of serial samples from 32 patients suggested that the manufacturing process successfully preserved stem-like memory T cells in the final product, resulting in a diverse and proliferative CAR T expansion following infusion. CAR T cells also maintained a diverse T-cell receptor repertoire, particularly in patients with long-term persistence. The researchers concluded that “T-Charge… successfully preserved stem-like memory T cell clones in the final product, leading to a highly heterogeneous and proliferative CAR T expansion with durable persistence.”
A fourth-generation BCMA CAR T-cell therapy, InstanCART, has exhibited promising results in the treatment of RRMM during a phase 1 clinical trial. Typically, CAR T-cell therapy has prolonged production times and high costs. The traditional production process, which the China-based researchers have called TraditionCART, takes 9–14 days, leading to extended vein-to-vein times and disease progression during production. By contrast, InstanCART, manufactured using the Instant Manufacturing Platform, offers a streamlined production process, optimizing T cell function. The latest phase 1 clinical trial compared the safety and efficacy of TraditionCART and InstanCART in RRMM patients. Both approaches demonstrated favorable safety profiles, with no grade 3 or greater neurotoxicity or CRS observed. However, InstanCART showed lower rates of grade 3 AEs than did TraditionCART. Notably, InstanCART achieved an ORR of 100%. There was no statistically significant difference in PFS and OS between InstanCART and TraditionCART. However, the expansion and duration of InstanCART cells was significantly higher than TraditionCART cells, highlighting its potential for enhanced therapeutic benefit. According to the researchers, InstanCART was well tolerated and showed noninferior efficacy and more encouraging pharmacokinetic profile than TraditionCART for RRMM therapy. The study is ongoing, and long-term follow-up will assess durable efficacies.
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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 Legend Biotech USA Inc.
