Studies presented at the 21st International Myeloma Society (IMS) Annual Meeting, held September 25–28 in Rio de Janeiro, focused on several important areas:
The evolving landscape of quadruplet therapy represents a shift towards more intensive initial therapy for NDMM patients. Adding a monoclonal antibody (eg, daratumumab or isatuximab) to standard three-drug regimens has shown to significantly improve outcomes for NDMM patients, whether or not they subsequently receive an autologous stem cell transplant (ASCT). The anti-CD38 antibodies daratumumab and isatuximab were recently approved as part of quadruplet therapy for NDMM.
Daratumumab (dara) is FDA-approved as part of quadruplet therapy for NDMM patients. On September 20, 2024, the FDA also approved isatuximab (isa) in combination with VRd for transplant-ineligible (TI) NDMM patients. Updates were presented on several studies:
In the latest PERSEUS update, at a median follow-up of 47.5 months, PFS was found to be superior with dara-VRd vs VRd across all cytogenetic risk subgroups. In addition, MRD-negativity rates were significantly higher with dara-VRd: 77.3% vs 48.1% in standard-risk patients (P<0.0001) and 73.1% vs 49.3% in high-risk patients (P<0.0001)—defined as the presence of ≥1 of the following cytogenetic abnormalities: del(17p), t(4;14), t(14;16), gain (1q21), and amp(1q21). Sustained MRD negativity for ≥12 months was also higher with dara-VRd.
Likewise, in TI or transplant-deferred NDMM patients, at a median follow-up of 58.7 months, results from the CEPHEUS study indicated that the PFS was significantly higher with dara-VRd (HR, 0.57; P=0.0005), with a 54-month PFS rate of 68.1% vs 49.5%. The overall MRD-negativity rate was also significantly higher with dara-VRd (60.9%) than with VRd alone (39.4%; P<0.0001). Results from PERSEUS and CEPHEUS support the use of dara-containing quadruplets as a standard of care (SoC) for NDMM.
For isatuximab, data from the IMROZ phase 3 study at a median follow-up of 59.7 months showed that the median PFS was not reached for isa-VRd, compared to 54.3 months for VRd (HR 0.596; 98.5% CI 0.406–0.876; P=0.0005) in TI NDMM patients. Isa-VRd also led to significantly higher rates of MRD negativity in patients with CR (55.5% vs 40.9%; P=0.003; by NGS at 10-5) and sustained MRD negativity for ≥12 months (46.8% vs 24.3%; P<0.0001). These results support the use of isa-VRd as another option to dara-VRd in TI NDMM patients.
Another study of isatuximab, BENEFIT, compared isaRd with or without the addition of weekly bortezomib (isa-VRd) in TI NDMM patients. At a median follow-up of 23.5 months, the 18-month MRD-negative rate at 10-5 (by NGS) was significantly higher with isa-VRd (53%, 95% CI 44-61) than with isaRd (26%, 95% CI 19-34; P<0.0001), also supporting the use of isa-VRd in non-frail TI NDMM patients.
Isatuximab is also being evaluated in combination with carfilzomib, lenalidomide, and dexamethasone (Isa-KRd). The IFM2020-02 MIDAS study evaluated the efficacy and safety of Isa-KRd induction therapy in NDMM patients. Among the 791 patients enrolled, the ORR was 95%, with 91% achieving very good partial response (VGPR) or better. Postinduction, the MRD negativity rate (by NGS) was 63% at a sensitivity of 10-5 and 47% at 10-6. The most common grade 3/4 adverse events (AEs) were neutropenia (25%), thrombocytopenia (5%), and infections (7%), with no new safety issues reported.
Another experimental quadruplet involves the addition of the anti-BCMA ADC belantamab mafodotin to VRd. In the phase 2 GEM-BELA-VRd trial, after 1 year of maintenance, the ORR was 96%, with a sCR/CR rate that improved over time to 82%. The MRD negativity rate was 91.2%. Ocular AEs such as blurred vision, foreign body sensation, dry eyes, and eye irritation occurred in 41.9% of patients during induction, though these improved before ASCT. Hematologic toxicity and infections, including respiratory infections, were manageable and as expected. At a median follow-up of 28.5 months, the 2-year PFS was 78%.
Belantamab mafodotin continues to be studied in the RRMM setting, with positive data from the DREAMM-7 and DREAMM-8 studies. The drug is expected to make a comeback on the market for use as a second-line option for RRMM patients; FDA application filing is expected by the end of 2024.
Several studies focused on special populations, including patients ≥65 years and patients with high-risk disease.
Although the PERSEUS trial showed a reduced risk of progression or death with dara-RVd relative to RVd in patients 18–70 years old, the impact in patients ≥65 years (25.5% of patients) was less robust than in patients <65 years. To further investigate the benefit of dara-RVd in patients ≥65, researchers analyzed outcomes in 1,000 consecutive NDMM patients treated with RVd between January 2007 and August 2016 and 326 NDMM patients treated with dara-RVd induction therapy from April 2018 to August 2022. Results showed that patients ≥65 had a 4-year PFS of 95% with dara-RVd, compared to 59% with RVd. The ≥VGPR rate was also higher in patients ≥65 treated with dara-RVd (88.7%) than in those treated with RVd (66.4%). The findings suggest that despite the less pronounced benefit observed in the phase 3 PERSEUS trial, dara-RVd still provides a significant PFS advantage in older patients in the real-world setting.
Results from the GMMG-CONCEPT trial confirm the potency of isa-KRd in inducing and maintaining MRD-negative remissions in in high-risk NDMM patients. Researchers evaluated isa-KRd in patients with high-risk NDMM, defined as ISS stage 2 or 3 and any of the following chromosomal abnormalities: del17p, t(4;14), t(14;16), or ≥3 copies 1q21(amp1q21). At a median follow-up of 54 months, transplant-eligible patients had a 4-year PFS rate of 59.4% and an OS rate of 72.3%, whereas TI patients had 4-year PFS and OS rates of 54.3% and 65.9%, respectively. Achieving MRD negativity (by NGS at 10-5) was associated with a significantly improved PFS and was more pronounced in patients who remained MRD-negative (HR 0.11, 95% CI: 0.05–0.28).
Another analysis of data from the GMMG-CONCEPT trial assessed cardiovascular biomarkers. Although elevated NT-proBNP levels were common (76% of patients) before treatment, they did not predict cardiovascular AEs (CVAEs). However, baseline high-sensitive troponin I (hs-TnI) levels of ≥2.9 ng/L were associated with a significantly higher risk of developing CVAEs during treatment (P=0.0059); patients with baseline hs-TnI levels <2.9 ng/L were less likely to experience CVAEs, indicating that hs-TnI could be a predictive biomarker for cardiovascular risk in this high-risk patient population.
The CC-220-MM-001 trial was designed to evaluate a novel triplet regimen combining iberdomide, daratumumab, and dexamethasone (IberDd) in TI NDMM patients. Iberdomide is an experimental thalidomide analog that works as a cereblon E3 ligase modulator (CELMoD) and has a higher binding affinity than lenalidomide or pomalidomide. At a median follow-up of 11.14 months, the ORR was 97.3%, with 45.2% achieving ≥CR and 84.9% achieving ≥VGPR. MRD negativity at 10-5 was observed in 45.2% of patients with a response of ≥VGPR. Grade 3/4 treatment-emergent AEs (TEAEs) occurred in 93.3% of patients, primarily hematologic, including neutropenia (74.7%) and febrile neutropenia (12%). These results indicate that IberDd has promising efficacy and a manageable safety profile with the convenience of oral dosing in this patient population.
Iberdomide is currently in phase 3 clinical trials as single-agent maintenance therapy compared to Revlimid for NDMM patients following ASCT and in combination with daratumumab-dex compared to bortezomib-daratumumab-dex for RRMM patients.
Lenalidomide used as a single agent is considered standard maintenance therapy after transplant, but studies are under way to investigate combination approaches or novel approaches such as with the CELMoD iberdomide. As noted, MRD-guided approaches are also being studied to optimize maintenance duration.
Daratumumab combined with lenalidomide (dara-R) vs R alone as maintenance therapy was evaluated in the AURIGA phase 3 study of NDMM patients. The study found that the addition of dara to R significantly increased the MRD-negativity conversion rate at 12 months (50.5% vs 18.8%; OR 4.51; 95% CI: 2.37–8.57; P<0.0001). At a median follow-up of 32.3 months, PFS also favored the dara-R group (HR 0.53; 95% CI: 0.29–0.97) with an estimated 30-month PFS rate of 82.7% compared to 66.4% for R alone. The safety profile was manageable, with no new AEs observed.
MRD is being assessed as a measure for evaluating treatment efficacy, determining the need for treatment modification, and potentially allowing for treatment cessation in some patients. To date, no standard for using MRD in practice has been established. Several studies presented at IMS shed light on the utility of MRD in guiding treatment decisions.
One study evaluating the long-term dynamics of MRD in MM patients highlighted the importance of periodic MRD re-evaluation. An analysis of 313 patients who achieved a complete response (CR) after first-line therapy found that one third of patients changed MRD status over time (measured by next-generation flow cytometry). Of note, patients who went from MRD-positive to MRD-negative showed a more favorable prognosis than those who remained consistently MRD negative. The study also suggested that MRD status changes were accompanied by alterations in bone marrow composition, warranting further study. Ultimately, the changing dynamics of MRD status suggest the need for periodic MRD re-evaluation in patients.
Several methods are currently available for measuring MRD in MM, all of which require bone marrow biopsy samples. Techniques for assessing MRD from blood samples, such as through mass spectrometry (MS), are under investigation. Liquid chromatography-MS (LC-MS) may be useful for identifying exceptional responders, according to an analysis of two pooled studies of NDMM patients (N=74). In this analysis, the researchers determined that LC-MS allowed for sensitive detection of monoclonal protein in peripheral blood, though MALDI-TOF MS is the most frequently used method due to its high-throughput and cost-effectiveness. The study found that LC-MS demonstrated approximately 10 times more sensitivity than the commonly used MALDI-TOF MS. In this analysis, MRD negativity by LC-MS was linked to longer progression-free survival (PFS), with a significant hazard ratio (0.12) compared to patients showing positive by standard methods. The results suggest that LC-MS, along with bone marrow MRD assessment, may improve prognostic accuracy in NDMM, offering a potential pathway to more personalized treatment.
A phase 2 study evaluating the utility of MRD in guiding cessation of lenalidomide maintenance therapy in standard-risk patients (International Staging System [ISS] 1 or 2) found that patients with prolonged MRD-negative status (>3 years after cessation of maintenance therapy; assessed by multiparametric flow cytometry) had a low risk of progression. Of the 43 patients enrolled, 84% remained MRD-negative at 12 months post cessation, and the 24-month MRD-negative rate was 82% (95% CI 69%–96%). PFS at 24 months was 91% (95% CI 81%–100%). Durable MRD negativity (at 24 months) for standard-risk patients was 87% vs 66% for high-risk or stage not reported. The results suggest that stopping lenalidomide maintenance in standard-risk patients with prolonged MRD-negative status is feasible, with a low risk of progression.
Another phase 2 study, MILESTONE, assessed the feasibility of using postinduction MRD status to defer autologous stem cell transplantation (ASCT) in NDMM patients. Of the 20 patients enrolled, 5 achieved MRD negativity (<10-5 via next-generation sequencing [NGS]) postinduction and deferred ASCT. At a median follow-up of 18.4 months, there were no cases of disease progression or deaths, and the overall response rate (ORR) was 100%, with CR or better in 80% of patients. These findings suggest that MRD-guided treatment may offer an opportunity to safely defer ASCT, a concept that will be further evaluated in the ongoing phase 2 MASTER-2 trial.
The standard of care for MM patients who have relapsed after 1–3 lines of therapy includes combination regimens with agents from three classes: proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs). Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, was recently FDA-approved for the treatment of adult RRMM patients who have received ≥1 prior line of therapy, including a PI and an IMiD, and are refractory to lenalidomide. Studies presented at IMS included a 3-year follow-up of the phase 3 CARTITUDE-4, on which the latest cilta-cel approval is based, as well as data on several novel agents.
Findings from the CARTITUDE-4 study continue to support the overall benefit-risk profile of cilta-cel vs SoC in the early-relapse setting. The 3-year follow-up data showed a significant improvement in OS compared to SoC in patients with lenalidomide-refractory MM. After a median follow-up of 34 months, median OS was not reached in either treatment group, with an HR of 0.55 (95% CI, 0.39–0.79; P=0.0009), indicating a 45% reduction in the risk of death relative to SoC. PFS was also notably longer with cilta-cel, with a median PFS not reached (95% CI, 34.50 mo–NE) vs 11.79 months (95% CI, 9.66–14.00) in the SoC group. The ORR was significantly higher with cilta-cel (85% vs 67%), and the median time to symptom worsening was not reached with cilta-cel and 34.33 months with SoC (HR, 0.38; 95% CI, 0.24–0.61; P<0.0001). Both treatment arms showed similar rates of grade 3/4 AEs, though cilta-cel showed a favorable impact on quality of life and survival outcomes.
BMS-986393 demonstrated promising safety and efficacy in RRMM patients who had 1–3 prior regimens. In this phase 1 study, 31 patients received a single infusion of BMS-986393 at 150 × 106 CAR T cells. At a median follow-up of 4.9 months, the ORR was 96%, including a CR rate of 42%, with 87% of responses ongoing. TEAEs were reported in 97% of patients, with 81% experiencing grade 3/4 TEAEs; however, there were no deaths, and all cytokine release syndrome (CRS) cases (81%) were mild (grade 1/2) and resolved. Similarly, ICANS cases were mild (grade 1/2) and occurred in 10% of patients. As seen with other GPRC5D-targeted agents, AEs of the mouth, nails, or skin occurred in 48% of patients (grade 1/2). These results suggest that BMS-986393 has a favorable safety profile and warrant further evaluation in this setting.
Two reports from the DREAMM-8 trial were presented at IMS, providing evidence for the efficacy and safety of belantamab mafodotin-based regimens that could support regulatory approval in the U.S. DREAMM-8 is a phase 3 trial comparing belantamab mafodotin plus pomalidomide and dexamethasone (BPd) vs bortezomib plus pomalidomide and dexamethasone (PVd) in 302 patients who had a median of 1 prior lines of therapy.
Results with a median follow-up of 21.78 months showed median PFS not reached for the BPd arm (95% CI, 20.6–NR) compared to 12.7 months (95% CI, 9.1–18.5) for PVd (HR 0.52; 95% CI, 0.37–0.73; P<0.001). The ORR was 77% with BPd vs 72% with PVd, with a higher rate of CR or better in the BPd group (40% vs 16%). Although ocular AEs were more frequent with BPd (89% vs 30% in PVd), the safety profile was manageable and consistent with the known profiles of the agents.
Another presentation of patient-reported outcomes (PROs) from DREAMM-8 indicated that global health status/quality of life (GHS/QOL), physical functioning, fatigue, and pain were maintained over time in both treatment groups. There were no significant differences (≥10 points) between the two arms in these domains. Patients receiving BPd reported a higher incidence of vision-related function worsening and ocular symptoms, but these improved for most patients within a median of 57 days. Most symptomatic AEs were reported as low severity, with blurred vision and fatigue more commonly reported at higher levels in the BPd arm. Overall, both BPd and PVd treatments resulted in stable health-related QOL and were generally well tolerated.
The phase 2 IFM study evaluated the efficacy and safety of an all-oral triplet combination of iberdomide, ixazomib, and dexamethasone in older MM patients at first relapse. Seventy patients (median age 76, range 70–87) were included, with 81% previously treated with bortezomib, 87% previously treated with lenalidomide (74% refractory) and 40% treated with daratumumab (37% refractory). After a median follow-up of 14 months, the 12-month PFS was 52%, and the OS was 85%. The ORR was 65%, including 36% VGPR. The treatment was well tolerated, with the most common grade 3/4 AEs being neutropenia (46%), thrombocytopenia (9%), and infection (8%). Four patients discontinued treatment due to a serious AE. These results suggest that this oral triplet regimen offers a favorable efficacy and safety profile for older MM patients, including those who are refractory to lenalidomide and daratumumab.
For MM patients who have relapsed after >3 lines of therapy, SoC depends on prior treatment and increasingly involves bispecific antibodies (bsAbs; teclistamab, talquetamab, or elranatamab); and/or CAR T-cell therapy (cilta-cel or ide-cel). Several studies at IMS focused on novel agents, and there was a retrospective comparison of cilta-cel and ide-cel.
Two retrospective studies investigated the safety and efficacy of idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) CAR T-cell therapies in RRMM patients. The first study was a retrospective chart review of data from 586 RRMM patients treated with cilta-cel (n=236) or ide-cel (n=350). Cilta-cel was associated with a higher likelihood of grade ≥3 CRS (OR 6.19; 95% CI, 2.10–18.24) and delayed neurotoxicity (OR 33.01; 95% CI, 4.38–248.48) but showed improved treatment responses, including a higher rate of CR or better (OR 2.49; 95% CI, 1.68–3.69). Patients treated with cilta-cel also had longer PFS (HR 0.47; 95% CI, 0.36–0.63) and OS (HR 0.66; 95% CI, 0.46–0.95) compared to those treated with ide-cel. Despite a less favorable safety profile, cilta-cel demonstrated superior efficacy and survival benefits.
The second study assessed 236 RRMM patients from 16 US academic centers who received a cilta-cel infusion. Median age was 64 years, with 30% of patients having penta-refractory disease, 34% extramedullary disease, 39% high-risk cytogenetics, and 6% plasma cell leukemia. Median prior lines of therapy was 6; 14% of patients had prior BCMA therapy, and 4% had prior bsAb therapy. CRS occurred in 75% of patients (5% grade ≥3), ICANs (4% grade ≥3) in 14%, and hemophagocytic lymphohistiocytosis-like syndrome in 2%. Delayed neurotoxicity occurred in 10% of patients with median onset at 24 days and resolved in 54% of patients at last follow-up; 21% of patients died with ongoing symptoms. Severe infections occurred in 21% of patients and second primary malignancies in 8.5%. ORR and CR rates were 89% and 70%, respectively. Twelve-month PFS rate was 68%. Inferior PFS was observed in patients with prior BCMA therapy, high-risk cytogenetics, and extramedullary disease. These results suggest that cilta-cel use is associated with longer PFS; however, patient selection and monitoring for AEs is critical.
The phase 1b TRIMM-2 study evaluated the combination of talquetamab (CD3 × GPRC5D), daratumumab, and pomalidomide in heavily pretreated RRMM patients. The combination showed a promising depth and durability of response. Among 77 patients (median 6 prior lines of therapy), the ORR was 81.8%, with 53.2% achieving a CR or better. The median duration of response was 22.1 months (95% CI, 13.6–27.0), and the median PFS was 15.5 months (95% CI, 11.7–24.4). The most common AEs included neutropenia (77.9% with 68.8% grade 3/4) and CRS (74.0%, all grade 1/2).
Another phase 1b study, RedirecTT-1, assessed the combination of talquetamab (CD3 × GPRC5D) and teclistamab (CD3 × BCMA) in patients with triple-class exposed RRMM. Among 94 patients treated at a median follow-up of 20.3 months, the ORR was 79.5%, and the probability of patients remaining in response at 18 months was 85.9%. The most common AEs included CRS (78.7%, mostly grade 1/2) and neutropenia (73.4%, with 68.1% grade 3/4). This dual-targeting bsAb combination showed consistent efficacy across dose levels and in patients with high-risk features, supporting further study in phase 2.
An ongoing phase 1b study, MagnetisMM-30, is under way to evaluate the safety and efficacy of combining elranatamab (CD3 × BCMA) with iberdomide. Part 1 of the study will involve dose escalation, and part 2 will optimize the dose. Patients will receive SC elranatamab weekly and oral iberdomide for 21 days in each 28-day cycle.
Results from several phase 1 and 2 studies evaluating CAR T cell therapy were reported, generally showing promising outcomes and acceptable toxicity.
| CAR T-cell therapy* | ||||
| Durcabtagene autoleucel (PHE885) | HBI0101 | P-BCMA-ALLO1 | Anitocabtagene autoleucel (anito-cel) |
|
| Study phase | 2 | 1 | 1 | 1 |
| N | 145 | 84 | 34 | 38 |
| ORR (%) | 92 | 92 | NA | 100 |
| CR rate (%) | 53 | 55 | NA | 76 |
| CRS (%) | 96 (6 grade ≥3) | 95 (19 grade 3) | 29 (all grade ≤2) | 95 (2 grade ≥3) |
| Neurotoxicity (%) | 13 (4 grade ≥3) | 4 (0 grade ≥3) | 3 (grade 2) | 18 (5 grade ≥3) |
| Additional findings | 6-month PFS, 86% (FAS, ≥6 months follow-up) | MRD negative, 74%; median OS, NR | No dose-limiting toxicities or GvHD; Most common grade ≥3 AEs: neutropenia, 61%; leukopenia, 55%; lymphopenia 45% | MRD negative, 89% (at 10-5); median DOR, PFS, and OS not reached; 24-month estimated PFS rate: 56% |
*Comparison between these studies should be undertaken with caution, because these drugs have not been compared in a head-to-head fashion and each trial varied in its design and eligibility requirements.
AEs, adverse events; CRS, cytokine release syndrome; FAS, full analysis set; GvHD, graft-versus-host disease; MRD, minimal residual disease; NA, not available; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.
Results from a phase 1/2 trial evaluating three new agents in RRMM patients were presented: an ADC targeting BCMA with a novel amanitin payload, a CELMoD, and a BCL2 inhibitor. Preliminary results show initial safety profiles and responses in heavily pretreated RRMM patients.
| Novel agent* | |||
| HDP-101 | Mezigdomide | Sonrotoclax | |
| Drug class | ADC | CELMoD | BCL2 inhibitor |
| Study phase | 1/2a | 1/2 | 1b/2 |
| N | 18 | 13 | 20 with t(11;14) |
| Treatment | Single-agent | Combined with tazemetostat and dexamethasone | Combined with dexamethasone |
| Safety |
· No dose-limiting toxicities (including ocular disorders) · Mild transient thrombocytopenia in the highest dose cohort |
· Common grade 3/4 TEAEs · Neutropenia, 46.2% · Anemia,15.4% |
· Common TEAEs · Insomnia, 30% · Diarrhea, fatigue, and nausea, 25% each · Hematologic toxicity was minimal |
| Efficacy |
· PR, 3 pts (highest dose) · SD, 1 pt (lowest dose) |
· ORR, 53.8% · sCR, 1 pt · VGPR, 2 pts |
· ORR, 80% · 40% ≥VGPR |
*Comparison between these studies should be undertaken with caution, because these drugs have not been compared in a head-to-head fashion and each trial varied in its design and eligibility requirements.
ADC, antibody-drug conjugate; CELMoD, cereblon E3 ligase modulatory drug; TEAEs, treatment-emergent adverse events; PR, partial response; SD, stable disease; sCR stringent complete response; VGPR, very good partial response; ORR, overall response rate.
Jointly provided by the MMRF and RedMedEd.
Support for this activity has been provided through sponsorships from Pfizer Inc, and Sanofi US and by an educational grant from Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC.
