Several presentations at this year’s American Society of Clinical Oncology (ASCO) Annual Meeting and European Hematology Association (EHA) 2024 Hybrid Congress featured new data from multiple myeloma (MM) studies. In many cases, the emerging data indicate promising outcomes associated with newer treatment approaches, including CD38-targeting monoclonal antibodies, chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies (bsAbs), and antibody–drug conjugates (ADCs).
Results from several trials support the use of isatuximab (isa) or daratumumab (dara) in combination with bortezomib, lenalidomide, and dexamethasone (VRd), representing a new standard of care (SoC) for newly diagnosed MM (NDMM).
Data from the phase 3 IMROZ study of NDMM patients were presented at both ASCO and EHA (and published in the New England Journal of Medicine). Overall, 446 patients underwent randomization (median age, 72; range, 55-80). Thierry and colleagues reported that isa-VRd significantly improved progression-free survival (PFS), with a median PFS not reached vs 54.3 months for VRd (HR [hazard ratio] 0.596, 98.5% confidence interval [CI] 0.406–0.876, P=0.0005). The projected median PFS approached 90 months. In addition, complete response (CR) rates and minimal residual disease (MRD) negativity were higher in the isa-VRd group. Sustained MRD negativity at 10-5 by next-generation sequencing (defined as MRD negative for ≥12 months) favored isa-VRd over VRd (46.8% vs 24.3%; P<0.0001). MRD negativity was associated with improved PFS in both treatment groups, but to a lesser extent in patients treated with VRd (similar survival benefit in patients with sustained MRD negativity). Serious adverse events (AEs) were reported in 70.7% of patients receiving isa-VRd and 67.4% of those receiving VRd. The incidence of grade ≥3 infection was 44.9% with isa-VRd and 38.1% with VRd (for both groups, incidence was lower in patients who received antibiotic prophylaxis than in those who did not).
These data are now under review with the FDA to support a new indication for isatuximab in combination with VRd for the treatment of adult transplant-ineligible NDMM patients. A decision is expected in the fall of 2024.
The phase 3 GMMG-HD7 trial of isatuximab, presented at EHA, also supported use of isa-VRd followed by autologous stem cell transplant (ASCT) in NDMM patients. Interim results showed that patients receiving Isa-VRd after transplantation had significantly higher rates of very good partial response [VGPR] or better (82.8% vs 68.7%; OR 2.19, 95% CI 1.49–3.23, P<0.0001) and CR or better (43.5% vs 34.0%; OR 1.5, 95% CI 1.08–2.07, P=0.013) compared to those receiving VRd without isatuximab. Additionally, MRD negativity rates were significantly higher in the isa-VRd group (66.2% vs 47.7%; OR 2.13, 95% CI 1.56–2.92, P<0.001).
The phase 3 PERSEUS trial evaluated the addition of daratumumab to VRd vs VRd alone in NDMM patients. The study found that the addition of daratumumab was associated with a higher rate of CR or greater and MRD negativity at various depths and time points compared to VRd alone; for example, MRD negativity at 10-6 at 36 months was 63.9% vs 30.8%, P<0.0001, respectively. Sustained MRD negativity for ≥12 months was also higher in the dara-VRd group. More patients (who remained MRD positive following consolidation therapy) in the dara-VRd group than the VRd group achieved MRD negativity at 10-6 (62.3% vs 31%; P<0.0001) with maintenance therapy. Sustained MRD negativity (at 10-6 for 12 months) was 34.4% in patients receiving dara-VRd and 12.7% in patients receiving VRd (P<0.0001).
According to Sonneveld and colleagues, “these data further support dara-VRd followed by dara-R maintenance as a new SoC for patients with NDMM and highlight the benefit of daratumumab in maintenance.”
These data are now under review with the FDA to support a new indication for daratumumab in combination with VRd for induction and consolidation treatment and with lenalidomide (dara-R) for maintenance treatment of adult NDMM patients. A decision is expected in the summer of 2024.
Data from two CARTITUDE cohorts showed a benefit for cilta-cel. CARTITUDE-4 evaluated cilta-cel vs SoC in patients with functional high-risk (FHR) MM after 1–3 prior lines of therapy; FHR was defined as the development of progressive disease within 18 months of receiving ASCT or the start of initial frontline therapy. In a subgroup analysis, cilta-cel significantly improved PFS compared to SoC in FHR patients (median PFS not reached vs 12 months, HR 0.27, 95% CI, 0.1–0.6, P=0.0006). Additionally, cilta-cel resulted in a higher rate of ≥CR (68% vs 39%, OR 3.3, 95% CI 1.3–8.4). These findings support the use of cilta-cel in high-risk MM and demonstrated a manageable safety profile.
Likewise, in the CARTITUDE-2 cohort, Roeloffzen and colleagues evaluated cilta-cel with or without lenalidomide maintenance in patients with NDMM and a suboptimal response (<CR) to ASCT. At a median follow-up of 22 months, 80% (12/15) of patients with MRD-evaluable disease achieved MRD negativity at 10-5, with a 94% overall response rate (≥CR, 94%). PFS and overall survival (OS) rates at 18 months were 94%. Treatment-emergent AEs (TEAEs) included neutropenia (94%), lymphopenia (65%), and cytokine release syndrome (CRS) in 82% of patients, all grade 1/2.
According to the researchers, these data “show promising efficacy and safety with cilta-cel with or without lenalidomide maintenance in patients… who achieved a [suboptimal response] after ASCT frontline therapy.”
The KarMMa-2 Cohort 2B phase 2 study evaluated ide-cel in patients who had functional high-risk MM (those who relapsed within 18 months of first-line therapy without undergoing ASCT). The results indicated that ide-cel provides deep, durable responses with a manageable safety profile in high-risk patients with early relapse MM. In 31 patients treated, the ORR was 94% (95% CI 79%–99%), with a 71% CR rate. High MRD negativity rates were observed at 12 and 24 months in patients achieving partial response or better. The median duration of response (DOR) was not reached, with a 24-month DOR rate of 65%; PFS rates were 70% at 12 months and 63% at 24 months. Grade 3/4 AEs were reported in 94% of patients, primarily neutropenia (94%) and thrombocytopenia (35%), but no grade ≥3 CRS or neurotoxicity was observed.
The DESCAR-T registry evaluated outcomes in RRMM patients who experienced early progression after ide-cel therapy. The study highlights the need for better prognostic factors for ide-cel and suggests that bsAbs, particularly those targeting different antigens, may improve outcomes for patients relapsing early on after ide-cel. In 221 patients, 79 relapsed, with a median time to relapse of 5.5 months. The median OS from the first subsequent antimyeloma therapy was 8.4 months, and PFS was 2.6 months. Patients with early relapse (≤6 months) had worse outcomes, with a median PFS of 2.5 months vs 7.8 months for later relapse (P=0.041) and a median OS of 5.4 months vs not reached for later relapse (P=0.053). Patients receiving bsAbs showed a higher median PFS (3.8 months) compared to other therapies (1.8 months, P=0.008), with anti-GPRC5D bsAbs showing better outcomes than anti-BCMA bsAbs. According to the researchers, patients relapsing after Ide-cel had a poor outcome even with the use of bsAbs.
“This reinforces the need for better prognostic factors to select patients before ide-cel. In case of early relapse after ide-cel, our results seem to favor the use of a bsAb, especially directed against a different target than BCMA.”
Novel CAR T-cell therapies reported on—including zevorcabtagene autoleucel (zevor-cel), a fully human anti-BCMA CAR T-cell therapy—demonstrated high ORRs and deep remissions in the LUMMICAR01 phase 2 study. A fully humanized approach may result in reduced immunogenicity and increased persistence relative to murine therapy. Another anti-BCMA CAR T-cell therapy, anitocabtagene autoleucel (anito-cel), demonstrated significant efficacy and manageable toxicity in the iMMagine-1 phase 1 study. A third agent, OriCAR-017, which targets GPRC5D, showed a 100% ORR and an excellent safety profile in the phase 1 Polaris study.
| CAR T cell agent | Zevo-cel | Anito-cel | OriCAR-017 |
| Target | BCMA | BCMA | GPRC5D |
| Study | Phase 2 LUMMICAR-1 | Phase 1 iMMagine |
Phase 1 POLARIS |
| No. patients | 102 | 38 | 10 |
| Median no. prior therapies (range) | 4 (3-15) | 4 (3-16) | 5.5 (3-17) |
| Efficacy | |||
| ORR (%) | 92.2 | 100 | 100 |
| Responses (%) | 71.6, sCR/CR 19.6, VGPR |
76, sCR/CR 16, VGPR |
80, sCR 20, VGPR |
| MRD negativity rate (%) | 100 in sCR/CR (at 10-5) | 89 in evaluable pts (at 10-5) | 100 (threshold NR) |
| Median DOR (mos) | NR | Not reached | 10.43 |
| PFS | NR | 92%, 6 mo 76%, 12 mo 64%, 18 mo 56%, 24 mo |
Median 11.4 (mos) |
| Side effects | |||
| CRS, all grades (grade 3/4), % | 90.2 (6.9) | 95 (3) | 100 (0) |
| Neurotoxicity/ICANS, all grades (grade 3/4), % | 2 (0) | 18.4 (5.3) | 0 (0) |
NR, not reported
Also presented were data on novel CAR T-cell agents being evaluated in NDMM following induction therapy: GC012F is an autologous BCMA and CD19 dual-targeting CAR-T therapy that uses the FasTCAR-T platform, enabling next-day manufacturing rather than the standard 9–14 days. Another agent, eque-cel, is a fully human BCMA-targeting CAR-T therapy, evaluated in the FUMANBA-2 study.
| CAR T-cell agent | GC012F (FasTCAR-T) | Eque-cel |
| Target | BCMA × CD19 | BCMA |
| Study | Phase 1 | Phase 1 FUMANBA-2 |
| No. patients | 22 | 16 |
| Patient population | HR NDMM | HR NDMM |
| High-risk features | 91%, R-ISS stage II or III 55%, EMD 32%, 1q21 ≥4 copies 9%, IgD subtype |
37.5%, R-ISS stage III 25%, EMD 62.5% double-hit cytogenetics 12.5% triple-hit |
| Efficacy | ||
| ORR (%) | 100 | 100 |
| Responses (%) | 95.5, sCR | 93.8, sCR/CR |
| MRD negativity rate (%) | 100 (at 10-6) | 100 (at 10-5) |
| Median DOR (mos) | Not reached | Not reached |
| PFS | 95.45%, 18 mo | 93.8%, 6 mo 84.4%, 12 mo |
| Side effects | ||
| CRS, all grades (grade 3/4), % | 27 (0) | 68.8 (0) |
| Neurotoxicity, all grades (grade 3/4), % | 0 (0) | 0 (0) |
HR, high risk
Currently, the bsAbs approved for MM include elranatamab (CD3 × BCMA), talquetamab (CD3 × GPRC5D), and teclistamab (CD3 × BCMA), which are the preferred options for RRMM after at least four prior therapies. All three bsAbs carry boxed warnings for CRS and neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS).
Long-term follow-up of the MajesTEC-1 study found that prophylactic tocilizumab effectively reduced CRS incidence, supporting its potential use for outpatient teclistamab administration. In 24 RRMM patients, the incidence of CRS was reduced to 25% (all grade 1 or 2), compared to 72% in the overall study population. The median time to CRS onset was 2 days, and all CRS events resolved without leading to teclistamab discontinuation. The ORR was 73%, with 59% achieving ≥VGPR. No new safety signals were observed.
Likewise, the phase 2 OPTec study evaluated the use of prophylactic tocilizumab to reduce CRS in RRMM patients receiving teclistamab in an outpatient setting. In an initial cohort of 5 patients, no grade ≥3 CRS or neurotoxicity (ICANS) events were observed, indicating that prophylactic tocilizumab may mitigate the CRS risk associated with teclistamab. The study continues to enroll patients to further evaluate the safety and efficacy of this approach.
Results from the phase 3 MajesTEC-7 study in NDMM patients ineligible for or not intending to undergo ASCT showed a manageable safety profile and promising early efficacy for teclistamab in combination with daratumumab and lenalidomide. In 26 patients, 92.3% remained on treatment with a median follow-up of 10.2 months. TEAEs occurred in all patients, with 84.6% experiencing grade 3/4 TEAEs. Common grade 3/4 TEAEs included neutropenia (50%), febrile neutropenia (19.2%), infections (30.8%). CRS occurred in 61.5% of patients (all grade 1) and ICANS in 1 patient. The ORR was 92.3%, with 73.1% achieving ≥CR.
Data from the MagnetisMM-3 study indicate that monotherapy with the BCMA-targeting bsAb elranatamab provides deep, durable responses and favorable long-term survival in patients with heavily pretreated RRMM. In 123 BCMA-naïve patients, the ORR was 73.1% for those with 2–3 prior lines of therapy and 57.7% for those with ≥4 prior lines. The median PFS was not reached for patients with 2–3 prior lines of therapy and 13.3 months for those with ≥4 prior lines. The median OS was 24.6 months, with higher survival rates in patients with fewer prior therapies.
At ASCO, a “trials in progress” update was presented regarding the upcoming MagnetisMM-32 phase 3 study, which will compare the efficacy of elranatamab vs SoC in this patient population. Standard therapies are elotuzumab, pomalidomide, dexamethasone (EPd); pomalidomide, bortezomib, dexamethasone (PVd); and carfilzomib plus dexamethasone (Kd). The study population will include approximately 492 RRMM patients who have received prior anti-CD38 therapy. The primary end point will be PFS, and the key secondary end point will be OS.
Several investigational bsAbs are being evaluated in RRMM; studies were presented on cevostamab, ABBV-383, and linvoseltamab.
Cevostamab appears to have promising efficacy and a manageable safety profile in heavily pretreated RRMM patients. Cevostamab, an investigational bsAb targeting FcRH5 and CD3, was evaluated in the CAMMA 2 phase 1/2 study. Patients with RRMM were triple-class refractory and had received prior BCMA-targeted ADC or CAR T-cell therapy. In 21 patients, the ORR was 67%, with 38% achieving ≥VGPR. Patients previously treated with an ADC had an ORR of 60%; those with prior CAR T-cell therapy had an ORR of 73%. Grade 3–4 AEs occurred in 62% of patients, primarily neutropenia (38%), anemia (29%), and thrombocytopenia (24%). CRS occurred in 71% of patients, all grade 1–2.
ABBV-383, which targets BCMA × CD3, was evaluated in a phase 1 study of 220 RRMM patients who had received ≥3 prior lines of therapy. The dose of 60 mg every 4 weeks, considered optimal, demonstrated an ORR of 65% and a VGPR rate of 50%. CRS was reported in 43% of patients at this dose, with mostly grade 1 events. Grade 3/4 neutropenia, anemia, and thrombocytopenia were observed in 14%, 24%, and 10% of patients, respectively. Grade 3/4 infection occurred in 34%. The findings suggest that 60 mg Q4W ABBV-383 is effective and has a manageable safety profile, warranting further investigation.
Linvoseltamab, a BCMA × CD3 bsAb, also showed promising efficacy and a manageable safety profile in heavily pretreated RRMM patients. Patients treated with a 200-mg dose (N=117) showed an ORR of 71%, with 62% achieving a ≥VGPR and 46% achieving ≥CR. The median DOR was not reached, with a 12-month probability of maintaining response at 78% for all responders and 92% for those with ≥CR. Median PFS and OS were also not reached, with 12-month probabilities of 69% for PFS and 75% for OS. CRS was reported in 46% of patients, primarily grade 1–2. These results are also published in the Journal of Clinical Oncology. The target action date for the FDA’s decision regarding linvoseltamab is August 22, 2024.
Though the ADC belantamab mafodotin (belamaf) was withdrawn in November 2022, it remains under investigation in two phase 3 studies (DREAMM-7 and DREAMM-8). Belamaf was withdrawn after it did not meet the primary end point of having a PFS superior to pomalidomide plus dexamethasone in the DREAMM-3 trial. However, the latest trial data show significant PFS benefits compared to standard treatments in RRMM patients. Based on these new positive trial data, belamaf will be submitted to the FDA for potential re-approval in the US market by the end of 2024.
Results were presented at EHA from the phase 3 DREAMM-7 study, which compared belamaf with daratumumab, both in combination with bortezomib and dexamethasone (ie, BVd vs dara-Vd), in RRMM patients who had received ≥1 line of therapy. These results were also published in the New England Journal of Medicine.
In 494 patients, BVd significantly improved PFS with a median PFS of 36.6 months vs 13.4 months for DVd (HR 0.41, 95% CI 0.31–0.53, P<0.00001). The ORR was higher with BVd (82.7%) than with dara-Vd (71.3%). Median DOR was 35.6 months for BVd vs 17.8 months for dara-Vd. Grade 3/4 AEs were more frequent in the BVd arm (90%) than in the dara-Vd arm (67%), with serious AEs reported in 50% and 37% of patients, respectively. Ocular AEs were more frequent with BVd than dara-Vd (79% vs 29%). Grade ≥3 ocular AEs included blurred vision, dry eyes, and cataract. Significant changes in visual acuity occurred in 34%. These findings suggest that BVd may have potential for becoming a new SoC for RRMM, demonstrating significant efficacy and a manageable safety profile.
Another update from DREAMM-7, presented at ASCO, also suggested that BVd has potential in RRMM, particularly for patients with high-risk genomic alterations (those with ≥1 of t[4;14], t[14;16], or del[17p13]). In the intent-to-treat population of 494 patients, BVd showed greater benefit in lenalidomide-refractory patients (median PFS 25.0 vs 8.6 months, HR 0.31, 95% CI 0.19–0.48) and those with high-risk cytogenetics (median PFS 33.2 vs 10.5 months, HR 0.31, 95% CI 0.18–0.52).
Data from the phase 3 DREAMM-8 study support the combination of belamaf plus pomalidomide and dexamethasone (BPd) as another potential SoC, offering significant PFS benefits and deeper, more durable responses. The findings are also now published in the New England Journal of Medicine. The DREAMM-8 study compared BPd with pomalidomide, bortezomib, and dexamethasone (PVd) in RRMM patients who had received at least one prior line of therapy including lenalidomide. In 302 patients, BPd significantly improved PFS compared to PVd (NR vs 12.7 months, HR 0.52, 95% CI 0.37–0.73, P<0.001). The ORR was 77% with BPd vs 72% with PVd, and the rate of ≥CR was 40% vs 16%, respectively. AEs were manageable, with grade 3/4 ocular AEs (blurred vision, dry eye, and foreign body sensation) more frequent in the BPd arm (43% vs 2%).
Iberdomide was investigated as a part of a fully oral regimen in combination with the proteasome inhibitor ixazomib and dexamethasone in older patients. Another study in RRMM patients evaluated venetoclax or pomalidomide in combination with dexamethasone in patients with t(11;14), the most common chromosomal translocation in MM, associated with an overexpression of the BCL-2 protein.
Findings reported from the Phase 2 IFM study suggest that the all-oral iberdomide, ixazomib, and dexamethasone (I2D) regimen may be an effective and manageable treatment option for older MM patients at first relapse, including those refractory to prior lenalidomide and daratumumab therapy. In 70 patients with a median age of 76, the ORR was 64%, with 33% achieving a VGPR. The median PFS was 13 months, and the 12-month OS was 85% (95% CI 77%–95%). In patients who were refractory to both lenalidomide and daratumumab, the median PFS was 10 months. The regimen was well tolerated, with common grade 3–4 AEs being neutropenia (46%), thrombocytopenia (9%), and infection (8%).
A biomarker subgroup analysis of the phase 3 CANOVA study suggests that venetoclax-dexamethasone (VenDex) may be more effective than pomalidomide-dexamethasone (PomDex) in patients with high BCL2 gene expression or gain(1q). Patients with amp(1q) did not benefit from either treatment.
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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 education grant from Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC.
