CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 16, 2024
Expiration: February 15, 2025
IMROZ: Phase III Study of Isatuximab Plus VRd vs VRd for Transplant-Ineligible, Newly Diagnosed MM
Shaji K. Kumar, MD:
At ASCO 2024, some very important trials in patients with newly diagnosed multiple myeloma (ND MM) were presented as well as subgroup analyses from previously reported trials.
The IMROZ trial was a phase III study that evaluated the addition of the CD38-targeted monoclonal antibody (mAb) isatuximab (Isa) to the triplet bortezomib/lenalidomide/dexamethasone (VRd) backbone (Isa-VRd) compared with VRd for patients with autologous stem cell transplant (ASCT)–ineligible ND MM. These are patients, aged 18-80 years, not considered eligible for transplant because of either age or comorbidities. The VRd backbone, especially modified VRd at reduced doses, has been commonly used in this patient population for quite some time. However, this is the first phase III study exploring the addition of a CD38 mAb to VRd for patients not eligible for ASCT.
Patients were randomized 3:2 to receive either Isa-VRd vs VRd. VRd induction included bortezomib 1.3 mg/m2 SC every 2 weeks, lenalidomide 25 mg, and dexamethasone 20 mg for four 6-week cycles. Induction was followed by 4-week cycles of continuous treatment with either Isa-plus lenalidomide/dexamethasone (Rd) or Rd alone. The primary endpoint of the study was PFS.1,2 Crossover from Rd to Isa-Rd was allowed upon progression.
IMROZ: Baseline Characteristics
Looking at the baseline characteristics, the study predominantly included patients aged 65-80 years, with approximately one quarter of the patients being 75-80 years of age.1,2 This is important because the age group of 65-70 years, and sometimes up to 75 years, can be considered for ASCT in current practice, depending on patient fitness and comorbidities.
Looking at the Revised International Staging System (R-ISS) stage, small proportions of patients were stage III (11%). In terms of high-risk cytogenetic abnormalities, approximately 15% to 20% of the patients had high-risk abnormalities such as del(17p), t(4;14), and t(14;16). There were also quite a few patients, approximately 12%, with amplification of 1q21.1,2
IMROZ: PFS in ITT Population, Interim Analysis
The primary endpoint of the trial—PFS in the ITT population—was met. As shown here, PFS was significantly improved with the addition of Isa to the VRd backbone. At a median follow-up of 59.7 months, the 60-month PFS rate was 63.2% with Isa-VRd vs 45.2% with VRd (HR: 0.60; 98.5% CI: 0.41-0.88; P <.001). The median PFS has not yet been reached with Isa-VRd and was 54 months with VRd.1,2
IMROZ: PFS Subgroup Analysis
All evaluated subgroups appear to have benefited with the addition of Isa, including patients with extramedullary disease (EMD).1,2
However, patients with high-risk cytogenetics did not appear to have much benefit, but this could change with longer follow-up. Patients with high cytogenetic risk and 1q21 abnormality did seem to have some benefit.1,2
IMROZ: Response, MRD Negativity, OS, and QoL
Although the ORR was similar between the 2 groups (91.3% and 92.3%), the rate of very good partial response (VGPR) or better and complete response (CR) or better were higher with Isa-VRd compared with VRd (89.1% vs 82.9% and 74.7% vs 64.1%, respectively). These data suggest that Isa-VRd resulted in an improved depth of response compared with VRd alone.
The rate of MRD negativity is also important, as this is a known predictor of eventual survival outcomes for patients with MM. The MRD negativity rate in the overall population and within the group of patients who are in a complete response was better with the addition of Isa. Furthermore, the rate of sustained MRD negativity was almost doubled with the addition Isa (46.8% vs 24.3%).1,2
IMROZ: Safety Summary
In terms of safety, it is important to note that even though the treatment-emergent AEs were quite similar overall, the incidence of grade ≥3 events appeared to be higher with Isa-VRd compared with VRd (91.6% vs 84.0%), as was the grade 5 treatment-emergent AEs (11.0% vs 5.5%), which was predominantly related to infections.1,2
However, patients receiving Isa-VRd remained on treatment for almost twice as long as patients receiving VRd alone. Therefore, it is important to look the AE profile while adjusting for the patient-year exposure.
Looking at the rate of treatment-emergent AEs per patient-year, the overall AE incidence does not appear to be significantly different between the 2 groups, but one does need to keep in mind the increased risk of infections overall in this older and more fragile patient population.
IMROZ: Safety Summary
Breaking down the specific types of AEs observed, neutropenia was more common in patients receiving Isa-VRd (87.5% for any grade, 54.4% for grade ≥3) vs VRd (80.1% for any grade, 37.0% for grade ≥3). Similarly, the rate of infection was higher in patients receiving Isa-VRd (91.3% for any grade, 44.0% for grade ≥3) vs VRd (86.7% for any grade, 38.1% for grade ≥3), particularly pneumonia (any grade: 30.0% vs 19.3%, respectively). The rate of gastrointestinal toxicity (eg, diarrhea) was also slightly increased with the addition of Isa.
Looking at the incidence of infections and second primary malignancies adjusted for the patient-year exposure, they seem to be fairly comparable between the two groups.1,2
IMROZ: Clinical Implications
Based on these data from the phase III IMROZ trial, the addition of Isa to VRd leads to better PFS and rate of MRD negativity compared with VRd alone in patients with ND MM who are not eligible for ASCT. The safety profile with Isa-VRd is similar to the 3-drug regimen, but the risk of infections must be considered.
These data certainly add the possibility of using a quadruplet regimen in an older patient population not eligible for ASCT, a concept that has already been broadly accepted in patients eligible for ASCT. However, since adding Isa to VRd proved beneficial, and considering data from the MAIA study showing that the addition of daratumumab to Rd is effective in this patient population with a median survival of PFS of approximately 60 months,3 the question arises: How much additional benefit does bortezomib provide?
BENEFIT: Phase III Trial of Isa-VRd vs Isa-Rd in Patients With Transplant-Ineligible ND MM
That question brings us to the BENEFIT trial, which aimed to answer whether we need a 4-drug regimen with bortezomib in this older, ASCT-ineligible population.
The phase III BENEFIT trial enrolled patients aged 65-79 years with ND MM who were nonfrail and ineligible for ASCT (N = 270) to receive either Isa-VRd or Isa-Rd. In this trial, bortezomib 1.3 mg/m2 was given once weekly for 12 cycles and then monthly up to 18 cycles, and both arms received Isa 10 mg/kg IV weekly for the first cycle and then bimonthly up to 12 cycles, followed by monthly dosing along with lenalidomide 25 mg. Dexamethasone 20 mg was given up to cycle 12.4,5
BENEFIT: Baseline Characteristics
The baseline characteristics were similar between arms. Similar to the IMROZ trial, the BENEFIT study predominantly included patients aged 70 years or older, with approximately one third of the patients being aged 75 years or older.
A small proportion of patients were R-ISS stage III (8%) and approximately 10% had high-risk cytogenetic abnormalities.4,5
BENEFIT: Rate of MRD Negativity in ITT
The primary endpoint of MRD negativity was significantly improved at 12 months and 18 months with Isa-VRd compared with Isa-Rd, both at 10-5 and 10-6 sensitivity. At 18 months, the rate of MRD negativity at 10-6 was 36% with Isa-VRd vs 17% with Isa-Rd (odds ratio: 2.74; 95% CI: 1.54-4.87; P = .0006).4,5
It is important to remember that the median follow-up of this study is only 23.5 months compared with 59.7 months with the IMROZ trial.
BENEFIT: Rate of MRD Negativity and CR in ITT
Similarly, the MRD negativity rate in patients who achieved a CR was significantly improved with the addition of bortezomib to the Isa-Rd combination.4
BENEFIT: MRD Subgroup Analysis
Although this is a limited number of patients and a relatively short follow-up, it is important to note that there are no striking differences among subgroups, including by age or cytogenetic risk. 4,5
BENEFIT: ORR, PFS, OS in ITT
As one would have anticipated from the MRD negativity rate, the CR rate was significantly better with Isa-VRd vs Isa-Rd, as was the rate of VGPR or greater. The 24-month PFS rate was similar between the 2 arms at this time point (85.2% vs 80.0%), but the data are still immature with only a 23.5-month median follow-up. 4,5
BENEFIT: Treatment Exposure and Safety
The overall duration of therapy between the 2 groups is comparable, which is expected because very few patients have progressed at this point in time.
Looking at the treatment-emergent AEs, the rate of grade ≥3 events were quite similar, as were the discontinuation rates between the 2 groups, especially when adjusted for the patient-year exposure. 4,5
BENEFIT: Safety
Of great relevance with this particular regimen is the use of bortezomib and the potential neuropathy that may result.
Although there was not a significant difference in hematologic toxicity between the 2 groups, the incidence of peripheral neuropathy is higher with the addition of bortezomib to Isa-Rd (any grade, 52% vs 28%).4,5
Taken together with the IMROZ trial, this is something that we have to consider. Although quadruplet therapy results in improved efficacy, it is not without toxicity and we must monitor these patients very closely for neuropathy and infections.
BENEFIT: Clinical Implications
The phase III BENEFIT trial confirmed that the addition of bortezomib to Isa-Rd is an important component of the quadruplet regimen, and the ORR points toward use of the quadruplet rather than a triplet regimen with CD38 mAb plus Rd. In addition, the safety was very consistent with what we have seen in the past.
These data, along with the data from the phase III IMROZ trial showing that the addition of Isa to VRd leads to better PFS and rate of MRD negativity compared with VRd alone in patients with ND MM who are not eligible for ASCT, suggest the possibility of using a quadruplet regimen in an older patient population not eligible for ASCT.
The one question that is still not answered from these studies is whether everyone needs therapy with 4 different agents, or if we could select those patients who need more intensive therapy in a response-adapted fashion. The ongoing phase III EQUATE trial may help answer this question (NCT04566328). This trial is enrolling patients with ND MM and not eligible for ASCT to receive 9 cycles of induction therapy with daratumumab plus Rd followed by randomization with MRD stratification to consolidation with daratumumab plus Rd, with or without bortezomib, followed by daratumumab plus lenalidomide maintenance. I would encourage everyone to consider enrolling eligible patients on this clinical trial.
PERSEUS: MRD Analysis: VRd With or Without Daratumumab in ND MM Eligible for ASCT
Now we shift to trials in patients with ND MM who are eligible for ASCT. The phase III PERSEUS trial evaluated the addition of daratumumab—for induction, consolidation, and maintenance—to VRd in ASCT-eligible patients with ND MM.6 This trial had previously demonstrated an improvement in PFS with the quadruplet compared with the triplet regimen. The current analysis evaluated whether there was a deepening of response and MRD negativity with the addition of daratumumab during maintenance therapy.
PERSEUS MRD Analysis: Depth of Response Over Time in ITT Population
This particular analysis looked at how the depth of response changed over time. It was very clear that the quadruplet regimen resulted in a higher rate of CR or greater and rate of VGPR at the completion of induction, ASCT, and consolidation, leading to deeper responses overall.7
PERSEUS MRD Analysis: Cumulative MRD-Negativity Rates in ITT Population
As these are patients with ND MM and they are receiving highly effective therapies, assessing the rates of MRD negativity may help predict long-term efficacy. Similar to the rates of response, the rates of MRD negativity (both 10-5 and 10-6 sensitivity) was almost twice as high with daratumumab plus VRd vs VRd at the end of consolidation (57.5% vs 32.5% at 10-5 and 34.4% vs 16.1% at 10-6, respectively). Furthermore, that difference in MRD negativity persisted beyond the end of the consolidation, up to 36 months as of the current follow-up.7
PERSEUS MRD Analysis: Sustained MRD Negativity Rates in ITT Population
The other important concept that is emerging in MM is that of sustained MRD negativity rates. We know that patients who have sustained MRD negativity have improved PFS and OS compared with those who do not.
Here, one can see that the rate of sustained MRD negativity, at ≥12 months or ≥18 months, is improved with the quadruplet compared with the triplet regimen.7
PERSEUS MRD Analysis: MRD Negativity in Subgroup With High-Risk MM
In the subgroup of patients from this trial with high-risk disease, the rates of MRD negativity and sustained MRD negativity were approximately double in the quadruplet compared with the triplet arms.7 This is important because this is one subgroup where we often lose MRD negativity more rapidly.
PERSEUS MRD Analysis: MRD Conversion Rates During Maintenance and PFS by MRD Negativity Status
The conversion rate from MRD positive to MRD negative during the maintenance phase was also higher with daratumumab and lenalidomide maintenance compared with maintenance with lenalidomide monotherapy.7 These data suggest that the addition of daratumumab may be beneficial at all stages of treatment.
However, there are ongoing clinical trials specifically asking the question of how much a CD38 mAb contributes to the maintenance setting in a patient who has already received a CD38 mAb as part of induction and consolidation, including the DRAMMATIC trial (NCT04071457) and the GMMG HD7 trial (NCT03617731). Hopefully, these additional trials will continue to define the approach forward for our patients.
PERSEUS MRD Analysis: Clinical Implications
Overall, I think quadruplet therapy with a CD38-targeted mAb plus VRd is the gold standard induction therapy for ASCT-eligible patients with ND MM. The question of whether the addition of a CD38-targeted mAb to lenalidomide maintenance is preferable still remains open, although the data from PERSEUS seems to point toward a continued advantage of using daratumumab in this setting.
DREAMM-8: Phase III Trial of Belantamab Mafodotin Plus Pom/Dex vs Bortezomib Plus Pom/Dex in R/R MM
In addition to data in the newly diagnosed setting, other important trials provided information on novel approaches within the R/R patient population.
The phase III DREAMM-8 trial evaluated belantamab mafodotin, a BCMA-directed antibody–drug conjugate, in combination with pomalidomide/dexamethasone (BPd) vs bortezomib/pomalidomide/dexamethasone (PVd) in patients with R/R MM previously treated with ≥1 line of therapy (including lenalidomide) and progressive disease on or after their most recent therapy.8,9
Essentially, this was a head-to-head comparison of belantamab mafodotin vs bortezomib in patients who have received ≥1 prior line of therapy. The PVd regimen was similar to that used in the OPTIMISMM trial.10
DREAMM-8: Treatment History
When considering treatment for patients with R/R MM, prior treatment history is important to consider. In this trial, approximately one half of the patients had 1 prior line of therapy and approximately one third had 2 or 3 prior lines of therapy.8,9
DREAMM-8: PFS (Primary Endpoint)
There was a significant improvement in PFS for patients treated with BPd compared with PVd (median PFS was not reached vs 12.7 months, respectively; HR: 0.52; 95% CI: 0.37-0.73; P <.001).8,9
DREAMM-8: Other Efficacy Endpoints
The ORR was 77% with BPd vs 72% with PVd, and the rate of CR or better was much higher with BPd compared with PVd (40% vs 16%, respectively). The rate of MRD negativity among patients who achieved CR or better was also increased with BPd vs PVd (24% vs 5%, respectively). The median duration of response was not reached with BPd vs 17.5 months with PVd.
Similarly, the median PFS2 was not reached with BPd vs 22.4 months with PVd (HR: 0.61; 95% CI: 0.43-0.86), and the median OS was not reached with BPd or PVd arm, but the HR suggested a benefit with PVd (0.77; 95% CI: 0.53-1.14).8,9
DREAMM-8: Subsequent Antimyeloma Therapy
Of interest, more patients in the BPd arm received a CD38-targeted mAb as a subsequent therapy compared with those who in the PVd arm, even though a similar percentage of patients received prior CD38-targeted mAb before enrolling on this study (25% to 29%).8,9 This is now standard of care for patients with R/R MM and is important to consider when assessing OS in this study.
DREAMM-8: Safety Overview
The AE profile was fairly similar between the 2 arms in this study, with the exception of the incidence of ocular events, as would be expected, given the high ocular toxicity that is seen with belantamab mafodotin. The ocular events in the BPd arm were all managed with either dose holds (83%) or modifying the dosing frequency (59%) and only 9% of patients experienced ocular events leading to permanent discontinuation of treatment.8,9
DREAMM-8: AEs of Special Interest
Looking at the AEs of special interest, the rate of infections was higher in the BPd arm compared with those receiving PVd (82% vs 68%), as were ocular events (89% vs 30%).8,9
DREAMM-8: Time to Onset and Resolution of Ocular Adverse Events, Quality-of-Life Analysis
The median time-to-onset of ocular events was approximately 3-4 months, and the median time to resolution was almost 2 months.8,9 This will be important to consider as we start treating patients with this drug if it gets approved and returns to the market.
DREAMM-8: Clinical Implications
In the phase III DREAMM-8 trial, the addition of belantamab mafodotin to pomalidomide/dexamethasone (Pd) certainly seems superior to bortezomib for patients with R/R MM and clearly showed that the safety and tolerability was fairly consistent with what has been previously seen with these combinations that include belantamab mafodotin.
Similar data have been reported for the phase III DREAMM-7 trial, which compared belantamab mafodotin with bortezomib/dexamethasone vs daratumumab with bortezomib/dexamethasone in patients with R/R MM after ≥1 prior line of therapy.11
Together, these data suggest that there may be a role for belantamab mafodotin for patients with R/R MM.
CARTITUDE-4: Post Hoc Subgroup Analysis of Cilta-Cel in Patients Progressing After 1 Prior Therapy
We conclude with a discussion of a few studies that focused on patients with specific unmet needs. One is a subgroup analysis of the phase III CARTITUDE-4 trial, which evaluated ciltacabtagene autoleucel (cilta-cel), a BCMA-targeted CAR T-cell therapy, vs standard-of-care therapy with PVd or daratumumab plus Pd in patients with R/R MM who had received 1-3 prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug. Reports showed that there was a significant improvement in PFS with cilta-cel.12
This particular subgroup analysis evaluated 136 patients (68 in each arm) who had received 1 prior line of therapy, including those with functionally high-risk disease (relapsed within 18 months after ASCT or start of initial first line therapy in those without ASCT). It is important to note that the majority of these patients were functionally high risk, with 40 patients in the group that received cilta-cel and 39 patients who received standard therapy.
There was a significant benefit in the rate of CR or better, MRD negativity, and PFS with cilta-cel over standard therapy, in both the overall subgroup of patients who had received 1 prior line of therapy and among those with functionally high-risk disease.13
CARTITUDE-2: Cohort D: Cilta-Cel With or Without Len Maintenance in ND MM After Suboptimal Response to ASCT
The next dataset was in a group of patients who did not achieve an optimal response to ASCT. The phase II CARTITUDE-2 trial assessed cilta-cel as treatment in multiple different settings, including cohort D, which enrolled patients with ND MM who achieved less than a CR after ASCT (N = 17). After safety assessment with the first 5 patients, the remaining12 patients received lenalidomide maintenance after cilta-cel infusion for ≤2 years.14
Although the median follow-up was only 22.4 months, the rate of CR or better was 94.1% and 70.6% of patients achieved MRD negativity. With the exception of 1 patient, all were progression free at 18 months, with an18-month PFS rate of 93.8%.12
This is a small group of patients, so it is difficult to draw definitive conclusions, but this is certainly very interesting data exploring the possibility of using cilta-cel earlier in the course of the disease.
Retrospective Review of Ide-Cel Efficacy in Patients With Extramedullary MM
Next, there was an analysis looking at the real-world efficacy of idecabtagene vicleucel (ide-cel), the other currently approved BCMA-targeted CAR T-cell therapy, in patients from 11 academic centers with R/R MM who were evaluated for extramedullary disease (EMD). Among 351 patients with R/R MM treated with ide-cel, 84 (24%) had EMD prior to infusion.
In this analysis, patients with EMD had a lower ORR after 30 days vs those without EMD (58% vs 69%, respectively). The discrepancy was even greater at 90 days (ORR: 52% vs 82%; odds ratio: 0.24; 95% CI: 0.1-0.4; P <.001) because some of these patients with EMD actually progress in that time period.15
Similarly, both PFS and OS were inferior in patients with EMD compared with those without EMD,15 which suggests that we still have a significant challenge to optimize care for those patients with MM and EMD.
Although AEs were fairly similar between those with EMD and those without, it was intriguing that patients with EMD tended to have more hematologic toxicity and were more likely to require a stem cell boost.15 This may be because of a complex interaction of the disease biology at this point in time.
MajesTEC-1: Longer-term Data on Prophylactic Tocilizumab for CRS With Teclistamab in R/R MM
Finally, interesting data from the pivotal phase I/II MajesTEC-1 trial evaluated the prophylactic use of tocilizumab for CRS with the BCMA-targeted bispecific antibody teclistamab. The initial results of the MajesTEC-1 trial led to the approval of teclistamab for patients with R/R MM after ≥4 lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and a CD38-targeted mAb. Along with the other currently available bispecific antibodies talquetamab, which targets GPRC5D, and elranatamab, which is BCMA-directed, step-up dosing is required initially to help mitigate the risk of CRS and that often limits how much we can use these agents.
A cohort of patients in the MajecTEC-1 trial were given prophylactic tocilizumab ≤4 hours before the first step-up dose of teclistamab, in addition to standard premedication with dexamethasone, acetaminophen, and diphenhydramine. With the prophylactic use of tocilizumab, there was a significant reduction in the rate of CRS (25.0% vs 72.1% without tocilizumab). Of importance, there was also no impact on response (ORR: 72.7% with tocilizumab vs 63.0% without).16 If anything, those who received prophylactic tocilizumab perhaps had a better ORR.
Conclusions
Overall, there were quite a few trials with exciting data presented at ASCO 2024.
For patients with ND MM, quadruplet regimens with a CD38-targeted mAb plus VRd are now considered standard of care. Although these quadruplet regimens were previously considered standard for ASCT-eligible patients, they should now also be considered for older (up to 80 years of age) or ASCT-ineligible patients, based on data from the IMROZ and BENEFIT trials with Isa. However, the potential use of quadruplet therapy needs to be considered in the context of each patients’ frailty, functional status, and preferences with appropriate dose modifications that were introduced into the quadruplet regimens in these trials.
Regarding maintenance therapy for patients with ND MM after quadruplet therapy induction and consolidation, the PERSEUS trial suggested a potential advantage with adding daratumumab to lenalidomide, but I think additional trials are needed before we routinely start adding daratumumab maintenance for all patients.
In the R/R MM setting, the DREAMM-8 study showed that belantamab mafodotin is highly effective when combined with standard MM backbone therapy, such as pomalidomide/dexamethasone, but there is continuing concern over the risk of ocular toxicity. From these phase III data, it appears that ocular toxicity can be managed with dose modifications and a less intense schedule.
Finally, for patients with R/R MM and high-risk disease—whether because of cytogenetics, EMD, or primary refractoriness—although they may respond well to CAR T-cell therapy, the durability of these treatments remains in question.
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