CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurses: 1.00 Nursing contact hour
Physicians: maximum of 1.00 AMA PRA Category 1 Credit™
Pharmacists: 1.00 contact hour (0.1 CEUs)
Released: March 07, 2024
Expiration: March 06, 2025
PERSEUS: Primary Analysis of Phase III Trial with VRd ± Dara in Patients With NDMM Eligible for ASCT
Sagar Lonial, MD, FACP:
We will start our discussion with the primary analysis of the PERSEUS trial, which was a late-breaking abstract presented at ASH 2023.
This was a randomized phase III trial assessing the efficacy of bortezomib (V), lenalidomide (R), and dexamethasone (d) with or without daratumumab (D), an anti-CD38 mAb, in transplant-eligible adults with newly diagnosed multiple myeloma.1,2
Patients received 4 cycles of induction therapy consisting of VRd with or without daratumumab, followed by autologous stem cell transplant. Patients then received 2 cycles of consolidation therapy matching their induction therapy. Patients in the D-VRd arm received maintenance D-R, while patients in the VRd arm received maintenance R monotherapy. After 7 cycles, if patients receiving D-R were MRD-negative, they were switched to maintenance with R alone. Otherwise, patients with MRD positivity received D-R until progression of disease.
The primary endpoint was PFS, with other key secondary endpoints being CR or better, MRD negativity rate, and overall survival (OS).1,2
Of note, this trial builds upon the results of the phase II GRIFFIN trial, which compared a similar approach with VRd induction, autologous stem cell transplant, and VRd consolidation followed by single agent R until progression vs the same regimen with daratumumab incorporated throughout.3 This study previously showed that incorporating daratumumab throughout treatment improved the depth of response and PFS, but the PERSEUS trial used subcutaneous instead of intravenous administration of daratumumab, with every 4 week dosing, and allowed discontinuation of maintenance daratumumab for patients with sustained MRD negativity.
PERSEUS: Baseline Characteristics
Sagar Lonial, MD, FACP:
This study enrolled approximately 700 patients across multiple countries. The median age was approximately 60 in both treatment arms.1,2 Of importance, approximately 20% of patients in both arms were high-risk by cytogenetics, and approximately 4% had more than 1 extramedullary plasmacytoma. In terms of staging, approximately 15% of patients were International Staging System (ISS) stage III at the time of study entry.
PERSEUS: Patient Disposition
Sagar Lonial, MD, FACP:
Considering patient disposition and the proportions of patients who completed each step of treatment (induction, stem cell transplant, consolidation, and entering maintenance), outcomes were relatively balanced in both arms, except for 3 key criteria.1,2
The rate of discontinuation, discontinuation due to AEs, and disease progression leading to discontinuation were greater in patients who received VRd compared to the D-VRd arm. This speaks to the fact that the addition of daratumumab to the standard treatment regimen likely mitigated early discontinuation due to AEs and prevented or slowed disease progression.
PERSEUS Primary Analysis: PFS (Primary Endpoint)
Sagar Lonial, MD, FACP:
For the primary endpoint of PFS, results were impressive with a significant difference in 48-month PFS rate (HR: 0.42; 95% CI: 0.30-0.59; P = <.0001).1,2 In the group of patients who received D-VRd, the 48-month PFS rate was 84%, compared to 68% in the group of patients who received VRd alone.
Similar to the results reported in the phase II GRIFFIN study, PFS diverges around 12 months. I think these data imply 2 things.
First, the standard treatment is actually very effective and performed as one would have expected in the context of a transplant-eligible patient population.
Second, although it took longer for the addition of daratumumab to make a difference in the rate of progression, by 4 years there is a substantial difference in the percentage of patients experiencing disease progression. These data highlight the power and potency of adding an anti-CD38 antibody to induction, consolidation, and maintenance therapy for newly diagnosed multiple myeloma.
PERSEUS Primary Analysis: PFS Subgroup Analysis
Sagar Lonial, MD, FACP:
Looking at subgroups, nearly all patients benefited from the addition of daratumumab.1,2 There are a few groups, including patients with high and indeterminate cytogenic risk, non-White patients, and patients older than 65 years of age, where the benefit is less clear. However, these subgroups were relatively small, preventing investigators from conclusively determining whether addition of daratumumab impacts these patients differently.
PERSEUS Primary Analysis: Key Secondary Endpoints
Sagar Lonial, MD, FACP:
For the key secondary endpoint of CR or better, 87.9% of patients treated with D-VRd achieved CR or better, compared to 70.1% of patients who received VRd alone (P <.001).1,2 The MRD negativity rate at sensitivities of both 10-5 and 10-6 was statistically significant between treatment arms (P <.0001). Of note, among patients who received D-VRd, the percentage with MRD negativity at an assay sensitivity of 10-6 was almost double that of patients who received VRd alone.
The sustained MRD negativity at 12 months is the most important benchmark of efficacy. It is clear that addition of daratumumab provides a significant benefit over standard treatment.
MRD negativity was improved among patients who received D-VRd, including post consolidation and overall, regardless of assay sensitivity. In essentially every trial, the addition of daratumumab seems to improve the MRD negativity rate. These data further affirm these results.
Data on the other secondary endpoint of OS are currently immature and are forthcoming.
PERSEUS Primary Analysis: Safety
Sagar Lonial, MD, FACP:
Efficacy must always be balanced with safety. The addition of daratumumab was associated with minimal differences in AEs.1,2
With regards to hematologic AEs, there was more thrombocytopenia and neutropenia in the D-VRd arm.1,2 This is not surprising, since the combination of an IMiD, such as pomalidomide and lenalidomide, with an anti-CD38 mAb is associated with increased risks of neutropenia and thrombocytopenia in the relapsed setting.4,5 Fortunately, this can be addressed by dose modifications.
There was no difference between treatment arms in any grade or grade 3/4 anemia or febrile neutropenia.
Overall, most treatment-emergent AEs were relatively similar between the 2 arms, with a slightly higher incidence of infectious complications associated with D-VRd.1,2 This is a well-known phenomenon with daratumumab, and healthcare professionals (HCPs) are attuned to the need for prophylactic antimicrobials and empiric IVIG in certain subsets of patients to mitigate these risks.6 We now have a better understanding of the potential for infectious complications associated with daratumumab that perhaps was missing early on in this trial.
D-RVd vs RVd Induction Therapy for Transplant-Eligible Patients With NDMM: Real-world Outcomes
Sagar Lonial, MD, FACP:
Although the PERSEUS trial clearly demonstrated a significant benefit, the question now is whether real-world evidence supports these results.
In 2018, at the Winship Cancer Institute of Emory University, we switched to D-RVd as our standard induction therapy. At ASH this year, Dr Nisha Joseph, also from the Winship Cancer Institute of Emory University, presented data on real-world outcomes of treatment with D-RVd compared to RVd.
This was a retrospective, comparative analysis of the efficacy and safety of induction therapy with D-RVd vs RVd in newly diagnosed, transplant-eligible patients with standard- or high-risk multiple myeloma.7 Patients received either D-RVd or RVd as induction therapy, followed by autologous stem cell transplant. Subsequently, patients of standard risk received lenalidomide maintenance until disease progression, and patients of high risk received PI/IMiD maintenance therapy for 3 years or until disease progression.
The primary endpoint was the rate of CR or better; key secondary endpoints included PFS, OS, very good partial response or better, and MRD negativity.7 Since D-RVd has only been in use for the last few years, the RVd control arm, with 10-years of follow-up, included a larger number of patients with longer follow-up compared with the D-RVd arm.
D-RVd vs RVd: Baseline Characteristics
Sagar Lonial, MD, FACP:
At baseline, the 325 patients in the D-RVd group were similar to the 1000 patients in the RVd group in terms of demographics.7 Approximately 35% to 40% were Black and approximately 45% were female. For R-ISS staging, both treatment groups were relatively similar, with D-RVd having a slightly lower percentage of high-risk patients compared to RVd (15.4% vs 17.8%), which was not significantly different.
D-RVd vs RVd: Response Rates Over Time
Sagar Lonial, MD, FACP:
When assessing response rates after induction therapy and then again after transplantation, the rate of response improved over time regardless of which treatment was received.
For example, patients who received D-RVd induction therapy had approximately double the rate of stringent CR or better (from 21.5% to 42.8%) in the post-transplant setting. Similarly, patients who received RVd induction therapy had improved the rate of stringent CR or better (from 35.9% to 67.5%) in the post-transplant setting.
The rate of very good partial response or better for patients who received D-RVd improved from 86.4% after induction to 95.6% after transplant while patients who received RVd improved from 67.5% to 86.8% after transplant.
D-RVd vs RVd: Survival
Sagar Lonial, MD, FACP:
The PFS data were the most striking from this analysis. Although there was not much difference between treatment arms in the 1-year PFS rate—98% for patients who received D-RVd compared to 93% for patients who received RVd—marked differences come to light starting with 3-year PFS and resulted in an HR of 0.34 (91% CI: 0.2-0.67; P <.001).7
The 4-year PFS rate was 85% for patients who received D-RVd vs 61% for those who received RVd.1,2 These data are very similar to results reported from PERSEUS trial.
With respect to OS, there is a trend towards improved OS among patients who received D-RVd (HR: 0.53; 91% CI: 0.3-0.96; P = .037), with a 2-year OS rate of 94% compared to patients who received RVd at 91%.7 These data affirm the improvements in PFS reported in the PERSEUS trial and demonstrate that those improvements may translate to a difference in OS as well.1,2
D-RVd vs RVd: Survival by Risk
Sagar Lonial, MD, FACP:
The differences in PFS are particularly pronounced in patients with high-risk disease: the 2-year PFS rate was 83% in patients treated with D-RVd, vs 69% in those treated with RVd.7 The 2-year OS rate was 94% in the D-RVd arm, compared to only 79% in the RVd arm.
These results suggest that the addition of daratumumab may be important not just for patients with standard-risk disease, but also those with high-risk disease.7 Although the benefits of adding daratumumab were more pronounced for high-risk patients, there was numerical benefit in PFS and OS for standard-risk patients as well.
Currently, providers may only consider adding daratumumab to induction therapy for treatment of high-risk patients with newly diagnosed multiple myeloma. I would argue that these data, combined with the data from the PERSEUS trial, suggest that daratumumab adds benefit in both standard-risk and high-risk patients.1,2,7
D-RVd vs RVd: PFS by R-ISS and Race
Sagar Lonial, MD, FACP:
These findings were consistent among different races and ISS stages. Regardless of race or ISS stage, evident differences in median PFS favor the use of D-RVd compared to RVd alone.7
D-RVd vs RVd: Multivariate Analysis of OS and PFS
Sagar Lonial, MD, FACP:
In the multivariate analysis of OS and PFS, the hazard ratios also favor the use of D-RVd induction for almost all subgroups, similar to the results of the PERSEUS trial.1,2,7
Altogether, these real-world data are very similar to the findings from randomized phase III trials.
IsKia EMN24: Phase III Trial of IsaKRd vs KRd in Transplant-Eligible Patients With NDMM
Sagar Lonial, MD, FACP:
There are currently 2 CD38-directed mAbs approved for multiple myeloma: daratumumab and isatuximab. Currently, daratumumab is approved in both the newly diagnosed setting and for R/R multiple myeloma while isatuximab is approved in the R/R setting. However, there are ongoing trials with isatuximab combinations for newly diagnosed multiple myeloma.
The plenary session at ASH included the IsKia EMN24 trial, which was a randomized phase III trial of IsaKRd vs KRd in transplant-eligible patients with newly diagnosed multiple myeloma, with 151 patients enrolled in each arm.8
Patients received 4 cycles of induction therapy with either IsaKRd or KRd, followed by autologous stem cell transplant. Patients then went on to 4 cycles of IsaKRd or KRd consolidation and 12 cycles of light consolidation with IsaKRd and KRd.
The primary endpoint of this study was MRD negativity after consolidation therapy.8 Secondary endpoints included MRD negativity after induction therapy, PFS, and sustained MRD negativity throughout follow-up.
IsKia EMN24: Baseline Characteristics
Sagar Lonial, MD, FACP:
The baseline characteristics of the participants in this trial were relatively similar between the 2 treatment arms, with approximately 18% being categorized as high-risk and approximately 10% of patients in both arms having more than 2 high-risk cytogenetic abnormalities.8 Each treatment arm also had relatively similar proportions of patients within each R2-ISS or R-ISS stage.
IsKia EMN24: Patient Disposition
Sagar Lonial, MD, FACP:
In terms of patient disposition, roughly the same number of patients discontinued treatment in each group: 25 in the IsaKRd arm vs 15 in the KRd arm.8
Considering the most common reasons for treatment discontinuation, the rates of AEs and disease progression were relatively similar between the 2 groups.
Of note, 4 patients in the IsaKRd group discontinued due to medical decisions, while no patients in the KRd group cited medical decisions for discontinuation. There were 4 patient deaths in the IsaKRd arm, compared to only 1 in the KRd arm.
IsKia EMN24: MRD Negativity by Treatment Phase
Sagar Lonial, MD, FACP:
For the primary endpoint, MRD negativity (at 10-5) after consolidation therapy was 77% in the IsaKRd group vs 67% in the KRd group, resulting in an odds ratio of 1.67 (P = .049).8 At a 10-6 cutoff, the MRD negativity rate after consolidation therapy was 67% among patients who received IsaKRd vs 48% among patients who received KRd, with an odds ratio of 2.29 (P <.001).
The MRD data was also assessed by treatment phase, with patients in the IsaKRd arm consistently demonstrating increased MRD negativity at each phase.8
At the 10-5 cutoff, MRD negativity in the IsaKRd group compared to the KRd group was 45% vs 26% post induction, 64% vs 49% post stem cell transplant, and 77% vs 67% post consolidation.
At the 10-6 cutoff, MRD negativity in the IsaKRd group compared to the KRd group was 27% vs 14% post induction, 52% vs 27% post stem cell transplant, and 67% vs 48% post consolidation.
MRD negativity observed in the IsaKRd group was similar to the PERSEUS trial, with patients in the anti-CD38 or isatuximab arm demonstrating almost double the rate of MRD negativity compared to patients who did not receive isatuximab.1,2,8
IsKia EMN24: MRD Negativity by Cytogenic Risk
Sagar Lonial, MD, FACP:
Treatment with IsaKRd was also associated with improved MRD negativity in patients of all risk categories, with benefit being more pronounced in patients with high-risk cytogenic abnormalities.8
At the 10-5 cutoff, among patients with very high-risk genetics (defined as 2 or more cytogenetic abnormalities), MRD negativity in the IsaKRd group was 77% compared to 53% in the KRd group. There was also benefit in the cohort of patients with no cytogenetic abnormalities; MRD negativity was 79% and 72% in the IsaKRd and KRd groups, respectively.
Similarly, among patients with no high-risk cytogenetic abnormalities, MRD negativity at the 10-6 cutoff was 65% in the IsaKRd group vs 48% in the KRd group.8 Among patients with very high-risk genetics, the MRD negativity rate was 77% for IsaKRd vs 27% for KRd. This is the endpoint that I am the most excited for: MRD negativity was 2.5 times higher in patients with 2 or more high-risk cytogenetics who were treated with IsaKRd compared to patients who were treated with KRd.
IsKia EMN24: Safety
Sagar Lonial, MD, FACP:
Now let us consider safety. In terms of hematologic toxicities, both treatment arms experienced similar rates of anemia, although higher rates of grade 3 and 4 neutropenia occurred with IsaKRd.8 The IsaKRd group also experienced slightly higher rates of any grade thrombocytopenia, though the rate of grade 3 or 4 thrombocytopenia was similar in both groups. This is not surprising, since treatment with an anti-CD38 mAb and an IMiD typically does result in a slightly higher incidence of neutropenia.4,5 This can be managed with dose modifications or G-CSF, as needed.
The rate of infectious complications, excluding COVID-19, was relatively similar between the 2 arms.8 The rate of SARS-CoV-2 infection was slightly higher with IsaKRd, at 26% vs 19% with KRd.
The addition of isatuximab does not appear to exacerbate the risk of hypertension and thromboembolic disease known to be associated with carfilzomib-based approaches.8,9 Altogether, the rate of AEs is relatively balanced between the 2 arms.
Anti-CD38 Monoclonal Antibodies in Newly Diagnosed Multiple Myeloma: Clinical Implications
Overall, the phase III IsKia EMN24 trial demonstrated improved rates of MRD negativity with the addition of Isa to KRd vs KRd alone. Factoring in the collective outcomes of this trial, the PERSEUS trial, and the real-world data from the Winship Cancer Institute, the addition of an anti-CD38 antibody with either VRd, KRd, or lenalidomide plus dexamethasone (for older, frail patients) should now be considered standard of care for patients with newly diagnosed multiple myeloma.
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