CME
Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™
Released: March 21, 2023
Expiration: March 20, 2025
Shaji K. Kumar, MD:
Lenalidomide maintenance following induction, ASCT, and consolidation is standard of care for patients with newly diagnosed active MM, but the optimal duration of maintenance is an ongoing area of investigation.
In 3 phase III studies, patients randomly assigned to lenalidomide maintenance after ASCT given until disease progression experienced an improvement in median TTP vs placebo. 7-9 The PFS benefit of maintenance therapy with lenalidomide was confirmed with a meta-analysis of these trials.10 Similarly, the Myeloma XI trial demonstrated improved PFS with maintenance lenalidomide vs observation, including in patients with high-risk disease.11
The optimal duration of maintenance therapy has also been discussed in the context of the IFM 2009 and DETERMINATION trials. The IFM 2009 trial compared the addition of ASCT to induction with bortezomib/Rd (VRd) along with 2 cycles of consolidation and limited duration lenalidomide maintenance therapy, with lenalidomide administered for a maximum of a year.12 The phase III DETERMINATION trial was similar in design to IFM 2009, with VRd induction without or without ASCT, but was followed by indefinite lenalidomide maintenance until progression.13
Results from the DETERMINATION trial confirmed the PFS advantage seen with the addition of ASCT as a part of initial MM therapy, like what was reported in the phase III IFM 2009 trial. However, there are some differences in the PFS outcome between the 2 trials, which has been ascribed to the fact that those in the DETERMINATION trial stayed on maintenance until disease progression.
The question related to the ideal duration of maintenance therapy remains open in MM, both in transplant and nontransplant settings. There are ongoing trials that will help us answer this question, such as the ENDURANCE trial, which includes a second randomization to indefinite vs the limited duration of 2 years with lenalidomide maintenance.14
In the meantime, an analysis from the UK group sought to use the existing data from the Myeloma XI trial with a statistical modeling approach evaluating outcomes based on lenalidomide maintenance duration.15
Shaji K. Kumar, MD:
The Myeloma XI trial is an open-label, randomized phase III study with three randomizations, including induction therapy, transplant, and maintenance. In total, 1248 patients with newly diagnosed, symptomatic, transplant-eligible MM were randomized to either lenalidomide maintenance or observation after completing induction therapy and ASCT. The assigned induction therapy consisted of ≥4 cycles of either cyclophosphamide/thalidomide/dexamethasone (CTD), cyclophosphamide/lenalidomide/dexamethasone (CRD); or carfilzomib/cyclophosphamide/lenalidomide/dexamethasone (KCRD).
This trial has a long follow-up, with a median follow-up of 44.7 months and median duration of lenalidomide treatment of 28 cycles. Endpoints included overall PFS, PFS2 (second progression or death), landmark PFS by genetic risk subgroups, and MRD status.
In this report, a series of landmark PFS and PFS2 analyses were performed at various time points after randomization to help understand the point at which lenalidomide maintenance is no longer beneficial than no maintenance.
Shaji K. Kumar, MD:
Looking at the baseline characteristics, 730 patients were randomized to lenalidomide maintenance, and 518 patients were randomized to observation. In general, this patient population is as expected for newly diagnosed MM. The median age of patients was 61 years, and most patients had a WHO performance status of 0 or 1 and an International Staging System stage (ISS) of I or II. The underlying cytogenetic risk characteristics are also as expected, with approximately one third of the patients in both arms having a gain (1q) lesion and the typical distribution of other high risk cytogenetic abnormalities, including t(4;14), t(14;16), t(14;20), and del(17p).
Shaji K. Kumar, MD:
When looking at the overall trial data, you can see that lenalidomide maintenance was associated with a significant improvement in the PFS. In this trial, the median PFS with lenalidomide was 64 months vs 32 months with observation (HR: 0.52; 95% CI: 0.45-0.61; P <.001). These data are comparable with what has been observed in other phase III trials looking at lenalidomide maintenance.
Using PFS2 as a surrogate for OS, there is still a benefit for lenalidomide maintenance compared with observation (HR: 0.66; 95% CI: 0.54-0.81; P <.0001).
Shaji K. Kumar, MD:
An improvement in PFS for standard risk patients and for high-risk or ultra-high-risk patients was demonstrated with lenalidomide vs observation, which is consistent with findings from the other studies. The magnitude of benefit observed in the high-risk or ultra-high-risk patient population in this trial is larger than what has been reported in other trials and may have been because of some of these patients receiving suboptimal induction therapy that did not contain both lenalidomide and a PI, such as CTD or CRD.
Shaji K. Kumar, MD:
A benefit with lenalidomide maintenance was seen in both patients who were MRD negative (HR: 0.72; 95% CI: 0.55-0.95; P <.022) and MRD positive (HR: 0.37; 95% CI: 0.27-0.50; P <.0001). However, there was significantly more benefit observed for patients who were MRD positive at the beginning of randomization to maintenance.
Shaji K. Kumar, MD:
A series of landmark analyses of median PFS and PFS2 was performed at 2 years, 3 years, 4 years, and 5 years from randomization to either lenalidomide maintenance or observation. An improvement in median PFS with lenalidomide maintenance was demonstrated most clearly at the 2-year and 3 year landmark (P <.0001), with the difference in PFS for lenalidomide maintenance vs observation decreasing at the 4-year and 5-year landmark. By the 5-year PFS landmark analysis, there was no significant benefit with lenalidomide maintenance (P = .672).
A similar, but less pronounced, trend was seen with the landmark analyses of median PFS2.
Shaji K. Kumar, MD:
The investigators also assessed the landmark analyses of median PFS by cytogenetic risk and MRD status at the time of randomization. There are limited conclusions that can be drawn from the subgroup analyses, given that the number of patients in each subgroup is low, particularly at the longer time points.
However, at the 2-year and 3-year landmarks, there is an improvement in median PFS with lenalidomide maintenance for patients with standard risk MM (P = .032 and P = .019, respectively), like the data in the overall population. In the high-risk or ultra-high-risk subgroup, the P values are no longer significant beyond the 2 year landmark analysis.
When comparing by MRD status, there was no significant difference in PFS beyond the 2-year landmark analysis for patients with MRD-negative disease at the time of randomization. However, for patients with MRD-positive disease at the time of randomization, there was an improvement in median PFS with lenalidomide maintenance at the 2-year, 3-year, and 4-year landmark analyses.
These data suggest that a longer duration of lenalidomide maintenance may improve outcomes in patients with MRD-positive disease at the start of maintenance therapy. There was also a benefit for lenalidomide maintenance therapy beyond 2 or 3 years for patients with both standard-risk and high-risk MM. Longer follow-up is needed, but these data suggest that there may not be added benefit in continuing lenalidomide maintenance after 4 or 5 years.
Shaji K. Kumar, MD:
The investigators also assessed the landmark analyses of median PFS in the subgroup of patients with sustained MRD negativity, defined as sustained MRD negativity at 6 months after maintenance began. Patients with sustained MRD negativity who received lenalidomide maintenance had a trend toward PFS benefit vs those who received observation only (HR: 0.61; 95% CI: 0.34-1.09; P <.095). The 2 year landmark analysis also showed a PFS benefit with lenalidomide maintenance over observation (HR: 0.44; 95% CI: 0.21-0.92; P <.029). By the 3-year mark, there were too few patients to make any conclusions, but a trend toward a PFS benefit with lenalidomide remains (HR: 0.50; 95% CI: 0.16-1.57; P <.237).
Shaji K. Kumar, MD:
Considering the impact of lenalidomide maintenance on hematologic toxicity is important, particularly with prolonged therapy. Neutropenia and thrombocytopenia were observed across all time points with lenalidomide maintenance. The overall rate of these AEs was quite comparable over time, with a decrease in the rate of grade 2/3 events over time. No worsening bone marrow suppression was noted in this analysis.
Shaji K. Kumar, MD:
The authors concluded that this analysis of the phase III Myeloma XI trial demonstrated ongoing PFS improvement with continuing lenalidomide maintenance beyond 4-5 years compared with no maintenance in patients with newly diagnosed MM after induction and ASCT. This is one of the first datasets that we can use to extrapolate information on the optimal duration of lenalidomide maintenance. However, it is also important to remember that there are significant drawbacks to these kind of analyses because, in general, patients who stay on treatment longer are the ones who just tend to do better, even in their natural course of disease. Such analyses can be used to inform additional studies, but it is difficult to draw any conclusions to inform clinical practice. Based on the sum total of available data, continuing lenalidomide maintenance until disease progression, to the extent that patients can tolerate it, remains a reasonable approach until there are data to the contrary.
Sagar Lonial, MD:
These data are hypothesis generating, but there are many caveats. The largest caveat is the differences in PFS data from this trial and other similar studies. The median PFS with lenalidomide maintenance for all patients was 64 months, whereas the median PFS for standard risk patients was 67 months, and the median PFS for high-risk patients was 38 months. Based on previous studies, it seems odd that there was not more of an improvement in median PFS in the standard-risk subgroup. For example, in the DETERMINATION study, the median PFS was 67.5 months in the overall patient population but 82.3 months for patients with standard risk MM.13
For a patient who has achieved sustained MRD negativity at 3 years and was experiencing AEs related to lenalidomide, a case could be made to discontinue lenalidomide maintenance at that point. However, it is recommended that patients not having substantial AEs continue receiving lenalidomide maintenance until disease progression.
Sagar Lonial, MD:
Currently, there is no standard treatment approach for patients with high-risk newly diagnosed MM. Multiple prognostic factors for MM have been described with genetic abnormalities and response to the treatment being considered the most robust factors.16 Furthermore, the definition of risk is dynamic as the response to treatment changes with different treatment modalities.16 Patients with high-risk disease do not benefit as much from intensive treatment as standard-risk patients, but most patients with MM receive similar treatment.16,17
The UK OPTIMUM/MUKnine a study was designed to determine risk status for patients with newly diagnosed MM by performing molecular screening within 8 weeks.17 Participants identified as having ultra-high-risk MM or primary plasma cell leukemia were eligible for the MUKnine b portion, a single-arm phase II study of intensified therapy, with the goal of assessing therapy for a series of patients that typically are not enrolled on most other clinical trials.
This UK OPTIMUM/MUKnine study evaluated a unique 5 drug combination regimen with up to 6 cycles of daratumumab and cyclophosphamide plus VRd (DaraCVRd) followed by ASCT and consolidation with 6 cycles of Dara-VRd followed by 12 cycles of daratumumab plus bortezomib/lenalidomide, and then maintenance therapy with daratumumab plus lenalidomide until progression. The primary endpoints of the study were PFS at 18 months compared with historical data from the Myeloma XI trial with KCRd/CRd, ASCT, and lenalidomide maintenance.18
It is important to note that this 5-drug combination regimen may not be easily tolerated by all patients. The addition of daratumumab to cyclophosphamide and lenalidomide might be a challenge because of increased risk of cytopenias and infections. Furthermore, the phase II EVOLUTION study suggested that the addition of cyclophosphamide to VRd did not seem to improve ORR or 1-year PFS rate.19
Sagar Lonial, MD:
In this analysis, 107 patients were enrolled on the OPTIMUM/MUKnine trial and compared with 120 patients from the Myleoma XI trial. The median age of enrolled patients was similar between trials, at a median of 60 years of age in the OPTIMUM/MUKnine trial vs 62 years of age in the Myeloma XI trial. ISS stage and ECOG performance status were also similar.
The percentage of patients with high-risk cytogenetics was also similar between trial populations. In total, 53% of patients in the OPTIMUM/MUKnine trial and 56% of patients in Myeloma XI had double-hit genetics, and 77% in the OPTIMUM/MUKnine trial compared with 72% in Myeloma XI were classified as high risk based on SKY92 gene expression signature. Approximately 30% of patients in each trial had both double-hit and a high-risk SKY92 gene expression profile. Of the 107 patients in the OPTIMUM/MUKnine trial, 92 received ASCT and 74 completed consolidation 2.
Sagar Lonial, MD:
The primary endpoint assessed the 18-month PFS rate between both populations. A probability comparison showed a 99.5% chance that treatment with the DaraCVRd OPTIMUM/MUKnine protocol was superior to the KCRd/CRd Myeloma XI regimen at a median follow-up of 27.1 months (95% CI: 25.1-29.3). The 30-month PFS rate post consolidation 2 was 77% in the OPTIMUM/MUKnine study vs 39.8% in Myeloma XI, which suggests almost a doubling of the remission duration.
In addition, the OS estimates were also higher in the OPTIMUM/MUKnine study vs Myeloma XI. The 30-month OS rate post consolidation 2 was 83.5% in the OPTIMUM/MUKnine study vs 73.5% in Myeloma XI.
Sagar Lonial, MD:
Looking at MRD negativity in high-risk MM is an important first step, but ultimately it is PFS that matters. In the UK OPTIMUM/MUKnine cohort, there is loss of sustained MRD negativity at 10-5. Post consolidation 2, 46.7% of patients achieved MRD negativity, which declined a bit compared with posttransplant, where it was 63.6% of patients. Although 84% of patients were MRD negative, post ASCT remained MRD negative at the end of consolidation 2. This finding suggests the importance of sustained MRD negativity as opposed to a single timepoint being of relevance.
Sagar Lonial, MD:
When assessing safety, nothing unusual was reported. The amount of hematologic toxicity is as expected. During consolidation 2, grade ≥3 anemia, thrombocytopenia, and neutropenia were experienced in 3.8%, 27.5%, and 43.8% of patients, respectively. Infection rates appear reasonable, with grade ≥3 rates of 15% overall, given the intensity of therapy and the fact that patients received daratumumab in combination with a triplet or quadruplet during many phases of their therapy. No COVID-19 deaths were reported in the study.
Sagar Lonial, MD:
The UK OPTIMUM/MUKnine trial protocol included proactive dose reduction recommendations beginning at grade 1 AEs, which allowed patients to remain on study treatment. As such, 31% of patients required dose reductions because of bortezomib, and 42.5% of patients required dose reductions because of lenalidomide. For daratumumab, 98.8% of patients did not require any dose modifications.
Sagar Lonial, MD:
The investigators concluded that the 18-month PFS probability comparison of 99.5% chance superiority at 27.1 months median follow-up suggested a very high remission duration compared with Myeloma XI. This is not unexpected because of the intensive consolidation and maintenance therapy with daratumumab plus lenalidomide until progression. Most providers in the United States are now using an IMiD/PI as maintenance therapy for high-risk patients anyway, so the consolidation 2 with daratumumab plus bortezomib/lenalidomide for 12 cycles followed by daratumumab plus lenalidomide maintenance until progression is similar.
These data from the UK OPTIMUM/MUKnine trial further validate the idea that an intensive combination induction regimen, ASCT, aggressive consolidation, and then maintenance with combination therapy can improve outcomes in high-risk patients. Similarly, the phase II FORTE trial randomized participants with newly diagnosed MM into 3 induction–intensification–consolidation groups—KRd plus ASCT followed by KRd consolidation, KRd12 (12 KRd cycles), or carfilzomib plus cyclophosphamide plus dexamethasone (KCd) plus ASCT followed by KCd consolidation—was along with a second randomization to maintenance with carfilzomib plus lenalidomide or lenalidomide alone.20 This trial showed that more patients in the KRd group achieved at least a VGPR after induction compared with the KCd group, and the 3-year PFS in the maintenance comparison improved with carfilzomib plus lenalidomide vs lenalidomide.20 Findings from the FORTE trial and other trials with combination maintenance therapy suggest that this approach seems to be important for the high-risk cohort. Whether this approach is necessarily the way to go vs just using an IMiD/PI with or without an anti-CD38 in the maintenance phase is open for discussion.
Shaji K. Kumar, MD:
One of the highlights of ASH 2022 was the focus on the high-risk patient population in general. In addition to the presentation of these data, the phase II GMMG-CONCEPT trial of isatuximab plus KRd (isa-KRd) as induction and consolidation in ASCT-eligible or ASCT-ineligible patients with high-risk MM showed high rates of MRD negativity at the end of consolidation.21 Furthermore, retrospective data from Memorial Sloan Kettering Cancer Center evaluating outcomes with KRd and VRd induction in high-risk patient populations reported an improvement in PFS for patients receiving KRd vs VRd.22
These data also lead to additional questions for clinical practice. It is important to consider what contribution, if any, cyclophosphamide has in the induction therapy with dara-VCRd for patients with high-risk MM. It is quite possible that the efficacy findings would be similar with dara-VRd instead of dara-VCRd, based on historical data suggesting that cyclophosphamide contributes little in the first-line setting.
It is difficult to compare across trials, but another question is what the best PI is for patients with high-risk disease. The GMMG-CONCEPT study used isa-KRd and ASCT instead of a CD38-targeted monoclonal antibody plus VRd, and subgroup analyses from the FORTE trial and the ENDURANCE trials suggested that patients with gain/amp(1q) might have an advantage when receiving carfilzomib vs bortezomib.14,20 The FORTE trial with carfilzomib-based therapy showed PFS benefits with KRd plus ASCT and carfilzomib/lenalidomide maintenance for patients with high-risk MM, including those with gain/amp(1q).23 However, the ENDURANCE trial compared KRd with VRd, but both arms received maintenance with lenalidomide alone and showed inferior PFS with both KRd and VRd induction in patients with gain/amp(1q) or del(1p).24
The optimal 4 drug regimen for patients with high-risk newly diagnosed MM remains unclear, but including an anti-CD38 antibody, a PI, and an IMiD will likely be the minimum for induction, and a maintenance therapy with an IMiD combined with either a PI or an anti-CD38 antibody is likely going to be the backbone on which we will have to make further improvements.
Shaji K. Kumar, MD:
An ongoing question in MM is the role of ASCT for older patients with newly diagnosed MM. Many phase III studies have demonstrated an improvement in PFS with ASCT in patients with newly diagnosed MM who are younger than 65 years of age; however, the best approach for older patients is unclear. When used as HDT to be followed by ASCT, melphalan is dosed at 200 mg/m2 (MEL200) but in practice, the dose can be reduced in patients considered unfit for MEL200.25 Previous studies comparing outcomes with MEL200 to MEL dosed at 140 mg/m2 (MEL140) have had conflicting results.25
There have been multiple retrospective studies, including CIBMTR data, that have shown that patients older than 65 years of age can also benefit from ASCT.26 However, by principle, retrospective analyses include a highly selected group of patients from single institutions that were selected to receive ASCT for numerous reasons, which are not entirely captured in a retrospective analysis.
The phase III DSMM XIII trial is an important study assessing this question because it is a prospective trial that evaluated standard therapy with Rd with or without ASCT in patients with newly diagnosed MM who were in the age group of 60-75 years.
Shaji K. Kumar, MD:
DSMM XIII is a large open-label phase III study that enrolled 348 patients with newly diagnosed MM aged 60-75 years who were eligible for intensity-reduced HDT-ASCT and had an ECOG performance status of 0-2.27 Patients were randomized to receive either Rd, which was continued until disease progression, or Rd induction for 3 cycles, followed by ASCT with MEL140 and lenalidomide maintenance (Rd + MEL140 + R) that was given until disease progression. In this trial protocol, ASCT could include single or double transplant, which is one of the issues with study interpretation.
The primary endpoint of this study was PFS. The median follow-up was 68 months at the time of analysis, and patients in the Rd + MEL140 +R arm received 12 median cycles of lenalidomide maintenance following ASCT, whereas patients in the Rd arm received a median of 16 cycles of Rd.
Shaji K. Kumar, MD:
The patient population enrolled on DSMM XIII was fairly balanced in terms of the underlying baseline characteristics. The median age was 67-68 years with a median of 0.8-0.9 months since diagnosis. Most patients had a standard-risk cytogenetic profile. It is also important to note that approximately 11% of the patients had an ECOG performance status ≥2, which is not typical in the setting of a study evaluating ASCT, and 23% to 24% had renal impairment.
Shaji K. Kumar, MD:
Stem cell mobilization was performed in 76% of the patients who received continuous Rd vs 73% of patients who received Rd followed by planned ASCT. After stem cell mobilization, 72% of patients in continuous Rd arm continued Rd, whereas 66% of the patients in the Rd + MEL140 + R arm received an ASCT, as intended, and 59% received lenalidomide maintenance after ASCT. Nearly one third of the patients did not receive the treatment as assigned, particularly in the context of ASCT. AEs were the reason for discontinuation for 43% in the Rd + MEL140 + R arm and 28% in the Rd arm.
Shaji K. Kumar, MD:
Both treatment arms had similar response outcomes, with an ORR of 89.1% with Rd + MEL140 + R vs 87.9% with Rd. The rate of CR or stringent CR appeared to be marginally higher in the Rd + MEL140 + R arm (CR 14.9% in the Rd + MEL140 + R arm vs 13.4% in the Rd arm; stringent CR 12.1% in the Rd + MEL140 + R arm and 7.6% in the Rd arm).
Shaji K. Kumar, MD:
There was no difference between the arms in PFS, the primary endpoint, both in the ITT patient population (HR: 1.15; 95% CI: 0.87-1.51; P = .32) and the per-protocol population (HR: 1.14; 95% CI: 0.86-1.51; P = .36). Median PFS in the ITT patient population was 32 months in the Rd + MEL140 + R arm and 38 months in the Rd arm. Median PFS in the per-protocol patient population was 34 months in the Rd + MEL140 + R arm and 40 months in the Rd arm.
Shaji K. Kumar, MD:
The OS rates were similar with or without the MEL140 and transplant (HR: 0.99; 95% CI: 0.70-1.38; P = .93 in the ITT population) (HR: 0.96; 95% CI: 0.66-1.39; P = .81 in per-protocol population). Median OS in the ITT patient population was 94 months in the Rd+MEL140+R arm and 84 months in the Rd arm. Median OS in the per-protocol patient population was 95 months in the Rd+MEL140+R arm and 86 months in the Rd arm.
Shaji K. Kumar, MD:
When the data are viewed by age group, there was no difference in PFS between arms for patients aged 60-70 years (P = .14) or 71-75 years (P = .61). Median PFS in patients aged 60-70 years was 32 months in the Rd+MEL140+R arm and 42 months in the Rd arm. Median PFS in patients aged 71-75 years was 33 months in the Rd+MEL140+R arm and 32 months in the Rd arm.
Shaji K. Kumar, MD:
Again, there was no difference on OS observed between arms depending upon the disease stage, whether patients had ISS I or II (P = .52) or ISS III stage disease (P = .35). The median OS in patients with ISS stage I/II disease was 96 months in both arms. The median OS in patients with ISS stage III disease was 66 months in the Rd + MEL140 + R arm and 56 months in the Rd arm.
Shaji K. Kumar, MD:
The median PFS was 40 months for those patients who received an ASCT, keeping in mind that only 66% of the patients ended up getting a transplant in the Rd + MEL140 + R arm. Of those, 38 patients (21.8% of entire arm) ended up getting a single transplant and 77 patients (44.2% of entire arm) received a double transplant.
Shaji K. Kumar, MD:
There were no significant differences in the development of second primary malignancies. In total, 11% patients in the Rd + MEL140 + R arm and 14% of patients in the Rd arm had secondary primary malignancies. The numbers are consistent with what was previously observed in the transplant setting with maintenance.
Shaji K. Kumar, MD:
In this study, the investigators concluded that use of ASCT with MEL140 and lenalidomide maintenance did not significantly improve the PFS for patients with newly diagnosed MM who were between 60 and 75 years of age compared with continuous Rd without ASCT. However, there are several caveats. The first caveat is that this study used MEL140 conditioning for ASCT, and we know that outcomes with MEL140 are not as good as with MEL200.26 DSMM XIII utilized MEL140 for the older, more frail patient population enrolled on this study. However, based on these data, if patients are unable to tolerate MEL200 conditioning, they may not be appropriate candidates for ASCT.
Another caveat is that the interpretation of these data is impeded by inconsistencies in treatment. Only 66% patients in the Rd + MEL140 + R arm received ASCT, and 44.2% received a tandem transplant. Although patients who were not randomized to receive ASCT continued on the Rd until progression, patients on the Rd+MEL140+R arm discontinued dexamethasone after 3 cycles of induction therapy. It is difficult to determine if these inconsistencies have much of an implication in the results of this trial, but they could cloud some of the comparisons and results observed in this study.
Sagar Lonial, MD:
There are a few challenges with this dataset. For patients up to age 72, most providers in the United States likely would give MEL200 for ASCT and would only consider MEL140 for patients older than 70 79 years of age as a standard. However, we would also not recommend Rd induction but would prefer a triplet-based induction regimen, like VRd. So, we must consider the impact of suboptimal induction and the impact of the MEL dose in this trial. If patients received VRd induction followed by MEL140 and ASCT followed by lenalidomide maintenance, they may achieve longer PFS. Many groups have published on the benefit of transplant, regardless of dose, in patients older than 70 years of age. This is the first randomized trial to assess ASCT, regardless of the dose of MEL in patients older than 70 years of age. However, it may have been useful to limit enrollment to patients aged 70 years or older to really understand the impact of ASCT with MEL140 and then given triplet combination as induction instead of a doublet.
Sagar Lonial, MD:
Continuing with the discussion of how to manage older, frail patients with newly diagnosed MM, the IFM 2017 03 trial aimed to assess a dexamethasone sparing treatment approach in this patient population. The rationale for this trial design is to understand whether dexamethasone is needed or if using a limited course of dexamethasone is feasible.
IFM 2017-03 was an open-label, multicenter phase III trial in patients who were 65 years of age or older with newly diagnosed MM and an IFM frailty score ≥2.28 Patients were randomized either to receive daratumumab plus lenalidomide (DR with a limit course of low dose dexamethasone 20 mg once weekly during cycles 1 and 2 and as pre/postmedication along with subcutaneous daratumumab or to receive standard treatment with Rd.
Sagar Lonial, MD:
The baseline characteristics were similar between the 2 treatment arms in this trial. It is important to highlight the percentage of patients that had a frailty score >2. In the group of patients who received DR, 41% of patients had a frailty score of 3, 22% had a frailty score of 4, and 9% had a frailty score of 5. In addition, approximately 60% of patients enrolled were older than 80 years in both arms.
So, this is not the standard patient population that typically is included in clinical trials. This patient population represents more of a real-world population, including a large percentage of patients who have MM.
Sagar Lonial, MD:
At this analysis, the ORR was 96% in patients receiving DR vs 85% in patients receiving Rd (P =.001). In addition, rates of CR and VGPR or better were higher with DR vs Rd (17% vs 10% and 64% vs 43%, respectively).
MRD negativity at 10-5 was also higher in patients receiving DR vs those receiving Rd (10% vs 3%, respectively). Of importance, the percentage of patients who achieved VGPR or better increased over time and, by Month 12, 71% of patients receiving DR achieved VGPR or better vs 55% with Rd.
Sagar Lonial, MD:
The safety profile of the dexamethasone-sparing DR regimen was not worse than the standard treatment with Rd. For example, there were similar rates of treatment discontinuation and rates of serious AEs between treatment arms.
It was quite interesting to also observe similar rates of infectious complications between the 2 arms (13% with DR vs 18% with Rd). One might anticipate more infections in the daratumumab containing arm, as this is a common AE with many daratumumab-based combinations. However, perhaps tapering down dexamethasone quickly with DR had a significant impact on reducing the rate of infectious complications with this regimen.
We already know that DR has a higher rate of neutropenia, so the higher rate of hematologic AEs, including neutropenia, with DR vs Rd (55% vs 26%) was not a surprise.
Sagar Lonial, MD:
The safety data by frailty score also appear relatively similar. The rate of non–COVID-19 infections or pneumonia was slightly lower in patients receiving DR compared with Rd regardless of frailty score. However, the rate of COVID-19 infections was a bit higher, at 10% with DR vs 6% with Rd for those with frailty score 4 and 5.
Sagar Lonial, MD:
The authors concluded that with the dexamethasone-sparing regimen, DR, there was a high ORR, comparable with what we typically see with Rd, and higher MRD negativity rates with a favorable safety profile without an increase in pneumonia or non–COVID-19 infections, likely because of less dexamethasone. We are currently awaiting longer follow-up for information on the median PFS comparison between these 2 regimens. However, unless the median PFS is shorter with DR, dexamethasone-sparing treatment with DR may certainly become a very valuable regimen for older, frailer patients. It also teaches us an important lesson about the ability to taper down or discontinue dexamethasone earlier on.
Shaji K. Kumar, MD:
This is an important study that adds 1 more piece of evidence to the theme that less dexamethasone is better. The phase III E4A03 ECOG trial showed that lower dose dexamethasone (40 mg once weekly) improved OS vs dexamethasone 40 mg on a 4-day schedule for patients with newly diagnosed MM treated with Rd.29 Then, a phase III trial from the Italian EMN group showed that 9 cycles of Rd followed by maintenance with lenalidomide alone had similar efficacy to Rd with continued dexamethasone.30 Now, IFM 2017-03 suggested that discontinuing dexamethasone after the first 1 or 2 cycles, except as needed for prophylaxis with subcutaneous daratumumab, may be better than using a regimen that contains dexamethasone.
The disadvantage of this study is that it does not directly compare DR with the limited dexamethasone vs the standard regimen with daratumumab/lenalidomide/dexamethasone, as it was evaluated in the MAIA study.31 The IFM 2017-03 trial was designed before results from MAIA became available, so the question remains whether full dose dexamethasone for a few cycles is better than a very small dose of dexamethasone for a longer time period.
There is a higher rate of neutropenia in the dexamethasone-sparing arm in IFM 2017-03, which has also been observed in other studies as well. Treatment with lenalidomide is known to increase the risk of neutropenia, and this may be amplified with the combination of daratumumab. It is thought that steroids, including dexamethasone, can help alleviate the risk of neutropenia, so the question is whether 40 mg of dexamethasone weekly is preferred or if a smaller dose of dexamethasone continued for a longer period would help mitigate the risk of neutropenia.
Sagar Lonial, MD:
Dexamethasone can add some benefit in terms of symptom management but certainly not at the doses that we typically use. Very low–dose dexamethasone for symptom management may be able to enhance the efficacy of lenalidomide. However, this study gives us food for thought for discontinuation or tapering dexamethasone much earlier.
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