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Sagar Lonial, MD:
The GRIFFIN trial was a randomized phase II study of 207 patients with newly diagnosed MM who are ASCT-eligible.2,13 Patients were randomized to either VRd or daratumumab plus VRd (D-VRd). Patients on the VRd arm (n = 103) received 4 cycles of VRd induction, followed by ASCT, 2 consolidation cycles of VRd, and ongoing lenalidomide maintenance cycles. The D-VRd arm (n = 104) received the same regimen with the addition of daratumumab in the induction, consolidation, and maintenance phases. The primary endpoint was stringent CR (sCR) by the end of consolidation.
Previous reports from the GRIFFIN trial showed that D-VRd improved the rate of stringent CR (sCR) by the end of post-ASCT consolidation (42.4% vs 32.0% with VRd; odds ratio: 1.57; 95% CI: 0.87-2.82; 1-sided P = .068) and met the prespecified primary endpoint with 1-sided α of 0.10. Responses continued to deepen at longer follow-up with sCR rates of 62.6% with D-VRd vs 45.4% with VRd (P = .0177) reported at a median follow-up of 22.1 months.13
In this analysis of the maintenance phase of the GRIFFIN trial presented at ASH 2021, investigators assessed efficacy and safety after patients completed 2 years of maintenance treatment with either daratumumab plus lenalidomide (D-R) or lenalidomide alone (R).2
Sagar Lonial, MD:
Patients were stratified by ISS disease stage and creatinine clearance. The arms were well balanced in age, sex, Eastern Cooperative Oncology Group performance status, and cytogenetics.
Sagar Lonial, MD:
At the 2‑year point in the maintenance phase, what jumped out was the significant difference between the D-VRd and the VRd arms in the sCR response (66% vs 47%, respectively; P = .0096) and in the percentage of CR (16% vs 13%, respectively; P = .0013).
Sagar Lonial, MD:
This table breaks out the percentage of responses after each phase of treatment—after induction, consolidation, and 1-year and 2-year maintenance phases. It illustrates the increasing positive impact of both regimens, as responses deepen over time at each time point in therapy.
Sagar Lonial, MD:
In the intention-to-treat population, MRD negativity rates remained significantly higher in the D-VRd arm vs the VRd arm at both the 10-5 threshold (64% vs 30%; P = .0001) and the 10-6 threshold (36% vs 15%; P = .0007) after 2 years of maintenance therapy. Rates of MRD negativity were also higher in the D-VRd arm vs the VRd arm in those who achieved ≥CR at both the 10-5 threshold (78% vs 47%; P = .0003) and the 10-6 threshold (43% vs 22%; P = .0121). The 10-6 threshold is what I am most interested in, and the MRD negativity rate is almost double for the D-VRd arm.
The second key point to consider is the rate of sustained MRD negativity. Like the FORTE study,14 where the depth of response as measured by the rate of ≥sCR is similar between the 2 highly effective regimens, the rate of sustained MRD negativity was higher for patients who received ASCT vs those who did not, and this corresponded to a significant reduction in the risk of progression or death. In GRIFFIN, I think the addition of daratumumab to VRd resulted in a much higher sustained MRD negativity rate for more than 12 months at 44.2% vs 12.6% for VRd, which again is an almost fourfold improvement in sustained MRD negativity.
The rate of MRD negativity was also assessed in patients with either standard-risk or high-risk cytogenetics after 24 months of maintenance. Although the difference was much greater for patients with standard risk, there was still an improvement with the addition of daratumumab to VRd in patients with high-risk cytogenetics. However, there were some other differences in patient population based on cytogenetic risk that favored daratumumab, and these numbers suggest the need for additional data to understand the potential benefit more fully with daratumumab in this risk group.
Sagar Lonial, MD:
This study was not powered for PFS or OS, and median PFS and OS have not been reached in either group. The rates of PFS at 36 months favor D-VRd over VRd (89.7% vs 81.2%, respectively) and the HR for PFS was 0.46 (95% CI: 0.21-1.01).
The OS results are almost identical in both arms at 24 and 36 months, with the HR for OS of 0.90 (95% CI: 0.32-2.57). These comparisons mimic what we have seen in the RVD1000 series.15 Although this is a small set of patients, it does show similar trends to larger data sets. It will be interesting to continue to assess long-term PFS and OS from this trial, but I think the results will hold up and be a good reference point for the potential added benefit of daratumumab in the front-line setting.
Sagar Lonial, MD:
Although we see higher percentages of neutropenia, thrombocytopenia, and leukopenia in the D-VRd cohort, the addition of daratumumab to VRd did not increase the rates of other treatment-emergent AEs appreciably. Overall, the rates of TEAEs were as expected, based on the known safety profiles of these agents.
Sagar Lonial, MD:
Focusing on key AEs with onset during the maintenance phase, there was a slightly higher incidence of any upper respiratory tract infection in the D-VRd arm compared with VRd (53% vs 41%). But the overall rate of infection and the rate of pneumonias and other non-upper respiratory tract infections were similar. This finding was a surprise to me, based on other data with daratumumab. But based on this randomized assessment, the long-term administration of daratumumab does not seem to result in a dramatic increase in infections, which is important to note.
Sagar Lonial, MD:
The long-term results of the phase II GRIFFIN trial suggest that rate of sCR, depth of response, and durability of response for ASCT-eligible, treatment-naive patients are better with the addition of daratumumab to VRd in the induction and consolidation phases.2 Likewise, adding daratumumab to lenalidomide maintenance continued to show significant improvement in response vs lenalidomide maintenance alone. The rate of PFS at 36 months is also beginning to diverge, with HR for PFS of 0.46. There were no new safety concerns identified at this point.13,15 These safety results may be a result of significant vigilance in terms of infection prophylaxis, including intravenous immunoglobulin use in appropriate patients, but this is a lesson learned with chronic daratumumab administration even before this trial.
Shaji Kumar, MD:
I think this is a very important trial, especially given that VRd is increasingly the backbone that we are trying to build on for newly diagnosed MM. The daratumumab/VRd combination is highly effective, and I agree with you about the importance of the MRD negativity 10‑6 threshold. The deeper the response achieved, the longer the response will last, particularly for high‑risk patients.
I think the GRIFFIN trial also leaves several questions unanswered, including the question of the length of therapy needed for a 4-drug regimen. This question is further highlighted by the data from the CASSIOPEIA trial, which showed that there was a benefit with daratumumab maintenance vs observation in a second randomization in this trial; however, the benefit with daratumumab maintenance was primarily in patients who were not exposed to daratumumab during induction and consolidation.4 Given that there is no second randomization in GRIFFIN, we do not know what would have happened if some of these patients had gone off daratumumab after a defined period of time or not received maintenance therapy. I hope that the GMMG-HD7 study5 and the ongoing phase III PERSEUS study (NCT03710603)16 can give us some answers regarding the role of daratumumab in maintenance for patients who receive daratumumab as part of induction therapy.
The other unanswered question from this trial is why a significant number of patients in both arms did not proceed with maintenance therapy. In the D-VRd arm, 87% of patients proceeded to D-R maintenance but only 68% of patients in the VRd arm proceeded to R maintenance. The loss of patients in the VRd arm was more surprising than the D-VRd arm when you look at the data from the GRIFFIN trial.
Sagar Lonial, MD:
Yes, I think you bring up an important point. These and other studies show that we can safely use maintenance therapy to prolong the disease-free interval for MM. Our current treatment paradigm hinges on “the longer you can keep patients on therapy, the better.” I suspect we will see additional data to support this in the near future. Many of the treatment decisions in GRIFFIN were driven by the protocol, but in the RVD1000 series, the median PFS was 65 months for all patients, and the median duration of lenalidomide maintenance was 64 months.15
I think that keeping patients on maintenance therapy, even at a low dose, is an important concept for MM. In clinical practice, after patients have achieved CR for an extended time (eg, 2 years) and reached a certain depth of response, some clinicians consider discontinuing maintenance. However, that is not the model that produces long PFS and maximum depth.
Although there are specific AEs (eg, chronic diarrhea) and other issues that are associated with long‑term administration of lenalidomide. Strategies to mitigate or address those AEs are important strategies to keep patients on maintenance to maximize duration of that first remission.
Shaji Kumar, MD:
GEM2014MAIN is a randomized phase III trial of 332 patients with newly diagnosed MM and stable disease or better who were treated on the GEM12MENOS65 trial. Patients underwent induction with VRd, ASCT, and VRd consolidation. In GEM2014MAIN, all patients received maintenance treatment in 28-day cycles with lenalidomide 15 mg/day on Days 1-21 and dexamethasone 20 mg/day on Days 1-4 and 9-12. One arm also received the oral drug ixazomib 4 mg/day on Days 1, 8, and 15 of the cycles. After 2 years, patients who achieved MRD negativity discontinued treatment. Patients who were MRD positive continued with Rd maintenance alone for 3 years.17
Lenalidomide has become the standard maintenance therapy in the post‑transplant setting. However, some data have suggested that adding a PI or daratumumab can improve the duration of response, particularly for patients with high-risk disease. This GEM2014MAIN study assessed ixazomib, an oral PI, in this setting.
Shaji Kumar, MD:
Patients were randomized to receive ixazomib plus Rd (IRd) (n = 171) or Rd alone (n = 161). Patient characteristics and prognostic factors were evenly distributed across treatment arms; however, the proportion of patients who achieved sCR or CR and MRD negativity on the GEM12MENOS65 trial was slightly skewed toward the IRd arm.
Shaji Kumar, MD:
Improvement in the depth of response during maintenance was seen in both the IRd and Rd arms, with improvement to sCR and CR in 16.4% vs 19.4%, respectively, and improvement in MRD negativity in patients who achieved sCR/CR in 8.2% vs 13.3%, respectively.
These numbers tend to favor the Rd arm, but these data could be confounded by the initial smaller proportion of patients in a deep response at enrollment onto the GEM2014MAIN trial.
Shaji Kumar, MD:
There was no difference in the rate of PFS at 5 years with the addition of ixazomib to Rd (IRd: 62% vs Rd: 63%; P = .785) at a median follow-up of 56 months. There was also no difference in OS at 5 years with the addition of ixazomib to Rd (P = .875).
In addition, no appreciable differences were found between the 2 arms in various subgroup analyses, including based on the ISS stage, cytogenetics, MRD status, or extramedullary disease. Although PFS for both arms was virtually the same, investigators reported that PFS was significantly prolonged for patients in both groups who were MRD negative vs those who were MRD positive at 2 years (P <.0001).
Shaji Kumar, MD:
This study reported greater toxicity with IRd, leading to dose reduction and discontinuation of ixazomib, as anticipated. Thrombocytopenia was significantly more prevalent with IRd compared with Rd (16.3% vs. 7.4%; P = .011). Also, 9.3% of the patients who received ixazomib discontinued treatment because of AEs.
Shaji Kumar, MD:
After induction with VRd, followed by ASCT and VRd consolidation, this trial failed to demonstrate an advantage of adding ixazomib to Rd as 2 years of maintenance therapy. These results have limited implications for our current clinical practice because we do not typically include dexamethasone with lenalidomide maintenance. Furthermore, other studies with ixazomib maintenance have suggested that ixazomib offers only a modest improvement in PFS as maintenance, not to the same degree as has been shown in lenalidomide maintenance trials.18,19
In this context, using Rd combination maintenance is likely more effective than lenalidomide alone and the incremental addition of ixazomib produced limited results. Whether ixazomib has a role to play with lenalidomide as maintenance may never be addressed, especially since we have more effective therapies and agents moving into the maintenance setting.
Sagar Lonial, MD:
I agree, and I think this trial may have been trying to ask too many questions at once. Using IRd as maintenance for a standard‑risk patient does not make a lot of sense to me. In my clinical practice, we use lenalidomide alone as maintenance therapy for patients with standard-risk MM and reserve more aggressive maintenance with an IMiD, a PI, and dexamethasone for patients with high-risk features. When we do use dexamethasone for high-risk patients, we typically remove the steroids after 1 year of maintenance.
I do have some patients with high-risk MM receiving IRd maintenance; however, these patients were previously on VRd maintenance and were switched to IRd after they already had achieved a response to VRd consolidation and maintenance. These patients were doing well on triplet maintenance but did not want to come into the office as frequently, particularly during the height of the pandemic, so we switched them to the all-oral IRd regimen.
The GEM2014MAIN study used ixazomib from the beginning and, therefore, included patients who might not have responded to standard-of-care VRd. This may account for why even the high‑risk patients did not see an appreciable difference in the treatment.
I also wonder whether this study was powered to see a difference in the high‑risk group. This was not a large study, and it is possible that we may have seen differences with a bigger sample size. I think the patient population was too heterogeneous, which may have prevented showing where ixazomib can add its greatest benefit.
Shaji Kumar, MD:
I agree and focusing on the patient population most likely to benefit may be the better strategy to assess potential benefit with IRd.
Continuity of therapy is probably most important for high-risk patients. One of the disadvantages of all the ixazomib maintenance trials is the limited duration of maintenance. Had we focused on the high‑risk patient population and given maintenance until progression, we might have seen an impact on controlling the disease.
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