CME
Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™
Released: March 22, 2021
Expiration: March 21, 2022
Sagar Lonial, MD:
Patients with newly diagnosed MM who are eligible for autologous stem cell transplantation (ASCT) typically receive induction therapy with bortezomib (V) plus lenalidomide (R) and dexamethasone (d) (VRd) followed by ASCT, consolidation,1,2 and R maintenance therapy.3,4
GRIFFIN was a multicenter, open-label, randomized phase II trial comparing daratumumab (D) plus VRd (D-VRd) induction and daratumumab plus lenalidomide (D-R) maintenance with VRd induction and R maintenance in 207 patients newly diagnosed with MM.5,6 A primary analysis (median follow-up: 13.5 months) found that D-VRd increased the rate of stringent CR (sCR) by the end of consolidation (42.4% for D-VRd vs 32.0% for VRd; 1-sided P = .068), increased the rate of measurable residual disease (MRD) negativity (median follow-up: 22.1 months; 51.0% D-VRd vs 20.4% VRd), and increased estimated 24-month PFS (95.8% vs 89.8%).
Sagar Lonial, MD:
At ASH 2020, Kaufman and colleagues7 presented updated data on GRIFFIN after 12 months of maintenance therapy to help answer the question of the role of D-R in the maintenance setting. As mentioned, enrolled patients (N = 207) were ASCT eligible, had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2, and had creatinine clearance ≥ 30 mL/min. Patients were randomized 1:1 to receive D-VRd induction and consolidation after ASCT followed by D-R maintenance (n = 104) or VRd induction and consolidation after ASCT followed by R maintenance (n = 103).
Daratumumab was given IV at 16 mg/kg on Days 1, 8, and 15 of cycles 1-4 (induction) and on Day 1 of cycles 5-6 (consolidation). During maintenance from cycles 7-32, 16 mg/kg daratumumab was administered every 4 or 8 weeks. Bortezomib was given SC on Days 1, 4, 8, and 11 of cycles 1-6 at 1.3 mg/m2. Lenalidomide was given PO at 25 mg on Days 1-14 of cycles 1-6, 10 mg was given on Days 1-21 of cycles 7-9 at the start of maintenance, and if tolerated 15 mg was given on Days 1-21 of cycles 10-32. Dexamethasone was given PO on Days 1, 2, 8, 9, 15, and 16 at 20 mg for cycles 1-6.
The primary endpoint of this study was sCR by the end of consolidation with a 1-sided α = .1. Secondary endpoints were MRD, CR, ORR, and increased VGPR.
Sagar Lonial, MD:
The median age of patients in the D-VRd and VRd arms were similar at 59 and 61 years, respectively. Approximately 60% of patients in each arm were male. Approximately 90% of patients had an ECOG PS 0-1 and baseline creatinine clearance > 50 mL/min. By cytogenic profile, approximately 15% of patients in both arms were at high risk, and approximately 13% of enrolled patients had International Staging System (ISS) stage III MM.
Sagar Lonial, MD:
The median follow-up at the maintenance therapy cutoff was 27.4 months, at which time 87% of patients receiving D-VRd and 68% of patients receiving VRd had begun maintenance therapy. Discontinuation during maintenance therapy occurred in 12% of patients receiving D-VRd and 17% of patients receiving VRd.
At the 12-month maintenance cutoff, 63.6% of patients in the D-VRd arm achieved sCR compared with 47.4% in the VRd arm (P = .0253), which is quite striking. To put this into perspective, 47.4% is similar to what our group has observed in a study of 1000 “real-world” patients who received VRd.8 There also was a significant improvement in ≥ CR response (P = .0014). These data showed that daratumumab significantly improved the depth of response in newly diagnosed MM patients compared with VRd therapy alone.
Sagar Lonial, MD:
The difference in MRD negativity is even more striking. The frequency of MRD-negative patients in the intention-to-treat population was more than doubled within the D-VRd arm (62.5%) compared with the VRd arm (27.2%; P < .0001).
Durable MRD negativity lasting ≥ 6 months was achieved in 37.5% of the D-VRd arm and 7.8% of the VRd arm (P < .0001). MRD negativity lasting ≥ 12 months was achieved in 28.8% of the D-VRd arm and 2.9% of the VRd arm (P < .0001).
Although there is a major focus on when and how to do MRD testing, I think durable or sustained MRD negativity is the heart of what we are trying to achieve.
Sagar Lonial, MD:
The PFS and OS data after maintenance therapy differentiate the GRIFFIN study from one of the major flaws in the phase III CASSIOPEIA trial.9 The GRIFFIN trial compared R maintenance alone vs the addition of daratumumab to R maintenance, but the CASSOPEIA trial only included randomization between daratumumab vs observation in the maintenance phase.
At a median follow-up of 27.4 months, median PFS and OS were not reached in either study arm. This speaks to the power of a strong induction regimen followed by maintenance therapy in driving durable PFS and OS, as well as the difficulty in being able to see differences in PFS and OS between these approaches with shorter follow-up.
Based on these data, whether you give R maintenance alone or D-R maintenance, patients are able to achieve durable PFS and OS. There are hints toward an improvement in PFS with D-R maintenance, but longer follow-up is needed to confirm this.
Sagar Lonial, MD:
Nothing was new or unexpected in terms of treatment-emergent adverse events (TEAEs). The most common hematologic TEAE was neutropenia, which occurred in 61% of patients in the D-VRd arm and 39% of patients in the VRd arm. Neutropenia was grade 3/4 in 43% of the D-VRd group and 24% of the VRd group. Thrombocytopenia, leukopenia, anemia, and lymphopenia also were common in both groups.
Of note, upper respiratory tract infections were common, affecting 68% of the D-VRd group and 50% of the VRd group. Grade 3/4 upper respiratory tract infections occurred in 5% of patients receiving D-VRd and 2% of patients receiving VRd. When managing patients receiving longer-term daratumumab administration, we need to pay attention to the potential for infections, with antibiotic prophylaxis and considerations for IVIG administration as needed. At my center, we do not routinely give IVIG as prophylaxis but will consider it for patients with hypogammaglobulinemia who are at high risk for or are exhibiting signs of infection.
It is also important to note that infusion-related reactions occurred in 43% of the D-VRd group, with 6% of these reactions being grade 3/4.
Sagar Lonial, MD:
As I mentioned before, upper respiratory tract infections were common across both treatment groups, with slightly more infections in the D-VRd arm. After upper respiratory tract infections, pneumonia, sinusitis, influenza, and nasopharyngitis were the most common infections observed. The rate of any grade and grade ≥ 3 infections were similar between treatment arms.
Sagar Lonial, MD:
The phase II GRIFFIN trial included ASCT-eligible patients with newly diagnosed MM who were randomized to receive D-VRd followed by D-R maintenance or VRd followed by R maintenance. D-VRd followed by D-R maintenance led to significant improvements in sCR and depth of response compared with VRd followed by R maintenance.
Many patients had achieved sCR at the 12-month maintenance cutoff: 63.6% of the D-VRd group compared with 47.4% of the VRd group (P = .0253). Responses deepened over time, with more patients in the D-VRd group achieving ≥ CR compared with previous analyses (P = .0014). Safety at the 12-month maintenance cutoff also was in keeping with the primary analysis, and the 27.4-month follow-up survival data are encouraging, with a 24-month PFS of 94.5% and OS of 94.7%.
Shaji Kumar, MD:
The combination therapy VRd has been the default initial treatment for newly diagnosed MM, particularly in ASCT-eligible patients. In older, often frailer patients who are ASCT-ineligible, we historically used either VRd-lite or a doublet therapy, such as Rd.
Now, based on data from the ALCYONE trial and the primary analysis of the MAIA trial, daratumumab is approved in combination with bortezomib, melphalan, and prednisone or Rd for newly diagnosed, ASCT-ineligible patients with MM.10
In the primary analysis of the ongoing, large, multicenter, open-label, randomized phase III MAIA trial (N = 737), the addition of daratumumab to Rd (D-Rd) reduced risk of progression or death by 44% and increased MRD negativity rates (24.2% for D-Rd vs 7.3% for Rd alone) in patients who were newly diagnosed with MM and ASCT ineligible.11 The MAIA trial was pivotal in changing the treatment approach for older patients who are ASCT ineligible.
Shaji Kumar, MD:
At ASH 2020, my colleagues and I presented an updated analysis of MAIA with a longer-term follow-up of approximately 4 years.12,13
Enrolled patients had an ECOG PS 0-2 and creatinine clearance ≥ 30 mL/min. Patients were stratified by ISS (I vs II vs III), region (North America vs other), and age (younger than 75 years vs 75 years or older). Patients were randomized 1:1 to receive D-Rd (n = 368) or Rd (n = 369).
Daratumumab was administered IV at 16 mg/kg every week for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks for cycles 7+. Lenalidomide was administered PO every day at 25 mg on Days 1-21 of each cycle, and dexamethasone was given once weekly PO or IV at 40 mg. Enrolled patients continued on 28-day cycles of therapy until disease progression or unacceptable toxicity occurred.
The primary endpoint of MAIA was PFS, with secondary endpoints of time to progression, change in MRD by next-generation sequencing, time to second disease progression (PFS2), OS, ORR, and safety.
Shaji Kumar, MD:
Baseline characteristics were well‑balanced between the 2 arms. The median age was 73 years, and approximately 15% of patients had an ECOG PS of 2. ISS stage distribution was fairly even between stages I, II, and III, as was the frequency of patients with measurable disease. As one would expect, nearly 15% of patients had a high‑risk cytogenic profile.
Shaji Kumar, MD:
At this analysis, the median duration of study treatment was 42.8 months for patients in the D-Rd arm and 22.6 months for patients in the Rd arm. Discontinuation of study treatment occurred in 48.4% of the D-Rd group and 74.8% of the Rd group, with 23.4% of patients in the D-Rd group and 31% of patients in the Rd group stopping due to progressive disease. An additional 24.5% of patients in the D-Rd group stopped receiving lenalidomide but continued on daratumumab therapy. There were 107 deaths in the D-Rd arm and 132 deaths in the Rd arm.
Shaji Kumar, MD:
A distinct benefit for PFS has emerged with the longer-term follow-up of this study (median follow-up: 47.9 months). Patients in the D-Rd arm continue to have a PFS benefit compared with the Rd arm, with a 48‑month PFS of 60% vs 38% for Rd (HR: 0.54; 95% CI: 0.43-0.67; P < .0001).
Shaji Kumar, MD:
Median PFS favors D-Rd in almost all patient subgroups, which is important with longer‑term follow-up. Even high‑risk patients seem to benefit more from D-Rd vs Rd, something that was not quite evident at the time of the initial analysis. A benefit with D-Rd is also evident in patients with an ECOG PS ≥ 2 and in patients with compromised renal function. It is important to note that patients 75 years of age or older appeared to have comparable benefits to patients younger than 75 years of age.
Shaji Kumar, MD:
With the longer follow-up, patients’ responses seemed to deepen, with 34% of patients achieving sCR with D-Rd at a median follow-up of 47.9 months vs 30% at a median follow-up of 28 months. The rates of ≥ CR and ≥ VGPR were higher with D-Rd compared with Rd, regardless of the median follow-up time.
In addition, the median duration of response (DoR) was not yet reached for the D-Rd arm and was 44.3 months for the Rd arm.
Shaji Kumar, MD:
MRD assessments show a significantly higher percentage of MRD-negative patients in the D-Rd arm compared with the Rd arm, with the percentage continuing to increase over time. The latest data from the 47.9-month update showed that 31% of patients in the D-Rd arm are MRD negative vs 10% of patients in the Rd arm (P < .0001). In patients with high-risk cytogenetics, 23% of patients in the D-Rd arm achieved MRD negativity vs 2% in the Rd arm.
Similar to the data seen in the GRIFFIN trial, sustained MRD negativity also is appreciable here, with 20% of patients in the D-Rd group having ≥ 6 months of sustained MRD negativity vs 5% of patients in the Rd group (P < .0001). Greater than 12 months of sustained MRD negativity was achieved in 16% of patients receiving D-Rd vs 3% of patients receiving Rd.
Shaji Kumar, MD:
The other important data from the updated analysis are the PFS2 results, often considered a surrogate for OS. It is clear that the OS data for this trial will require longer follow-up to mature, but this update revealed that, although median PFS2 has not yet been reached for patients receiving D-Rd, median PFS2 with Rd was 51.3 months and the HR was 0.65 (95% CI: 0.52-0.83; P = .0005). This suggests that we can anticipate an OS benefit for D-Rd.
Shaji Kumar, MD:
For patients planning to continue therapy until progression, consideration of potential adverse events (AEs) is important. In this report, the median duration of study treatment was 42.8 months for the D-Rd arm and 22.6 months for the Rd arm. AEs were associated with long‑term treatment—particularly hematologic toxicity, including lymphopenia and the risk of infections—which was brought up in the context of D-VRd in the GRIFFIN study of ASCT-eligible patients. Overall, however, D-Rd was fairly well‑tolerated and had a manageable AE profile in this population of older, ASCT-ineligible patients.
Of note, treatment discontinuation due to TEAEs is significantly less frequent in patients receiving D-Rd compared with patients receiving Rd. Only 11% of patients receiving D-Rd have discontinued treatment vs 22% of patients receiving Rd, further showing that D-Rd is well-tolerated.
Shaji Kumar, MD:
The phase III MAIA trial compared D-Rd with Rd alone in older, ASCT-ineligible patients with newly diagnosed MM. With long-term follow-up, D-Rd maintained a significant PFS advantage over Rd alone, with no new safety signals reported. The median PFS has not been reached in the D-Rd group and was 34.4 months in the Rd group (HR: 0.54; 95% CI: 0.43-0.67; P < .0001). There was an improved depth of response with D-Rd, including a 3-fold improvement in MRD negativity (31% vs 10% with Rd alone; P < .0001). These benefits are also evident in patients with high-risk cytogenic profiles. Study investigators concluded that the data continued to support the use of first-line D-Rd among older or less fit patients with newly diagnosed MM.
Sagar Lonial, MD:
Patients who are ASCT ineligible and newly diagnosed with MM are diverse, necessitating individualized treatment. However, continuous Rd-based regimens continue to be the standard of care. Use of proteasome inhibitors (PIs) continuously or to higher cumulative doses improves long-term outcomes for patients with MM,14-16 but PIs requiring IV or SC dosing can be challenging due to treatment burden and tolerability.
Ixazomib is an oral PI suitable for continuous dosing with predictable and manageable AEs.17 Ixazomib is FDA approved in combination with Rd for patients with MM after ≥ 1 previous therapy.18 The TOURMALINE-MM2 trial, presented at ASH 2020, compared oral ixazomib-Rd with Rd alone in ASCT-ineligible patients with newly diagnosed MM.
Sagar Lonial, MD:
TOURMALINE‑MM2 was a randomized, double-blind phase III study that enrolled 705 adult patients newly diagnosed with MM who were ineligible for ASCT.19,20 Patients were randomized to receive ixazomib plus Rd (n = 351) or placebo plus Rd (N = 354) for cycles 1-18. Patients in the ixazomib-Rd arm continued on ixazomib-R for cycles 19+, and patients in the placebo arm received placebo-R for cycles 19+. This treatment approach replaced bortezomib with ixazomib to give an immunomodulatory‑PI backbone vs the traditional Rd used in previous phase III trials.
Enrolled patients had an ECOG PS ≤ 2 and creatinine clearance ≥ 30 mL/min. Stratification was based on age (younger than 75 years vs 75 years or older), ISS disease stage (I vs II vs III), and Brief Pain Inventory-Short Form worst pain score (< 4 vs ≥ 4). The primary endpoint was PFS, and secondary endpoints were OS, CR, and pain response rate.
Sagar Lonial, MD:
The ixazomib-Rd and placebo-Rd arms were balanced in terms of baseline characteristics. The median age of patients in both arms was approximately 74 years, with approximately 44% of all patients 75 years of age or older. An ECOG PS of 0/1 and ISS stage of I and II were most common. Approximately 40% of patients had expanded high-risk cytogenetics, including t(4;14), t(14;16), del(17p), and amp(1q21). A Brief Pain Inventory-Short Form worst pain score ≥ 4 was present in 54% of patients.
Sagar Lonial, MD:
In this report, there was a clear positive trend in median PFS favoring ixazomib-Rd. In the overall patient population, median PFS was 35.3 months with ixazomib-Rd vs 21.8 months with placebo-Rd (HR: 0.830; 95% CI: 0.676-1.018; P = .073). However, because this difference did not reach statistical significance, the study did not meet its primary endpoint.
If we look at the subgroup analysis, a trend toward a benefit with ixazomib-Rd vs placebo-Rd remains. The median PFS of patients with expanded high-risk cytogenetics was 23.8 months in patients receiving ixazomib-Rd vs 18.0 months for patients receiving placebo-Rd (HR: 0.690; 95% CI: 0.506-0.941). There was also a notable median PFS benefit for patients with a baseline creatinine clearance ≤ 60 mL/min at 40.0 months for ixazomib-Rd and 19.4 months for placebo-Rd (HR: 0.625; 95% CI: 0.450-0.869). In patients with an ISS stage of III, median PFS was 27.9 months for ixazomib-Rd vs 16.1 months for placebo-Rd (HR: 0.736; 95% CI: 0.466-1.163). Patients younger than 75 years of age had a median PFS of 41.4 months in the ixazomib-Rd arm and 26.2 months in the placebo-Rd arm (HR: 0.799; 95% CI: 0.608-1.049), and patients 75 years of age or older had a median PFS of 27.9 months in the ixazomib-Rd arm and 20.5 months in the placebo-Rd arm (HR: 0.871; 95% CI: 0.640-1.186).
Overall, the PFS data suggest activity and benefit for ixazomib-Rd over Rd alone, even though they did not meet the primary endpoint of the study.
Sagar Lonial, MD:
Moving on to key secondary endpoints, median OS was not reached in either group at the time of data cutoff (HR: 0.998; 95% CI: 0.790-1.261; P = .988). By contrast, the median time to progression was nearly double in the ixazomib-Rd arm compared with the placebo-Rd arm at 45.8 months vs 26.8 months, respectively (HR: 0.738; 95% CI: 0.589-0.925; P = .008). The frequency of ORR was similar between the arms at 82.1% for ixazomib-Rd and 79.7% for placebo-Rd (P = .436). However, 25.6% of patients receiving ixazomib-Rd vs 14.1% of patients receiving placebo-Rd achieved CR or sCR (P < .001).
Sagar Lonial, MD:
TEAEs were similar for ixazomib-Rd and placebo-Rd, and no new safety signals were observed. TEAEs occurred in 96.6% of the ixazomib-Rd arm and 92.6% of the placebo-Rd arm. There were slightly more grade ≥ 3 TEAEs in the ixazomib-Rd arm vs the placebo-Rd arm (70.9% vs 57.0%, respectively).
Dose reduction due to TEAEs occurred in 59.6% of patients receiving ixazomib-Rd and 54.2% of patients receiving placebo-Rd. On‑study deaths were similar, occurring in 7.6% of patients in the ixazomib-Rd arm and 6.3% of patients in the placebo-Rd arm.
Sagar Lonial, MD:
The most commonly observed TEAEs of any grade were consistent with known AEs for ixazomib therapy. Although many TEAEs had a similar incidence in both groups, ixazomib was associated with an increased frequency of gastrointestinal TEAEs such as diarrhea (61.0% for ixazomib-Rd vs 46.1% for placebo-Rd), nausea (37.0% vs 27.8%), and vomiting (29.7% vs 13.2%). Rash was also more common in patients receiving ixazomib-Rd (56.2% vs 46.1%), as was thrombocytopenia (20.6% vs 9.5%) and, to a lesser degree, peripheral neuropathy (33.9% vs 27.5%).
Sagar Lonial, MD:
The phase III TOURMALINE-MM2 trial compared ixazomib-Rd with placebo-Rd in patients with newly diagnosed MM who were ASCT ineligible. The addition of ixazomib to Rd led to a 13.5-month improvement in PFS vs Rd alone, although this was not statistically significant (35.3 months vs 21.8 months; HR: 0.830; 95% CI: 0.676-1.018; P = .073). Consistent with results from the TOURMALINE-MM1 trial,21 ixazomib-Rd improved PFS vs placebo-Rd in patients with expanded high-risk cytogenetics. Ixazomib-Rd also yielded clinically meaningful improvements in time to progression and CR compared with placebo-Rd and was tolerated with a manageable safety profile.
It is hard to say that we are going to change what we are doing based on this study, but I think it had a benefit for some patient populations and is something we should consider as an all‑oral alternative to other triplets in frail, older patients with MM who are ineligible for ASCT.
Shaji Kumar, MD:
With the addition of new agents, the treatment of newly diagnosed MM has greatly improved over the past decade. It is interesting to see that, with these regimens in the upfront setting, we are easily looking at 4-5 years of freedom from progression after diagnosis, which is quite significant progress. In the ASCT‑eligible patient population, the IFM 2009, CASSIOPEIA, and GRIFFIN trials all have shown that VRd is a very effective combination regimen. The question now is whether to continue using VRd or to transition to quad therapy with VRd plus daratumumab for initial therapy.
Sagar Lonial, MD:
I think that the paradigm is moving toward 4- vs 3-drug combinations in fit patients who can tolerate intensive therapy because there seems to be a clear benefit for early intensive therapy based on the rates of sCR/CR and MRD negativity in these trials.
For frail patients, things are more complicated. First, I think we need better tools to define frail patients than the arbitrary age cutoff of 65 years. Whether we use the International Myeloma Working Group (IMWG) frailty index,16 which we and many other healthcare professionals use, or something else, we need better tools to define frail patients. Second, for the truly frail patient, 4-drug therapies are more difficult due to the increased need to minimize toxicity. Selecting an appropriate therapy from the outset is very important for frail patients because they may not get a second chance at therapy. Regimens such as the one in MAIA clearly demonstrate very long, durable responses. TOURMALINE-MM2 suggests that all-oral approaches can offer significant benefit for frail, elderly, renal‑compromised patients, as well.
The second piece, which did not come up in our discussion, is the continued role of ASCT in patient management. If we were to summarize the big highlights of ASH 2020, bispecific antibodies would be one, but so would the resurgence of ASCT. A few studies clearly demonstrated the benefit of high‑dose therapy not just in achieving deep responses, but also in achieving durable MRD negativity. As I mentioned earlier, durable MRD negativity is becoming a very important benchmark in the clinic. It is clear from many studies presented at ASH 2020 that ASCT allows a more durable, MRD‑negative PFS.
Shaji Kumar, MD:
I agree. It is important to remember, when looking at the various regimens we have available for first-line therapy, to also consider ASCT and appropriate maintenance therapy to maximize the response to induction and maintain this long duration of a disease-free interval for patients with MM after their initial diagnosis.
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