CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Nurses: 1.00 Nursing contact hour
Released: April 26, 2023
Expiration: April 25, 2024
Current Considerations for Initial Treatment of Myeloma for Younger, Fit Patients
The current goal for the initial treatment of MM, whether it be in young, fit patients or older patients, is to maximize the depth and duration of response using a combination of drugs, but also allow administration of therapies with limited toxicity.32
VRd Induction Has Been Standard of Care
For patients with newly diagnosed MM who are considered eligible for ASCT, do we use an induction regimen that is 3 or 4 drugs? A few clinical trials are evaluating this question. The combination of VRd has become the standard induction therapy based on the results of the SWOG S0777 trial that evaluated VRd vs Rd.33 That trial clearly showed that VRd induction therapy was associated with improved PFS and OS. Subsequently, the ENDURANCE study investigated whether carfilzomib instead of bortezomib would be associated with better outcomes, but showed no additional benefit in standard-risk patients (those who are not going to an early ASCT).34 The question of whether KRd is better than VRd for high-risk patients remains unanswered from prospective trials at this time.
Other approaches are determining whether VRd can be enhanced by adding additional drugs to this combination. Two clinical trials evaluated the addition of elotuzumab to VRd.35,36 Neither demonstrated added benefit with the addition of elotuzumab. We have seen a benefit, however when an anti CD38 mAb, such as daratumumab or isatuximab, is added to the combination of bortezomib, IMiD, and dexamethasone.35,37,38
Clinical Trials With Quad Therapy in NDMM
The CASSIOPEIA 2-part, multicenter, open-label phase III trial was the first to look at the addition of an anti-CD38 mAb (daratumumab) to bortezomib/thalidomide/dexamethasone (VTd). Patients were randomized to receive VTd vs dara-VTd before transplant with the same regimen for consolidation, followed by a second randomization looking at daratumumab maintenance vs no maintenance.38 The control arm of this trial differed from current practice where VRd is used as induction therapy.
The GRIFFIN multicenter, open-label phase II trial was the second trial that randomized patients to VRd vs dara-VRd prior to transplant and after, followed by maintenance with 1 or 2 drugs.37
Daratumumab-Based Quads: Depth of Response
Both trials showed that the addition of an anti CD38 mAb does improve the overall response rate and the depth of response, as indicated by the proportion of patients achieving sCR or MRD negativity.37,38
GRIFFIN Update: MRD-Negativity Rates
In the GRIFFIN trial, a significant improvement in MRD-negativity rates was seen with the addition of daratumumab to VRd. By the end of 2 years of maintenance therapy, 14% vs 10% of patients had converted to MRD negative from MRD positive at the end of consolidation.39
GRIFFIN Update: PFS (ITT Population)
The CASSIOPEIA trial has clearly shown an improvement in PFS and OS with the addition of daratumumab to VTd. However, the data becomes slightly more difficult to interpret, as it was not done using the standard VRd regimen and half of the patients did not receive any maintenance therapy.38
In the GRIFFIN trial there was a significant improvement in MRD-negativity rates with the addition of daratumumab to VRd, and there appeared to be an improvement in PFS (55% reduction in risk of death or PD). However, due to the limited power of this randomized phase II trial, differences in terms of maintenance therapy received, and patients going off study, many questions remain unanswered.37
GRIFFIN Update: Infections Summary
Furthermore, the GRIFFIN trial demonstrates that although the addition of daratumumab to VRd is well tolerated in this transplant eligible population, it does come at the cost of increased risk of infections associated with the use of an antiCD38 mAb.39
Isatuximab-VRd: GMMG-HD7 Induction Phase
Additional studies have also been investigating the addition of an anti CD38 mAb to VRd. The GMMG-HD7 trial was an open-label phase III study that evaluated the addition of isatuximab to VRd vs VRd.35 It showed that the addition of isatuximab did improve the primary endpoint of MRD-negativity rate before patients went on to an ASCT. This trial also included a second randomization to isatuximab/lenalidomide vs lenalidomide maintenance. This will address an important question since patients in the CASSIOPEIA trial who received daratumumab as part of induction therapy did not seem to derive as much benefit with an anti CD38 mAb when administered as part of their maintenance treatment.
Is Upfront ASCT Still the Standard of Care?
Once patients receive induction therapy, whether it be with 3 or 4 drugs, another question is whether they will benefit from an ASCT. We have more recent data on the use of ASCT in the context of VRd induction therapy from the IFM/DFCI-2009 studies.40,41
Phase III IFM 2009: VRd ± ASCT in Newly Diagnosed MM
The IFM 2009 trial showed that an ASCT after VRd induction did lead to improved PFS. However, this did not translate to improved OS, as these patients may also have had access to ASCT later in their treatment course.40
DETERMINATION: VRd ± ASCT in Newly Diagnosed MM
The DFCI-2009 (DETERMINATION) trial was a similarly designed study. Like IFM 2009, DETERMINATION showed that an ASCT in the upfront setting after induction therapy with VRd was associated with significantly improved PFS (67.5 months vs 46.2 months; HR: 1.53; 95% CI: 1.23-1.91). Also similar to IFM 2009, the DETERMINATION trial did not show an improvement in OS.
These 2 trials provide important insights into the treatment of MM. One is that in patients with newly diagnosed MM who are eligible for an ASCT, use of upfront transplant does translate to improved PFS. As long as these patients have access to ASCT at the time of first relapse, the OS is not necessarily any better, but it allows for decision making in consultation with patients.41
DETERMINATION: PFS by Cytogenetic Risk
Another important insight, particularly highlighted by the DETERMINATION trial, was the significant improvement in outcomes among patients with high-risk cytogenetics. The median PFS for VRd+ASCT was 55.5 months compared with 17.1 months with VRd alone (HR: 1.99; 95% CI: 1.21-3.26) in the high-risk cytogenetics group compared with 82.3 months vs 53.2 months in those with standard-risk cytogenetics.
The DETERMINATION trial builds on prior data showing that use of ASCT in the upfront setting in patients with high-risk cytogenetics is important. The treatment algorithms that are currently being followed have all consistently called for an early ASCT in the high-risk patient population.42
DETERMINATION: Quality of Life Metrics
There has been concern that ASCT can be associated with significant worsening in patients’ quality of life (QoL). However, according to the QoL measurements in the DETERMINATION trial, a transient worsening in QoL occurs while patients are undergoing transplant, but there is no lasting impact on the QoL metrics.42
FORTE: KRd-ASCT vs KCd-ASCT vs KRd12
The IFM 2009 and DETERMINATION trials are not the only studies that have shown the benefit of an ASCT. The FORTE trial was a randomized phase II trial that asked 2 questions: In patients undergoing ASCT upfront, do they need to receive a regimen like KRd or can we use KCd? And if you are receiving induction with KRd, do you need an ASCT?43
FORTE: PFS From First Randomization
The FORTE trial clearly demonstrated that the combination of KRd induction therapy followed by ASCT was associated with the best PFS,43 very similar to what was seen in DETERMINATION and IFM 2009. The 4-year PFS rate from first randomization was 69% with KRd+ASCT, 56% with KRd12, and 51% with KCd+ASCT. Of importance, FORTE also showed that in patients who are planning to receive an ASCT, KRd is a better induction therapy than KCd, which finally clarified the debate surrounding use of a regimen other than a PI and IMiD.43
FORTE: Cytogenetic Subgroup Analysis of PFS With KRd + ASCT vs KRd12
When you look at the cytogenetic high-risk group itself, it is very clear that KRd+ASCT was associated with a better outcome, even though patients with multiple high-risk cytogenetic abnormalities continue to have poor outcomes overall.44
Maintenance Therapy: Moving Beyond Single-Agent Lenalidomide?
Once patients undergo ASCT, the question becomes: What do we do to control the clone beyond the ASCT? When moving beyond single-agent lenalidomide as maintenance therapy, should we use alternative single-agent therapies like ixazomib and daratumumab or add agents like PIs and anti-CD38 monoclonal antibodies?37,38,43,45,46
PFS and OS With Lenalidomide Maintenance After ASCT in MM: Meta-analysis of 3 Phase III Trials
We know that if no maintenance treatment is administered, patients have a median PFS of only about 2-3 years. The current standard of care is to use single-agent lenalidomide as maintenance for these patients. This is based on the meta-analysis of 3 phase III trials, which demonstrated an improved PFS with the use of lenalidomide maintenance, approximately doubling the PFS from 2 to 4 years.47 An improved OS with the use of lenalidomide maintenance has also been shown. Based on these data, lenalidomide maintenance post-ASCT is universally considered to be the standard of care. Next, the question is: How do we improve upon this?
Phase III Myeloma XI Trial: PFS With Len Maintenance in ASCT-Eligible Patients by Cytogenetic Risk
This data has also been confirmed by the phase III Myeloma XI trial.48 The PFS benefit observed with lenalidomide among the high-risk patients (median 38 months vs 21 months) was greater than what was seen in the meta-analysis, and may be partly due to the fact that these patients did not receive an induction therapy that would be considered appropriate per current practice.
Myeloma XI Trial: PFS From Maintenance Randomization by MRD-Negativity Status
The Myeloma XI trial also showed that the PFS benefit from maintenance therapy with lenalidomide was applicable to all patients, particularly those who were MRD-positive at the time of randomization.48 The PFS in the MRD-negative group was 59 months vs 44 months with lenalidomide vs observation, respectively, compared with 47 months vs 18 months in the MRD-positive subset. This highlights the importance of obtaining a deep response as well as the cumulative effect of the underlying risk, the depth of response, and the ongoing therapy, all of which individually contribute to improved outcomes.
Phase III TOURMALINE-MM3: PFS With Maintenance Ixazomib vs Placebo in Newly Diagnosed MM
The phase III TOURMALINE-MM3 trial investigated the oral PI, ixazomib, as maintenance in patients undergoing ASCT.45 The results demonstrated an improvement in PFS of approximately 5 months. This is not as much of an impact as with lenalidomide maintenance, but this was a limited duration of maintenance therapy. Although this trial does not make a case for replacing lenalidomide, it is important to know that there is another option available for maintenance therapy for patients who are unable to tolerate an IMiD.
CASSIOPEIA Part 2: Dara vs Observation Maintenance
Daratumumab has also been explored in the context of maintenance therapy. In part 2 of the CASSIOPEIA trial, patients with PR or better after completion of part 1 treatment (N = 886) were randomized to receive daratumumab maintenance vs observation, with the daratumumab administered every 8 weeks until progression.49
CASSIOPEIA Part 2: PFS of Daratumumab Maintenance vs Observation
CASSIOPEIA part 2 showed that the use of daratumumab maintenance was associated with a significantly improved PFS compared with observation (HR: 0.53; 95% CI: 0.42-0.68).49
CASSIOPEIA Part 2: PFS From Second Randomization by Induction/Consolidation and Maintenance Therapies
CASSIOPEIA also demonstrated that the patients who did not do as well were those who did not receive daratumumab as either induction or maintenance.49
These results raised 2 questions: What is the appropriate duration of daratumumab needed as part of initial therapy? And is maintenance with daratumumab required if daratumumab was received as induction therapy? These questions currently remain unanswered.
VRd as Maintenance Therapy for Patients With High-Risk MM
It is clear that patients with high-risk cytogenetic abnormalities derive less benefit with lenalidomide maintenance and still continue to have poor outcomes. Thus, improving outcomes in this subgroup by using 2-drug maintenance regimens, with an IMiD and a PI, is of interest. Retrospective data from Emory University seems to suggest that using VRd for maintenance is better than 1 in patients with high-risk features.46
FORTE: PFS of KR vs R Maintenance
Subsequently, data from the FORTE trial,43 and comparisons between the SWOG S1211 and ENDURANCE trials all seem to indicate a better outcome when using a PI along with an IMiD as maintenance for high-risk patients. Therefore, this has become a standard of care approach for patients with high-risk cytogenetic abnormalities.
Now, patients with high-risk cytogenetic abnormalities should undergo an ASCT after first-line induction therapy and then subsequently receive 2-drug maintenance therapy.
What about MRD?
The goal of first-line therapy for active MM is to ensure patients, especially those who are high-risk, achieve a deep response. Multiple retrospective studies have shown that the best outcomes for high-risk patients are associated with achieving an MRD negative state and maintaining MRD negativity. MRD negativity is associated with improved long-term outcomes and MRD-guided treatment decisions are being explored in ongoing clinical trials. Additionally, MRD is being evaluated as a potential surrogate endpoint.50
Key Points for Clinical Practice: Treatment of Newly Diagnosed Transplant-Eligible MM
Treatment Considerations for ASCT-Ineligible Patients
For patients who are not eligible to undergo an ASCT, regimens and treatment approaches need to be modified to enhance tolerability while maintaining outcomes. The dose of certain treatments and the optimal agent from each class of therapy can be adjusted based on the underlying disease characteristics and the patient profile. For example, patients with renal dysfunction will need the lenalidomide dose to be reduced based on renal function. Those with cardiac dysfunction should avoid drugs like carfilzomib. In patients with underlying peripheral neuropathy, using carfilzomib instead of bortezomib would be a reasonable approach.32,51
Age is an Important Issue
Age is an important issue that determines whether patients can undergo ASCT. Beyond the transplant, age should be taken into consideration when determining the dose and schedule of therapies to use. This is because age comes with multiple comorbidities, including conditions such as ischemic heart disease, hypertension and diabetes. In addition, older patients are often frail, have limited social support and mobility, and have altered drug metabolism.51
FIRST Trial: Survival With Rd Continuous vs Rd for 18 Mo vs MPT in Older or ASCT-Ineligible Patients
Historically, patients who are older and cannot undergo an ASCT have been investigated separately in clinical trials. The FIRST trial was the initial study that demonstrated that we could use a melphalan-free regimen in older patients. It was clear that those who received Rd, whether continuously or for a limited duration, had better outcomes than those who received melphalan/prednisone/thalidomide (MPT). The median PFS was 26.0 months, 21.0 months, and 21.9 months for Rd continuous, Rd every 18 months, and MPT, respectively. Median OS was 59.1 months, 62.3 months, and 49.1 months, respectively.52
SWOG S0777: VRd vs Rd in Newly Diagnosed MM Without Immediate Intent for ASCT
The SWOG S0777 trial improved upon this concept by adding bortezomib, and demonstrated that VRd did benefit both younger and older patients when compared to Rd.33
Phase II Trial: VRd-lite in Older or ASCT-Ineligible Patients With Newly Diagnosed MM
Subsequent studies have explored the approach of dose modulating VRd, as in the VRd-lite regimen, in older patients or those ineligible for ASCT. This regimen uses a less intensive therapy, but still appears to provide outcomes similar to those observed in younger patients receiving the full dose regimen.53
MAIA: Dara-Rd vs Rd in ASCT-Ineligible NDMM
What really made a significant impact for older patients has been the results of the MAIA study, which randomized patients to Dara-Rd vs Rd. The primary endpoint of the study was PFS and secondary endpoints included time to progression (TTP), complete response (CR)/sCR, MRD by next-generation sequencing, PFS2, OS, overall response rate (ORR), and safety.54,55
MAIA: Updated PFS and OS
In this large phase III trial, it was clear that the addition of daratumumab not only improved PFS, but also OS. It is important to note that the PFS with Dara-Rd exceeds 5 years, a number that had not previously been observed in this older, more frail patient population.54,55
MAIA: Impact of Frailty
In fact, when evaluating the PFS by frailty, both frail and non-frail patients benefited from the addition of daratumumab to Rd.55
MAIA: Safety
The addition of daratumumab did not seem to significantly impact safety, and patients appeared to tolerate this treatment well. There was some increased risk of hematological toxicity as well as infection, which need to be carefully monitored in patients receiving this combination.56
ALCYONE: Open-Label Phase III Study Design
Other phase III trials have also investigated adding daratumumab to previously existing regimens. The ALCYONE study added daratumumab to bortezomib/melphalan/prednisone (VMP) in transplant-ineligible patients with newly diagnosed MM. The primary endpoint of the study was PFS and secondary endpoints included ORR, very good partial response (VGPR) or better, CR or better, MRD negativity, OS, and safety.57,58
ALCYONE: PFS With D-VMP vs VMP Alone in Newly Diagnosed Transplant-Ineligible MM
The ALCYONE trial demonstrated an improved PFS with the addition of daratumumab to VMP (median 37.3 months vs 19.7 months.59
ALCYONE: OS With D-VMP vs VMP Alone in Newly Diagnosed Transplant-Ineligible MM
ALCYONE also demonstrated an improved OS with the combination of daratumumab plus VMP.59 However, this regimen is not commonly used in the United States, as we have stopped using melphalan upfront in older patients with MM.
TOURMALINE-MM2: Study Design
Other studies have attempted to build upon the success observed with VRd. The TOURMALINE-MM2 trial evaluated the addition of ixazomib to Rd. Patients with newly diagnosed MM who were not eligible for ASCT were randomized to receive ixazomib-Rd vs Rd. The primary endpoint was PFS, and secondary endpoints included OS, CR, and pain response rate.60
TOURMALINE-MM2: PFS
TOURMALINE-MM2 showed that there was some improvement in PFS with the addition of ixazomib to Rd.60 In fact, the median PFS of 35.3 months seen with ixazomib-Rd is similar to what we have seen in older patients treated with VRd lite type regimens. However, this did not lead to statistical significance and ixazomib-Rd is not currently approved for initial therapy of newly diagnosed MM.
Dexamethasone Discontinuation
As treatments for MM have continued to improve, questions have arisen as to whether we need dexamethasone and whether we need to continue dexamethasone for as long as we have been. One Italian study investigated discontinuing dexamethasone after the first 9 cycles of therapy and reducing the dose of lenalidomide. This trial clearly showed that the outcomes are, in fact, better with the preemptive discontinuation of dexamethasone after the initial 9 cycles.61
Phase III IFM2017-03 Trial: Dexamethasone Sparing-Regimen in Frail Patients With Newly Diagnosed MM
More recently, data from the IFM 2017-03 trial showed that we can spare the dexamethasone beyond the first couple of cycles in patients receiving the combination of daratumumab and lenalidomide.62 The outcome is similar to what we have seen with dexamethasone containing regimens. It seems that the field is moving towards either discontinuing dexamethasone altogether or using it in the least amount possible in patients with MM.
Key Points for Clinical Practice: Treatment of Newly Diagnosed Transplant-Ineligible MM
Supportive Care
Along with the MM specific therapy in newly diagnosed patients, it is also important to consider supportive care management, of which infection prophylaxis plays a significant role. Phase III trials have demonstrated that prophylactic antibiotic therapy in the initial 2-3 months may provide some benefit.63,64 Patients receiving an antiCD38 mAb and/or PIs need to be on herpes zoster prophylaxis.32 Patients receiving IMiDs may have an increased risk of venous thromboembolism and need to be on thromboprophylaxis in a risk adapted manner.32,65,66 Bone modulating agents such as bisphosphonates and denosumab play an important role as well. And of course, symptomatic management of MM is important.
Select Adverse Events and Prophylaxis by Drug Class
The specific toxicities associated with certain drugs need to be considered as well. If a patient has significant neuropathy that develops in the context of a PI such as bortezomib, then this drug may need to be discontinued, or symptomatic management instituted.67
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