|INTERESTING ONGOING TRIALS
|Year : 2019 | Volume
| Issue : 1 | Page : 76-82
Induction therapy in newly diagnosed multiple myeloma: Current research scenario and questions for the future
Bhausaheb Bagal, Avinash Bonda
Department of Medical Oncology, Tata Memorial Hospital, HBNI, Mumbai, Maharashtra, India
|Date of Web Publication||9-Sep-2019|
Tata Memorial Center, Parel, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
The outcomes of patients with newly diagnosed multiple myeloma (NDMM) have substantially improved over the last decade. Besides improved staging, diagnostic and prognostic tools leading to better risk-stratified approaches, a major contributing factor has been better induction regimens. The major emphasis of the current clinical research is on the development of induction regimens capable of producing a deep and durable remission as measured by minimal residual disease negativity, which correlates with a better overall survival. This review explores the current changing landscape of induction therapy in NDMM and discusses implications for the current clinical practice.
Keywords: Induction therapy, multiple myeloma, outcomes
|How to cite this article:|
Bagal B, Bonda A. Induction therapy in newly diagnosed multiple myeloma: Current research scenario and questions for the future. Cancer Res Stat Treat 2019;2:76-82
|How to cite this URL:|
Bagal B, Bonda A. Induction therapy in newly diagnosed multiple myeloma: Current research scenario and questions for the future. Cancer Res Stat Treat [serial online] 2019 [cited 2019 Sep 17];2:76-82. Available from: http://www.crstonline.com/text.asp?2019/2/1/76/266462
| Introduction|| |
The outcomes of patients with multiple myeloma (MM) have improved remarkably over the last decade. Besides improved staging, diagnostic and prognostic tools leading to a better risk-stratified approach, a major area of improvement has been the establishment of potent induction regimens leading to deep and long-lasting remissions. Conventional MM therapy can be divided into different phases including induction, consolidation, and maintenance, with each phase having defined goals and outcome measures. As one moves from induction to maintenance, the disease burden decreases necessitating and enabling different therapeutic approaches [Figure 1].
|Figure 1: Multiple myeloma treatment paradigm. ASCT: Autologous stem cell transplant, chemo: chemotherapy|
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Induction regimens have evolved over time. Steroid combinations with alkylators/anthracyclines were used for a long time prior to the advent of novel agents. The novel agent-based two-drug induction regimens have been shown to be superior to the older alkylator/anthracycline-based regimens in terms of antimyeloma activity as well as safety. Within the context of novel agent-based regimens, there is less reliance on steroids, and most of the induction regimens now use low-dose dexamethasone which has a better safety profile and similar activity compared to the traditional high-dose dexamethasone. The toxicity profile of novel agents is different, allowing them to be effectively combined with cytotoxic drugs and other novel agents. This has led to a plethora of three-drug combination studies with improved results and even questioning the value of autologous stem cell transplantation (ASCT) in newly diagnosed MM (NDMM) patients. The SWOG S0777 study showed that the addition of bortezomib to lenalidomide-dexamethasone (Rd) was associated with a higher response rate, depth of response, progression-free survival (PFS), and overall survival (OS). Similarly and not surprisingly, the addition of bortezomib to thalidomide-dexamethasone (Td) was associated with similar PFS benefits. The IFM/DFCI study addressed the question of whether ASCT can be deferred given the activity of lenalidomide–bortezomib–dexamethasone (RVd) and confirmed the value of ASCT in the setting of novel agent-based therapy. Bortezomib–cyclophosphamide–dexamethasone (VCd) and bortezomib–thalidomide–dexamethasone (VTd) are the two commonly used regimens in European countries, whereas RVd has been the preferred regimen in the USA. Recently, the use of RVd by European physicians has increased, whereas the carfilzomib-based regimen, i.e., carfilzomib–lenalidomide–dexamethasone (KRd), is being increasingly used in the USA, particularly for high-risk patients. The current clinical trials aim to further build on these regimens using newer drugs or more potent second-generation novel agents as a triplet or a quadruplet regimen.
| Goals of Induction Therapy|| |
The induction regimen is aimed at relieving disease-related symptoms and reversing the end-organ damage as early as possible with minimal side effects. This initial therapy sets the stage for deep and prolonged disease control, thereby improving survival. The goals of an ideal induction regimen are as follows:
- Reversing the disease-related complications promptly
- Decreasing the risk of early morbidity and mortality
- Rapid and effective disease control, while not interfering with stem cell collection at the same time
- Should be well tolerated with minimal side effects.
Perhaps, the most important requirement, the efficacy of the regimen, is judged by the response rate, the depth of response, and the duration of response. The depth of response can now be precisely measured and monitored over the course of therapy with the use of minimal residual disease (MRD). MRD has been shown to correlate with time to progression, PFS, and OS and serves as an important surrogate endpoint for clinical trials.,,,
| Minimal Residual Disease and Induction Therapy|| |
As the efficacy of upfront therapy has improved, precise response assessment has become relevant. With technological advancement, assessment of MRD has become an important tool to assess the depth of response in patients who have no measurable M-protein detected. MRD negativity to a level of 10−6 has been shown to better predict PFS and OS and has emerged as an important surrogate marker for survival in patients with high-risk disease. Its use in routine practice is not standard as of now, but MRD assessment is particularly useful in clinical trials evaluating the newer more potent regimens. MRD may have a potential role in therapeutic decision-making as well, although this remains to be established. Maintenance therapy may influence outcomes, irrespective of the MRD status, and hence, it is important to understand the impact of maintenance therapy in trials reporting the outcomes based on MRD status. Additional response assessment tools such as positron emission tomography-computed tomography may further improve the prognostic ability of MRD. MRD negativity might have a role in deciding additional therapy, for example, the type of maintenance therapy and its duration, but there seems to be greater interest in clinical trials on decision-making in patients with MRD positivity. Ongoing studies on therapeutic decision-making based on MRD status will answer these questions in the near future. In line with building evidence on its utility, recently, the American Food and Drug Administration (US-FDA) has approved a next-generation sequencing-based platform, clonoSEQ for MRD testing.
| Ways to Improve on the Current Standard of Care – triplet Induction Regimens|| |
Studies looking at improving the induction regimens in NDMM have used one of the following strategies:
- Addition of another cytotoxic drug (alkylator/anthracyclines) to the novel agent-based triplet
- Regimen with next-generation proteasome inhibitor (PI) or immunomodulatory drugs (IMiDs)
- Sequential use of drugs in induction versus multidrug combination regimen
- Newer monoclonal antibody-based triplet and quadruplet regimens
- Individualized/personalized induction regimens based on genomic alteration.
We will review some of these studies [Table 1] exploring the utility of the above strategies in detail below.
|Table 1: Recent randomized studies comparing induction regimens in newly diagnosed multiple myeloma|
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Strategy 1: Addition of a cytotoxic drug
Nonoverlapping toxicity of IMiDs and PI allows for the addition of another cytotoxic drug to the IMiD/PI backbone. In the EVOLUTION study led by Dr. Shaji Kumar, the RVd, VCd, and VDCR (cyclophosphamide added to RVd) induction regimens were compared. The VDCR regimen did not result in an improvement in efficacy over the triplets. The VDCR regimen resulted in increased neutropenia (44% in VDCR, 10% in RVd, and 30% in VCd); two treatment-related deaths were reported in the VDCR arm, whereas none occurred in the other two arms. In another study, the addition of liposomal doxorubicin to RVd was found to be associated with similar response rates. Both these studies suggested that addition of cytotoxic chemotherapy drug to a triplet regimen containing two novel agents was of little benefit and was associated with increased hematological toxicity. Surprisingly, however, a regimen of KCRd (carfilzomib–cyclophosphamide–lenalidomide–dexamethasone) in the United Kingdom Myeloma XI plus study was reported to be well tolerated and led to quick and deeper responses and prolonged PFS as compared to the triplet of cyclophosphamide–lenalidomide–dexamethasone (CRd) or cyclophosphamide–thalidomide–dexamethasone (CTd). The study had a complex design and enrolled over 4000 patients in the UK. We will discuss this study in more detail below.
Overall, this approach of adding a cytotoxic drug does not appear to lead to an improvement in outcomes. This may be because these drugs are not very potent, and they may not add much in terms of efficacy when the induction regimen already contains highly effective novel agents. However, such an approach may be appealing and should be explored in resource-limited settings given their low cost and the potential benefit in a select subset of patients such as plasma cell leukemia or extramedullary disease.
Strategy 2: Use of next-generation proteasome inhibitor or immunomodulatory drug in a novel agent-based triplet
Newer PI and IMiDs promise to be better in terms of antimyeloma activity as well as have an improved safety profile. Carfilzomib has been reported to be active in bortezomib-refractory patients and has a different side effect profile than bortezomib. Carfilzomib-based induction with KRd was evaluated in the Italian FORTE study. Interestingly, this study also looked at the possibility of delaying transplant in the face of the use of the potent KRd regimen. NDMM patients who were eligible for transplant were randomized to receive KRd induction, followed by ASCT, and then KRd consolidation (KRd→ASCT→KRd) versus 12 cycles of KRd (KRd12) versus carfilzomib–cyclophosphamide–dexamethasone (KCd) induction, and again followed by ASCT and KCd consolidation (KCd→ASCT→KCd). The study reported a similar response and MRD negativity rate from KRd→ASCT→KRd and from KRd12 but a significantly higher response and MRD negativity rate in both these arms compared to the KCd→ASCT→KCd arm. Although the two strategies that included the KRd regimen were equivalent in terms of MRD negativity, a longer follow-up is needed to conclude equivalence as not only the depth of response, but also the durability of response needs to be demonstrated. The KRd regimen was well tolerated; hematological toxicities were similar and nonhematological toxicities, mainly dermatological and liver enzyme abnormalities, were more common compared to KCd., It should be noted that the IFM/DFCI study exploring deferred transplant with the use of the potent induction regimen of RVd reported that 21% of patients presented with refractory disease at the time of relapse and many could not undergo transplant at relapse. Hence, a longer follow-up is needed to draw any definitive conclusions about the possibility of deferring the ASCT even with the use of KRd. The Myeloma XI study used the carfilzomib-based quadruplet regimen. Although the KCRd regimen was better than the IMiD-based triplet regimens (CTd and CRd), among the IMiD-based triplets, CRd led to better response rates, PFS, and OS (discussed in detail below). No study has compared the pomalidomide-based triplet regimen to the lenalidomide-based regimen; given its better safety profile in patients with renal failure and reported activity in lenalidomide-refractory patients, such a study would be interesting.
Strategy 3: Optimizing the induction regimen based on response
Given the heterogeneity of disease at presentation and incurable nature of disease, sequencing of available therapy is an important area of clinical research. Adapting the therapy based on the response may spare patients from drug-related side effects and will be economical, but leaves scope for clonal evolution and the development of potentially refractory disease at the time of relapse. Prospective studies have tested the approach of response-adapted therapies.
The Myeloma XI study was a very large randomized trial that enrolled more than 4000 patients from the UK. It had pathways for both transplant-eligible and transplant-ineligible patients. The study looked at the efficacy of a quadruplet regimen of KCRD versus a triplet of CTd or CRd. The study continued the induction regimen beyond four cycles if required in transplant-eligible patients until the maximal response beyond four cycles. The patients in the transplant pathway who attained very good partial response (VGPR)/complete response (CR) following four cycles of induction underwent ASCT immediately, whereas those with a partial response (PR) or minimal response were randomized to receive either a bortezomib-based salvage regimen (VCd) or to no salvage regimen before ASCT. The remaining patients, i.e., patients with progressive disease (PD)/stable disease, were all given a salvage bortezomib-based regimen (VCd). Thus, this large study essentially compared the sequential versus combinational approach of IMiD (lenalidomide/thalidomide) and PI (bortezomib/carfilzomib). Among the patients who received the triplet regimen, the patients on the CRd arm did better as compared to those on the CTd arm in terms of response rates (VGPR or better response occurred in 60% vs. 53%) as well as PFS (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.75–0.96; median PFS in CRd arm was 35.9 months vs. 32.9 months in the CTd arm; P= 0.0116) and OS (3-year OS, 82.9% vs. 77.0%; HR, 0.77; 95% CI, 0.63–0.93; P= 0.0072). The quadruplet regimen in the transplant-eligible patients reported at the annual meeting of the American Society of Hematology (ASH) 2018 led to quicker and deep remissions and prolonged PFS (HR, 0.63; 95% CI, 0.51–0.76; median PFS in patients treated with KCRd was not reached vs. 36.2 months in patients treated with CTd/CRd; P < 0.0001). The benefit was consistent in all subgroups including high-risk and ultra-high-risk patients and the upfront quadruplet regimen led to better results than the response-adapted strategy. The VCd regimen in patients with PR/minimal response was associated with deepening of response in 50% of patients. An exploratory analysis of patients requiring four versus more than four induction cycles to achieve maximal response was performed. There was no difference in the outcomes in these two groups, suggesting a difference in the kinetics of response rather than different sensitivities to the induction regimens.,, The change in the regimen in patients with minimal or no response did lead to a deepening of the response pretransplant in 50% of patients, but did not affect the long-term outcomes. Thus, this study supports the strategy of continuation of the induction regimen beyond four cycles in responding patients until the maximal response is achieved pre-ASCT. In patients with less responsive disease, even though changing the regimen to a more potent one leads to deepening of the response in about half of the patients, the long-term outcome remains poor and a different therapeutic approach is needed.
Strategy 4: Monoclonal antibody-based triplets and quadruplet induction regimens
Two US-FDA-approved antibodies in myeloma, namely, daratumumab and elotuzumab target CD38 and SLAMF7, respectively. Isatuximab, a next-generation IgG1-κ antibody targeting CD38, is being studied in MM and seems to have promising activity in early-phase studies.,
This study randomized NDMM patients not eligible for transplant to VMP (bortezomib + melphalan + prednisone) versus VMP + daratumumab. This was the first Phase III randomized controlled trial studying the addition of daratumumab to VMP, a standard induction regimen in this patient population. The addition of daratumumab resulted in a statistically significantly higher objective response rate (ORR, 90.9% vs. 73.9%; P < 0.001), rate of CR or better (42.6% vs. 24.4%; P < 0.001), MRD negativity (22.2% vs. 6.3%; P < 0.001), as well as superior PFS (HR, 0.5; 95% CI, 0.38–0.65; P < 0.001). The regimen was well tolerated in this elderly cohort of patients in whom the median age was 71 years. There was a higher risk of infectious complications in the daratumumab arm; Grade 3 or higher infection rates were 23.1% vs. 14.7%, but similar rates of other hematological adverse events were seen and only one patient discontinued daratumumab due to a serious adverse event (SAE).
The MAIA study randomized transplant-ineligible NDMM patients to Rd with or without daratumumab. The primary endpoint of the study was PFS and the secondary endpoints were ORR, CR, MRD negativity, and OS. The study met its primary endpoint with a median PFS of 32 months in the Rd arm versus not reached in daratumumab–Rd arm; HR, 0.56; 95% CI, 0.43–0.73; P < 0.001. The addition of daratumumab was associated with an increase in the risk of hematological (neutropenia 50.0% vs. 35.3%) and infectious complications (pneumonia rates 13.7% vs. 7.9%), which was consistent with the earlier reported safety profile of daratumumab–Rd.
Part I of this study compared VTd with VTd–daratumumab in induction and two consolidation cycles posttransplant in NDMM patients. The primary endpoint was the stringent CR (sCR) rate postconsolidation with ASCT. The study randomized 1085 patients. Addition of daratumumab to the VTd triplet resulted not only in higher sCR (29% vs. 20%, odds ratio, 1.60; 95% CI, 1.21–2.12; P= 0.0010), MRD negativity (64% vs. 44%; P < 0.0001), and better PFS (not reached in either arm; HR, 0.47; 95% CI, 0.33–0.67; P < 0.0001), but also a trend toward better OS (14 vs. 32 deaths; HR, 0.43; 95% CI, 0.23–0.80) at an early follow-up time point of 18 months. This study for the first time showed that the addition of a monoclonal antibody to an IMiD–PI triplet in the transplant setting may improve survival. Part II of this study is ongoing and will be assessing the effect of 2 years of daratumumab maintenance. A study with a similar design in transplant-eligible NDMM patients using a VRd backbone (the Perseus Study) will be reported soon, which may be more relevant as VTd is not commonly used outside Europe.
This study compared daratumumab–RVd to RVd alone in transplant-eligible NDMM patients. The safety run-in Phase II part was reported at the annual meeting of the ASH in 2018 in 16 patients. The investigators reported an acceptable safety profile and encouraging response rates with deepening of the depth of response postinduction, consolidation, and maintenance (VGPR or better in 100% of patients, CR or better in 63%, and SAE in three patients, but no therapy discontinuation). The randomized portion of the trial has completed enrollment, and early data should be reported soon. Similar to the Perseus Study, the results of this study are eagerly awaited as the current standard-of-care induction regimen RVd is being challenged against a monoclonal antibody-based quadruplet.
In summary, daratumumab-based regimens appear to be additive to the standard novel agent-based doublet and triplet regimens with promising early results and tolerable safety profile. Given the greater benefit of daratumumab in earlier lines of therapy, daratumumab-based induction regimens represent an important advance and a major milestone in the therapy of MM.
| Ongoing Studies With Important Induction Questions|| |
The Endurance study led by Dr. Shaji Kumar is comparing two PIs, bortezomib and carfilzomib, head to head as KRd versus VRd induction in nonhigh-risk NDMM patients and will be useful in choosing the best PI for induction regimens. The trial has completed accrual, and results are expected soon. Similarly, the SWOG 1211 will test the value of the addition of elotuzumab to VRd induction in high-risk NDMM patients.
| Issues With Design and Interpretation of a Study and Cost of Therapy|| |
Given the constant evolution of therapeutic options and the time it takes for a Phase III study to mature, the standard of care often changes, and this makes results more difficult to interpret. Trials often use surrogate outcome markers as endpoints for early results, and such evidence is necessary which may be sufficient for regulatory approval, but the implications of such a positive study for clinical practice may not be straightforward. Often, trials with such an aim are hardwired to meet their primary endpoint, but the clinical relevance of such an endpoint has to be kept in mind while interpreting the study. The daratumumab combination studies MAIA, ALCYONE, and CASTOR typically have used continuous administration of daratumumab until PD, while the therapy in the comparator arm is not indefinite. This is likely to affect endpoints such as PFS, which can be impacted not only by the efficacy of the induction regimen but also by the use of maintenance therapy.
Besides the study results, many factors such as patient preferences, tolerance, convenience, and cost of therapy are important considerations for clinical practice. Often, many newer regimens offer a marginal clinical benefit but come at a huge cost to patients, and we need to be mindful about our recommendations.
| Conclusion|| |
Induction regimens are headed for a quadruplet regimen incorporating IMiD, PI, and a monoclonal antibody for NDMM patients and the dream of an R-CHOP-like regimen for myeloma seems to be finally coming true.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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