On Wednesday 27 March 2019, during the 45th Meeting of the European Society for Blood and Marrow Transplantation (EBMT) in Frankfurt, Germany, Mohamad Mohty, Hospital Saint-Antoine and University Pierre & Marie Curie, Paris, FR, explained the evolution of induction regimens in multiple myeloma (MM) and presented the results from a subgroup analysis of the real-world, clinical experience, EMMOS study. The Multiple Myeloma Hub has covered this session in two articles. The first part is below and discusses how induction regimens have evolved, and the second part (available here) presents the subgroup analysis.1
In transplant-eligible patients with newly diagnosed multiple myeloma (NDMM), it is well established that the aim of initial induction regimens is to initiate deep responses, minimize tumor cells below the level of minimal residual disease (MRD) negativity and avoid toxic side-effects which may subsequently prevent the patient undergoing autologous stem cell transplantation (ASCT). This is because a deeper response to initial treatment is correlated with a longer progression-free survival (PFS) after ASCT.
Professor Mohty highlighted the following studies as having shaped the evolution of induction regimens in MM.
1. IFM 2005-011,2
Historically, the triplet regimen of vincristine + doxorubicin + dexamethasone (VAD) was the standard of care. No clinical trials using alternative combinations were able to show an improvement over VAD until the IFM 2005-01 study of bortezomib + dexamethasone (VD) versus VAD. This study showed the doublet combination, VD, was able to achieve higher complete response (CR) rates and very good partial response or better (≥VGPR) in patients at a median follow up of 32.2 months as shown in Table 1.
Table 1: updated results from the IFM 2005-01 study of VAD versus VD*
(N = 218)
(N = 223)
- ASCT 1
- ASCT 2
- ASCT 1
- ASCT 2
PFS (all patients)
- Patients with ISS II & III
- Patients with t(4;14) +/- del(17p)
36.0 months (P = 0.064)
33 months (P = 0.006)
33 months (P = 0.113)
*This data has been updated with unpublished data from Harrouseau J-L et al. and was presented during Professor Mohty’s presentation.
ISS, International Staging System
Studies then progressed to show that newer triplet regimens containing bortezomib and an immunomodulatory drug (IMiD), such as lenalidomide or thalidomide, were superior to the VD doublet. Historically, the most widely used is the bortezomib + thalidomide + dexamethasone (VTD) triplet.
The phase III GIMEMA study, with a median follow-up of 124 months, showed that the VTD triplet was superior compared to thalidomide + dexamethasone (TD). This was noted particularly in relation to median PFS (59.6 months vs 40.7 months, P < 0.0001) and estimated an 10-year overall survival (OS) (60% vs 46%, P = 0.007).
3. IFM 2013-041,4
In a study comparing the VTD triplet (n = 169) to a bortezomib + cyclophosphamide + dexamethasone triplet (VCD) triplet (n = 169), ≥VGPR rates were 66.3% versus 56.2%, P = 0.05, demonstrating the superiority of VTD.
Following on from triplet regimens, studies are now looking at quadruplet therapies, incorporating novel agents such as the anti-CD38 monoclonal antibody, daratumumab.
An ongoing phase III study (NCT02541383) is assessing the addition of daratumumab to VTD (dara-VTD) as induction therapy compared to VTD alone. The study design is as shown below:
- Part 1: induction and consolidation
- Induction (4 cycles) of VTD or dara-VTD
- Consolidation (2 cycles) of VTD or dara-VTD
- Part 2: maintenance
- Observation until progressive disease (PD) in the VTD arm
- Daratumumab maintenance once weekly for 8 weeks until PD in the dara-VTD arm
The topline results from the CASSIOPEIA trial (as covered by the MM Hub here) have shown dara-VTD is superior to VTD with a stringent CR (sCR) of 28.9% versus 20.3% (odds ratio: 1.60, 95% CI, 1.21–2.12, P ≤ 0.001).
Another option being assessed in trials is the swap of thalidomide to lenalidomide based on the findings that lenalidomide is highly active in myeloma and may cause less toxicity.7
This study has shown that the triplet bortezomib + lenalidomide + dexamethasone (VRD) is feasible. In the study, patients were treated with six cycles of induction with VRD, followed by ASCT and then two cycles of consolidation with VRD. Of 320 evaluable patients, this regimen achieved MRD-negativity in 58% of patients after consolidation.
The next step in these trials will be to investigate the quadruplet of daratumumab with VRD compared to VRD alone.
The phase II GRIFFIN study of daratumumab + VRD compared to VRD alone in NDMM has so far shown a manageable toxicity profile, consistent to studies involving daratumumab and VRD alone. MRD-negativity was achieved in 50% of patients after consolidation (10-5 threshold by next-generation sequencing [NGS]).
The last step in the evolution of MM induction regimens, so far, is to change the components of the triplet therapy. For example, using second-generation proteasome inhibitors (PI) such as carfilzomib, instead of bortezomib, and adding daratumumab to create a new quadruplet option.
MMY1001 is a phase 1b study of daratumumab in combination with the triplet of carfilzomib + lenalidomide + dexamethasone (KRd) in 22 patients with NDMM who are both transplant eligible and ineligible. High response rates were observed with daratumumab + KRd: 21 response-evaluable patients achieved an overall response rate of 100%, including 43% stringent CR, 14% CR, 33% VGPR and 10% PR. The safety profile observed was consistent with previous reports of daratumumab and KRd.
The use of different induction regimens in MM has evolved over time. The incorporation of newer, novel agents into already established, effective, triplet regimens, plus the emerging quadruplet regimens, are expected to provide additional benefit to patients.
Professor Mohty went on to introduce a subgroup analysis from the EMMOS study (NCT01241396) of the real-world experience of induction regimens in MM. This is covered in the second part of this article, which can be accessed here.