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My paper of the month - Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplantation in multiple myeloma

by Mohamad Mohty

Each month one member of the EBMT Scientific Council will select and comment a recent paper in the field of stem cell transplantation and cellular therapy that was published in high ranked journals.

For this month Newsletter, Mohamad Mohty, Chair of the Acute Leukaemia Working Party, comments on the publication entitled “Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplantation in multiple myeloma”, published in Blood.

Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplantation in multiple myeloma

Authors: Rosiñol L, Oriol A, Rios R, Sureda A, Blanchard MJ, Hernández MT, Martínez-Martínez R, Moraleda JM, Jarque I, Bargay J, Gironella M, de Arriba F, Palomera L, Gonzalez-Montes Y, Marti J, Krsnik I, Arguiñano JM, Gonzalez ME, Gonzalez AP, Casado LF, Lopez-Anglada L, Paiva B, Mateos MV, San Miguel J, Lahuerta JJ, Bladé J.

Blood. 2019 Sep 4. pii: blood.2019000241. doi: 10.1182/blood.2019000241.

Article summary:

Induction is a key step for the success of high-dose chemotherapy and autologous stem cell transplantation (auto-SCT) in transplant-eligible multiple myeloma (MM) patients. This phase 3 PETHEMA/GEM2012 study, reported on 458 patients aged ≤ 65 years with newly diagnosed and transplant-eligible MM. The study assessed the use of bortezomib (subcutaneous), lenalidomide, and dexamethasone (VRD) for 6 cycles followed by high-dose chemotherapy and auto-SCT. The trial found VRD to be a highly effective induction regimen prior to auto-SCT. Of note, responses improved and deepened over time: in patients who initiated cycle 6 of induction (n=426), the ≥ very good partial response (VGPR) rates were 56% by cycle 3, 64% by cycle 4, 68% by cycle 5, and 70% after induction. The complete response (CR) rate of 33% after induction in the intent-to-treat (ITT) population, which was similar in the 92 patients with high-risk cytogenetics (35%), also deepened with further treatment (44% after auto-SCT and 50% after consolidation). Rates of undetectable minimal residual disease (MRD; median 3 × 10−6 sensitivity) in the ITT population also increased from induction (29%) to transplant (42%) and consolidation (45%). The most common grade ≥3 treatment-emergent adverse events during induction were neutropenia (13%) and infection (9%). Grade ≥2 peripheral neuropathy during induction was 17%, with a low frequency of grade 3 (4%) and grade 4 (0.2%) events. The authors concluded that VRD is an effective and well-tolerated regimen for induction in transplant-eligible MM with a deepening of response throughout induction and over the course of treatment.

Commentary:

The auto-SCT procedure for MM comprises several key steps: induction, stem cell mobilization, high-dose chemotherapy followed by stem cell infusion, and post-transplant therapy (including maintenance therapy with or without prior consolidation). For almost 3 decades, the standard induction regimen prior to auto-SCT consisted of 3-4 cycles of vincristine, adriamycin and dexamethasone (historical VAD regimen). The IFM2005-01 randomized trial was the first trial to show the superiority of a novel-agent based induction (namely bortezomib and dexamethasone, VD) over VAD. The VD regimen served as a backbone to develop triplet induction regimens such as VTD (bortezomib, thalidomide, dexamethasone) or VCD (bortezomib, cyclophosphamide, dexamethasone), both of which were proven to be superior to doublets such as VD or TD (thalidomide and dexamethasone). Of note, another IFM randomized trial could show a slight superiority of VTD over VCD in terms of response rate. Interestingly, none of the aforementioned triplet regimens explored the issue of the number of cycles, and investigators continued to use the classical 3-4 cycles based on the historical VAD experience. However, one must admit, that given the potential serious toxicity of agents such as thalidomide (non-reversible peripheral neuropathy) or cyclophosphamide (cytopenia and its corollary of infectious complications), the issue of the number of cycles of induction prior to auto-SCT was not deemed to be very important by most investigators, especially given the capacity to deliver 2 or 3 cycles of consolidation to deepen the response rate after auto-SCT.

The VRD regimen was initially developed in the relapsed MM setting and proved rapidly to be highly effective with a remarkable safety profile, especially a very low rate of severe peripheral neuropathy when combined to subcutaneous bortezomib. Very rapidly, VRD moved into the frontline setting, and was viewed by most experts as the “standard” induction regimen prior to auto-SCT, since it combines the efficacy of VTD without its added toxicity! The latter positive ratio of efficacy and safety was clearly shown in the trial by Rosinol et al. In addition, given its good tolerance and feasibility, Rosinol et al. took this regimen a step further, and administered VRD in up to 6 cycles (in contrast to the common historical dogma of 3-4 cycles). The former strategy proved to be highly effective as it allowed for a continuous improvement in the disease response, including achievement of MRD negativity in a substantial number of patients before auto-SCT. These results are of utmost importance, because a deep MRD status is increasingly considered a major goal of MM therapy, because it probably serves as a surrogate marker for improved survival. Overall, the findings from this large Spanish trial will be highly influential and will encourage many investigators to opt for a “longer” induction phase of up to 6 cycles, toxicity allowing.

However, MM therapy is a rapidly evolving field, and one may wonder how such a “long” induction phase would compare to a quadruplet regimen-based induction administered over a shorter period of time? In this regard, the recent CASSIOPEIA international randomized trial evaluated whether the addition of daratumumab to VTD (Dara-VTD) before (induction) and after auto-SCT (consolidation) would improve the stringent complete response rate in patients with newly diagnosed MM. The latter study showed the clinical benefit of Dara-VTD given in up to 4 cycles as a major regimen for induction in transplant-eligible patients with newly diagnosed MM. As a matter of fact, and given the impressive results of Dara-VTD, it is possible that a Dara-VRD-based induction regimen (currently being tested in prospective trials) will also probably show a significant benefit in this arena. Nevertheless, one should not ignore issues related to cost and access to such quadruplet regimens, though they can also challenge the whole concept of auto-SCT if shown to be feasible over a long period (eg. a quadruplet regimen administered for one year) and able to induce deep MRD negativity. While waiting for the results of such trials, auto-SCT preceded by a “long” induction with VRD will likely remain a standard of care for many years in many patients across the globe.

Recommended articles:

1. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet 2010; 376: 2075-85.

2. Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. Journal of clinical oncology 2010; 28: 4621-9.

3. Harousseau JL, Avet-Loiseau H. Minimal Residual Disease Negativity Is a New End Point of Myeloma Therapy. Journal of clinical oncology 2017; 35: 2863-5.

4. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet 2019; 394: 29-38.

5. Moreau P, Avet-Loiseau H, Facon T, et al. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood 2011; 118: 5752-8; quiz 982.

6. Moreau P, Hulin C, Macro M, et al. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood 2016; 127: 2569-74.

7. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010; 116: 679-86.