Treatment protocols in the age of modern substances

We are in the era of new efficient compounds against multiple myeloma. Nevertheless, high-dose chemotherapy followed by autologous stem cell transplantation remains an essential part of the first-line treatment of biologically fit patients.

In 2017, first-line treatment of multiple myeloma will continue to be based on whether or not a patient qualifies for high-dose chemotherapy with melphalan followed by autologous stem cell transplantation (ASZT). Several years ago, a randomized phase III trial demonstrated that high-dose chemotherapy should not be abandoned in transplant-eligible patients, even in the era of new myeloma-specific drugs [1]. The major criticism of this study was that instead of the currently recommended bortezomib-based three-drug combinations, only a two-drug combination with lenalidomide and dexamethasone (RD) was used as induction therapy, which is less effective in terms of response rates.

Two large studies have been presented in recent months in which the induction therapies used meet current standards. In the EMN02/HOVON95 trial, bortezomib, cyclophosphamide, and dexamethasone (VCD) were used as induction, after which patients received one to two high-dose chemotherapies/ASCT or conventional intensification with bortezomib, melphalan, and prednisone (VMP), depending on the center. In addition to a second randomization between short or no consolidation, all patients received maintenance therapy with lenalidomide until progression. The more intensive treatment significantly improved patients’ progression-free survival. The EMN02/HOVON95 trial was also the first to prospectively test the value of consolidation with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD). This measure also further improved the progression-free survival (PFS) of the patients [2,3]. The issue of consolidation after high-dose chemotherapy/ASCT was also highlighted in the STAMINA study. Induction was not predetermined, and patients were randomized to receive either further high-dose chemotherapy in terms of tandem transplantation, four cycles of VRD, or no consolidation after initial high-dose chemotherapy with ASZT. Subsequently, all patients received lenalidomide as maintenance therapy. In this study, no differences were found between the three arms, so the benefit of consolidation therapy, whether with a second high-dose chemotherapy or the conventional combination VRD, seems questionable. However, one must keep in mind when evaluating this study that neither the type nor the duration of induction treatment was predetermined (in contrast to the EMN02/HOVON95 study) and that approximately one-third of the patients in the tandem arm had not received the second high-dose chemotherapy, which somewhat diminishes the power of the study [4].

The French IFM trial used bortezomib, lenalidomide, and dexamethasone (VRD) as induction, and patients either received high-dose chemotherapy with ASZT followed by an additional two cycles of VRD as consolidation after three cycles or continued VRD treatment with an additional five cycles for a total treatment duration of eight cycles. Patients in both arms also subsequently received maintenance therapy with lenalidomide and dexamethasone until progression. Better response rates as well as prolongation of PFS were observed with high-dose chemotherapy/ASCT [5]. The fact that no difference in overall survival was seen suggests that delayed high-dose chemotherapy with ASZT in relapse is also conceivable as a salvage option. Because depth of response and duration to next therapy in multiple myeloma are reliable markers of patient prognosis, high-dose chemotherapy should remain integrated into future initial treatment strategies of biologically fit patients, along with new-generation agents that are as potent as possible.

Induction protocol

With regard to the optimal induction protocol, new insights have been gained in recent years: In the French IFM2013-04 study, a combination of bortezomib, the immunomodulatory substance thalidomide and dexamethasone (VTD) achieved better/lower response rates than the combination of bortezomib, cyclophosphamide and dexamethasone (VCD) – which is also very commonly used in Switzerland. However, VTD is associated with higher rates of polyneuropathies (some irreversible) [6]. Because it is not possible to assess the extent to which subsequent use of potentially neuropathic agents might be affected, many hemato-oncologists are reluctant to use this potent combination. Recently, the U.S. SWOG trial S-0777 evaluated the combination of bortezomib, lenalidomide, and dexamethasone (VRD) as first-line therapy against lenalidomide and dexamethasone (RD). Lenalidomide is a second-generation immunomodulator (IMID) and a derivative of thalidomide. It is more effective and causes virtually no neuropathies. High-dose chemotherapy with ASZT was not an integral part of first-line treatment in this study. By the time of the final analysis, approximately 10% of patients had left the study because of this and were censored at that time. Treatment with VRD resulted in significant improvement in PFS and overall survival of patients compared with RD [7]. Based on these data, current knowledge suggests that VRD can be considered the most effective first-line treatment, whether or not the patient is to receive a transplant. However, the side effect profile is correspondingly worse than that of RD, so caution is advised, especially in elderly and fragile patients. For these patients, RD remains a very good option for first-line therapy. Whether treatment with RD should be given until progression or only for a total of 18 months could not be answered with final certainty even after the most recent final analysis of the FIRST trial. Although RD to progression showed an improvement in PFS and overall survival compared with the standard combination of melphalan, prednisone, and thalidomide (MPT), overall survival was not better compared with treatment with RD given for 18 months only [8]. Another suitable option for elderly nontransplant patients is the two-drug combination of bortezomib and dexamethasone (VD). The combination of bortezomib, melphalan, and prednisone (VMP) can also still be considered an option according to the results of the VISTA trial, especially since a randomized comparison with VRD is not available. With all the statistical limitations of a cross-study comparison, it can nevertheless be stated that the overall survival of the non-transplanted patients treated with VRD in the SWOG trial was significantly higher compared to the patients treated with VMP in the VISTA trial. To achieve a profound and long-lasting response, a sufficiently long duration of therapy is necessary, over a period of twelve (VMP) to at least 18 (VRD or RD) months. Particularly in older patients, attention must be paid to tolerability and the development of side effects such as polyneuropathy and adynamia, so that the drug dose can be adjusted in good time or treatment interrupted if necessary.

VRD is not yet approved as a first-line therapy in Switzerland, so that coverage by health insurance must be requested before treatment can begin. Since prolonged treatment with lenalidomide in particular can impair bone marrow reserve and thus stem cell mobilization, early contact with the transplant center is necessary, especially for younger patients, in order to plan stem cell collection and transplantation in a timely manner.

Conservation

Maintenance therapy with lenalidomide can now be considered the standard treatment after completion of primary treatment. In a large pooled analysis of available trial data, this resulted in an improvement in overall patient survival, with the exception of the subgroup of patients with high-risk cytogenetic constellations [9]. These patients instead benefit from maintenance therapy with bortezomib [10].

Antiresorptive therapy

All patients with newly diagnosed multiple myeloma requiring therapy should also receive antiresorptive therapy with zoledronic acid, as this not only reduces the rate of skeletal-related complications but may also favorably affect overall survival [11]. In case of intolerance or existing contraindications for the administration of zoledronic acid, e.g. severe renal insufficiency, the administration of denosumab may be considered instead, although here, too, prior cost coverage must be obtained from the patient’s insurer [12].

Literature:

Palumbo A, et al: Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 2014 Sep 4; 371(10): 895-905.
Cavo M, et al: Intensification Therapy with Bortezomib-Melphalan-Prednisone Versus Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: An Intergroup, Multicenter, Phase III Study of the European Myeloma Network (EMN02/HO95 MM Trial). ASH 2016; Abstract 673.
Sonneveld P, et al: Consolidation Followed By Maintenance Therapy Versus Maintenance Alone in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma (MM): A Randomized Phase 3 Study of the European Myeloma Network (EMN02/HO95 MM Trial). ASH 2016; Abstract 242.
Stadtmauer EA, et al.Comparison of Autologous Hematopoietic Cell Transplant (autoHCT), Bortezomib, Lenalidomide (Len) and Dexamethasone (RVD) Consolidation with Len Maintenance (ACM), Tandem Autohct with Len Maintenance (TAM) and Autohct with Len Maintenance (AM) for up-front Treatment of Patients with Multiple Myeloma (MM): Primary Results from the Randomized Phase III Trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 – StaMINA Trial). ASH 2016; LBA-1.
Attal M, et al: Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med 2017 Apr 6; 376(14): 1311-1320.
Moreau P, et al: VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood 2016 May 26; 127(21): 2569-2574.
Durie BG, et al: Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet 2017 Feb 4; 389(10068): 519-527.
Hulin C, et al: Updated Outcomes and Impact of Age With Lenalidomide and Low-Dose Dexamethasone or Melphalan, Prednisone, and Thalidomide in the Randomized, Phase III FIRST Trial. J Clin Oncol 2016 Oct 20; 34(30): 3609-3617.
McCarthy PL, et al: Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis. J Clin Oncol 2017 Jul 25: JCO2017726679. DOI: 10.1200/JCO.2017.72.6679 [Epub ahead of print].
Goldschmid H, et al: Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia 2017 Jul 4. DOI: 10.1038/leu.2017.211 [Epub ahead of print].
Morgan GJ, et al: Long-term follow-up of MRC Myeloma IX trial: survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res 2013 Nov 1; 19(21): 6030-6038.
Raje N, et al: An International, Randomized, Double Blind Trial Comparing Denosumab With Zoledronic Acid (ZA) for the Treatment of Bone Disease in Patients (Pts) With Newly Diagnosed Multiple Myeloma.^16th International Myeloma Workshop (IMW) 2017; Abstract 546.