The Combination of Bortezomib and Lenalidomide (VR) Consolidation Post-ASCT, in the Absence of Dexamethasone and Bisphosphonates, Improves Response Rates and Bone Metabolism in Newly Diagnosed Patients with Multiple Myeloma
Authors: Terpos Evangelos , Kastritis Efstathios , Christoulas Dimitrios , Eleutherakis-Papaiakovou Evangelos , Gavriatopoulou Maria , Kalapanida Despoina , Bakogeorgos Marios , Roussou Maria , Dimopoulos Meletios A. 
Published: November 2019

Abstract
Consolidation therapy post autologous stem cell transplantation (ASCT) with combinations of bortezomib with an IMiD (thalidomide or lenalidomide) and dexamethasone has been evaluated in patients with multiple myeloma (MM) in an attempt to deepen responses and to improve survival. Bortezomib, IMiDs and steroids have been usually administered in various combinations. However, it is not clear if the use of dexamethasone is needed in consolidation regimens. The primary endpoint of this prospective study was to explore the efficacy of VR consolidation without dexamethasone in newly-diagnosed MM patients who received bortezomib-based induction treatment and then underwent high dose melphalan (HDM) and ASCT. Secondary endpoints included: safety, time to progression (TTP), time to next treatment (TtNT), OS and the effects of VR on bone metabolism in the absence of bisphosphonates administration.
Between January 2010 and November 2013, 59 consecutive patients (30M/29F, median age 54 year, range 37-68 years) who achieved at least stable disease post-ASCT were entered into this study. Consolidation consisted of 4 cycles of VR, which started on day 100 post-ASCT. Bortezomib was given at a dose of 1.3 mg/m2, iv (or sc when it was available), on days 1, 4, 8 and 11 of a 21-day cycle, while lenalidomide was given at a dose of 25 mg, p.o., daily on days 1-14. Patients did not receive any bisphosphonate during or post-ASCT as well as throughout the period of VR consolidation. Bone remodeling was studied by the measurement of the following serum indices on the day of stem cell collection prior to ASCT and then before and after VR consolidation (3 measurements for each patient): i) osteoclast regulators [soluble receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin], ii) osteoblast inhibitors dickkopf-1 (Dkk-1) and sclerostin, iii) bone resorption markers (CTX and TRACP-5b) and iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)].
Before HDM, one (1.7%) patient had achieved a stringent complete remission (sCR), one (1.7%) was in CR, 30 (50.8%) were in very good partial remission (vgPR), 22 (37.3%) were in PR, while 5 (8.5%) patients had stable disease. After ASCT, 34 (57.6%) patients improved their status of response; in total, 14 (23.7%) patients achieved a sCR, one (1.7%) CR, 35 (59.3%) vgPR and 9 (15.3%) PR. After VR consolidation, 23/59 (39%) patients further improved their status of response; overall, 30 (50.8%) patients achieved a sCR, one (1.7%) CR, 26 (44.1%) vgPR and two (3.4%) PR.
The most important adverse events (>10% of the patients) included neutropenia (68%, grade 3/4 23%), thrombocytopenia (59%, grade 3/4 7%), peripheral neuropathy (56%, grade 3/4 2%), anemia (50%, grade 3/4 4.5%), skin rash (34%, grade 3/4 9%), infections (34%, no grade 3/4), fatigue (20%, no grade 3/4), diarrhea (16%, no grade 3/4) and constipation (14%, 2% grade 3/4). No patient developed deep vein thrombosis. Fifteen patients (34.1%) experienced at least one infectious episode (grade 1 and 2); the majority included viral or bacterial infections of the upper respiratory tract.
Post-VR consolidation there was a reduction of sRANKL/OPG ratio and of sclerostin (p<0.001) in all patients. Patients who achieved at least vgPR showed higher reductions of sRANKL/OPG and sclerostin compared to patients who achieved a PR (p<0.01). There was no reduction of markers of bone resorption (CTX and TRACP-5b) during the study period, possibly due to the dramatic reduction of these markers during induction therapy when zoledronic acid was given. Furthermore, there were no alterations in Dkk-1, bALP and OC, despite the use of bortezomib which has bone anabolic effects. This may be due to the enhanced expression of Dkk-1 caused by lenalidomide and the short period of observation. No skeletal-related events (SREs) were observed during the study period.
The median follow-up after the ASCT was 31 months (range: 7-49 months) and 14 of 44 (31.8%) patients have progressed. The median TTP and TtNT after the ASCT have not been reached yet. The probability of 4-year without progression was 55%.
We conclude that 4 cycles of VR consolidation without dexamethasone is an effective regimen which improves the quality of response in approximately 40% of patients and produces long TTP. In the absence of bisphosphonates, VR consolidation has beneficial effects on bone metabolism and is related with no SREs.

Disclosures
No relevant conflicts of interest to declare.