Lenalidomide, Adriamycin, and Dexamethasone (RAD) As Induction Therapy for Patients with Newly Diagnosed Multiple Myeloma Who Are Eligible for Autologous Transplantation (ASCT): A Phase 2 Study from the Greek Myeloma Study Group
Authors: Terpos Evangelos , Katodritou Eirini , Symeonidis Argiris , Zagouri Flora , Gerofotis Antonis , Christopoulou Georgia , Gavriatopoulou Maria , Christoulas Dimitrios , Kourakli Alexandra , Konstantinidou Pavlina , Kastritis Efstathios , Dimopoulos Meletios A 
Published: October 2019

Abstract
RAD combination is highly effective for patients with relapsed/refractory multiple myeloma (MM), but there is limited data for its efficacy on newly-diagnosed patients (NDMM). Although lenalidomide exerts its function, at least partially, through the inhibition of interactions between myeloma and stromal cells, there is no information for the effect of RAD on bone metabolism and angiogenesis in NDMM. The primary endpoint of this phase 2 study was the assessment of overall response rate (ORR) after 4 cycles of RAD induction in NDMM patients who are eligible for ASCT. Secondary endpoints included toxicity, PFS, TTP, and TtNT. Exploratory endpoints included: i) the yield of stem cell collection after RAD; ii) the effects of RAD on biochemical markers of bone metabolism: CTX, TRACP-5b, bone-alkaline phosphatase (bALP), P1NP, osteocalcin, soluble RANKL, osteoprotegerin (OPG) and dickkopf-1 (Dkk-1) and iii) the effects of RAD on angiogenic cytokines: angiopoietin- (Angp) 1 & -2, angiogenin (Ang), VEGF and bFGF.
Main inclusion criteria were: i) NDMM patients eligible for ΑSCT; ii) Κarnofsky performance status ≥ 60; iii) platelet count ≥100x109/L, neutrophil count ≥1.5x109/L. Main exclusion criteria included: i) serum ALT or AST >3-fold or bilirubin >2-fold the upper normal limit; ii) eGFR <60 ml/min; iii) prior malignancy; iv) severe heart or lung disease. According to treatment schedule, lenalidomide was administered at a dose of 25 mg, po, daily, on days 1-21 of a 28-day cycle; dexamethasone was given at a dose of 40 mg, po, on days 1, 8, 15, and 22, while adriamycin was administered as IV bolus infusion at a dose of 9 mg/m2, on days 1-4 of each cycle. RAD was repeated on day 28 if the neutrophil count was >1.5x109/L and the platelet count was >50x109/L. All patients received anti-coagulation with LMWH and monthly zoledronic acid.
Between November 2014 and February 2016, 45 patients were enrolled. Median age was 56 years (range: 37-69 years); 28 (62%) patients had IgG, 12 (27%) IgA, 4 (9%) light chain only and one IgM MM; 18 (40%) patients had ISS-1, 22 (49%) ISS-2 and 5 (11%) ISS-3 disease. Osteolytic lesions were present in 33 (73%) patients. Seven (15.5%) patients had elevated serum LDH (>250 U/l) and 3 (6.6%) had hypercalcemia (>11 mg/dl). All but one patient completed 4 cycles of RAD. Best response included one (2.2%) CR, 8 (17.8%) VGPRs, 21 (46.7%) PRs, for an ORR of 66.7%, while 14 (31%) patients had stable disease and one progressed during the 4th cycle of treatment. Adverse events of grade 3 or 4 included: anemia (4 patients, 9%), neutropenia (3 patients, 6.6%), febrile neutropenia (one patient), hypocalcemia (one patient), acute renal failure (one patient), pulmonary embolism (one patient), fatigue (one patient) and pathological fracture (one patient). Forty (89%) patients had adequate stem cell collection post-RAD induction (mean±SD: 8.94±6.50 x106/kg CD34+ cells). Three patients failed to collect adequate number of stem cells and two patients refused to proceed to stem cell collection.
Patients at baseline had elevated levels of CTX, TRACP-5b, sRANKL/OPG, Dkk-1, Ang, VEGF, VEGF-A, bFGF and reduced levels of Angp-1/Angp-2, bALP and P1NP compared to 30 healthy subjects of similar age and gender (p<0.01 for all comparisons). RAD therapy resulted in a reduction of circulating CTX (from 0.74±0.30 ng/ml at baseline to 0.54±0.14 ng/ml on day 28 of the fourth cycle; p=0.03), TRACP-5b (from 3.42±1.28 U/l to 1.25±1.10 U/l; p<0.01), Ang (from 420±120 ng/ml to 250±110 ng/ml; p=0.02), VEGF (from 260±97 pg/ml to 108±66 pg/ml; p=0.01) and bFGF (from 1.23±0.42 pg/ml to 0.32±0.18 pg/ml; p<0.01). On the contrary, RAD increased serum levels of bALP (from 11.5±5.1 μg/L to 15.3±6.7 μg/L, p=0.036), P1NP (from 45±15 mg/l to 110±57 mg/l; p=0.028) and Ang-1/Ang-2 ratio (13.3±10.9 to 18.8±12.6; p=0.022). These alterations occurred irrespective of response, although patients who achieved at least VGPR tended to have more profound differences in the above parameters.
We conclude that RAD resulted in successful induction for NDMM patients and produced an ORR of approximately 67%. RAD reduced bone resorption and increased bone formation; the latter has not been previously described with lenalidomide-based regimens. Furthermore, RAD reduced angiogenic cytokines and this supports the action of the regimen also through the disruption of the interactions between myeloma and stromal cells.

Disclosures
Terpos: Celgene: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; BMS: Consultancy, Honoraria; Novartis: Honoraria; Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding. Katodritou:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Genesis: Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Symeonidis:Amgen: Honoraria; Roche: Honoraria; Takeda: Consultancy, Honoraria; Genesis: Honoraria. Kourakli:Genesis: Consultancy, Honoraria. Kastritis:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Genesis: Consultancy, Honoraria. Dimopoulos:Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.