Treatment of Patients with Relapsed/Refractory Multiple Myeloma (MM) with Lenalidomide and Dexamethasone with or with Bortezomib Depending on Prior Neurotoxicity: Prospective Evaluation of the Impact of Cytogenetic Abnormalities and Assessment of Bone Met.
Authors: Dimopoulos Meletios A. , Kastritis Efstathios , Christoulas Dimitrios , Migkou Magdalini , Gavriatopoulou Maria , Zagouri Flora , Terpos Evangelos 
Published: April 2020

Abstract
Lenalidomide and dexamethasone (RD) is an effective combination for patients with relapsed/refractory MM and the addition of bortezomib (BRD) may be associated with improved activity. In an ongoing prospective study patients with pre-existing peripheral neuropathy grade &lt;2 receive BRD and those with grade ≥ 2 receive RD. Purposes of this study: 1) Inclusion of patients with renal impairment and dosing of lenalidomide according to a proposed normogram; 2) impact of cytogenetic abnormalities on response and progression; 3) evaluation of bone metabolism markers before and after treatment. Up to July 2008, 53 patients have been included regardless of their performance status and renal function; the only exclusion criterion is prior treatment with lenalidomide. Patients with prior neuropathy grade&lt;2 receive B at a dose 1 mg/m2 on days 1, 4, 8 and 11, R at a dose of 15 mg daily for 14 days (or at a lower dose if creatinine clearance (CrCl) &lt;30 ml/min) and D 40 mg PO on days 1 to 4. Courses are repeated every 21 days. Patients with prior neuropathy grade 32 receive R on days 1 to 21 according to creatinine clearance (25 mg/day for CrCl&gt;50 ml/min, 10 mg/day for CrCl 30–50 ml/min, 15 mg every other day for CrCl 15–30 ml/min, and for patients on dialysis 15 mg three times per week on the day after dialysis) and D 40 mg PO on days 1–4 and 15–18 for the first 4 cycles and only on days 1–4 thereafter, every 28 days. At baseline, conventional metaphase cytogenetics and FISH (after cell sorting) for del13q, del17p, add1q21, t (4;14), t (14;16) is performed in all patients. All patients receive DVT prophylaxis with aspirin 100 mg unless they were already on coumadine or LMWH for pre-existing DVT or for other indications, mainly atrial fibrillation. So far 23 patients have received BRD and 30 patients RD. Median time from first treatment to this study is 35 months (range 3–217) and median number of prior treatments are 3 (range 1 to 8). Prior treatment with thalidomide (thal): 85% (53% thal resistant), prior treatment with B: 83% (45% B resistant), prior treatment with D: 100% (D resistant (65%), presence of at least one adverse cytogenetic abnormality by FISH in 45.5%, non-hyperdiploid karyotype in 23%. Thirty percent of patients had baseline CrCl &lt; 50 ml/min, LDH&gt;300 IU/dL (normal &lt;225 IU/dL) in 19%, ISS 3 in 34%. Patient characteristics and cytogenetic findings were similar among BRD and RD treated patients with the exception of more B-pretreated patients in BRD. On intent to treat basis, 48 patients are evaluable for response so far: 52% achieved at least a PR (31% PR, 13% VGPR, 8% CR). Response after BRD and RD was 52% for both. Response in thal-resistant and B-resistant patients: 32% and 50% respectively. At least a PR according to del13q, del17q, t(4;14), add1q21 was documented in 33%, 17%, 33% and 27% of patients respectively, in 80% of patients with hyperdiploid and in 10% with a non-hyperdiploid karyotype (p=0.007). Among 41 patients on low-dose aspirin, only one developed DVT. Hematologic toxicities≥G3 included anemia (19%), thrombocytopenia (17%), neutropenia (32%). In patients receiving RD deterioration of neuropathy was recorded in 27%. After BRD, 35% of patients experienced Grade 32 neuropathy. Other common toxicities included infections (≥G3 in 17%) and fatigue (≥G3 in 21%). Variables associated with shorter time to progression included thalidomide resistance, high LDH, non-hyperdiploid karyotype and FISH abnormality. After treatment with either RD or BRD, RANKL serum levels as well as markers of bone resorption (CTX and TRACP-5b) were significantly reduced. However, the reduction of RANKL and RANKL/osteoprotegerin ratio was higher after BRD than after RD (p=0.02). BRD patients also reduced dickkopf-1 (Dkk-1) serum levels, while RD patients showed a slight increase of serum Dkk-1 [p (BRD vs. RD)=0.01]. In only BRD patients an increase in bone formation markers (bALP and osteocalcin; p=0.01) was shown. We conclude that RD and BRD may be active in several patients with thal and/or B resistance. These regimens are clearly more active in patients with hyperdiploid karyotypes and they may overcome to a certain extend the adverse prognosis of cytogenetic abnormalities detected by FISH but not that of del17p. Low-dose aspirin prophylaxis is effective. The addition of bortezomib to RD is associated with higher anti-osteoclastic effect and with enhanced osteoblastic activity.