Maria Gavriatopoulou

Treatment of patients with relapsed/refractory multiple myeloma with lenalidomide and dexamethasone with or without bortezomib: prospective evaluation of the impact of cytogenetic abnormalities and of previous therapies

We prospectively studied the impact of several cytogenetic abnormalities (CAs) in patients with relapsed/refractory myeloma who received lenalidomide and dexamethasone (RD) with or without the addition of bortezomib (V). On the basis of the presence of previous neuropathy, 50 patients were treated with RD and 49, without preexisting neuropathy, with VRD. The overall response rate was 63%, similar for RD and VRD. Poor risk cytogenetics were associated with lower response rates in RD (P=0.01), but not in VRD (P=0.219). The median progression-free survival (PFS) was similar for RD (9 months) and VRD (7 months). The median overall survival (OS) for all patients was 16 months, with no differences between RD or VRD regimens. Poor risk cytogenetics, especially del17p, resistance to previous thalidomide, elevated lactate dehydrogenase (LDH) and presence of extramedullary disease were associated with inferior response to therapy and shorter PFS and OS. The impact of other CAs on OS was more pronounced in RD. In conclusion, the presence of CAs is an important adverse prognostic factor for patients with relapsed/refractory myeloma, but resistance to previous thalidomide, elevated LDH and presence of extramedullary disease remain of major prognostic importance. The outcome of patients with del17p remains extremely poor even with VRD combination.

Extensive bone marrow infiltration and abnormal free light chain ratio identifies patients with asymptomatic myeloma at high risk for progression to symptomatic disease

Asymptomatic multiple myeloma (AMM) is characterized by a constant risk of progression to symptomatic myeloma. To evaluate previously recognized risk factors and to identify high-risk features we analyzed 96 patients with AMM and at least 18 months of follow-up. The progression rate at 1,2, and 3 years was 8%, 15% and 26%, respectively, and the projected 5-year progression rate was 38%. Extensive bone marrow (BM) infiltration, abnormal free light chain (FLC) ratio and serum monoclonal (M)-protein⩾3 gr/dl were the most significant factors for progression, whereas the type of heavy (IgG vs IgA) or light chain or immunoparesis of the uninvolved immunoglobulins were not. Abnormal marrow signal of magnetic resonance imaging of the spine was associated with a significant risk of progression (median 15 months, P=0.001). Extensive BM infiltration ⩾60% (hazard ratio, HR: 13.7, P<0.001) and FLC ratio⩾100 (HR: 9, P=0.003) independently identified a ‘very high-risk’ group, which included 12.5% of patients with AMM and who progressed ⩽18 months from initial diagnosis. Development of anemia and/or lytic bone lesions were the most common features of symptomatic progression. In conclusion, there is a subgroup of patients who have a substantial risk of progression to symptomatic disease that can be detected at diagnosis (either by extensive BM infiltration⩾60% or FLC ratio⩾100) and may be considered for immediate treatment.

Reversibility of Renal Impairment in Patients With Multiple Myeloma Treated With Bortezomib-Based Regimens: Identification of Predictive Factors

PURPOSE Renal impairment is a frequent complication of multiple myeloma (MM) and is associated with significant morbidity and increased early death rate. Bortezomib is active and well tolerated in patients with MM who present or develop renal impairment. PATIENTS AND METHODS We analyzed 46 consecutive patients who presented with renal impairment in order to evaluate the impact of bortezomib on the improvement of renal function and to identify predictive factors associated with renal response. All patients received bortezomib with dexamethasone with or without other agents. RESULTS Renal response was documented in 59% of patients within a median of 11 days (range, 8-41 days). Two of 9 patients who required dialysis became dialysis independent. A complete renal response (CRrenal) was documented in 30% of patients. Toxicities were similar to those seen in myeloma patients without renal failure who were treated with bortezomib-based regimens. Patients with light chain-only myeloma had a higher probability of achieving a renal response, and previously untreated patients had a higher probability for complete resolution of renal impairment, while light chain-only myeloma was independently associated with a shorter time to renal response. The degree of renal impairment was not predictive of the probability for renal response or CRrenal; however, in a subset of patients for whom cystatin C was available, a baseline cystatin C > 2 mg/L or cystatin C calculated estimated glomerular filtration rate < 30 mL/min were associated with a lower probability of CRrenal. CONCLUSION We conclude that bortezomib-based regimens may improve renal function in the majority of myeloma patients with renal impairment.

Reversibility of renal failure in newly diagnosed patients with multiple myeloma and the role of novel agents

The purpose of this analysis was to assess the effect of novel agent-based regimens on the improvement of renal impairment (RI) in newly diagnosed patients with multiple myeloma. Ninety-six consecutive patients with RI received conventional chemotherapy (CC)-based regimens (n=32), IMiDs-based regimens (n=47) or bortezomib-based regimens (n=17) as frontline therapy. Improvement of RI was more frequent in patients treated with novel agents (79% in IMiD- and 94% in bortezomib-treated groups versus 59% in CC-treated group; p=0.02). Bortezomib-based regimens and CrCl>30 ml/min at baseline independently correlated with a higher probability of at least renal partial response (PRrenal) and with a shorter time to PRrenal or better. Thus bortezomib-based regimens may be the preferred treatment for newly diagnosed myeloma patients with RI.

A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis.

In this phase 1/2 study, we explored the feasibility and activity of an oral regimen of lenalidomide with low-dose dexamethasone and low-dose oral cyclophosphamide (RdC) in patients with primary systemic light chain amyloidosis. RdC was given for up to 12 cycles in prespecified cohorts at escalated doses: 13 patients were treated in phase 1 and 24 in phase 2; 65% were previously untreated, and most had renal and/or cardiac involvement and elevated cardiac biomarkers. Lenalidomide 15 mg/d and cyclophosphamide 100 mg/d were further evaluated in phase 2. On intention to treat, 20 (55%) patients achieved a hematologic response, including 3 (8%) complete remissions. Hematologic responses were seen at all dose levels and in 4 of 5 patients who had received bortezomib previously. An organ response was recorded in 22% of patients on intention-to-treat and in 40% of patients who survived at least 6 months. The median time to progression was 10 months and the 2-year survival was 41%. Fatigue, nonneutropenic infections, and rash were the most common toxicities. The results of the present study show that RdC is an oral regimen with activity in primary systemic light chain amyloidosis and may be an additional treatment option, especially for patients with preserved organ function or for patients who cannot receive or who relapse after bortezomib. This study is registered at www.clinicaltrials.gov as NCT00981708.

Lenalidomide and dexamethasone for the treatment of refractory/relapsed multiple myeloma: Dosing of lenalidomide according to renal function and effect on renal impairment

Objectives:  Lenalidomide and dexamethasone (LenDex) is an active regimen for relapsed/refractory multiple myeloma (MM). However, there is limited data for the effect of LenDex on renal impairment (RI) and on renal reversibility.

Re-evaluation of prognostic markers including staging, serum free light chains or their ratio and serum lactate dehydrogenase in multiple myeloma patients receiving novel agents

International Staging System (ISS), serum free light chain ratio (sFLCR) and lactate dehydrogenase (LDH) are well known, easily assessed independent prognostic indicators of outcome in multiple myeloma (MM). The purpose of the study was to re‐examine the prognostic contribution of these variables in a multicenter setting with special attention to MM patients treated with autologous stem cell transplantation (ASCT) or novel agents (NA). Three hundred and five symptomatic newly diagnosed MM patients were retrospectively studied. Twenty‐seven per cent, 32% and 41% were in ISS stages 1, 2, and 3, respectively. Fifty‐six per cent of them presented kappa light chain monoclonality; median sFLCR was 27.04 (0.37–1.9 × 105) and 47.97 (0.26–2.3 × 107) for kappa patients and lambda patients, respectively; patients with sFLCR above median constituted the high sFLCR group. Thirty‐one per cent of patients had increased LDH. As first line treatment, 55.7% received conventional treatment and 44.3% NA. After induction, 24% underwent ASCT, whereas 76% received NA at any line, either bortezomib (82.5%), thalidomide (48%) or lenalidomide (27%). When the 305 patients were analyzed together, staging, high sFLCR and abnormal LDH were predictive of survival. The same was true for patients that never received NA, whereas neither high sFLCR nor abnormal LDH constituted adverse factors in patients that received NA frontline. In the last group of patients, no difference was observed between ISS stages 2 and 3. The median 5‐year survival of patients that never received NA versus those who did frontline was 29% vs 47%, 7% vs 52% and 24% vs 40% in patients with abnormal LDH, high sFLCR and ISS stage 3, respectively (p = 0.03, p < 0.00001 and p = 0.035). In conclusion, patients gaining the most from NA are those with an aggressive disease as reflected by advanced stage, abnormal LDH and high sFLCR. In addition, the adverse impact of these three variables is obscured by NA. Copyright

Dickkopf-1: a suitable target for the management of myeloma bone disease

Bone disease remains a major problem in the management of patients with multiple myeloma (MM) and is characterized by the presence of lytic lesions due to increased osteoclastic activity and reduced osteoblast function. Wingless-type and integrase 1 (Wnt)/β-catenin signaling is a central pathway for bone development and homeostasis. Dickkopf-1 (Dkk-1) is a soluble inhibitor of Wnt, which disrupts osteoblast differentiation and action. Dkk-1 is produced by myeloma cells and overexpressed in myeloma microenvironment of patients with extensive bone disease. In addition to its direct inhibitory effect of Dkk-1 on osteoblasts, Dkk-1 disrupts the Wnt3a-regulated osteoprotegerin and receptor activator of NF-κB ligand (RANKL) expression in osteoblasts and thus it indirectly enhances osteoclast function in MM. Dkk-1 serum and bone marrow plasma levels are increased in MM patients and correlated with advanced International Staging System stage and presence of osteolytic lesions. Preclinical studies in mouse myeloma models showed that targeting Dkk-1 with neutralizing anti-Dkk-1 antibodies resulted in increased numbers of osteoblasts, reduced numbers of multinucleated osteoclasts and increased bone volume. The bone anabolic effect of anti-Dkk-1 may also be associated with reduced myeloma burden. These data show that Dkk-1 has a pivotal role in bone health and disease and is a novel target for the management of myeloma patients with lytic bone disease.

Increased bone mineral density in a subset of patients with relapsed multiple myeloma who received the combination of bortezomib, dexamethasone and zoledronic acid

Bone disease is a major complication of multiple myeloma (MM) [1]. Bortezomib is the first-in-class proteasome inhibitor, with established anti-myeloma activity and beneficial effect on bone metabolism in preclinical studies [2]. In the clinical setting, bortezomib increases bone formation markers, reduces serum levels of osteoblast inhibitor dickkopf-1 [3], increases osteoblast counts in trephine biopsies [4] and inhibits osteoclast function [3, 5]. However, there are no data for bortezomib effect on bone mineral density (BMD) of myeloma patients. To evaluate this effect, we studied 27 consecutive patients (16 males/11 females; median age 69.5 years) with relapsed MM who received the combination of bortezomib plus dexamethasone (VD) and zoledronic acid (ZA): 17 had immunoglobulin G, 6 immunoglobulin A, 3 light-chain and 1 non-secretory MM. Seven patients had International Staging System-1 (ISS-1) MM at diagnosis, while 9 had ISS-2 and 11 ISS-3 MM. The median number of previous lines of therapies was 2 (range 1–5). Bortezomib was given at the standard dose of 1.3 mg/m on days 1, 4, 8 and 11 of a 21-day cycle, while dexamethasone was given at a dose of 20 mg, p.o., the day of bortezomib administration and the following day. All patients received monthly ZA according to their renal function. BMD of the lumbar spine (L1–L4, anteroposterior view) and femoral neck (FN) was measured by dual energy X-ray absorptiometry (DXA) using a Hologic QDR-1000 scanner at baseline (days 27 to day 1 of cycle 1) and then on day 21 of cycle 4 and 1 month after cycle 8. Evidence of myeloma bone disease at the time of relapse was documented by plain radiography. All patients had measurements of urinary Ntelopeptide of collagen type-I (NTX; a sensitive bone resorption marker) and serum bone-specific alkaline phosphatase (bALP) and osteocalcin (OC) (bone formation markers), pre-VD and every month post-VD, using enzyme-linked immunosorbent assay methodology as previously described [3,5]. Differences between preand post-treatment values of the studied parameters were evaluated using the Wilcoxon rank sum test. The study was conducted with ethical committee approval and under the guidelines of the Declaration of Helsinki.

Treatment of light chain deposition disease with bortezomib and dexamethasone

Light chain deposition disease (LCDD) is a rare plasma cell dyscrasia characterized by deposition of immunoglobulin fragments. The kidneys are almost always affected while heart, liver and other tissues are occasionally involved. About 50% of patients with LCDD have concurrent myeloma, however most