Patient Characteristics and Outcomes of Relapsed/Refractory Multiple Myeloma in Patients Treated with Proteasome Inhibitors in Germany.

INTRODUCTION: Real-world data reflects treatments and outcomes in clinical practice in contrast with controlled clinical trials. This study evaluates real-life multiple myeloma (MM) patients receiving proteasome inhibitor (PI)-based treatments in the second or third therapy line in 2017 in Germany. METHODS: This is a retrospective chart review on adult relapsed/refractory MM patients treated with ≥1 dose of a PI-based regimen in either the second or the third line of therapy. Participating physicians had ≥3 years of clinical experience in treating symptomatic MM patients and used PI according to the label. RESULTS: Distinct patient profiles for each PI-based regimen emerged. Younger, fitter, transplant-eligible patients received novel PI triplets such as carfilzomib in combination with lenalidomide and dexamethasone (KRd) or IRd. Patients receiving lenalidomide in first-line therapy mostly received lenalidomide-free regimens in second-line therapy. In high-risk patients, no clear treatment patterns could be ascertained. The complete response rates were highest with KRd (13.0%), followed by carfilzomib in combination with dexamethasone (Kd) (5.7%) and bortezomib (4.8%). The very good partial response rates were highest with IRd (76.9%), followed by KRd (53.7%), Kd (25.7%), and bortezomib (20.5%). None of the KRd- or IRd-treated patients responded below a partial response. DISCUSSION/CONCLUSION: Clear patient profiles for each PI type were observed. In second-line therapy, younger, fitter, transplant-eligible patients received novel-PI-based triplets, e.g., KRd or IRd. Patients treated with lenalidomide in first-line therapy mostly received lenalidomide-sparing regimens in second-line therapy. In high-risk patients no clear treatment patterns could be ascertained due to the limited sample size.

Ixazomib-Thalidomide-Dexamethasone for induction therapy followed by Ixazomib maintenance treatment in patients with relapsed/refractory multiple myeloma.

BACKGROUND: Ixazomib-revlimid-dexamethason showed significant activity in relapsed/refractory multiple myeloma (RRMM). Here, we evaluate ixazomib in combination with thalidomide and dexamethasone for induction treatment followed by ixazomib maintenance therapy in RRMM patients. METHODS: Ninety patients have been included. Ixazomib-thalidomide-dexamethasone (4 mg, day 1, 8, 15; 100 mg daily; and 40 mg weekly) was scheduled for eight cycles followed by maintenance with ixazomib for one year. RESULTS: The overall response rate was 51.1%, 23.3% achieved CR or VGPR and 10% MR resulting in a clinical benefit rate of 61.1%. In patients completing ≥2 cycles, the rates were 60.5%, 27.6% and 68.4%, respectively. Median progression-free survival (PFS) was 8.5 months in all, and 9.4 months in those completing ≥2 cycles. Response rates, PFS and overall survival (OS) were similar in patients with and without t(4;14) and/or del(17p), but PFS and OS was significantly shorter in patients with gain of 1q21. Multivariate regression analysis revealed gain of 1q21 as the most important factor associated with OS. Ixazomib maintenance resulted in an upgrade in the depth of response in 12.4% of patients. Grade 3/4 toxicities were relatively rare. CONCLUSIONS: Ixazomib-thalidomide-dexamethasone followed by ixazomib maintenance therapy is active and well tolerated in patients with RRMM. TRIAL REGISTRATION NUMBER: NCT02410694.

Diagnosis and treatment of multiple myeloma in Germany: analysis of a nationwide multi-institutional survey.

A nationwide, multi-institutional survey was performed in 2011 and 2015 to analyze routine practice for myeloma patients outside clinical trials in Germany. We contacted university hospitals, community hospitals, and office-based hematologists in order to enter clinical data from newly diagnosed and relapsed patients into an online platform. Complete datasets were available for 478 (2011) and 515 (2015) patients. While median age at diagnosis increased from 70 to 72 years, patients had fewer concomitant diseases (2011 61%; 2015 51%) and presented with equal performance status (ECOG 0-1, 2011 66%; 2015 68%). Cytogenetic analysis was performed in 53% (2011) and 59% (2015). Patients ≥70 years, or patients with comorbidities who were no candidates for autologous transplantation (ASCT), were less frequently tested for cytogenetic abnormalities (p = 0.001, respectively). There were more candidates for ASCT ≥65 years in 2015 (57%) than in 2011 (27%). Bortezomib was used in 92% of transplant-eligible and 66% of transplant-ineligible patients as frontline therapy in 2015. Application of bortezomib and lenalidomide for the first relapse changed from 2011 (bortezomib 45%; lenalidomide 27%) to 2015 (bortezomib 28%; lenalidomide 54%). For the second relapse, application of lenalidomide decreased from 2011 (36%) to 2015 (23%). Pomalidomide entered treatment for the second relapse in 2015 (11% of patients). Taken together, we demonstrate that results from clinical trials are implemented into general practice in Germany.

Stem cell mobilization and autologous stem cell transplantation after pretreatment with bendamustine, prednisone and bortezomib (BPV) in newly diagnosed multiple myeloma.

INTRODUCTION: Reliable information on stem cell toxicity and mobilization of stem cells for autologous stem cell transplantation (SCT) after induction treatment with a combination of bendamustine, prednisone and bortezomib (BPV) is missing. MATERIALS AND METHODS: A retrospective analysis of peripheral blood stem cell mobilization and autologous SCT was performed in 35 patients with MM who had received at least one cycle of a BPV-induction therapy consisting of bendamustine 60 mg/m(2) on days 1 and 2, bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 and prednisone 100 mg on days 1, 2, 4, 8 and 11 between October 2008 and May 2014. The mobilization regimen consisted of cyclophosphamide 4 g/m(2) and G-CSF (2 × 5 µg/kg). Apheresis was started as soon as peripheral CD34(+) counts exceeded 20 × 10(6)/L with a harvest target of 8 × 10(6) CD34(+)/kg. The minimal accepted target was 2 × 10(6) CD34(+)/kg. The transplantation conditioning therapy consisted of melphalan 200 mg/m(2). RESULTS: A median number of two (range 1-5) BPV cycles were given. The majority of patients (n = 31, 89 %) responded with two sCR, five nCR, 11 VGPR and 13 PR after BPV induction. Three patients had MR, and one SD. Stem cell mobilization and harvest were successful in all patients. In 19 of 35 patients (54 %), a single apheresis was sufficient to reach the target. The median number of aphereses was one (range 1-4), and the median CD34(+) cell-count/kg was 13.5 (range 3.2-33.1)  × 106. All patients received an autologous SCT. Engraftment was successful in 34 of 35 patients. The median time to a leukocyte count >l × 10(9)/L was 11 days, and the time to untransfused platelet count of >50 × 10(9)/L was 13 days. Thirty-four patients (97 %) responded after the autologous SCT with 11 sCR, two CR, seven nCR, seven VGPR and seven PR. The progression-free survival at 18 months was 87 %, and overall survival was 92 %. CONCLUSION: Stem cell mobilization and autologous SCT are feasible in MM patients who have received BPV-induction therapy .

Lenalidomide and dexamethasone for acute light chain-induced renal failure: a phase II study.

We prospectively evaluated the activity and tolerance of lenalidomide-dexamethasone in 35 patients with acute light chain-induced renal failure. The lenalidomide dose was adapted to the estimated glomerular filtration rate and dexamethasone was given at high dose in cycle one and at low dose thereafter. Four patients died within the first two cycles, and five discontinued therapy leaving 26 patients for the per-protocol analysis. Responses were observed in 24/35 (68.6%) patients of the intent-to-treat population. Complete response was noted in seven patients (20%), very good partial response in three patients (8.6%), partial response in 14 patients (40%), and minimal response in one patient (2.9%). Renal response was observed in 16 (45.7%) patients: five (14.2%) achieved complete, four (11.4%) partial and seven (20%) minor renal responses. Five of 13 patients who were dialysis dependent at baseline became dialysis independent. The median time to myeloma and to renal response was 28 days for both parameters, while the median time to best myeloma and best renal response was 92 and 157 days, respectively. The median estimated glomerular filtration rate increased significantly in patients with partial response or better from 17.1 mL/min at baseline to 39.1 mL/min at best response (P=0.001). The median progression-free and overall survival was 5.5 and 21.8 months, respectively, in the intent-to-treat population and 12.1 and 31.4 months, respectively, in the per-protocol group. Infections, cardiotoxicity, anemia and thrombocytopenia were the most frequent toxicities. In conclusion, the lenalidomide-dexamethasone regimen achieved rapid and substantial myeloma and renal responses. The trial was registered under EUDRACT number 2008-006497-15.

Analytical performance and diagnostic potential of immunoassays determining intact immunoglobulin kappa/lambda ratios in monoclonal gammopathies.

BACKGROUND: Hevylite chain (HLC) assays with specificity for epitopes at the junction between heavy and light chains of intact immunoglobulins (Ig) allow quantification of Ig kappa/lambda ratios of the three major Ig classes. Calculated Ig kappa/lambda ratios outside the reference range indicate a monoclonal background. The primary aim of the present study was to analytically validate HLC assays and to investigate their diagnostic potential in relation to immunofixation electrophoresis (IFE) as the standard method for identification of monoclonal proteins (MPs). A second aim was to investigate the diagnostic potential of HLC assays in disease monitoring. METHODS: Precision, linearity, accuracy, sensitivity, and specificity of HLC assays for Ig classes A, G, and M were determined as parameters of analytical performance. The diagnostic performance of HLC assays in the detection of MPs was investigated in patient sera revealing monoclonal bands in IFE (n = 156). The utility of the assays in disease monitoring was investigated in a proof of principal approach by quantification of HLC ratios in subsequent sera from stem cell transplanted (ScTx) myeloma patients (n = 4). RESULTS: All six HLC assays revealed analytical performances suitable for application in routine diagnostics. With regard to diagnostic performance, all samples with IgA MPs in IFE (n = 54) could be identified in the HLC IgA assay. Of sera showing IgG MP in IFE (n = 69), 57 could be identified in the HLC IgG assay, whereas 12 had normal IgG kappa/lambda ratios. Of sera showing IgM MP in IFE (n = 26), 25 could be identified in the HLC IgM assay, 1 serum revealed a normal IgM kappa/lambda ratio. ScTx patients achieving IFE-negative remission had normal HLC ratios. Those who failed to achieve IFE-negative remission showed normalization of conventional monitoring parameters but revealed HLC ratios never reaching reference range. CONCLUSIONS: HLC assays exhibit analytical performances suitable for clinical routine application. Our preliminary data from ScTx patients suggest a diagnostic potential especially of HLC IgA assay in disease monitoring. Other than that, combined application of HLC assays does not represent an alternative to IFE in first line diagnostics, in particular due to the limited diagnostic performance of the HLC IgG assay.