Ruben Niesvizky

A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma

In a phase 2 open‐label study of the novel proteasome inhibitor bortezomib, 54 patients with multiple myeloma who had relapsed after or were refractory to frontline therapy were randomized to receive intravenous 1·0 or 1·3 mg/m2 bortezomib twice weekly for 2 weeks, every 3 weeks for a maximum of eight cycles. Dexamethasone was permitted in patients with progressive or stable disease after two or four cycles respectively. Responses were determined using modified European Group for Blood and Marrow Transplantation criteria. The complete response (CR) + partial response (PR) rate for bortezomib alone was 30% [90% confidence interval (CI), 15·7–47·1] and 38% (90% CI, 22·6–56·4) in the 1·0 mg/m2 (8 of 27 patients) and 1·3 mg/m2 (10 of 26 patients) groups respectively. The CR + PR rate for patients who received bortezomib alone or in combination with dexamethasone was 37% and 50% for the 1·0 and 1·3 mg/m2 cohorts respectively. The most common grade 3 adverse events were thrombocytopenia (24%), neutropenia (17%), lymphopenia (11%) and peripheral neuropathy (9%). Grade 4 events were observed in 9% (five of 54 patients). Bortezomib alone or in combination with dexamethasone demonstrated therapeutic activity in patients with multiple myeloma who relapsed after frontline therapy.

Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma

The incidence of venous thromboembolism (VTE) is more than 1‰ annually in the general population and increases further in cancer patients. The risk of VTE is higher in multiple myeloma (MM) patients who receive thalidomide or lenalidomide, especially in combination with dexamethasone or chemotherapy. Various VTE prophylaxis strategies, such as low-molecular-weight heparin (LMWH), warfarin or aspirin, have been investigated in small, uncontrolled clinical studies. This manuscript summarizes the available evidence and recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for thrombosis associated with thalidomide/lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors include diagnosis and hyperviscosity. VTE is very high in patients who receive high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with ⩽1 risk factor for VTE. LMWH (equivalent to enoxaparin 40 mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2–3 is an alternative to LMWH, although there are limited data in the literature with this strategy. In the absence of clear data from randomized studies as a foundation for recommendations, many of the following proposed strategies are the results of common sense or derive from the extrapolation of data from many studies not specifically designed to answer these questions. Further investigation is needed to define the best VTE prophylaxis.

Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma

BACKGROUND Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma. METHODS We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival. RESULTS Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in the carfilzomib group reported superior health-related quality of life. CONCLUSIONS In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number, NCT01080391.).

International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple Myeloma

Several imaging technologies are used for the diagnosis and management of patients with multiple myeloma (MM). Conventional radiography, computed tomography (CT), magnetic resonance imaging (MRI) and nuclear medicine imaging are all used in an attempt to better clarify the extent of bone disease and soft tissue disease in MM. This review summarizes all available data in the literature and provides recommendations for the use of each of the technologies. Conventional radiography still remains the ‘gold standard’ of the staging procedure of newly diagnosed and relapsed myeloma patients. MRI gives information complementary to skeletal survey and is recommended in MM patients with normal conventional radiography and in all patients with an apparently solitary plasmacytoma of bone. Urgent MRI or CT (if MRI is not available) is the diagnostic procedure of choice to assess suspected cord compression. Bone scintigraphy has no place in the routine staging of myeloma, whereas sequential dual-energy X-ray absorptiometry scans are not recommended. Positron emission tomography/CT or MIBI imaging are also not recommended for routine use in the management of myeloma patients, although both techniques may be useful in selected cases that warrant clarification of previous imaging findings, but such an approach should ideally be made within the context of a clinical trial.

Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma.

We present a pooled update of two large, multicenter MM-009 and MM-010 placebo-controlled randomized phase III trials that included 704 patients and assessed lenalidomide plus dexamethasone versus dexamethasone plus placebo in patients with relapsed/refractory multiple myeloma (MM). Patients in both studies were randomized to receive 25 mg daily oral lenalidomide or identical placebo, plus 40 mg oral dexamethasone. In this pooled analysis, using data up to unblinding (June 2005 for MM-009 and August 2005 for MM-010), treatment with lenalidomide plus dexamethasone significantly improved overall response (60.6 vs 21.9%, P<0.001), complete response rate (15.0 vs 2.0%, P<0.001), time to progression (median of 13.4 vs 4.6 months, P<0.001) and duration of response (median of 15.8 months vs 7 months, P<0.001) compared with dexamethasone-placebo. At a median follow-up of 48 months for surviving patients, using data up to July 2008, a significant benefit in overall survival (median of 38.0 vs 31.6 months, P=0.045) was retained despite 47.6% of patients who were randomized to dexamethasone-placebo receiving lenalidomide-based treatment after disease progression or study unblinding. Low β2-microglobulin and low bone marrow plasmacytosis were associated with longer survival. In conclusion, these data confirm the significant response and survival benefit with lenalidomide and dexamethasone.

Renal Impairment in Patients With Multiple Myeloma: A Consensus Statement on Behalf of the International Myeloma Working Group

Renal impairment is a common complication of multiple myeloma (MM). The estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula is the recommended method for the assessment of renal function in patients with MM with stabilized serum creatinine. In acute renal injury, the RIFLE (risk, injury, failure, loss and end-stage kidney disease) and Acute Renal Injury Network criteria seem to be appropriate to define the severity of renal impairment. Novel criteria based on eGFR measurements are recommended for the definition of the reversibility of renal impairment. Rapid intervention to reverse renal dysfunction is critical for the management of these patients, especially for those with light chain cast nephropathy. Bortezomib with high-dose dexamethasone is considered as the treatment of choice for such patients. There is limited experience with thalidomide in patients with myeloma with renal impairment. Thus, thalidomide can be carefully administered, mainly in the context of well-designed clinical trials, to evaluate if it can improve the rapidity and probability of response that is produced by the combination with bortezomib and high-dose dexamethasone. Lenalidomide is effective in this setting and can reverse renal insufficiency in a significant subset of patients, when it is given at reduced doses, according to renal function. The role of plasma exchange in patients with suspected light chain cast nephropathy and renal impairment is controversial. High-dose melphalan (140 mg/m(2)) and autologous stem-cell transplantation should be limited to younger patients with chemosensitive disease.

International myeloma working group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation

The role of high-dose therapy followed by autologous stem cell transplantation (ASCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. The choice of induction therapy has moved from conventional chemotherapy to newer regimens incorporating the immunomodulatory derivatives thalidomide or lenalidomide and the proteasome inhibitor bortezomib. These drugs combine well with traditional therapies and with one another to form various doublet, triplet, and quadruplet regimens. Up-front use of these induction treatments, in particular 3-drug combinations, has affected unprecedented rates of complete response that rival those previously seen with conventional chemotherapy and subsequent ASCT. Autotransplantation applied after novel-agent-based induction regimens provides further improvement in the depth of response, a gain that translates into extended progression-free survival and, potentially, overall survival. High activity shown by immunomodulatory derivatives and bortezomib before ASCT has recently led to their use as consolidation and maintenance therapies after autotransplantation. Novel agents and ASCT are complementary treatment strategies for MM. This article reviews the current literature and provides important perspectives and guidance on the major issues surrounding the optimal current management of younger, transplantation-eligible MM patients.

Phase I Study of Vorinostat in Combination with Bortezomib for Relapsed and Refractory Multiple Myeloma

Purpose: Vorinostat, a histone deacetylase inhibitor, enhances cell death by the proteasome inhibitor bortezomib in vitro. We sought to test the combination clinically. Experimental Design: A phase I trial evaluated sequential dose escalation of bortezomib at 1 to 1.3 mg/m2 i.v. on days 1, 4, 8, and 11 and vorinostat at 100 to 500 mg orally daily for 8 days of each 21-day cycle in relapsed/refractory multiple myeloma patients. Vorinostat pharmacokinetics and dynamics were assessed. Results: Twenty-three patients were treated. Patients had received a median of 7 prior regimens (range, 3-13), including autologous transplantation in 20, thalidomide in all 23, lenalidomide in 17, and bortezomib in 19, 9 of whom were bortezomib-refractory. Two patients receiving 500 mg vorinostat had prolonged QT interval and fatigue as dose-limiting toxicities. The most common grade >3 toxicities were myelo-suppression (n = 13), fatigue (n = 11), and diarrhea (n = 5). There were no drug-related deaths. Overall response rate was 42%, including three partial responses among nine bortezomib refractory patients. Vorinostat pharmacokinetics were nonlinear. Serum Cmax reached a plateau above 400 mg. Pharmacodynamic changes in CD-138+ bone marrow cells before and on day 11 showed no correlation between protein levels of NF-κB, IκB, acetylated tubulin, and p21CIP1 and clinical response. Conclusions: The maximum tolerated dose of vorinostat in our study was 400 mg daily for 8 days every 21 days, with bortezomib administered at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11. The promising antimyeloma activity of the regimen in refractory patients merits further evaluation. (Clin Cancer Res 2009;15(16):5250–7)

Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies

Carfilzomib, a selective proteasome inhibitor, was approved in 2012 for the treatment of relapsed and refractory multiple myeloma. Safety data for single-agent carfilzomib have been analyzed for 526 patients with advanced multiple myeloma who took part in one of 4 phase II studies (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005). Overall analyses of adverse events and treatment modifications are presented, as well as specific analyses of adverse events by organ system. Overall, the most common adverse events of any grade included fatigue (55.5%), anemia (46.8%), and nausea (44.9%). In the grouped analyses, any grade adverse events were reported in 22.1% for any cardiac (7.2% cardiac failure), 69.0% for any respiratory (42.2% dyspnea), and 33.1% for any grouped renal impairment adverse event (24.1% increased serum creatinine). The most common non-hematologic adverse events were generally Grade 1 or 2 in severity, while Grade 3/4 adverse events were primarily hematologic and mostly reversible. There was no evidence of cumulative bone marrow suppression, either neutropenia or thrombocytopenia, and febrile neutropenia occurred infrequently (1.1%). Notably, the incidence of peripheral neuropathy was low overall (13.9%), including patients with baseline peripheral neuropathy (12.7%). Additionally, the incidence of discontinuations or dose reductions attributable to adverse events was low. These data demonstrate that single-agent carfilzomib has an acceptable safety profile in heavily pre-treated patients with relapsed/refractory multiple myeloma. The tolerable safety profile allows for administration of full-dose carfilzomib, both for extended periods and in a wide spectrum of patients with advanced multiple myeloma, including those with pre-existing comorbidities.

Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide, lenalidomide or bortezomib- containing regimens

The past decade has witnessed a paradigm shift in the initial treatment of multiple myeloma with the introduction of novel agents such as thalidomide, lenalidomide, and bortezomib, leading to improved outcomes. High-dose therapy and autologous stem cell transplantation remains an important therapeutic option for patients with multiple myeloma eligible for the procedure. Before the advent of the novel agents, patients underwent stem cell collection prior to significant alkylating agent exposure, given its potential deleterious effect on stem cell collection. With increasing use of the novel agents in the upfront setting, several reports have emerged raising concerns about their impact on the ability to collect stem cells. An expert panel of the International Myeloma Working Group (IMWG) was convened to examine the implications of these therapies on stem collection in patients with myeloma and to develop recommendations for addressing these issues. Here we summarize the currently available data and present our perspective on the problem and potential options to overcome this problem. Specifically, we recommend early mobilization of stem cells, preferably within the first 4 cycles of initial therapy, in patients treated with novel agents and encourage participation in clinical trials evaluating novel approaches to stem cell mobilization.