Asher Chanan-Khan

A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma

Carfilzomib is a next-generation, selective proteasome inhibitor being evaluated for the treatment of relapsed and refractory multiple myeloma. In this open-label, single-arm phase 2 study (PX-171-003-A1), patients received single-agent carfilzomib 20 mg/m(2) intravenously twice weekly for 3 of 4 weeks in cycle 1, then 27 mg/m(2) for ≤ 12 cycles. The primary endpoint was overall response rate (≥ partial response). Secondary endpoints included clinical benefit response rate (≥ minimal response), duration of response, progression-free survival, overall survival, and safety. A total of 266 patients were evaluable for safety, 257 for efficacy; 95% were refractory to their last therapy; 80% were refractory or intolerant to both bortezomib and lenalidomide. Patients had median of 5 prior lines of therapy, including bortezomib, lenalidomide, and thalidomide. Overall response rate was 23.7% with median duration of response of 7.8 months. Median overall survival was 15.6 months. Adverse events (AEs) were manageable without cumulative toxicities. Common AEs were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Thirty-three patients (12.4%) experienced peripheral neuropathy, primarily grades 1 or 2. Thirty-three patients (12.4%) withdrew because of an AE. Durable responses and an acceptable tolerability profile in this heavily pretreated population demonstrate the potential of carfilzomib to offer meaningful clinical benefit. This trial was registered at www.clinicaltrials.gov as #NCT00511238.

Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3

A panel of members of the 2009 International Myeloma Workshop developed guidelines for standard investigative workup of patients with suspected multiple myeloma. Both serum and urine should be assessed for monoclonal protein. Measurement of monoclonal protein both by densitometer tracing and/by nephelometric quantitation is recommended, and immunofixation is required for confirmation. The serum-free light chain assay is recommended in all newly diagnosed patients with plasma cell dyscrasias. Bone marrow aspiration and/or biopsy along with demonstration of clonality of plasma cells are necessary. Serum β(2)-microglobulin, albumin, and lactate dehydrogenase are necessary for prognostic purposes. Standard metaphase cytogenetics and fluorescent in situ hybridization for 17p, t(4;14), and t(14;16) are recommended. The skeletal survey remains the standard method for imaging screening, but magnetic resonance imaging frequently provides valuable diagnostic and prognostic information. Most of these tests are repeated during follow-up or at relapse.

Randomized Phase III Trial of Fludarabine Plus Cyclophosphamide With or Without Oblimersen Sodium (Bcl-2 antisense) in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

PURPOSE Expression of Bcl-2 protein is associated with chemotherapy resistance and decreased survival in chronic lymphocytic leukemia (CLL). We evaluated whether oblimersen would improve response to chemotherapy in patients with relapsed or refractory CLL. PATIENTS AND METHODS Patients had received at least one prior fludarabine-containing regimen and were stratified on the basis of prior fludarabine response, number of prior regimens, and duration of response to last prior therapy. Patients were randomly assigned to 28-day cycles of fludarabine 25 mg/m2/d plus cyclophosphamide 250 mg/m2/d administered intravenously for 3 days with or without oblimersen 3 mg/kg/d as a 7-day continuous intravenous infusion (beginning 4 days before chemotherapy) for up to six cycles. The primary end point was the proportion of patients who achieved complete response (CR) or nodular partial response (nPR). RESULTS Of 241 patients randomly assigned, CR/nPR was achieved in 20 (17%) of 120 patients in the oblimersen group and eight (7%) of 121 patients in the chemotherapy-only group (P = .025). Achievement of CR/nPR was correlated with both an extended time to progression and survival (P < .0001). In patients who remained sensitive to fludarabine, oblimersen was associated with a four-fold increase in the CR/nPR rate and a significant survival benefit (P = .05). Oblimersen was frequently associated with thrombocytopenia and, rarely, tumor lysis syndrome and cytokine release reactions; the incidence of opportunistic infections and second malignancies was similar in both groups. CONCLUSION The addition of oblimersen to fludarabine plus cyclophosphamide significantly increases the CR/nPR rate in patients with relapsed or refractory CLL (particularly fludarabine-sensitive patients), as well as response duration among patients who achieve CR/nPR.

Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma

BACKGROUND Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma. METHODS In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival. RESULTS A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9.0%, P=0.001). Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these patients, they occurred during the first infusion. CONCLUSIONS Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone. (Funded by Janssen Research and Development; ClinicalTrials.gov number, NCT02136134.).

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.

Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy.

PURPOSE To assess efficacy and safety of single-agent bortezomib in previously untreated patients with multiple myeloma, investigate prevalence of baseline and treatment-emergent polyneuropathy, and identify molecular markers associated with response and neuropathy. PATIENTS AND METHODS Patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, for up to eight 21-day cycles. A subset of patients underwent neurophysiologic evaluation pre- and post-treatment. Bone marrow aspirates were performed at baseline for exploratory whole-genome analyses. Results Among 64 patients, 41% had partial response or better, including 9% complete/near-complete responses; median duration of response was 8.4 months. Response rates did not differ in the presence or absence of adverse cytogenetics. After median follow-up of 29 months, median time to progression was 17.3 months. Median overall survival had not been reached; estimated 1-year survival was 92%. Thirty-two patients successfully underwent optional stem-cell transplantation. Bortezomib treatment was generally well tolerated. At baseline, 20% of patients had sensory polyneuropathy. Sensory polyneuropathy developed during treatment in 64% of patients (grade 3 in 3%), but proved manageable and resolved in 85% within a median of 98 days. Neurologic examination, neurophysiologic testing, and measurements of epidermal nerve fiber densities in 35 patients confirmed pretreatment sensory neuropathy in 20% and new or worsening neuropathy in 63%. Pharmacogenomic analyses identified molecular markers of response and treatment-emergent neuropathy, which will require future study. CONCLUSION Single-agent bortezomib is effective in previously untreated myeloma. Baseline myeloma-associated neuropathy seems more common than previously reported, and bortezomib-associated neuropathy, although a common toxicity, is reversible in most patients.

5-Year Survival in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia in a Randomized, Phase III Trial of Fludarabine Plus Cyclophosphamide With or Without Oblimersen

PURPOSE A randomized trial of oblimersen plus fludarabine/cyclophosphamide (OBL-FC; n = 120) versus FC (n = 121) was conducted in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). The primary end point was met: the complete response (CR) rate, defined as complete or nodular partial response, was significantly greater with OBL-FC than with FC (17% v 7%; P = .025). Among patients with CR, response duration was significantly longer with OBL-FC than with FC (median not reached; > 36 months v 22 months; P = .03). Maximum benefit with OBL-FC, including a four-fold increase in CR rate and a survival benefit with 3 years of follow-up (hazard ratio, 0.53; P = .05), was observed in patients with fludarabine-sensitive disease. We evaluated long-term survival and poststudy CLL therapy among all randomly assigned patients. METHODS Poststudy CLL treatment information was collected. Patients were observed for survival for up to 5 years from the date of random assignment. RESULTS Poststudy CLL treatment was balanced between arms. Intent-to-treat analysis of 5-year survival showed no significant between-treatment difference (hazard ratio, 0.87; P = .34). Among the greater than 40% of patients with complete or partial remission, a significant 5-year survival benefit was observed with OBL-FC (hazard ratio, 0.60; P = .038). Among patients with fludarabine-sensitive disease who had previously demonstrated maximum benefit with OBL-FC, the previously observed survival benefit improved: a 50% reduction in the risk of death was observed (P = .004). CONCLUSION In relapsed/refractory CLL, OBL combined with FC offers patients who achieve complete or partial remission, as well as those who have fludarabine-sensitive disease, a significant survival benefit.

Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group

Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (⩾20%) and absolute number (⩾2 × 109/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL.

Sustained antibody responses depend on CD28 function in bone marrow-resident plasma cells.

CD28 signaling is essential for maintenance of long-term antigen-specific antibody production and for persistence of plasma cells in the bone marrow of mice.

Inhibition of heat shock protein 90 (HSP90) as a therapeutic strategy for the treatment of myeloma and other cancers.

Heat shock protein 90 (HSP90) is a molecular chaperone that is induced in response to cellular stress and stabilizes client proteins involved in cell cycle control and proliferative/anti‐apoptotic signalling. HSP90 is overexpressed in a range of cancers, and may contribute to tumour cell survival by stabilizing aberrant signalling proteins and by interfering with apoptosis. Tanespimycin, an HSP90 inhibitor, reduces tumour cell survival in vitro. In multiple myeloma (MM), HSP90 inhibition affects multiple client proteins that contribute to tumour cell survival, including the IGF1 receptor and the IL‐6 receptor, and elements of the PI3/Akt, STAT3, and MAPK signalling pathways. HSP90 inhibition also abrogates the protective effect of bone marrow stromal cells and inhibits angiogenesis and osteoclastogenesis. Tanespimycin acts synergistically with the proteasome inhibitor bortezomib in MM cells and tumour explants, possibly reducing their ability to resist bortezomib‐induced stress to the endoplasmic reticulum. The combination of tanespimycin and bortezomib has demonstrated significant and durable responses with acceptable toxicity in a phase I/II study in patients with relapsed and relapsed/refractory MM. HSP90 inhibition is a promising strategy in MM especially in combination with bortezomib; additional studies will further evaluate optimal dosings of candidate drugs and schedules, as well as confirm efficacy in comparative phase III trials.