Jeffrey L. Wolf

Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma

Bortezomib, as a single agent and in combination with dexamethasone, was examined as first‐line treatment in 32 consecutive patients with untreated symptomatic multiple myeloma. Patients received bortezomib 1·3 mg/m2 for a maximum of six 3‐week cycles; oral dexamethasone 40 mg was added if a less than partial response (PR) was achieved after two cycles or a less than complete response (CR) was achieved after four cycles. The response rate (CR + PR) was 88%, with undetectable paraprotein (CR) in 6%, and detectable by immunofixation only in 19% [near (n)CR]. All 32 patients completed the first two cycles of bortezomib alone, of whom 3% achieved CR, 9% nCR, and 28% PR. Ten patients received single‐agent bortezomib on study, and dexamethasone was added in 22, leading to 15 improved responses. The most common adverse events ≥grade 2 included sensory neuropathy (31%), constipation (28%), myalgia (28%) and fatigue (25%). Sensory neuropathy grade 2 or 3 was reversible within a median of 3 months in five of 10 patients. Bortezomib treatment did not affect stem cell mobilization in eight or transplantation in six patients. Bortezomib alone or in combination with dexamethasone is an effective induction therapy with a high CR and nCR rate and manageable toxicities in previously untreated patients with myeloma.

Widespread Genetic Heterogeneity in Multiple Myeloma: Implications for Targeted Therapy

We performed massively parallel sequencing of paired tumor/normal samples from 203 multiple myeloma (MM) patients and identified significantly mutated genes and copy number alterations and discovered putative tumor suppressor genes by determining homozygous deletions and loss of heterozygosity. We observed frequent mutations in KRAS (particularly in previously treated patients), NRAS, BRAF, FAM46C, TP53, and DIS3 (particularly in nonhyperdiploid MM). Mutations were often present in subclonal populations, and multiple mutations within the same pathway (e.g., KRAS, NRAS, and BRAF) were observed in the same patient. In vitro modeling predicts only partial treatment efficacy of targeting subclonal mutations, and even growth promotion of nonmutated subclones in some cases. These results emphasize the importance of heterogeneity analysis for treatment decisions.

Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma.

Combinations of bortezomib (V) and dexamethasone (D) with either lenalidomide (R) or cyclophosphamide (C) have shown significant efficacy. This randomized phase 2 trial evaluated VDC, VDR, and VDCR in previously untreated multiple myeloma (MM). Patients received V 1.3 mg/m2 (days 1, 4, 8, 11) and D 40 mg (days 1, 8, 15), with either C 500 mg/m2 (days 1, 8) and R 15 mg (days 1-14; VDCR), R 25 mg (days 1-14; VDR), C 500 mg/m2 (days 1, 8; VDC) or C 500 mg/m2 (days 1, 8, 15; VDC-mod) in 3-week cycles (maximum 8 cycles), followed by maintenance with V 1.3 mg/m2 (days 1, 8, 15, 22) for four 6-week cycles (all arms)≥very good partial response was seen in 58%, 51%, 41%, and 53% (complete response rate of 25%, 24%, 22%, and 47%) of patients (VDCR, VDR, VCD, and VCD-mod, respectively); the corresponding 1-year progression-free survival was 86%, 83%, 93%, and 100%, respectively. Common adverse events included hematologic toxicities, peripheral neuropathy, fatigue, and gastrointestinal disturbances. All regimens were highly active and well tolerated in previously untreated MM, and, based on this trial, VDR and VCD-mod are preferred for clinical practice and further comparative testing. No substantial advantage was noted with VDCR over the 3-drug combinations. This trial is registered at www.clinicaltrials.gov (NCT00507442).

Bone-Marrow Ablation and Allogeneic Marrow Transplantation in Acute Leukemia

Thirty-three patients with acute leukemia (15 with lymphoblastic leukemia and 18 with myeloblastic leukemia) were entered into a program of high-dose radiochemotherapy followed by allogeneic bone-marrow transplantation. These patients were in various clinical stages of disease. Of 10 in complete hematologic remission at the time of transplantation, seven were alive without maintenance therapy at the time of evaluation, eight to 35 months after grafting; one was in relapse. Of 11 who received transplants during partial remission, six were in remission without further treatment eight to 33 months after transplantation. In 12 the disease was refractory to chemotherapy when preparation for transplantation was started, and only one of them was alive and free of disease after 10 months. Recurrent leukemia, graft-versus-host disease, viral pneumonia, and early therapy-related toxicity were the major causes of failure. High-dose chemotherapy and total-body irradiation followed by allogeneic marrow transplantation performed during complete or partial remission can produce long-term remission of acute leukemia.

Phase II trial of the pan-deacetylase inhibitor panobinostat as a single agent in advanced relapsed/refractory multiple myeloma

1 University of California, San Francisco, San Francisco, CA, USA, 2 Hackensack University Medical Center, Hackensack, NJ, USA, 3 University of Heidelberg, Heidelberg, Germany, 4 Novartis Pharma AG, Basel, Switzerland, 5 Colorado Blood Cancer Institute, Denver, CO, USA, 6 Washington University, St. Louis, MO, USA, 7 University of Iowa, Iowa City, IA, USA, 8 Indiana University Cancer Center, Indianapolis, IN, USA, 9 Dana-Farber Cancer Institute, Boston, MA, USA and 10 Emory University, Atlanta, GA, USA

Bortezomib, dexamethasone, cyclophosphamide and lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION study

This phase 1 study (Clinicaltrials.gov: NCT00507442) was conducted to determine the maximum tolerated dose (MTD) of cyclophosphamide in combination with bortezomib, dexamethasone and lenalidomide (VDCR) and to assess the safety and efficacy of this combination in untreated multiple myeloma patients. Cohorts of three to six patients received a cyclophosphamide dosage of 100, 200, 300, 400 or 500 mg/m2 (on days 1 and 8) plus bortezomib 1.3 mg/m2 (on days 1, 4, 8 and 11), dexamethasone 40 mg (on days 1, 8 and 15) and lenalidomide 15 mg (on days 1–14), for eight 21-day induction cycles, followed by four 42-day maintenance cycles (bortezomib 1.3 mg/m2, on days 1, 8, 15 and 22). The MTD was the cyclophosphamide dose below which more than one of six patients experienced a dose-limiting toxicity (DLT). Twenty-five patients were treated. Two DLTs were seen, of grade 4 febrile neutropenia (cyclophosphamide 400 mg/m2) and grade 4 herpes zoster despite anti-viral prophylaxis (cyclophosphamide 500 mg/m2). No cumulative hematological toxicity or thromboembolic episodes were reported. The overall response rate was 96%, including 20% stringent complete response (CR), 40% CR/near-complete response and 68% ⩾very good partial response. VDCR is well tolerated and highly active in this population. No MTD was reached; the recommended phase 2 cyclophosphamide dose in VDCR is 500 mg/m2, which was the highest dose tested.

Deficiency of protein 4.2 in erythrocytes from a patient with a Coombs negative hemolytic anemia. Evidence for a role of protein 4.2 in stabilizing ankyrin on the membrane.

A patient with a mild hemolytic anemia and osmotically fragile, spherocytic erythrocytes was studied. Analysis of the erythrocyte membrane proteins by SDS-PAGE revealed a deficiency of protein 4.2 (less than 0.10% of normal). The protein 4.2-deficient erythrocytes contained normal amounts of all other membrane proteins, although the amount of band 3 was slightly reduced and the amount of band 6 (G3PD) was slightly elevated. The spectrin content of these cells was normal, as measured by both SDS-PAGE and radioimmunoassay. Erythrocytes from the patients biologic parents were hematologically normal and contained normal amounts of protein 4.2. Immunological analysis using affinity purified antibodies revealed that the patients protein 4.2 was composed of equal amounts of a 74-kD and 72-kD protein doublet, whereas the normal protein was composed primarily of a 72-kD monomer. Proteolytic digestion studies using trypsin, alpha-chymotrypsin and papain demonstrated that the patients protein 4.2 was similar but not identical to the normal protein. Binding studies showed that the protein 4.2-deficient membranes bound purified protein 4.2 to the same extent as normal membranes, suggesting that the membrane binding site(s) for the protein were normal. Depleting the protein 4.2-deficient membranes of spectrin and actin resulted in a loss of nearly two-thirds of the membrane ankyrin, whereas similar depletion of normal membranes resulted in no loss of ankyrin. Repletion of the protein 4.2-deficient membranes with purified protein 4.2 before spectrin-actin extraction partially prevented the loss of ankyrin. These results suggest that protein 4.2 may function to stabilize ankyrin on the erythrocyte membrane.

Autologous stem cell transplantation for acute myeloid leukemia in first remission

We studied the feasibility, toxicity, and efficacy of a 2-step approach to autologous stem cell transplantation for patients with acute myeloid leukemia in first remission. Step 1 consisted of consolidation chemotherapy including cytarabine 2000 mg/m2 twice daily for 4 days concurrent with etoposide 40 mg/kg by continuous infusion over 4 days. During the recovery from this chemotherapy, peripheral blood stem cells were collected under granulocyte colony-stimulating factor stimulation. Step 2, autologous stem cell transplantation, involved the preparative regimen of busulfan 16 mg/kg followed by etoposide 60 mg/kg and reinfusion of unpurged peripheral blood stem cells. A total of 128 patients were treated. During step 1, there was 1 treatment-related death. A median CD34+ cell dose of 14 (x10(6)/kg) was collected in 3 aphereses. Ten patients suffered relapse before transplantation, and 117 patients (91%) proceeded to transplantation. During step 2, there were 2 treatment-related deaths, and 35 patients subsequently suffered relapse. With median follow-up of 30 months, 5-year disease-free survival for all patients entered in the study is projected to be 55%. By cytogenetic risk group, 5-year disease-free survival is 73% for favorable-risk patients, 51% for intermediate-risk patients, and 0% for poor-risk patients. We conclude that this 2-step approach to autologous transplantation produces excellent stem cell yields and allows a high percentage of patients to receive the intended therapy. Preliminary efficacy analysis is very encouraging, with outcomes that appear superior to those of conventional chemotherapy.

Tanespimycin with bortezomib: activity in relapsed/refractory patients with multiple myeloma

Tanespimycin (17‐allylamino‐17‐demethoxygeldanamycin, 17‐AAG) disrupts heat shock protein 90 (HSP90), a key molecular chaperone for signal transduction proteins critical to myeloma growth, survival and drug resistance. In previous studies, tanespimycin monotherapy was well tolerated and active in heavily pretreated patients with relapsed/refractory multiple myeloma (MM). Preclinical data have shown antitumour synergy between tanespimycin and bortezomib, with more pronounced intracellular accumulation of ubiquitinated proteins than either drug alone, an effect attributed to the synergistic suppression of chymotryptic activity in the 20S proteasome. HSP70 induction has been observed in all Phase 1 tanespimycin studies in which it has been measured, with several separate reports of HSP70 overexpression protecting against peripheral nerve injury. In this Phase 2, open‐label multicentre study, we compared 1·3 mg/m2 bortezomib + three doses of tanespimycin: 50, 175 and 340 mg/m2 in heavily pretreated patients with relapsed and refractory MM and measured HSP70 expression and proteasome activity levels in plasma of treated patients. The study was closed prematurely for resource‐based reasons, precluding dose comparison. Nonetheless, antitumour activity was observed, with promising response rates and promising severity of peripheral neuropathy.

The Transplanted Kidney As a Source of Hepatitis B Infection

Excerpt Hepatitis B infection is relatively common in renal transplant patients. Sources of infection include multiple blood product transfusions, hemodialysis machines, and close contact of the im...