[Show abstract][Hide abstract] ABSTRACT: Cereblon (CRBN) mediates immunomodulatory drug (IMiD) action in multiple myeloma (MM). Using two different methodologies we identified 244 CRBN binding proteins and established relevance to MM biology by changes in their abundance after exposure to lenalidomide. Proteins most reproducibly binding CRBN (>4 fold versus controls) included DDB1, CUL4A, IKZF1, KPNA2, LTF, PFKL, PRKAR2A, RANGAP1 and SHMT2. After lenalidomide treatment abundance of 46 CRBN binding proteins decreased. We focused attention on two of these - IKZF1 and IKZF3. IZKF expression is similar across all MM stages or subtypes however IKZF1 is substantially lower in three of five IMiD resistant MM cell lines. The cell line (FR4) with the lowest IKZF1 levels also harbors a damaging mutation as well as a translocation which upregulates IRF4, an IKZF target. Clinical relevance of CRBN binding proteins was demonstrated in 44 refractory MM patients treated with pomalidomide and dexamethasone therapy in whom low IKZF1 gene expression predicted lack of response (0 of 11 responses in the lowest expression quartile). CRBN, IKZF1 and KPNA2 levels also correlate with significant differences in overall survival. Our study identifies CRBN binding proteins and demonstrates that in addition to CRBN, IKZF1 and KPNA2, expression can predict survival outcomes.
[Show abstract][Hide abstract] ABSTRACT: Cereblon (CRBN) mediates immunomodulatory drug (IMiD) action in multiple myeloma (MM). We demonstrate here that no patient with very low CRBN expression responded to IMiD plus dexamethasone therapy. In 53 refractory MM patients treated with pomalidomide and dexamethasone, CRBN levels predict for decreased response rates and significant differences in PFS (3.0 vs. 8.9 months, p<0.001) and OS (9.1 vs. 27.2 months, p=0.01) (lowest quartile vs. highest three quartiles). While higher CRBN levels can serve as a surrogate for low risk disease, our study demonstrates that low CRBN expression can predict resistance to IMiD monotherapy and is a predictive biomarker for survival outcomes.
[Show abstract][Hide abstract] ABSTRACT: Light-chain (AL) amyloidosis remains incurable despite recent therapeutic advances. Given the activity of the lenalidomide-alkylating agent combination in myeloma, we designed this phase 2 trial of lenalidomide, cyclophosphamide, and dexamethasone in AL amyloidosis. Thirty-five patients, including 24 previously untreated, were enrolled. Nearly one-half of the patients had cardiac stage III disease and 28% had ≥ 3 organs involved. The overall hematologic response (≥ partial response [PR]) rate was 60%, including 40% with very-good partial response or better. Using serum-free light chain for assessing response, 77% of patients had a hematologic response. Organ responses were seen in 29% of patients and were limited to those with a hematologic response. The median hematologic progression-free survival was 28.3 months, and the median overall survival was 37.8 months. Hematologic toxicity was the predominant adverse event, followed by fatigue, edema, and gastrointestinal symptoms. A grade 3 or higher toxicity occurred in 26 patients (74%) including ≥ grade 3 hematologic toxicity in 16 patients (46%) and ≥ grade 3 nonhematologic toxicity in 25 patients (71%). Seven patients (20%) died on study, primarily because of advanced disease. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) is an effective combination for treatment of AL amyloidosis and leads to durable hematologic responses as well as organ responses with manageable toxicity. The trial was registered at www.clinicaltrials.gov (NCT00564889).
[Show abstract][Hide abstract] ABSTRACT: Immunoglobulin light-chain (AL) amyloidosis is a rare, incurable plasma cell disorder. Its therapy has benefited immensely from the expanding drug armamentarium available for multiple myeloma. Pomalidomide in combination with weekly dexamethasone (Pom/dex) is active among patients with relapsed myeloma. In the present study, we explored the Pom/dex combination in patients with previously treated AL. Patients were eligible for this prospective phase 2 trial if they had had at least one prior regimen and if they had reasonably preserved organ function. Patients were treated with oral Pom/dex. Thirty-three patients were enrolled. The median age was 66 years. Median time from diagnosis to on-study was 37 months. Eighty-two percent had cardiac involvement. The confirmed hematologic response rate was 48%, with a median time to response of 1.9 months. Organ improvement was documented in 5 patients. The median overall and progression-free survival rates were 28 and 14 months, respectively; the 1-year overall and progression-free survival rates were 76% and 59%, respectively. There was a discordance between the hematologic response and the N-terminal pro-brain natriuretic peptide response. The most common grade 3-5 adverse events, regardless of attribution, were neutropenia and fatigue. We conclude that pomalidomide appears to be a valuable drug covering an unmet clinical need in patients with previously treated AL. The trial is registered at www.clinicaltrials.gov as NCT00558896.
[Show abstract][Hide abstract] ABSTRACT: Cardiac involvement predicts poor prognosis in light chain (AL) amyloidosis, and the current prognostic classification is based on cardiac biomarkers troponin-T (cTnT) and N-terminal pro-B-type natriuretic peptide (NT-ProBNP). However, long-term outcome is dependent on the underlying plasma cell clone, and incorporation of clonal characteristics may allow for better risk stratification.
We developed a prognostic model based on 810 patients with newly diagnosed AL amyloidosis, which was further examined in two other datasets: 303 patients undergoing stem-cell transplantation, and 103 patients enrolled onto different clinical trials.
We examined the prognostic value of plasma cell-related characteristics (ie, difference between involved and uninvolved light chain [FLC-diff], marrow plasma cell percentage, circulating plasma cells, plasma cell labeling index, and β(2) microglobulin). In a multivariate model that included these characteristics as well as cTnT and NT-ProBNP, only FLC-diff, cTnT, and NT-ProBNP were independently prognostic for overall survival (OS). Patients were assigned a score of 1 for each of FLC-diff ≥ 18 mg/dL, cTnT ≥ 0.025 ng/mL, and NT-ProBNP ≥ 1,800 pg/mL, creating stages I to IV with scores of 0 to 3 points, respectively. The proportions of patients with stages I, II, III and IV disease were 189 (25%), 206 (27%), 186 (25%) and 177 (23%), and their median OS from diagnosis was 94.1, 40.3, 14, and 5.8 months, respectively (P < .001). This classification system was validated in the other datasets.
Incorporation of serum FLC-diff into the current staging system improves risk stratification for patients with AL amyloidosis and will help develop risk-adapted therapies for AL amyloidosis.
Journal of Clinical Oncology 02/2012; 30(9):989-95. · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Novel agents are considered standard components of induction therapy for newly diagnosed patients with multiple myeloma. We retrospectively compared the results of three consecutive phase 2 clinical trials; RD (lenalidomide/dexamethasone, n=34), CRD (cyclophosphamide/lenalidomide/dexamethasone, n=53) and CyBorD (cyclophosphamide/bortezomib/dexamethasone, n=63) (N=150). Response rates after four cycles of treatment were: ≥near complete response (nCR), 12% vs. 2% vs. 41%, P<0·0001 and very good partial response or better, 35% vs. 30% vs. 65%, P=0·0003, respectively. With all cycles of therapy considered, ≥nCR was 35%, 15% and 41%, P=0·006. However, there is no evidence that one regimen produced superior progression-free survival (PFS) (median: 3·2 vs. 2·3 vs. 2·7years, P=0·11) or overall survival (3-year: 88% vs. 79% vs. 88%, P=0·23). Transplantation did not impact PFS (median: 2·7 vs. 2·3 years, P=0·41) but was associated with improved OS (3-year: 93% vs. 75%, P≤0·001). High genetic risk patients (n=40) had earlier relapse despite lenalidomide or bortezomib (median: 2·1 vs. 2·7years, P=0·45). Grade 3/4 toxicities were least with CyBorD while CRD had most toxicity. In conclusion, CyBorD demonstrated superior responses and less frequent serious toxicity but more neuropathy when compared to RD and CRD. Importantly, 80% of patients treated with modern therapeutic approaches are alive at 4years.
British Journal of Haematology 11/2011; 156(3):326-33. · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pomalidomide at doses of 2 or 4 mg/d has demonstrated excellent activity in patients with multiple myeloma (MM). We opened 2 sequential phase 2 trials using the pomalidomide with weekly dexamethasone (Pom/dex) regimen at differing doses to study the efficacy of this regimen in patients who have failed both lenalidomide and bortezomib. Pomalidomide was given orally 2 or 4 mg daily with dexamethasone 40 mg weekly. Thirty-five patients were enrolled in each cohort. Confirmed responses in the 2-mg cohort consisted of very good partial response (VGPR) in 5 (14%), partial response (PR) in 4 (11%), minor response (MR) in 8 (23%) for an overall response rate of 49%. In the 4-mg cohort, confirmed responses consisted of complete response (CR) in 1 (3%), VGPR in 3 (9%), PR in 6 (17%), MR in 5 (14%) for an overall response rate of 43%. Overall survival at 6 months is 78% and 67% in the 2- and 4-mg cohort, respectively. Myelosuppression was the most common toxicity. This nonrandomized data suggests no advantage for 4 mg over the 2 mg daily. Pomalidomide overcomes resistance in myeloma refractory to both lenalidomide and bortezomib. This trial is registered at http://ClinicalTrials.gov, number NCT00558896.
[Show abstract][Hide abstract] ABSTRACT: The inhibition of histone deacetylase (HDAC) can induce differentiation, growth arrest, and apoptosis in cancer cells. This phase II multicenter study was undertaken to estimate the efficacy of belinostat, a potent inhibitor of both class I and class II HDAC enzymes, for the treatment of myelodysplastic syndrome (MDS). Adults with MDS and ≤2 prior therapies were treated with belinostat 1,000 mg/m(2) IV on days 1-5 of a 21-day cycle. The primary endpoint was a proportion of confirmed responses during the first 12 weeks of treatment. Responding patients could receive additional cycles until disease progression or unacceptable toxicity. Twenty-one patients were enrolled, and all were evaluable. Patients were a median 13.4 months from diagnosis, and 14 patients (67%) had less than 5% bone marrow blasts. Seventeen patients (81%) were transfusion dependent. Prior therapy included azacytidine (n = 7) and chemotherapy (n = 8). The patients were treated with a median of four cycles (range, 1-8) of belinostat. There was one confirmed response-hematologic improvement in neutrophils-for an overall response rate of 5% (95% CI, 0.2-23). Median overall survival was 17.9 months. Grades 3-4 toxicities considered at least to be possibly related to belinostat were: neutropenia (n = 10), thrombocytopenia (n = 9), anemia (n = 5), fatigue (n = 2), febrile neutropenia (n = 1), headache (n = 1), and QTc prolongation (n = 1). Because the study met the stopping rule in the first stage of enrollment, it was closed to further accrual.
Annals of Hematology 05/2011; 91(1):33-8. · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The combination of lenalidomide and low-dose dexamethasone is an effective treatment for multiple myeloma (MM). Addition of alkylating agents to lenalidomide or thalidomide results in increased response rates and deeper responses. We designed this trial to study the combination of cyclophosphamide, lenalidomide, and dexamethasone (CRd) as initial therapy for MM. Fifty-three patients with previously untreated symptomatic MM was enrolled. Patients received 4-week treatment cycles consisting of lenalidomide (25 mg daily for 3 weeks), dexamethasone (40 mg weekly), and cyclophosphamide (300 mg/m(2) weekly for 3 weeks). A partial response or better was seen in 85% of patients including 47% with a very good partial response or better. The toxicities were manageable with over 80% of planned doses delivered; six patients went off study for toxicity. The median progression free survival (PFS) for the entire group was 28 months (95% CI: 22.7-32.6) and the overall survival (OS) at 2 years was 87% (95% CI: 78-96). Importantly, 14 patients with high-risk MM had similar PFS and OS as the standard-risk patients (n = 39). CRd is an effective and well-tolerated regimen for upfront therapy of MM with high response rates and excellent 2-year OS, and is suitable for long-term therapy.
American Journal of Hematology 04/2011; 86(8):640-5. · 4.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Between 2005 and 2008, we conducted separate phase II clinical testing of three distinct anti-VEGF therapies for patients with relapsed/refractory CLL. Collectively, 46 patients were accrued to trials of single-agent anti-VEGF antibody (bevacizumab, n = 13) or one of two receptor tyrosine kinase inhibitors (AZD2171, n = 15; sunitinib malate, n = 18). All patients have completed treatment. Patients received a median of two cycles of bevacizumab, AZD2171, or sunitinib malate. All three trials were closed early due to lack of efficacy. No complete or partial remissions were observed. Individually and collectively, these studies indicate that single-agent anti-VEGF therapy has minimal clinical activity for patients with relapsed/refractory CLL.
[Show abstract][Hide abstract] ABSTRACT: This two-stage, multi-institutional, randomized phase 2 trial assessed the toxicity and response rate associated with two treatment schedules of the histone deacetylase inhibitor, vorinostat (suberoylanilide hydroxamic acid; SAHA) in patients with relapsed acute myeloid leukemia and in selected untreated patients with high-risk acute myeloid leukemia.
Patients with relapsed or untreated acute myeloid leukemia who were not candidates for chemotherapy entered one of the two treatment arms. In both arms a total dose of 8400 mg of vorinostat was delivered in each 21-day cycle of treatment: in arm A the dose regimen was 400 mg daily whereas in arm B the dose regimen was 200 mg three times daily for 14 days followed by 1 week rest.
Data from all 37 patients were used for the analyses. In arm A (n=15), the confirmed complete remission rate was 0% (95% CI, 0% to 23%); this arm was closed at the planned interim analysis. In arm B (n=22), the confirmed complete remission rate was 4.5% (1 response; 95% CI, 0.4% to 24%), with a duration of response exceeding 398 days. The median time to treatment failure in arm A was 42 days (95% CI, 26 to 57); although a minimum of four cycles of treatment were planned, 11 patients (79%) received no more than two cycles. The median time to treatment failure in arm B was 46 days (95% CI, 20 to 71); 13 patients (59%) received no more than two cycles of treatment.
Vorinostat monotherapy demonstrated minimal activity in this group of patients with acute myeloid leukemia. Therapy was discontinued in many patients before the planned four cycles had been administered, either because of failure of vorinostat to control the leukocyte count or patients' and physicians' preference. Future studies of vorinostat in acute myeloid leukemia should focus on combinations with other drugs with which it might interact pharmacodynamically. ClinicalTrials.gov Identifier: NCT00305773.
[Show abstract][Hide abstract] ABSTRACT: Thalidomide and lenalidomide are immunomodulatory drugs (IMiDs) that produce high remission rates in the treatment of multiple myeloma. Pomalidomide is a new IMiD with high in vitro potency. We report, to our knowledge, the first phase II trial of pomalidomide administered in combination with low-dose dexamethasone for the treatment of relapsed or refractory multiple myeloma.
Pomalidomide was administered orally at a dose of 2 mg daily on days 1 through 28 of a 28-day cycle. Dexamethasone 40 mg daily was administered orally on days 1, 8, 15, and 22 of each cycle. Responses were recorded using the criteria of the International Myeloma Working Group.
Sixty patients were enrolled. Thirty-eight patients (63%) achieved confirmed response including complete response in three patients (5%), very good partial response in 17 patients (28%), and partial response in 18 patients (30%). Responses were seen in 40% of lenalidomide-refractory patients, 37% of thalidomide-refractory patients, and 60% of bortezomib-refractory patients. Responses were seen in 74% of patients with high-risk cytogenetic or molecular markers. Toxicity consisted primarily of myelosuppression. Grade 3 or 4 hematologic toxicity consisted of anemia (5%), thrombocytopenia (3%), and neutropenia (32%). One patient (1.6%) had a thromboembolic event. The median progression-free survival time was 11.6 months and was not significantly different in patients with high-risk disease compared with patients with standard-risk disease.
The combination of pomalidomide and low-dose dexamethasone is extremely active in the treatment of relapsed multiple myeloma, including high response rates in patients refractory to other novel agents.
Journal of Clinical Oncology 09/2009; 27(30):5008-14. · 18.04 Impact Factor