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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-03-0996.
PLENARY PAPER
From the Jerome Lipper Multiple Myeloma Center,
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; and
Celgene, Warren, NJ.
Thalidomide (Thal) can overcome drug resistance in multiple myeloma
(MM) but is associated with somnolence, constipation, and neuropathy.
In previous in vitro studies, we have shown that the potent
immunomodulatory derivative of thalidomide (IMiD) CC-5013 induces
apoptosis or growth arrest even in resistant MM cell lines and patient
cells, decreases binding of MM cells to bone marrow stromal cells
(BMSCs), inhibits the production in the BM milieu of cytokines
(interleukin-6 [IL-6], vascular endothelial growth factor [VEGF],
tumor necrosis factor- Multiple myeloma (MM) is the second most
common hematologic malignancy, affecting 14 400 new and 50 000 total
patients in the United States in 2001,1 and remains
incurable despite conventional and high-dose chemotherapy. To overcome
resistance to current therapies and improve patient outcome, novel
biologically based treatment approaches are needed that target
mechanisms whereby MM cells grow and survive in the bone marrow
(BM). Thalidomide (Thal), used empirically to treat MM based upon its
antiangiogenic activity and the increased angiogenesis observed in MM
BM, achieves responses even in refractory, relapsed
disease.2 Importantly, our in vitro and in vivo
preclinical studies both define a role for MM-host interactions in
regulating MM cell growth, survival, drug resistance, and migration in
the BM3-12 and demonstrate that Thal targets the MM cell
in its BM milieu to overcome classical drug resistance both in vitro
and in vivo in animal models.13-16 However, Thal has
significant and dose-limiting side effects, including somnolence,
constipation, and neuropathy, which has prompted the search for more
potent and less toxic Thal derivatives.
Immunomodulatory drugs (IMiDs) are potent Thal derivatives that
markedly stimulate T-cell proliferation, as well as interleukin-2 (IL-2) and interferon-
The remarkable in vitro and in vivo activity of CC-5013 against
resistant MM cells in preclinical studies provided the framework for
this phase 1 dose-escalation trial of CC-5013 in patients with relapsed
and refractory MM. Importantly, CC-5013 achieved either response or
stabilization of disease in 17 (71%) of 24 evaluable patients (90%
confidence interval [CI], 52%-85%) and demonstrated a
favorable toxicity profile. Our study therefore provides the basis for
the evaluation of CC-5013, either alone or in combination, to treat
patients with MM at earlier stages of disease.
Study objectives
Study design
Patients were assessed before and weekly for the first month after
treatment. Patients were hospitalized in the clinical research unit for
at least 72 hours after the first dose of CC-5013 and overnight on day
28. Patients who did not have either disease progression or DLT at day
28 continued on treatment until disease relapse or progression, with
monthly follow-up. Safety and efficacy assessments were performed at
each visit, with blood and urine samples collected for pharmacokinetics
on days 1 to 4 and day 28.
Patient selection
Treatment Each patient received CC-5013 as a single daily oral dose. Depending on the order of study entry and the tolerability of prior dose levels, patients received CC-5013 at 5, 10, 25, or 50 mg/d for the first 4 weeks. Accrual to the next higher dose level did not occur until the safety and tolerability of CC-5013 at prior dose level(s), when given for at least 4 weeks, had been established. Patients experiencing DLT during the first 28 days had therapy discontinued. After the first 4 weeks of treatment, dose reduction was permitted to manage any toxicity.Safety parameters Prior to enrollment, at each weekly and monthly visit, and either at the completion of the study or at premature discontinuation, evaluation of each patient included medical history and physical examination (to include assessment of peripheral neuropathy and measurement of vital signs), query for adverse events and concomitant medication use, and clinical laboratory testing (blood chemistry, hematology, urinalysis, and thyroid function testing [every 3 months]). Electrocardiograms (ECGs) were recorded at the first 4 weekly visits and monthly thereafter for the first 12 months of treatment. During the 72-hour inpatient period following the first dose administration, vital signs, ECGs, and adverse events were monitored and recorded at 1, 2, 4, and 8 hours. Adverse events and vital sign measurements were recorded every 8 hours thereafter, and ECGs were performed on days 2, 3, and 4. Severity of adverse experiences, including any clinical laboratory and vital sign abnormalities, were evaluated using common toxicity criteria. No drug-related renal compromise was observed.Response Response to treatment was assessed by using M-protein quantification (by protein electrophoresis) in serum and a 24-hour urine collection at screening, start of therapy, day 14 and day 28, as well as monthly thereafter (or upon early termination). Bone marrow aspirations and biopsies were performed at baseline, 3, 6, and 12 months, and/or at completion of therapy. A skeletal survey was also performed in patients who had abnormal pretreatment studies or as clinically indicated.Pharmacokinetics Blood and urine samples were collected for analysis of pharmacokinetic parameters on days 1 and 28. Specifically, blood samples were collected before dose as well as at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, and 24 hours after dose. In addition, blood samples were collected weekly for CC-5013 level determinations. Total urine was collected and assayed at 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours after drug administration. Appropriate noncompartmental pharmacokinetic parameters were estimated using the actual blood sampling times for each patient on day 1 and day 28. Values for noncompartmental pharmacokinetic parameters were calculated based on CC-5013 plasma concentration-time data obtained during each dosing period.Biostatistical analysis The MTD was identified using a standard phase 1 design (Figure 2). With this design, the probability of dose escalation was 0.97 if the true DLT rate was 5%. The 90% confidence intervals are reported on the percentage of patients who experience toxicity at the MTD and the percentage of patients who achieved reduction in their paraprotein.
Patients treated Twenty-seven patients with a median age of 57 years (range, 40-71 years) were enrolled. Two patients were removed from study on the first day of treatment due to rapid disease progression resulting in renal dysfunction, a known complication of MM, which rendered them ineligible. Of the 25 patients who received therapy, 19 were men and 6 were women. Immunoglobulin G (IgG) MM was present in 15 (60%), IgA in 7 (28%), and light-chain-only disease in 3 (12%) patients. Fifteen (60%) patients had undergone prior autologous stem cell transplantation (SCT), and 16 (64%) had received prior Thal. Patients received a median of 3 prior regimens (range, 2-6 regimens); all patients had relapsed MM, and 18 (72%) were refractory to salvage therapy.Toxicity profile The first 3 patients were treated for 28 days with CC-5013 5 mg/d without DLT. In the second cohort of 3 patients treated at 10 mg/d, 1 patient had DLT characterized by grade 3 leukopenia and neutropenia, resulting in her removal from study before day 28; 2 other patients tolerated the drug without complication, and an additional 3 patients treated at 10 mg/d also demonstrated no DLT. The patient who had the DLT previously experienced a similar reaction to Thal and to dexamethasone (Dex). CC-5013 was well tolerated within the first 28 days in all 3 patients treated at 25 mg/d; however, grade 3 thrombocytopenia and grade 4 neutropenia developed during the second month, resulting in 2 patients being removed from study. All 3 patients treated with CC-5013 at 50 mg/d tolerated therapy without DLT in the first 28 days, and an additional 10 patients were treated at 50 mg/d to better define toxicity and outcome. None of the patients (0 of 13) treated at 50 mg/d had DLT in the first 28 days (90% CI, 0%-21%).Overall, the median duration of CC-5013 therapy was 6 months (range, 2 weeks to 16 months), and 10 patients continued on treatment (4 patients
at 25 mg/d, 3 patients at 10 mg/d, and 3 patients at 5 mg/d).
Importantly, no significant somnolence, constipation, or neuropathy has
been seen in any cohort. Grade 3 and 4 myelosuppression developed in 12 of 13 patients treated with 50 mg/d CC-5013 beyond 28 days, eventually
prompting dose reduction and granulocyte colony-stimulating factor (G-CSF) support in all 12 patients, with a median
duration of 3 months (range, 2-4 months) of CC-5013 therapy at 50 mg/d. All 12 patients who were reduced to 25 mg/d of CC-5013 tolerated the
lower dose, and in aggregate 13 patients remained on therapy at this
dose for a median of 4 months (range, 2-8 months). Based on greater
exposures to CC-5013 for more than 28 days, we therefore conclude that
25 mg/d is the MTD. The most common adverse events for treated patients
(n = 25), including those observed after day 28, are presented
in Figure 3. Grade 3 neutropenia occurred in 15 (60%) of 25 patients (90% CI, 42%-76%) and grade 4 neutropenia in 4 (16%) of 25 patients (90% CI, 6%-33%). Grade 3 thrombocytopenia occurred in 5 (20%) of 25 patients (90% CI,
8%-38%).
Response Maximal paraprotein reductions observed in 24 patients who received at least 28 days of treatment are summarized in Table 1. Best responses of at least 25% reduction in paraprotein occurred in 17 (71%) of 24 evaluable patients (90% CI, 52%-85%), including at least 50% reduction in paraprotein in 7 (29%) of 24 patients (90% CI, 15%-48%). Stable disease (25% or less reduction in paraprotein) was noted in an additional 2 (8%) patients. Therefore, 17 (71%) of 24 patients (90% CI, 52%-85%) demonstrated benefit from treatment, including 11 (46%) patients who had received prior Thal. Eleven (85%) of 13 patients treated at 50 mg/d had at least 25% paraprotein reductions (90% CI, 59%-97%), and 5 (38%) of 13 patients (90% CI, 17%-65%) had at least 50% declines. Most responses have been at 25 mg/d (2 of 3 patients) and 50 mg/d CC-5013 (12 of 13 patients), although clinical activity was also seen in patients treated at both 5 mg/d (3 of 3 patients) and 10 mg/d (1 of 5 patients) dose levels. Median time to best response was 2 months (range, 1-11 months), and median duration of response was 6 months (range, 2-18 months).
Pharmacokinetic analysis CC-5013 was rapidly absorbed, with maximum plasma concentrations at a median Tmax (time of maximum concentration) of 1 hour or 1.5 hours on day 1 and day 28 in patients treated at each dose level. No trend in Tmax was noted with either increasing dose level or multiple dosings. Following Cmax (maximum concentration), plasma concentrations of CC-5013 declined in a predominantly monophasic manner, with elimination phase starting at 1 to 8 hours after dose on day 1 and day 28. The mean terminal elimination half-lives were 3.1 to 4.2 hours on both day 1 and day 28. There was little or no accumulation of CC-5013: The mean accumulation ratio of CC-5013 in plasma was 0.7 to 1.0, with a Cmax and area under the curve (AUC) (0-) of 0.8 to 1.2 on day 28 compared with day 1. Intersubject variability was generally low to moderate for AUC and Cmax, with values ranging from 10.6% to 51.8% and 3% to 33% on day 1 and day 28, respectively.Bone marrow examination Of the 13 patients treated with CC-5013 at 50 mg/d, 12 patients and a single patient developed grades 3 and 4 neutropenia, respectively; BM hemopoiesis was normal or improved in 10 and reduced in just 2 of these patients. In the 5 patients treated with 50 mg/d CC-5013 who developed grade 2 or 3 thrombocytopenia, megakaryocyte numbers were normal in 3 and mildly reduced in 2 cases. In aggregate, the BM findings were therefore most remarkable for the absence of hypoplasia despite low circulating peripheral counts.
Our long-term studies, both in vitro and in animal models, have shown the importance of host BM-MM cell interactions in promoting MM cell growth, survival, drug resistance, and migration in the BM microenvironment.3-12 Importantly, our studies have also shown that CC-5013 can target the MM cell in its BM milieu to overcome drug resistance in vitro as well as decrease tumor growth and extend survival in vivo in a murine model.13-16 The present clinical study now demonstrates both the safety and efficacy of CC-5013 in patients with refractory and relapsed MM. In aggregate, these studies therefore provide the framework for development of a new treatment paradigm using CC-5013 to target both the MM cell and its microenvironment, overcome drug resistance, and improve patient outcome. The choice of dose levels in this phase 1 clinical trial (5-50 mg/d) was targeted to achieve CC-5013 concentrations of approximately 25.9 to 259 ng/mL, levels that modulate the production of cytokines and inhibit MM cell proliferation in vitro. Importantly, except for an idiosyncratic reaction to CC-5013 that had also occurred to Thal, no DLT occurred within the first 28 days in any dose cohort; remarkably, no sedation, constipation, or neuropathy was seen. Twenty-five percent or greater reductions in paraprotein were observed in 17 (71%) of 24 evaluable patients. This anti-MM activity was remarkable given that 15 patients (60%) had undergone prior SCT and 16 patients (64%) had progressive disease despite Thal treatment. In addition, less than 25% paraprotein reductions were observed in an additional 2 patients. These data, coupled with the absence of somnolence, constipation, and neuropathy, support future phase 2 studies of CC-5013 for MM patients earlier in the course of their disease. Pharmacokinetic studies completed in 24 subjects reveal rapid absorption (Tmax 1-1.5 hours), monophasic elimination (half-life [T1/2] 3.1-4.2 hours), and low to moderate intersubject variability for AUC (11%-52%) and Cmax (3%-33%). In addition, there was no significant accumulation by day 28. The myelosuppression after day 28 seen in the patients treated with 50 mg/d CC-5013 is considered to be DLT. Furthermore, 13 of 15 patients treated at 25 mg/d remained on therapy at this dose for a median of 4 months (range, 2-8 months); therefore, 25 mg/d is considered MTD. The absence of significant marrow hypoplasia observed in most patients with cytopenias suggests etiologies other than BM suppression, which will be evaluated in future studies. Based upon the current study showing efficacy and tolerability of CC-5013, several future clinical phase 2 trials are planned in patients with refractory relapsed disease. First, because some patients treated with CC-5013 at 25 mg/d developed granulocytopenia and thrombocytopenia, a dosing regimen that cycles drug exposure, with time for granulocyte and platelet recovery, will attempt to achieve clinical benefit while avoiding myelosuppression. Second, given the activity of the drug seen at lower dose levels and the T1/2 of 3 to 4 hours, a comparative trial of 2 cycling regimens will be undertaken: 30 mg/d as a single daily dose versus 30 mg/d in divided doses. Third, because laboratory and clinical data have suggested at least additive effects of dexamethasone in combination with Thal,13,19,20 and our preclinical data suggest that Dex also enhances anti-MM activity of CC-5013,13,21 clinical trials will also determine whether the addition of dexamethasone to CC-5013 enhances its clinical efficacy in MM. Thal has achieved response rates of 30% in patients with refractory, relapsed MM and, when combined with dexamethasone, response rates of 64% in patients with newly diagnosed disease.2,20 However, somnolence, constipation, and neuropathy preclude its use in some patients. Because our study now shows that oral CC-5013 has antitumor activity, favorable pharmacokinetics, and acceptable toxicity in patients with relapsed and refractory MM, we will carry out clinical protocols of CC-5013, alone and in combination with dexamethasone, for the treatment of MM earlier in the disease course, including as initial treatment, therapy for first relapse, and maintenance therapy.
Submitted April 2, 2002; accepted May 1, 2002.
Prepublished online as Blood First Edition Paper, July 12, 2002; DOI 10.1182/blood-2002-03-0996.
Supported by National Institutes of Health grants RO-1 50947 and PO-78378, the Multiple Myeloma Research Foundation (T.H., C.M., R.L.), the Myeloma Research Fund (K.C.A.), and the Doris Duke Distinguished Clinical Research Scientist Award (K.C.A.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Kenneth C. Anderson, Dana-Farber Cancer Institute, Mayer 557, 44 Binney St, Boston, MA 02115; e-mail: kenneth_anderson{at}dfci.harvard.edu.
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 M. Q. Lacy, M. A. Gertz, A. Dispenzieri, S. R. Hayman, S. Geyer, B. Kabat, S. R. Zeldenrust, S. Kumar, P. R. Greipp, R. Fonseca, et al. Long-term Results of Response to Therapy, Time to Progression, and Survival With Lenalidomide Plus Dexamethasone in Newly Diagnosed Myeloma Mayo Clin. Proc., October 1, 2007; 82(10): 1179 - 1184. [Abstract] [Full Text] [PDF]
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 K. V. Rao Lenalidomide in the treatment of multiple myeloma Am. J. Health Syst. Pharm., September 1, 2007; 64(17): 1799 - 1807. [Abstract] [Full Text] [PDF]
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 B Sirohi, R Powles, D Lawrence, J Treleaven, S Kulkarni, A Leary, C Rudin, C Horton, and G Morgan An open, randomized, controlled, phase II, single centre, two-period cross-over study to compare the quality of life and toxicity experienced on PEG interferon with interferon-{alpha}2b in patients with multiple myeloma maintained on a steady dose of interferon-{alpha}2b Ann. Onc., August 1, 2007; 18(8): 1388 - 1394. [Abstract] [Full Text] [PDF]
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A. Dispenzieri, C. J. Klein, and M. L. Mauermann Lenalidomide therapy in a patient with POEMS syndrome Blood, August 1, 2007; 110(3): 1075 - 1076. [Full Text] [PDF]
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T. Kiziltepe, T. Hideshima, K. Ishitsuka, E. M. Ocio, N. Raje, L. Catley, C.-Q. Li, L. J. Trudel, H. Yasui, S. Vallet, et al. JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells Blood, July 15, 2007; 110(2): 709 - 718. [Abstract] [Full Text] [PDF]
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M. Wang, L. Zhang, X. Han, J. Yang, J. Qian, S. Hong, F. Samaniego, J. Romaguera, and Q. Yi Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways Blood, June 15, 2007; 109(12): 5455 - 5462. [Abstract] [Full Text] [PDF]
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 T. Kiziltepe, T. Hideshima, L. Catley, N. Raje, H. Yasui, N. Shiraishi, Y. Okawa, H. Ikeda, S. Vallet, S. Pozzi, et al. 5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells Mol. Cancer Ther., June 1, 2007; 6(6): 1718 - 1727. [Abstract] [Full Text] [PDF]
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M. Kobune, H. Chiba, J. Kato, K. Kato, K. Nakamura, Y. Kawano, K. Takada, R. Takimoto, T. Takayama, H. Hamada, et al. Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism Mol. Cancer Ther., June 1, 2007; 6(6): 1774 - 1784. [Abstract] [Full Text] [PDF]
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 P. G. Richardson, C. Mitsiades, R. Schlossman, N. Munshi, and K. Anderson New Drugs for Myeloma Oncologist, June 1, 2007; 12(6): 664 - 689. [Abstract] [Full Text] [PDF]
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S. Y. Kristinsson, O. Landgren, P. W. Dickman, A. R. Derolf, and M. Bjorkholm Patterns of Survival in Multiple Myeloma: A Population-Based Study of Patients Diagnosed in Sweden From 1973 to 2003 J. Clin. Oncol., May 20, 2007; 25(15): 1993 - 1999. [Abstract] [Full Text] [PDF]
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R. Fonseca and A. K. Stewart Targeted therapeutics for multiple myeloma: The arrival of a risk-stratified approach Mol. Cancer Ther., March 1, 2007; 6(3): 802 - 810. [Abstract] [Full Text] [PDF]
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A. Muto, M. Hori, Y. Sasaki, A. Saitoh, I. Yasuda, T. Maekawa, T. Uchida, K. Asakura, T. Nakazato, T. Kaneda, et al. Emodin has a cytotoxic activity against human multiple myeloma as a Janus-activated kinase 2 inhibitor Mol. Cancer Ther., March 1, 2007; 6(3): 987 - 994. [Abstract] [Full Text] [PDF]
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J. R. Walczak and M. A. Carducci Prostate Cancer: A Practical Approach to Current Management of Recurrent Disease Mayo Clin. Proc., February 1, 2007; 82(2): 243 - 249. [Abstract] [Full Text] [PDF]
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D. Verhelle, L. G. Corral, K. Wong, J. H. Mueller, L. Moutouh-de Parseval, K. Jensen-Pergakes, P. H. Schafer, R. Chen, E. Glezer, G. D. Ferguson, et al. Lenalidomide and CC-4047 Inhibit the Proliferation of Malignant B Cells while Expanding Normal CD34+ Progenitor Cells Cancer Res., January 15, 2007; 67(2): 746 - 755. [Abstract] [Full Text] [PDF]
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V. Sanchorawala, D. G. Wright, M. Rosenzweig, K. T. Finn, S. Fennessey, J. B. Zeldis, M. Skinner, and D. C. Seldin Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial Blood, January 15, 2007; 109(2): 492 - 496. [Abstract] [Full Text] [PDF]
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A. Dispenzieri, M. Q. Lacy, S. R. Zeldenrust, S. R. Hayman, S. K. Kumar, S. M. Geyer, J. A. Lust, J. B. Allred, T. E. Witzig, S. V. Rajkumar, et al. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis Blood, January 15, 2007; 109(2): 465 - 470. [Abstract] [Full Text] [PDF]
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P. Richardson, C. Mitsiades, R. Schlossman, I. Ghobrial, T. Hideshima, D. Chauhan, N. Munshi, and K. Anderson The Treatment of Relapsed and Refractory Multiple Myeloma Hematology, January 1, 2007; 2007(1): 317 - 323. [Abstract] [Full Text] [PDF]
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A. Chanan-Khan, K. C. Miller, L. Musial, D. Lawrence, S. Padmanabhan, K. Takeshita, C. W. Porter, D. W. Goodrich, Z. P. Bernstein, P. Wallace, et al. Clinical Efficacy of Lenalidomide in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia: Results of a Phase II Study J. Clin. Oncol., December 1, 2006; 24(34): 5343 - 5349. [Abstract] [Full Text] [PDF]
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R Baz, E Walker, M. Karam, T. Choueiri, R. Jawde, K Bruening, J Reed, B Faiman, Y Ellis, C Brand, et al. Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy Ann. Onc., December 1, 2006; 17(12): 1766 - 1771. [Abstract] [Full Text] [PDF]
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P. G. Richardson, E. Blood, C. S. Mitsiades, S. Jagannath, S. R. Zeldenrust, M. Alsina, R. L. Schlossman, S. V. Rajkumar, K. R. Desikan, T. Hideshima, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma Blood, November 15, 2006; 108(10): 3458 - 3464. [Abstract] [Full Text] [PDF]
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 S. Singhal and J. Mehta Multiple Myeloma Clin. J. Am. Soc. Nephrol., November 1, 2006; 1(6): 1322 - 1330. [Abstract] [Full Text] [PDF]
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 H. P. Sviggum, M. D. P. Davis, S. V. Rajkumar, and A. Dispenzieri Dermatologic adverse effects of lenalidomide therapy for amyloidosis and multiple myeloma. Arch Dermatol, October 1, 2006; 142(10): 1298 - 1302. [Abstract] [Full Text] [PDF]
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A. Tefferi, J. Cortes, S. Verstovsek, R. A. Mesa, D. Thomas, T. L. Lasho, W. J. Hogan, M. R. Litzow, J. B. Allred, D. Jones, et al. Lenalidomide therapy in myelofibrosis with myeloid metaplasia Blood, August 15, 2006; 108(4): 1158 - 1164. [Abstract] [Full Text] [PDF]
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G. Anderson, M. Gries, N. Kurihara, T. Honjo, J. Anderson, V. Donnenberg, A. Donnenberg, I. Ghobrial, M. Y. Mapara, D. Stirling, et al. Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1 Blood, April 15, 2006; 107(8): 3098 - 3105. [Abstract] [Full Text] [PDF]
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B. Barlogie, G. Tricot, E. Anaissie, J. Shaughnessy, E. Rasmussen, F. van Rhee, A. Fassas, M. Zangari, K. Hollmig, M. Pineda-Roman, et al. Thalidomide and Hematopoietic-Cell Transplantation for Multiple Myeloma N. Engl. J. Med., March 9, 2006; 354(10): 1021 - 1030. [Abstract] [Full Text] [PDF]
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 M. Haubitz and D. Peest Myeloma - new approaches to combined nephrological-haematological management Nephrol. Dial. Transplant., March 1, 2006; 21(3): 582 - 590. [Full Text] [PDF]
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 S. K Maier and J. M Hammond Role of Lenalidomide in the Treatment of Multiple Myeloma and Myelodysplastic Syndrome Ann. Pharmacother., February 1, 2006; 40(2): 286 - 289. [Abstract] [Full Text] [PDF]
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S. V. Rajkumar, E. Blood, D. Vesole, R. Fonseca, and P. R. Greipp Phase III Clinical Trial of Thalidomide Plus Dexamethasone Compared With Dexamethasone Alone in Newly Diagnosed Multiple Myeloma: A Clinical Trial Coordinated by the Eastern Cooperative Oncology Group J. Clin. Oncol., January 20, 2006; 24(3): 431 - 436. [Abstract] [Full Text] [PDF]
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P. Richardson and K. Anderson Thalidomide and Dexamethasone: A New Standard of Care for Initial Therapy in Multiple Myeloma J. Clin. Oncol., January 20, 2006; 24(3): 334 - 336. [Full Text] [PDF]
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R. Z. Orlowski Initial Therapy of Multiple Myeloma Patients Who Are Not Candidates for Stem Cell Transplantation Hematology, January 1, 2006; 2006(1): 338 - 347. [Abstract] [Full Text] [PDF]
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J. A. Zonder Thrombotic Complications of Myeloma Therapy Hematology, January 1, 2006; 2006(1): 348 - 355. [Abstract] [Full Text] [PDF]
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B. M. Augustson, G. Begum, J. A. Dunn, N. J. Barth, F. Davies, G. Morgan, J. Behrens, A. Smith, J. A. Child, and M. T. Drayson Early Mortality After Diagnosis of Multiple Myeloma: Analysis of Patients Entered Onto the United Kingdom Medical Research Council Trials Between 1980 and 2002--Medical Research Council Adult Leukaemia Working Party J. Clin. Oncol., December 20, 2005; 23(36): 9219 - 9226. [Abstract] [Full Text] [PDF]
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Y.-T. Tai, X.-F. Li, L. Catley, R. Coffey, I. Breitkreutz, J. Bae, W. Song, K. Podar, T. Hideshima, D. Chauhan, et al. Immunomodulatory Drug Lenalidomide (CC-5013, IMiD3) Augments Anti-CD40 SGN-40-Induced Cytotoxicity in Human Multiple Myeloma: Clinical Implications Cancer Res., December 15, 2005; 65(24): 11712 - 11720. [Abstract] [Full Text] [PDF]
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M. Cavo Myeloma therapy: the future is bright Blood, December 15, 2005; 106(13): 4018 - 4019. [Full Text] [PDF]
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S. V. Rajkumar, S. R. Hayman, M. Q. Lacy, A. Dispenzieri, S. M. Geyer, B. Kabat, S. R. Zeldenrust, S. Kumar, P. R. Greipp, R. Fonseca, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma Blood, December 15, 2005; 106(13): 4050 - 4053. [Abstract] [Full Text] [PDF]
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S. V. Rajkumar Thalidomide Therapy and Deep Venous Thrombosis in Multiple Myeloma Mayo Clin. Proc., December 1, 2005; 80(12): 1549 - 1551. [PDF]
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S. V. Rajkumar and R. A. Kyle Multiple Myeloma: Diagnosis and Treatment Mayo Clin. Proc., October 1, 2005; 80(10): 1371 - 1382. [Abstract] [PDF]
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T. Hideshima, D. Chauhan, P. Richardson, and K. C. Anderson Identification and Validation of Novel Therapeutic Targets for Multiple Myeloma J. Clin. Oncol., September 10, 2005; 23(26): 6345 - 6350. [Abstract] [Full Text] [PDF]
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 G. Saunders Overview of drug therapy for multiple myeloma Journal of Oncology Pharmacy Practice, September 1, 2005; 11(3): 83 - 100. [Abstract] [PDF]
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K. Ishitsuka, T. Hideshima, M. Hamasaki, N. Raje, S. Kumar, H. Hideshima, N. Shiraishi, H. Yasui, A. M. Roccaro, P. Richardson, et al. Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and -independent apoptosis Blood, September 1, 2005; 106(5): 1794 - 1800. [Abstract] [Full Text] [PDF]
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N. Raje, S. Kumar, T. Hideshima, A. Roccaro, K. Ishitsuka, H. Yasui, N. Shiraishi, D. Chauhan, N. C. Munshi, S. R. Green, et al. Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma Blood, August 1, 2005; 106(3): 1042 - 1047. [Abstract] [Full Text] [PDF]
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H. Yasui, T. Hideshima, M. Hamasaki, A. M. Roccaro, N. Shiraishi, S. Kumar, P. Tassone, K. Ishitsuka, N. Raje, Y.-T. Tai, et al. SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma Blood, July 15, 2005; 106(2): 706 - 712. [Abstract] [Full Text] [PDF]
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M. Cavo, E. Zamagni, P. Tosi, P. Tacchetti, C. Cellini, D. Cangini, A. de Vivo, N. Testoni, C. Nicci, C. Terragna, et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma Blood, July 1, 2005; 106(1): 35 - 39. [Abstract] [Full Text] [PDF]
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A. Dispenzieri Bortezomib for Myeloma -- Much Ado about Something N. Engl. J. Med., June 16, 2005; 352(24): 2546 - 2548. [Full Text] [PDF]
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M. Ladetto, S. Vallet, A. Trojan, M. Dell'Aquila, L. Monitillo, R. Rosato, L. Santo, D. Drandi, A. Bertola, P. Falco, et al. Cyclooxygenase-2 (COX-2) is frequently expressed in multiple myeloma and is an independent predictor of poor outcome Blood, June 15, 2005; 105(12): 4784 - 4791. [Abstract] [Full Text] [PDF]
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K.-R. Koh, M. Janz, M. Y. Mapara, B. Lemke, D. Stirling, B. Dorken, M. Zenke, and S. Lentzsch Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis Blood, May 15, 2005; 105(10): 3833 - 3840. [Abstract] [Full Text] [PDF]
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H. Zhang, V. Vakil, M. Braunstein, E. L. P. Smith, J. Maroney, L. Chen, K. Dai, J. R. Berenson, M. M. Hussain, U. Klueppelberg, et al. Circulating endothelial progenitor cells in multiple myeloma: implications and significance Blood, April 15, 2005; 105(8): 3286 - 3294. [Abstract] [Full Text] [PDF]
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K. Altundag, O. Altundag, O. Gundeslioglu, C. L. Crawford, H. G. Schneider, J. Sentry, R. A. Kyle, and S. V. Rajkumar Multiple Myeloma N. Engl. J. Med., February 24, 2005; 352(8): 840 - 841. [Full Text] [PDF]
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K. Podar and K. C. Anderson The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications Blood, February 15, 2005; 105(4): 1383 - 1395. [Abstract] [Full Text] [PDF]
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A. List, S. Kurtin, D. J. Roe, A. Buresh, D. Mahadevan, D. Fuchs, L. Rimsza, R. Heaton, R. Knight, and J. B. Zeldis Efficacy of Lenalidomide in Myelodysplastic Syndromes N. Engl. J. Med., February 10, 2005; 352(6): 549 - 557. [Abstract] [Full Text] [PDF]
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S. V. Rajkumar, P. G. Richardson, T. Hideshima, and K. C. Anderson Proteasome Inhibition As a Novel Therapeutic Target in Human Cancer J. Clin. Oncol., January 20, 2005; 23(3): 630 - 639. [Abstract] [Full Text] [PDF]
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P. G. Richardson, A. Kassarjian, and W. Jing Case 38-2004 - A 40-Year-Old Man with a Large Tumor of the Skull N. Engl. J. Med., December 16, 2004; 351(25): 2637 - 2645. [Full Text] [PDF]
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N. Raje, S. Kumar, T. Hideshima, K. Ishitsuka, D. Chauhan, C. Mitsiades, K. Podar, S. Le Gouill, P. Richardson, N. C. Munshi, et al. Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma Blood, December 15, 2004; 104(13): 4188 - 4193. [Abstract] [Full Text] [PDF]
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 A. Tefferi, W. J. Hogan, A. P. Wolanskyj, T. A. Shaw, G. E. Reyes, A. Hoering, R. F. McClure, and R. A. Mesa A Phase II Study of CC-5013 Treatment for Myelofibrosis with Myeloid Metaplasia: A Preliminary Report. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 1505 - 1505. [Abstract]
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 T. Hayashi, T. Hideshima, A. N. Nguyen, O. Munoz, K. Podar, M. Hamasaki, K. Ishitsuka, H. Yasui, P. Richardson, S. Chakravarty, et al. Transforming Growth Factor {beta} Receptor I Kinase Inhibitor Down-Regulates Cytokine Secretion and Multiple Myeloma Cell Growth in the Bone Marrow Microenvironment Clin. Cancer Res., November 15, 2004; 10(22): 7540 - 7546. [Abstract] [Full Text] [PDF]
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R. A. Kyle and S. V. Rajkumar Multiple Myeloma N. Engl. J. Med., October 28, 2004; 351(18): 1860 - 1873. [Full Text] [PDF]
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F. Chung, J. Lu, B. D. Palmer, P. Kestell, P. Browett, B. C. Baguley, M. Tingle, and L.-M. Ching Thalidomide Pharmacokinetics and Metabolite Formation in Mice, Rabbits, and Multiple Myeloma Patients Clin. Cancer Res., September 1, 2004; 10(17): 5949 - 5956. [Abstract] [Full Text] [PDF]
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P. Richardson and K. Anderson Immunomodulatory Analogs of Thalidomide: An Emerging New Therapy in Myeloma J. Clin. Oncol., August 15, 2004; 22(16): 3212 - 3214. [Full Text] [PDF]
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S.A. Schey, P. Fields, J.B. Bartlett, I.A. Clarke, G. Ashan, R.D. Knight, M. Streetly, and A.G. Dalgleish Phase I Study of an Immunomodulatory Thalidomide Analog, CC-4047, in Relapsed or Refractory Multiple Myeloma J. Clin. Oncol., August 15, 2004; 22(16): 3269 - 3276. [Abstract] [Full Text] [PDF]
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T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson Advances in biology of multiple myeloma: clinical applications Blood, August 1, 2004; 104(3): 607 - 618. [Abstract] [Full Text] [PDF]
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P. Richardson, R. Schlossman, S. Jagannath, M. Alsina, R. Desikan, E. Blood, E. Weller, C. Mitsiades, T. Hideshima, F. Davies, et al. Thalidomide for Patients With Relapsed Multiple Myeloma After High-Dose Chemotherapy and Stem Cell Transplantation: Results of an Open-Label Multicenter Phase 2 Study of Efficacy, Toxicity, and Biological Activity Mayo Clin. Proc., July 1, 2004; 79(7): 875 - 882. [Abstract] [PDF]
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R. A. Mesa, M. A. Elliott, G. Schroeder, and A. Tefferi Durable Responses to Thalidomide-Based Drug Therapy for Myelofibrosis With Myeloid Metaplasia Mayo Clin. Proc., July 1, 2004; 79(7): 883 - 889. [Abstract] [PDF]
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S. V. Rajkumar Thalidomide: Tragic Past and Promising Future Mayo Clin. Proc., July 1, 2004; 79(7): 899 - 903. [PDF]
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K. Podar, L. P. Catley, Y.-T. Tai, R. Shringarpure, P. Carvalho, T. Hayashi, R. Burger, R. L. Schlossman, P. G. Richardson, L. N. Pandite, et al. GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment Blood, May 1, 2004; 103(9): 3474 - 3479. [Abstract] [Full Text] [PDF]
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R. LeBlanc, T. Hideshima, L. P. Catley, R. Shringarpure, R. Burger, N. Mitsiades, C. Mitsiades, P. Cheema, D. Chauhan, P. G. Richardson, et al. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway Blood, March 1, 2004; 103(5): 1787 - 1790. [Abstract] [Full Text] [PDF]
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J.-L. Harousseau, J. Shaughnessy Jr., and P. Richardson Multiple Myeloma Hematology, January 1, 2004; 2004(1): 237 - 256. [Abstract] [Full Text] [PDF]
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B. Barlogie, J. Shaughnessy, G. Tricot, J. Jacobson, M. Zangari, E. Anaissie, R. Walker, and J. Crowley Treatment of multiple myeloma Blood, January 1, 2004; 103(1): 20 - 32. [Abstract] [Full Text] [PDF]
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A. Abdollahi, K. E. Lipson, A. Sckell, H. Zieher, F. Klenke, D. Poerschke, A. Roth, X. Han, M. Krix, M. Bischof, et al. Combined Therapy with Direct and Indirect Angiogenesis Inhibition Results in Enhanced Antiangiogenic and Antitumor Effects Cancer Res., December 15, 2003; 63(24): 8890 - 8898. [Abstract] [Full Text] [PDF]
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T. Hideshima, D. Chauhan, T. Hayashi, K. Podar, M. Akiyama, C. Mitsiades, N. MItsiades, B. Gong, L. Bonham, P. de Vries, et al. Antitumor Activity of Lysophosphatidic Acid Acyltransferase-{beta} Inhibitors, a Novel Class of Agents, in Multiple Myeloma Cancer Res., December 1, 2003; 63(23): 8428 - 8436. [Abstract] [Full Text] [PDF]
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M. A. Dimopoulos, A. Anagnostopoulos, and D. Weber Treatment of Plasma Cell Dyscrasias With Thalidomide and Its Derivatives J. Clin. Oncol., December 1, 2003; 21(23): 4444 - 4454. [Abstract] [Full Text] [PDF]
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E. Terpos, R. Szydlo, J. F. Apperley, E. Hatjiharissi, M. Politou, J. Meletis, N. Viniou, X. Yataganas, J. M. Goldman, and A. Rahemtulla Soluble receptor activator of nuclear factor {kappa}B ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index Blood, August 1, 2003; 102(3): 1064 - 1069. [Abstract] [Full Text] [PDF]
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 P. H. Schafer, A. K. Gandhi, M. A. Loveland, R. S. Chen, H.-W. Man, P. P. M. Schnetkamp, G. Wolbring, S. Govinda, L. G. Corral, F. Payvandi, et al. Enhancement of Cytokine Production and AP-1 Transcriptional Activity in T Cells by Thalidomide-Related Immunomodulatory Drugs J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 1222 - 1232. [Abstract] [Full Text] [PDF]
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J. B. Marriott, I. A. Clarke, A. Czajka, K. Dredge, K. Childs, H.-W. Man, P. Schafer, S. Govinda, G. W. Muller, D. I. Stirling, et al. A Novel Subclass of Thalidomide Analogue with Anti-Solid Tumor Activity in Which Caspase-dependent Apoptosis is Associated with Altered Expression of bcl-2 Family Proteins Cancer Res., February 1, 2003; 63(3): 593 - 599. [Abstract] [Full Text] [PDF]
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T. Hideshima, M. Akiyama, T. Hayashi, P. Richardson, R. Schlossman, D. Chauhan, and K. C. Anderson Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu Blood, January 15, 2003; 101(2): 703 - 705. [Abstract] [Full Text] [PDF]
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G. Mufti, A. F. List, S. D. Gore, and A. Y.L. Ho Myelodysplastic Syndrome Hematology, January 1, 2003; 2003(1): 176 - 199. [Abstract] [Full Text] [PDF]
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S. Barille-Nion, B. Barlogie, R. Bataille, P. L. Bergsagel, J. Epstein, R. G. Fenton, J. Jacobson, W. M. Kuehl, J. Shaughnessy, and G. Tricot Advances in Biology and Therapy of Multiple Myeloma Hematology, January 1, 2003; 2003(1): 248 - 278. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
[TNF-
(IFN-
, and IL-6 and
triggers increased secretion of IL-10. The CC-5013 concentration for
50% inhibition (IC50) of lipopolysaccharide (LPS)-induced
TNF-
B.
Blood.
1996;87:1104-1112