14 results on '"Richardson, P. G."'
Search Results
2. New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG).
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Ocio EM, Richardson PG, Rajkumar SV, Palumbo A, Mateos MV, Orlowski R, Kumar S, Usmani S, Roodman D, Niesvizky R, Einsele H, Anderson KC, Dimopoulos MA, Avet-Loiseau H, Mellqvist UH, Turesson I, Merlini G, Schots R, McCarthy P, Bergsagel L, Chim CS, Lahuerta JJ, Shah J, Reiman A, Mikhael J, Zweegman S, Lonial S, Comenzo R, Chng WJ, Moreau P, Sonneveld P, Ludwig H, Durie BG, and Miguel JF
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- Humans, Antineoplastic Agents therapeutic use, Multiple Myeloma drug therapy
- Abstract
Treatment in medical oncology is gradually shifting from the use of nonspecific chemotherapeutic agents toward an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second- and third-generation proteasome inhibitors (PIs), immunomodulatory agents and alkylators). Next, we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAbs), cell cycle-specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors and kinase inhibitors. Among this plethora of new agents or mechanisms, some are specially promising: anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Moreover, the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, which has produced exciting results in the relapsed/refractory setting.
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- 2014
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3. Induction of differential apoptotic pathways in multiple myeloma cells by class-selective histone deacetylase inhibitors.
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Hideshima T, Mazitschek R, Santo L, Mimura N, Gorgun G, Richardson PG, Raje N, and Anderson KC
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- Antineoplastic Agents toxicity, Cell Line, Tumor, Endoplasmic Reticulum Stress drug effects, Histone Deacetylase Inhibitors toxicity, Humans, Oligopeptides pharmacology, Antineoplastic Agents pharmacology, Apoptosis drug effects, Histone Deacetylase Inhibitors pharmacology, Multiple Myeloma metabolism, Signal Transduction drug effects
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- 2014
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4. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study.
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Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, Haessler J, Feather J, Hoering A, Moreau P, LeLeu X, Hulin C, Klein SK, Sonneveld P, Siegel D, Bladé J, Goldschmidt H, Jagannath S, Miguel JS, Orlowski R, Palumbo A, Sezer O, Rajkumar SV, and Durie BG
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- Adult, Aged, Aged, 80 and over, Antineoplastic Agents administration & dosage, Disease Progression, Female, Humans, Immunologic Factors administration & dosage, Male, Middle Aged, Multiple Myeloma pathology, Recurrence, Survival Analysis, Antineoplastic Agents therapeutic use, Immunologic Factors therapeutic use, Multiple Myeloma drug therapy
- Abstract
Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T(0)). The median age at diagnosis was 58 years, and time from diagnosis to T(0) was 3.3 years. Following T(0), 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T(0) in 94 patients (44%) including ≥ partial response in 69 (32%). The median overall survival and event-free survival from T(0) were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.
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- 2012
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5. Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials.
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Potts BC, Albitar MX, Anderson KC, Baritaki S, Berkers C, Bonavida B, Chandra J, Chauhan D, Cusack JC Jr, Fenical W, Ghobrial IM, Groll M, Jensen PR, Lam KS, Lloyd GK, McBride W, McConkey DJ, Miller CP, Neuteboom ST, Oki Y, Ovaa H, Pajonk F, Richardson PG, Roccaro AM, Sloss CM, Spear MA, Valashi E, Younes A, and Palladino MA
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- Animals, Drug Evaluation, Preclinical, Humans, Neoplasms metabolism, Proteasome Endopeptidase Complex metabolism, Antineoplastic Agents therapeutic use, Lactones therapeutic use, Neoplasms drug therapy, Protease Inhibitors therapeutic use, Proteasome Inhibitors, Pyrroles therapeutic use
- Abstract
The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique β-lactone-γ-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside.
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- 2011
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6. International Myeloma Working Group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation.
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Palumbo A, Sezer O, Kyle R, Miguel JS, Orlowski RZ, Moreau P, Niesvizky R, Morgan G, Comenzo R, Sonneveld P, Kumar S, Hajek R, Giralt S, Bringhen S, Anderson KC, Richardson PG, Cavo M, Davies F, Bladé J, Einsele H, Dimopoulos MA, Spencer A, Dispenzieri A, Reiman T, Shimizu K, Lee JH, Attal M, Boccadoro M, Mateos M, Chen W, Ludwig H, Joshua D, Chim J, Hungria V, Turesson I, Durie BG, and Lonial S
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- Humans, Transplantation, Autologous, Antineoplastic Agents administration & dosage, Hematopoietic Stem Cell Transplantation, Multiple Myeloma diagnosis, Multiple Myeloma therapy
- Abstract
In 2005, the first guidelines were published on the management of patients with multiple myeloma (MM). An expert panel reviewed the currently available literature as the basis for a set of revised and updated consensus guidelines for the diagnosis and management of patients with MM who are not eligible for autologous stem cell transplantation. Here we present recommendations on the diagnosis, treatment of newly diagnosed non-transplant-eligible patients and the management of complications occurring during induction therapy among these patients. These guidelines will aid the physician in daily clinical practice and will ensure optimal care for patients with MM.
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- 2009
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7. Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma.
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Raje N, Hideshima T, Mukherjee S, Raab M, Vallet S, Chhetri S, Cirstea D, Pozzi S, Mitsiades C, Rooney M, Kiziltepe T, Podar K, Okawa Y, Ikeda H, Carrasco R, Richardson PG, Chauhan D, Munshi NC, Sharma S, Parikh H, Chabner B, Scadden D, and Anderson KC
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- Animals, Apoptosis drug effects, Blotting, Western, Bone Marrow drug effects, Boronic Acids therapeutic use, Bortezomib, Caspases metabolism, Cell Adhesion drug effects, Cell Cycle drug effects, Cell Proliferation drug effects, Cyclin D1 genetics, Cyclin D1 metabolism, Cyclin-Dependent Kinase Inhibitor Proteins antagonists & inhibitors, Down-Regulation, Drug Evaluation, Preclinical, Drug Resistance, Neoplasm, Drug Synergism, Gene Expression Profiling, Humans, Insulin-Like Growth Factor I metabolism, Interleukin-6 metabolism, Male, Mice, Mice, SCID, Multiple Myeloma enzymology, Multiple Myeloma pathology, Oligonucleotide Array Sequence Analysis, Phosphorylation drug effects, Pyrazines therapeutic use, Retinoblastoma Protein metabolism, Stromal Cells drug effects, Transplantation, Heterologous, Tumor Cells, Cultured, Antineoplastic Agents therapeutic use, Cyclin D1 antagonists & inhibitors, Flavones therapeutic use, Multiple Myeloma drug therapy
- Abstract
Cyclin D dysregulation and overexpression is noted in the majority of multiple myeloma (MM) patients, suggesting its critical role in MM pathogenesis. Here, we sought to identify the effects of targeting cyclin D in MM. We first confirmed cyclin D mRNA overexpression in 42 of 64 (65%) patient plasma cells. Silencing cyclin D1 resulted in >50% apoptotic cell death suggesting its validity as a potential therapeutic target. We next evaluated P276-00, a clinical-grade small-molecule cyclin-dependent kinase inhibitor as a way to target the cyclins. P276-00 resulted in dose-dependent cytotoxicity in MM cells. Cell-cycle analysis confirmed either growth arrest or caspase-dependent apoptosis; this was preceded by inhibition of Rb-1 phosphorylation with associated downregulation of a range of cyclins suggesting a regulatory role of P276-00 in cell-cycle progression through broad activity. Proliferative stimuli such as interleukin-6, insulin-like growth factor-1 and bone-marrow stromal cell adherence induced cyclins; P276-00 overcame these growth, survival and drug resistance signals. Because the cyclins are substrates of proteasome degradation, combination studies with bortezomib resulted in synergism. Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM.
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- 2009
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8. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma.
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Breitkreutz I, Raab MS, Vallet S, Hideshima T, Raje N, Mitsiades C, Chauhan D, Okawa Y, Munshi NC, Richardson PG, and Anderson KC
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- B-Cell Activating Factor metabolism, Bone Resorption prevention & control, Boronic Acids pharmacology, Bortezomib, Cathepsin K, Cathepsins analysis, Cells, Cultured, Chemokine CCL3 metabolism, Humans, Integrin alphaVbeta3 analysis, Lenalidomide, Osteoclasts physiology, Osteoprotegerin blood, Proto-Oncogene Proteins physiology, Pyrazines pharmacology, RANK Ligand metabolism, Thalidomide pharmacology, Trans-Activators physiology, Transcription Factor AP-1 physiology, Tumor Necrosis Factor Ligand Superfamily Member 13 metabolism, Antineoplastic Agents pharmacology, Bone Remodeling drug effects, Multiple Myeloma drug therapy, Osteoclasts drug effects, Thalidomide analogs & derivatives
- Abstract
Osteolytic bone disease in multiple myeloma (MM) is caused by enhanced osteoclast (OCL) activation and inhibition of osteoblast function. Lenalidomide and bortezomib have shown promising response rates in relapsed and newly diagnosed MM, and bortezomib has recently been reported to inhibit OCLs. We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis in comparison with bortezomib. Both drugs decreased alpha V beta 3-integrin, tartrate-resistant acid phosphatase-positive cells and bone resorption on dentin disks. In addition, both agents decreased receptor activator of nuclear factor-kappaB ligand (RANKL) secretion of bone marrow stromal cells (BMSCs) derived from MM patients. We identified PU.1 and pERK as major targets of lenalidomide, and nuclear factor of activated T cells of bortezomib, resulting in inhibition of osteoclastogenesis. Furthermore, downregulation of cathepsin K, essential for resorption of the bone collagen matrix, was observed. We demonstrated a significant decrease of growth and survival factors including macrophage inflammatory protein-alpha, B-cell activating factor and a proliferation-inducing ligand. Importantly, in serum from MM patients treated with lenalidomide, the essential bone-remodeling factor RANKL, as well as the RANKL/OPG ratio, were significantly reduced, whereas osteoprotegerin (OPG) was increased. We conclude that both agents specifically target key factors in osteoclastogenesis, and could directly affect the MM-OCL-BMSCs activation loop in osteolytic bone disease.
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- 2008
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9. Novel etodolac analog SDX-308 (CEP-18082) induces cytotoxicity in multiple myeloma cells associated with inhibition of beta-catenin/TCF pathway.
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Yasui H, Hideshima T, Ikeda H, Ocio EM, Kiziltepe T, Vallet S, Okawa Y, Neri P, Sukhdeo K, Podar K, Chauhan D, Richardson PG, Raje N, Carrasco DR, and Anderson KC
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- Apoptosis drug effects, Cell Line, Tumor drug effects, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Etodolac pharmacology, Gene Expression Regulation, Neoplastic drug effects, Humans, Insulin-Like Growth Factor I antagonists & inhibitors, Insulin-Like Growth Factor I pharmacology, Interleukin-6 antagonists & inhibitors, Interleukin-6 pharmacology, Neoplasm Proteins antagonists & inhibitors, Poly(ADP-ribose) Polymerases metabolism, Antineoplastic Agents pharmacology, Cysteine Proteinase Inhibitors pharmacology, Heterocyclic Compounds, 3-Ring pharmacology, Multiple Myeloma pathology, Signal Transduction drug effects, TCF Transcription Factors antagonists & inhibitors, beta Catenin antagonists & inhibitors
- Abstract
We have reported previously that R-enantiomer of etodolac (R-etodolac), which is under investigation in phase 2 clinical trials in chronic lymphocytic leukemia, induces potent cytotoxicity at clinically relevant concentrations in multiple myeloma (MM) cells. In this study, we demonstrated that SDX-308 (CEP-18082), a novel analog of etodolac, has more potent cytotoxicity than R-etodolac against both MM cell lines and patient MM cells, including tumor cells resistant to conventional (dexamethasone, doxorubicine, melphalan) and novel (bortezomib) therapies. SDX-308-induced cytotoxicity is triggered by caspase-8/9/3 activation and poly (ADP-ribose) polymerase cleavage, followed by apoptosis. SDX-308 significantly inhibits beta-catenin/T-cell factor pathway by inhibiting nuclear translocation of beta-catenin, thereby downregulating transcription and expression of downstream target proteins including myc and survivin. Neither interleukin-6 nor insulin-like growth factor-1 protect against growth inhibition triggered by SDX-308. Importantly, growth of MM cells adherent to bone marrow (BM) stromal cells is also significantly inhibited by SDX-308. Our data therefore indicate that the novel etodolac analog SDX-308 can target MM cells in the BM milieu.
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- 2007
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10. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials.
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Jagannath S, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Cowan JM, and Anderson KC
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- Aged, Biopsy, Bone Marrow pathology, Bortezomib, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Cytogenetic Analysis, Humans, Middle Aged, Prognosis, Survival Analysis, Antineoplastic Agents therapeutic use, Boronic Acids therapeutic use, Chromosome Deletion, Chromosomes, Human, Pair 13, Multiple Myeloma drug therapy, Multiple Myeloma genetics, Multiple Myeloma mortality, Pyrazines therapeutic use
- Abstract
In multiple myeloma, deletion of chromosome 13 (del(13)) is associated with poor prognosis regardless of treatment. This study analyzed the impact of del(13) status on response and survival following treatment with either bortezomib or high-dose dexamethasone in patients in the SUMMIT and APEX trials. Additionally, matched-pairs subset analyses were conducted of patients with and without del(13), balanced for age and International Staging System parameters. In both SUMMIT and APEX, prognosis appeared to be poorer in bortezomib-treated patients with del(13) compared with patients with no del(13) by metaphase cytogenetics. In the SUMMIT and APEX matched-pairs analysis, response and survival appeared comparable in bortezomib-treated patients with or without del(13) by metaphase cytogenetics. However, patients with del(13) receiving dexamethasone in APEX appeared to have markedly decreased survival compared with those without del(13) by metaphase cytogenetics. These matched-pairs analyses suggest that bortezomib may overcome some of the poor impact of del(13) as an independent prognostic factor. However, sample sizes were very small; these findings require confirmation from further studies.
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- 2007
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11. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib:A multicenter international myeloma working group study
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Kumar S. K., Lee J. H., Lahuerta J. J., Morgan G., Richardson P. G., Crowley J., Haessler J., Feather J., Hoering A., Moreau P., LeLeu X., Hulin C., Klein S. K., Sonneveld P., Siegel D., Bladé J., Goldschmidt H., Jagannath S., Miguel J. S., Orlowski R., Palumbo A., Sezer O., Rajkumar S. V., Durie B. G. International Myeloma Working Group Abildgaard N, Abonour R, Alexanian R, Alsina M, Anderson KC, Attal M, Avet Loiseau H, Badros A, Baris D, Barlogie B, Bataille R, Beksaç M, Belch A, Ben Yehuda D, Bensinger B, Bergsagel PL, Bird J, Bladé J, Boccadoro M, Chanan Khan A, Chen WM, Child T, Chim J, Chng WJ, Comenzo R, Crowley J, Dalton W, Davies F, de Souza C, Delforge M, Dimopoulos M, Dispenzieri A, Drach J, Drake M, Durie BG, Einsele H, Facon T, Fantl D, Fermand JP, Fonseca R, Gahrton G, García Sanz R, Gasparetto C, Gertz M, Gibson J, Giralt S, Goldschmidt H, Greipp P, Hajek R, Hardan I, Hari P, Harousseau JL, Hata H, Hattori Y, Heffner T, Ho J, Hungria V, Ida S, Jacobs P, Jagannath S, Johnsen HE, Jian H, Joshua D, Jurczyszyn A, Kawano M, Kröger N, Kumar S, Kyle RA, Lacy M, Lahuerta JJ, Landgren O, Laubach J, Lee JH, LeLeu X, Lentzsch S, Lokhorst H, Lonial S, Ludwig H, Maiolino A, Mateos M, Mehta J, Mellqvist UH, Merlini G, Mikhael J, Morales AR, Moreau P, Morgan G, Nahi H, Munshi N, Niesvizky R, Nouel A, Novis Y, Orlowski R, Palumbo A, Pavlovsky S, Pilarski L, Powles R, Raje N, Rajkumar SV, Reece D, Reiman T, Richardson PG, Roodman D, Rosiñol L, San Miguel J, Sezer O, Shah JJ, Shaughnessy J, Shimizu K, Shustik C, Siegel D, Singhal S, Sonneveld P, Spencer A, Stadtmauer E, Stewart K, Terpos E, Tosi P, Tricot G, Turesson I, Van Camp B, Van Ness B, Van Riet I, Vande Broek I, Vanderkerken K, Vescio R, Vesole D, Waage A, Wang M, Weber D, Westin J, Wheatley K, Zonder J., CAVO, MICHELE, Kumar S.K., Lee J.H., Lahuerta J.J., Morgan G., Richardson P.G., Crowley J., Haessler J., Feather J., Hoering A., Moreau P., LeLeu X., Hulin C., Klein S.K., Sonneveld P., Siegel D., Bladé J., Goldschmidt H., Jagannath S., Miguel J.S., Orlowski R., Palumbo A., Sezer O., Rajkumar S.V., Durie B.G. International Myeloma Working Group Abildgaard N, Abonour R, Alexanian R, Alsina M, Anderson KC, Attal M, Avet-Loiseau H, Badros A, Baris D, Barlogie B, Bataille R, Beksaç M, Belch A, Ben-Yehuda D, Bensinger B, Bergsagel PL, Bird J, Bladé J, Boccadoro M, Cavo M, Chanan-Khan A, Chen WM, Child T, Chim J, Chng WJ, Comenzo R, Crowley J, Dalton W, Davies F, de Souza C, Delforge M, Dimopoulos M, Dispenzieri A, Drach J, Drake M, Durie BG, Einsele H, Facon T, Fantl D, Fermand JP, Fonseca R, Gahrton G, García-Sanz R, Gasparetto C, Gertz M, Gibson J, Giralt S, Goldschmidt H, Greipp P, Hajek R, Hardan I, Hari P, Harousseau JL, Hata H, Hattori Y, Heffner T, Ho J, Hungria V, Ida S, Jacobs P, Jagannath S, Johnsen HE, Jian H, Joshua D, Jurczyszyn A, Kawano M, Kröger N, Kumar S, Kyle RA, Lacy M, Lahuerta JJ, Landgren O, Laubach J, Lee JH, LeLeu X, Lentzsch S, Lokhorst H, Lonial S, Ludwig H, Maiolino A, Mateos M, Mehta J, Mellqvist UH, Merlini G, Mikhael J, Morales AR, Moreau P, Morgan G, Nahi H, Munshi N, Niesvizky R, Nouel A, Novis Y, Orlowski R, Palumbo A, Pavlovsky S, Pilarski L, Powles R, Raje N, Rajkumar SV, Reece D, Reiman T, Richardson PG, Roodman D, Rosiñol L, San Miguel J, Sezer O, Shah JJ, Shaughnessy J, Shimizu K, Shustik C, Siegel D, Singhal S, Sonneveld P, Spencer A, Stadtmauer E, Stewart K, Terpos E, Tosi P, Tricot G, Turesson I, Van Camp B, Van Ness B, Van Riet I, Vande Broek I, Vanderkerken K, Vescio R, Vesole D, Waage A, Wang M, Weber D, Westin J, Wheatley K, Zonder J., and Hematology
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,NATURAL HISTORY ,Antineoplastic Agents ,Context (language use) ,RELAPSE ,Article ,Recurrence ,Internal medicine ,medicine ,Humans ,Immunologic Factors ,Elotuzumab ,Survival analysis ,Multiple myeloma ,Aged ,Aged, 80 and over ,Isatuximab ,Bortezomib ,business.industry ,Hematology ,Middle Aged ,Pomalidomide ,medicine.disease ,Survival Analysis ,Surgery ,Regimen ,SURVIVAL ,Disease Progression ,Female ,Multiple Myeloma ,business ,medicine.drug - Abstract
Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T-0). The median age at diagnosis was 58 years, and time from diagnosis to T-0 was 3.3 years. Following T-0, 213 (74%) patients had a treatment recorded with one or more regimens (median = 1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0 in 94 patients (44%) including >= partial response in 69 (32%). The median overall survival and event-free survival from T-0 were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs. Leukemia (2012) 26, 149-157; doi:10.1038/leu.2011.196; published online 29 July 2011
- Published
- 2012
12. Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study.
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San-Miguel, J. F., Richardson, P. G., Sonneveld, P., Schuster, M. W., Irwin, D., Stadtmauer, E. A., Facon, T., Harousseau, J.-L., Ben-Yehuda, D., Lonial, S., Goldschmidt, H., Reece, D., Bladé, J., Boccadoro, M., Cavenagh, J. D., Neuwirth, R., Boral, A. L., Esseltine, D.-L., and Anderson, K. C.
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DRUG efficacy , *ANTINEOPLASTIC agents , *KIDNEY disease treatments , *MULTIPLE myeloma , *CREATININE , *PROGNOSIS ,THERAPEUTIC use of steroid hormones - Abstract
Renal impairment is associated with poor prognosis in multiple myeloma (MM). This subgroup analysis of the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib vs high-dose dexamethasone assessed efficacy and safety in patients with relapsed MM with varying degrees of renal impairment (creatinine clearance (CrCl) <30, 30–50, 51–80 and >80 ml min−1). Time to progression (TTP), overall survival (OS) and safety were compared between subgroups with CrCl 50 ml min−1 (severe-to-moderate) and >50 ml min−1 (no/mild impairment). Response rates with bortezomib were similar (36–47%) and time to response rapid (0.7–1.6 months) across subgroups. Although the trend was toward shorter TTP/OS in bortezomib patients with severe-to-moderate vs no/mild impairment, differences were not significant. OS was significantly shorter in dexamethasone patients with CrCl 50 vs >50 ml min−1 (P=0.003), indicating that bortezomib is more effective than dexamethasone in overcoming the detrimental effect of renal impairment. Safety profile of bortezomib was comparable between subgroups. With dexamethasone, grade 3/4 adverse events (AEs), serious AEs and discontinuations for AEs were significantly elevated in patients with CrCl 50 vs >50 ml min−1. These results indicate that bortezomib is active and well tolerated in patients with relapsed MM with varying degrees of renal insufficiency. Efficacy/safety were not substantially affected by severe-to-moderate vs no/mild impairment.Leukemia (2008) 22, 842–849; doi:10.1038/sj.leu.2405087; published online 17 January 2008 [ABSTRACT FROM AUTHOR]
- Published
- 2008
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13. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma.
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Dimopoulos, M. A., Oriol, A., Nahi, H., San-Miguel, J., Bahlis, N. J., Usmani, S. Z., Rabin, N., Orlowski, R. Z., Komarnicki, M., Suzuki, K., Plesner, T., Yoon, S.-S., Ben Yehuda, D., Richardson, P. G., Goldschmidt, H., Reece, D., Lisby, S., Khokhar, N. Z., O'Rourke, L., and Chiu, C.
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ANTINEOPLASTIC agents , *DEXAMETHASONE , *TREATMENT effectiveness , *MULTIPLE myeloma treatment , *DISEASE relapse , *PROGRESSION-free survival , *THERAPEUTICS , *CLINICAL trials , *COMPARATIVE studies , *DRUG resistance in cancer cells , *RESEARCH methodology , *MEDICAL cooperation , *MONOCLONAL antibodies , *MULTIPLE myeloma , *PROGNOSIS , *RESEARCH , *THALIDOMIDE , *EVALUATION research , *RANDOMIZED controlled trials , *KAPLAN-Meier estimator - Abstract
Background: Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma.Methods: In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival.Results: At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2.Conclusions: The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .). [ABSTRACT FROM AUTHOR]- Published
- 2016
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14. Management of relapsed multiple myeloma:Recommendations of the international myeloma working group
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Anuj Mahindra, Philippe Moreau, C. S. Chim, Brian G.M. Durie, Gösta Gahrton, J. Hou, Peter O'Gorman, W. J. Chng, KC Anderson, Elena Zamagni, Jo Caers, Xavier Leleu, Hans Erik Johnsen, Peter M. Voorhees, Antonio Palumbo, Jacob P. Laubach, Paul G. Richardson, Shaji Kumar, Artur Jurczyszyn, Sigurdur Y. Kristinsson, Murielle Roussel, P.L. McCarthy, H. Einsele, E. Terpos, Amitabha Mazumder, Tony Reiman, U. H. Mellqvist, Linda M. Pilarski, Robert Z. Orlowski, Jan Westin, Laurent Garderet, Matthew Streetly, Douglas E. Joshua, J. S. Miguel, M.A. Dimopoulos, Heinz Ludwig, Jiachuan Lu, Vincent Rajkumar, Ingemar Turesson, O. Sezer, Laubach, J, Garderet, L., Mahindra, A., Gahrton, G., Caers, J., Sezer, O., Voorhees, P., Leleu, X., Johnsen, H. E., Streetly, M., Jurczyszyn, A., Ludwig, H., Mellqvist, U. H., Chng, W. J., Pilarski, L., Einsele, H., Hou, J., Turesson, I., Zamagni, Elena, Chim, C. S., Mazumder, A., Westin, J., Lu, Jiachuan, Reiman, T., Kristinsson, S., Joshua, D., Roussel, M., O'Gorman, P., Terpos, E., Mccarthy, P., Dimopoulos, M., Moreau, Philippe, Orlowski, R. Z., Miguel, J. S., Anderson, K. C., Palumbo, A., Kumar, S., Rajkumar, V., Durie, B., and Richardson, P. G.
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medicine.medical_specialty ,Cancer Research ,medicine.medical_treatment ,Salvage therapy ,Antineoplastic Agents ,Hematopoietic stem cell transplantation ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Internal medicine ,Humans ,Medicine ,Disease management (health) ,Intensive care medicine ,Multiple myeloma ,Salvage Therapy ,Hematology ,business.industry ,Hematopoietic Stem Cell Transplantation ,Disease Management ,medicine.disease ,Surgery ,Clinical trial ,Transplantation ,Clinical research ,Anesthesiology and Pain Medicine ,Oncology ,030220 oncology & carcinogenesis ,Practice Guidelines as Topic ,Multiple Myeloma ,business ,030215 immunology - Abstract
The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.Leukemia accepted article preview online, 29 December 2015. doi:10.1038/leu.2015.356.
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- 2016
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