Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma
Abstract
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-α [TNF-α]) mediating growth and survival of MM cells, blocks angiogenesis, and stimulates host anti-MM natural killer (NK) cell immunity. Moreover, CC-5013 also inhibits tumor growth, decreases angiogenesis, and prolongs host survival in a human plasmacytoma mouse model. In the present study, we carried out a phase 1 CC-5013 dose-escalation (5 mg/d, 10 mg/d, 25 mg/d, and 50 mg/d) study in 27 patients (median age 57 years; range, 40-71 years) with relapsed and refractory relapsed MM. They received a median of 3 prior regimens (range, 2-6 regimens), including autologous stem cell transplantation and Thal in 15 and 16 patients, respectively. In 24 evaluable patients, no dose-limiting toxicity (DLT) was observed in patients treated at any dose level within the first 28 days; however, grade 3 myelosuppression developed after day 28 in all 13 patients treated with 50 mg/d CC-5013. In 12 patients, dose reduction to 25 mg/d was well tolerated and therefore considered the maximal tolerated dose (MTD). Importantly, no significant somnolence, constipation, or neuropathy has been seen in any cohort. Best responses of at least 25% reduction in paraprotein occurred in 17 (71%) of 24 patients (90% confidence interval [CI], 52%-85%), including 11 (46%) patients who had received prior Thal. Stable disease (less than 25% reduction in paraprotein) was observed in an additional 2 (8%) patients. Therefore, 17 (71%) of 24 patients (90% CI, 52%-85%) demonstrated benefit from treatment. 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.
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Lenalidomide maintenance has demonstrated a clear OS advantage (about 88% versus 80% at 3 years) with a hazard ratio for death of approximately 0.60.
“By contrast, lenalidomide has demonstrated a clear OS advantage (~88% versus 80% at 3 years) with a hazard ratio for death of approximately 0.6030,31,33,34.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [31]
Maintenance lenalidomide following induction therapy with or without autologous haematopoietic stem cell transplantation is a standard of care for patients with MM.
“Maintenance lenalidomide following induction therapy with or without autologous haematopoietic stem cell transplantation (auto-HSCT) is also a standard of care for patients with MM30,31.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [31]
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- Authors
- Richardson, P. G., Schlossman, R. L., Weller, E., Hideshima, T., Mitsiades, C., Davies, F., LeBlanc, R., Catley, L. P., Doss, D., Kelly, K., McKenney, M., Mechlowicz, J., Freeman, A., Deocampo, R., Rich, R., Ryoo, J. J., Chauhan, D., Balinski, K., Zeldis, J., & Anderson, K. C.
- Affiliations
- Harvard University (US)
- Corresponding author
- Anderson, Kenneth C.
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2002-11-01
- Volume
- 100
- Issue
- 9
- Pages
- 3063-3067
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2144531125
- Cited by
- 804
- References
- 21
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 11 · 2022: 10 · 2021: 15 · 2020: 7 · 2019: 11 · 2018: 12 · 2017: 16 · 2016: 17 · 2015: 26 · 2014: 18 · 2013: 31 · 2012: 46
- FWCI
- 29.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (P0-78378, R0-1 50947)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Health Sciences › Medicine › Oncology › Bone health and treatments
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- immunomodulators, thalidomide derivatives, relapsed multiple myeloma, drug resistance, thalidomide, dose-limiting toxicity, maximum tolerated dose, myelosuppression, angiogenesis inhibition, interleukin-6, vascular endothelial growth factor
- MeSH terms
- Lenalidomide, Adjuvants, Immunologic, Administration, Oral, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Combined Modality Therapy, Constipation, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Multiple Myeloma, Myeloma Proteins, Nervous System Diseases, Neutropenia, Remission Induction, Safety, Thalidomide, Thrombocytopenia, Transplantation, Autologous, Salvage Therapy, Treatment Outcome, Apoptosis, Drug Resistance, Neoplasm, Maximum Tolerated Dose, Peripheral Blood Stem Cell Transplantation
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