Single-agent thalidomide for treatment of first relapse following high-dose chemotherapy in patients with multiple myeloma

Fenk, Roland; Hoyer, Barbara; Steidl, Ulrich; Kondakci, Mustafa; Graef, Thorsten; Heuk, R; L, Ruf; Strupp, Corinna; Neumann, Frank; Up, Rohr; Hildebrandt, Barbara; Haas, Rainer; Kobbe, Guido

doi:10.1038/sj.leu.2403564

Cited by 3 publications

(2 citation statements)

References 9 publications

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“…According to recent review article of clinical trials of MM, the drugs used as a single agent for its anti-MM property were compared [56]. When these active drugs for MM sorted by best response rate, thalidomide was 59% [57], and higher than pomalidomide's 54% [58]. When sorted by average response rate, thalidomide was still higher than pomalidomide and lenalidomide [56].…”

Section: Discussionmentioning

confidence: 99%

Internal ribosome entry site of bFGF is the target of thalidomide for IMiDs development in multiple myeloma

Lien¹,

Horng²,

Hsu³

et al. 2014

Genes Cancer

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Although new analogues of immunomodulatory drugs (IMiDs) are being developed for MM, the molecular mechanism of these drugs remains unclear. In the current study, we used MM cell lines as a model to investigate the molecular mechanism of thalidomide and to compare its potency with IMiDs such as pomalidomide. We determined that thalidomide did not inhibit cell proliferation of RPMI8226 and U266 MM cells, whereas pomalidomide showed a significant inhibitory effect on these two MM cell lines. Interestingly, we further demonstrated that although thalidomide down-regulated bFGF translation through the inhibition of IRES even at 0.1 μg/ml, pomalidomide did not have a similar affect bFGF levels. A colony formation assay demonstrated that thalidomide and the bFGF knock-down clones caused a significant reduction in the clonogenic ability of MM cells, and treatment with exogenous bFGF can recover the clonogenic ability of thalidomide-treated cells and knock-down clones, but not that of pomalidomide-treated cells. This implies that thalidomide, but not pomalidomide, targets the IRES of FGF-2.In conclusion, our results highlight a non-cytotoxic anticancer drug target for thalidomide, the IRES of bFGF, and provide the mechanistic rationale for developing IMiDs as anti-cancer therapeutics in MM patients, with improved potency and fewer side effects.

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Section: Discussionmentioning

confidence: 99%

Internal ribosome entry site of bFGF is the target of thalidomide for IMiDs development in multiple myeloma

Lien¹,

Horng²,

Hsu³

et al. 2014

Genes Cancer

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“…5). Of these, melphalan was found to be the most potent (best result reported) single agent in MM treatment (75%), 3 followed by dexamethasone (63%), 4 lenalidomide (63%), 5 carfilzomib (60%), 6 thalidomide (59%), 7 pomalidomide (54%), 8 bortezomib (48%), 9 cyclophosphamide (43%), 10 prednisone (40%), 11 and doxorubicin (22%). 12 Additionally, 7 non–FDA-approved drugs met the threshold and showed activity > 22%:…”

Section: All Fda-approved Drugs Have a Single-agent Activity > 22%mentioning

confidence: 99%

Activity of 129 Single-Agent Drugs in 228 Phase I and II Clinical Trials in Multiple Myeloma

Kortuem

Zidich

Schuster

et al. 2014

Clinical Lymphoma Myeloma and Leukemia

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Background More than 400 preclinical studies report ≥ 1 compound as cytotoxic to multiple myeloma (MM) cells; however, few of these agents became relevant in the clinic. Thus, the utility of such assays in predicting future clinical value is debatable. Patients and Methods We examined the application of early-phase trial experiences to predict future clinical adoption. We identified 129 drugs explored as single agents in 228 trials involving 7421 patients between 1961 and 2013. Results All drugs in common use in MM (melphalan, dexamethasone, prednisone, cyclophosphamide, bendamustine, thalidomide, lenalidomide, pomalidomide, bortezomib, carfilzomib, and doxorubicin) demonstrated a best reported response rate of ≥ 22%. Older agents, including teniposide, fotemustine, paclitaxel, and interferon, also appear active by this criterion; however, if mean response rates from all reported trials for an agent are considered, then only drugs with a mean response rate of 15% partial response are in clinical use. Conclusion Our analysis suggests that thresholds of 20% for best or 15% for mean response are highly predictive of future clinical success. Below these thresholds, no drug has yet reached regulatory approval or widespread use in the clinic. Thus, this benchmark provides 1 element of the framework for guiding choice of drugs for late-stage clinical testing.

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Treatment of relapsed/refractory myeloma

Streetly¹,

Laubach²,

Richardson³

et al. 2013

Myeloma

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Single-agent thalidomide for treatment of first relapse following high-dose chemotherapy in patients with multiple myeloma

Cited by 3 publications

References 9 publications

Internal ribosome entry site of bFGF is the target of thalidomide for IMiDs development in multiple myeloma

Internal ribosome entry site of bFGF is the target of thalidomide for IMiDs development in multiple myeloma

Activity of 129 Single-Agent Drugs in 228 Phase I and II Clinical Trials in Multiple Myeloma

Treatment of relapsed/refractory myeloma

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