“Second Generation Thalidomide[ lenolidomide] is still a novel therapeutic agent for Multiple Myeloma Treatment

Authors

*Professor Pranab Kumar Bhattacharya MD(cal), FIC Path(Ind),  Professor andHead, Dept. of Pathology In-charge DCP Course WBUHS and DLT course ; *Miss Upasana Bhattacharya **Rupak Bhattacharya B.Sc(cal),M.Sc(JU);**Ritwik Bhattacharya B.com(cal); ****Dr .Shyamal Haldar MS(cal) Assoc. Professor **Soumyak Bhattacharya BHM, MSC Student PUSHA New Delhi;** Rupsa Bhattacharya of residence 7/51 Purbapalli, Sodepur, Kol-110;  ***Dalia Mukherjee BA(hons) cal, ***Miss Oindrila Mukherjee,*** Mr Debasis Mukherjee BSC(cal)  of residence Swamijinagar, Habra  *****Dr. Debasis Roy Barman  MD(AIIMS) Asst .Professor .*Dr Soma Das MBBS,DCH(cal); *Dr. Anuradha De, DCP(cal) MD(AIIMS)* Dr Ranu Roy Biswas MD(CAL) Asst Professor

 *Dept of Pathology,  School of Tropical Medicine Kolkata, 108, C.R avenue Calcutta-73, W.B , India** 7/51 Purbapalli; Sodepur; 24 Parganas(north) Kol-110 W.B, India  ;*** Swamijinagar, South Habra, North 24 Parganas ( West Bengal), India***** Dept of Onco-pathology.  Medical college Kolkata WB, India.

Perhaps best known and most successful example of drug re purposing for treatment of hematologic malignancies is long before identification of thalidomide as a novel therapeutic agent for treatment of multiple myeloma.  Success of thalidomide illustrated how a degree of serendipity is often useful in drug discovery and development. Thalidomide, first used in 1950s as  sedative hypnotic and as  treatment for nausea during pregnancy. However, the drug was subsequently withdrawn from market by FDA because of its teratogenic effects^{.[1 ]}Decades later, Celgene resurrected thalidomide and began evaluating its potential therapeutic value for treatment of several diseases, including DLE, aphthous ulcers in HIV syndromes and Behcet disease.^{[2,3 ]} Around that time, wife of a cardiologist with refractory myeloma was reviewing medical literatures, searching for a potential therapy for her husband. She contacted Dr Judah Folkman in Boston and discussed  anti angiogenic properties of thalidomide and potential use of this drug in myeloma. Based on  discussion, Celgene was contacted and thalidomide was obtained for compassionate use in this patient with myeloma. Although drug did not work well in her husband, it was tried further in 4 other patients. The results of this early pilot study were reported by Singhal et al, who treated patients with refractory myeloma with thalidomide on a compassionate-use protocol^.[4] One of these patients, with a very large tumor burden, did not respond to 2 prior cycles of high-dose chemotherapy, had  nearly complete remission within 3 months of initiating thalidomide therapy. Singhal et al ^[4] followed this observation up with  phase II study in 84 patients, previously treated and progressive myeloma. Patients were initially treated with 200 mg oral thalidomide daily, with fortnightly increases of 200 mg, for total  6 weeks and  final treatment dose of 800 mg. In his study, 10% of patients had a complete or nearly complete remission; 32% had reduction of serum or urine para-protein levels by at least 25%. These and subsequent studies led to the approval of thalidomide for the treatment of myeloma.[^5-7]. Thalidomide was initially licensed for  treatment of ENL  in 1998 by FDA US, and it was not until 2006 that thalidomide was approved for  treatment of myeloma ^{[ 11]} Later studies also demonstrated efficacy in myelodysplasia^.[8,9 ] Encouraged by these reports of efficacy,  more potent second-generation analog lenolidomide developed and has largely replaced thalidomide in  treatment of hematologic malignancies^.[10] Although initially evaluated in myeloma  its potential anti angiogenic effects(bFGF, VEGF) , thalidomide’s anti myeloma mechanism of action is much more complex and includes altering cell adhesion molecules and cytokine expression as well modulation of cell-mediated immunity. Indeed, its full mechanism of action in both myeloma and myelodysplasia remains still ill understood. Several adverse effects negatively affect patients. These  effects develop with prolonged treatment and include mostly cardiovascular, thromboembolic events ,dermatological, gastrointestinal, motor and/or sensitive peripheral neuropathy. Lenalidomide [30 mg once daily3-weeks-on/1-week-off schedule] has less toxic profile than its parent compound , is approved for treatment of relapsed and refractory MM in combination with dexamethasone, after first-line of therapy.  Among the other promising combinations for treatment of MM may be Proteasome Inhibitors [Bortezomib], TRAIL/Apo2L , Farnesyl transferase inhibitors

[tipifarnib], Heat shock protein 90 inhibitors [geldanamycinTanespimycin,] with combination bortezomib are all in vitro or phase II trials.  phosphodiesterase inhibitor papaverine and theadenosine receptor agonist chloro-IB-MECA,  when both acted synergistically with dexamethasone to induce cell death in myeloma cells. Of note, none of these combinations could have been predicted to have activity in myeloma solely through an understanding of disease biology or available[11] clinical data. Bortezomib-high-dose dexamethasone with/without a third drug (e.g. cyclophosphamide, Lenalidomide, doxorubicin)  is  however options for patients with any degree of renal impairment.

References

1] Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anti cancer agents. Nat Rev Cancer. 2004;4(4):314-322.

2] . Calabrese L, Fleischer AB. Thalidomide: current and potential clinical applications. Am J Med. 2000;108(6):487-495.

3]. Sheskin J. Thalidomide in the treatment of lepra reactions. Clin Pharmacol Ther. 1965;6:303-306.

4] Singhal S, Mehta J, Desikan R, et al. Anti tumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341(21):1565-1571.

5] . Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006;354(10):

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6] Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR. 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. 2006;24(3): 431-436

7] Alexanian R, Weber D, Giralt S, Delasalle K. Consolidation therapy of multiple myeloma with thalidomide-dexamethasone after intensive chemotherapy. Ann Oncol. 2002;13(7):1116-1119.

8]. Strupp C, Germing U, Aivado M, Misgeld E, Haas R, Gattermann N. Thalidomide for the treatment of patients with myelodysplastic syndromes. Leukemia. 2002;16(1):1-6.

                                                                                                

9] Bowen D, MacIlwaine L, Cavanagh J, et al. Thalidomide therapy for low-risk myelodysplasia .Leuk Res. 2005;29(2):235-236

10]. Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006; 108(10):3458-3464.

11] Mahadeo A. Sukhai, Paul A. Spagnuolo, Scott Weir, James Kasper, Lavonne Patton and Aaron D Schimmer .New sources of drugs for hematologic malignancies blood 2011 117: 6747-6755 doi:10.1182/blood-2011-02-315283 Pre published online April 21, 2011;
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