Thalidomide, lenalidomide, and pomalidomide are IMiDs (ImmunoModulatory Drugs), or CBMs (Cereblon Binding Molecules).

 


THALIDOMIDE

 

Thalidomide (Thalomid ®) has been approved by the FDA for the treatment of multiple myeloma in May 2006.

In patients with refractory myeloma, thalidomide has a response rate of about 30%, and the average duration of remission is approximately 6 months.

The lack of myelosuppression makes thalidomide an ideal agent for combination with chemotherapy agents.

Dose: 50-200 mg/day PO at night.
Plasma half-life is approximately 6 hours.
Mostly eliminated through urine and feces.

Adverse reactions:
  - CNS toxicity: weakness, sedation (somnolence: it should be taken at night)
  - Peripheral neuropathy
  - Skin rash
  - Bradycardia
  - Hypotension
  - Constipation
  - Subclinical hypothyroidism
  - Fetal malformations
  - Venous thromboembolism

Venous thromboembolism usually occurs within the first 6-12 months of therapy. Because of the risk for venous thromboembolism, antithrombotic prophylaxis is always recommended. This is often done with LMWH or full-dose warfarin, but aspirin may be sufficient in patients who receive thalidomide as single agent or in maintenance.

With prolonged use, many patients develop peripheral neuropathy, with development of numbness or “pin-and-needles” sensation, usually in hands and legs. Symptoms are usually irreversible if neuropathy is present for >6 months.

Contraindicated in pregnancy, because of teratogenic effects. Thalidomide was originally developed in 1954 and introduced in Germany in 1957, as a sedative. In 1961 it was withdrawn from the market, because it was found that its use was associated with severe fetal malformations, and almost 10,000 infants were affected.

Due to concerns of fetal risks, patients are required to enroll in a restricted distribution system, called STEPS (System for Thalidomide Education and Prescribing Safety program).

Precautions: fertile women must abstain from intercourse or use 2 methods of contraception. Perform pregnancy test within 24-h period prior to initiate therapy with thalidomide, weekly during the first month, and monthly thereafter. Patients should use protective clothing against exposure to sunlight.

Mechanism of action: see lenalidomide.

 

Thalidomide for treatment of multiple myeloma: 10 years later.
Blood. 2008 Apr 15;111(8):3968-77.
Palumbo A, Facon T, Sonneveld P, Bladè J, Offidani M, Gay F, Moreau P, Waage A, Spencer A, Ludwig H, Boccadoro M, Harousseau JL.
[Review]

Thalidomide dosing in patients with relapsed or refractory multiple myeloma.
Ann Pharmacother. 2003 Apr;37(4):571-6.
Thompson JL, Hansen LA.
[Review]

Thalidomide in patients with multiple myeloma and renal failure.
Br J Haematol. 2004 Apr;125(1):96-7.
Fakhouri F, Guerraoui H, Presne C, Peltier J, Delarue R, Muret P, Knebelmann B.

Polymorphisms of CYP2C19 gene are associated with the efficacy of thalidomide based regimens in multiple myeloma.
Haematologica. 2007 Sep;92(9):1246-9.
Li Y, Hou J, Jiang H, Wang D, Fu W, Yuan Z, Chen Y, Zhou L.
This study showed that polymorphisms of CYP2C19 gene influence the efficacy of thalidomide. Among 92 myeloma patients, the response rate to thalidomide was 63% in extensive metabolizers and 33% in poor metabolizers.

Identification of a primary target of thalidomide teratogenicity.
Science. 2010 Mar 12;327(5971):1345-50.
Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H.
These authors found that cereblon (CRBN), a protein encoded by a candidate gene for mental retardation, binds thalidomide and mediates its teratogenicity. Thalidomide inhibits the ubiquitin ligase activity of CRNB.

Low-dose vs. high-dose thalidomide for advanced multiple myeloma: a prospective trial from the Intergroupe Francophone du Myélome.
Eur J Haematol. 2012 Mar;88(3):249-59.
Yakoub-Agha I, Mary JY, Hulin C, Doyen C, Marit G, Benboubker L, Voillat L, Moreau P, Berthou C, Stoppa AM, Maloisel F, Rodon P, Dib M, Pegourie B, Casassus P, Slama B, Damaj G, Zerbib R, Harousseau JL, Mohty M, Facon T; Intergroupe Francophone du Myélome (IFM).
400 patients with relapsed/refractory myeloma were randomized to 100 vs 400 mg/day of thalidomide. The lower dose was better tolerated, and it produced similar outcomes. The 1-year overall survival rate was 69% with 100 mg, and 73% with 400 mg.

 

INDUCTION THERAPY

Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma.
J Clin Oncol. 2002 Nov 1;20(21):4319-23.
Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR, Geyer S, Iturria N, Fonseca R, Lust JA, Kyle RA, Witzig TE.
50 patients with newly diagnosed myeloma were treated with thalidomide 200 mg PO qhs + dexamethasone 40 mg PO on days 1-4, 9-12, and 17-20 in odd cycles and 40 mg PO on days 1-4 in even cycles. Cycles were repeated every 28 days. Response rate was 64%. The most frequent toxicities were DVT, constipation, and skin rash.

Thalidomide as salvage therapy for VAD-refractory multiple myeloma prior to autologous PBSCT.
Bone Marrow Transplant. 2002 Apr;29(7):577-80.
Ahmad I, Islam T, Chanan-Khan A, Hahn T, Wentling D, Becker JL, McCarthy PL Jr, Alam AR.

Thalidomide alone or with dexamethasone for previously untreated multiple myeloma.
J Clin Oncol. 2003 Jan 1;21(1):16-9.
Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R.
68 patients with newly diagnosed myeloma were treated with thalidomide 100-600 mg PO qhs with or without dexamethasone, for at least 3 months. Response rate was 36% with thalidomide alone and 72% with thalidomide + dexamethasone. CR was 16% with thalidomide + dexamethasone. Median time to remission was 4.2 months with thalidomide alone and 0.7 months with thalidomide + dexamethasone.

Effect of thalidomide on stem cell collection and engraftment in patients with multiple myeloma.
Bone Marrow Transplant. 2003 Sep;32(6):587-92.
Ghobrial IM, Dispenzieri A, Bundy KL, Gastineau DA, Rajkumar SV, Therneau TM, Lacy MQ, Witzig TE, Litzow MR, Christensen BR, Hayman S, Pribula CG, Gertz MA.
This is a retrospective study of 24 patients with newly diagnosed myeloma who received thalidomide, 200 mg PO qhs + dexamethasone as induction therapy before stem cell collection. Median exposure to thalidomide was 4 cycles (range: 2-7 cycles). When the thalidomide group was compared with a control group, there was no significant difference in number of stem cells collected, time to collection, and time to hematologic engraftment, and therefore the authors concluded that thalidomide does not affect peripheral cell mobilization or engraftment.

First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma.
Haematologica. 2004 Jul;89(7):826-31.
Cavo M, Zamagni E, Tosi P, Cellini C, Cangini D, Tacchetti P, Testoni N, Tonelli M, de Vivo A, Palareti G, Tura S, Baccarani M.
This is a phase II study of dexamethasone + thalidomide as first-line therapy in 71 patients with newly diagnosed myeloma. Thalidomide was given at a dose of 200 mg PO qhs, and dexamethasone at the dose of 40 mg PO on days 1-4, 9-12, and 17- 20 in odd cycles, and on days 1-4 in even cycles, for a total of 4 monthly cycles. Response rate was 66% (CR + VGPR 17%). DVT developed in 16% of patients.

Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma.
Blood. 2005 Jul 1;106(1):35-9.
Cavo M, Zamagni E, Tosi P, Tacchetti P, Cellini C, Cangini D, de Vivo A, Testoni N, Nicci C, Terragna C, Grafone T, Perrone G, Ceccolini M, Tura S, Baccarani M; Bologna 2002 study.

This is a retrospective matched case-control study of 200 patients with newly diagnosed myeloma, treated with either VAD (100 patients) or thalidomide + dexamethasone (TD, 100 patients) for 4 months as induction therapy before autologous stem cell transplantation. Results:
  - Response rate was 52% with VAD and 76% with TD (p <0.001)
  - Most important toxicities were neutropenia with VAD (12%) and DVT with TD (15%)
  - The median number of collected CD34+ cells/Kg was 10.5 million with VAD and 7.85 million with TD

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 Jan 20;24(3):431-6.
Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR; Eastern Cooperative Oncology Group.
This study demonstrated that dexamethasone + thalidomide (DT) induces superior response rates compared with single-agent dexamethasone (D) in 207 patients with newly diagnosed multiple myeloma. Patients were randomized to:
  - Dexamethasone (40 mg PO on days 1-4, 9-12, and 17-20) + thalidomide (200 mg PO qhs) (103 patients) or
  - Single-agent dexamethasone (104 patients)
Each cycle was 28 days.
Response rate was 63% in the DT group and 41% in the D group (p= 0.0017)
Toxicities were more frequent in the DT group, especially DVT (17% vs 3%), rash, bradycardia, and peripheral neuropathy.
This study established the combination of dexamethasone and thalidomide as the new (as of 2006) standard of care for the induction therapy of multiple myeloma.

Doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective well tolerated initial therapy for multiple myeloma.
Br J Haematol. 2006 Jan;132(2):155-61.
Hassoun H, Reich L, Klimek VM, Dhodapkar M, Cohen A, Kewalramani T, Zimman R, Drake L, Riedel ER, Hedvat CV, Teruya-Feldstein J, Filippa DA, Fleisher M, Nimer SD, Comenzo RL.
This is a phase II clinical trial of 45 myeloma patients treated with the AD-TD regimen: doxorubicin + dexamethasone for 2-3 months, followed by thalidomide + dexamethasone for 2 months. Response rate was 90.5% (CR 15.5%, nCR 20%, PR 49%). Venous thromboembolism was observed in 11% of cases (prophylaxis consisted of aspirin 81 mg/day).

Low efficacy of thalidomide in improving response after induction in multiple myeloma patients who are candidates for high-dose therapy.
Leuk Res. 2008 Jul;32(7):1085-90.
Corso A, Mangiacavalli S, Barbarano L, Montalbetti L, Mazzone A, Fava S, Varettoni M, Zappasodi P, Morra E, Lazzarino M.
This is a retrospective study of 74 myeloma patients treated with VAD induction therapy, followed by 3 months of thalidomide + dexamethasone (TD), in the attempt of achieving a deeper remission before stem cell transplantation. Results:
  - CR rate was 6% after VAD and 11% after TD
  - VGPR rate was 40% after VAD and 39% after TD
  - PR rate was 23% after VAD and 17% after TD
  - Progressive disease rate was 8% after VAD and 24% after TD
In view of the above results, and the presence of additional toxicities with TD, the authors concluded that intensification therapy with TD after VAD is not a useful therapeutic strategy.

Short-term thalidomide incorporated into double autologous stem-cell transplantation improves outcomes in comparison with double autotransplantation for multiple myeloma.
J Clin Oncol. 2009 Oct 20;27(30):5001-7.
Cavo M, Di Raimondo F, Zamagni E, Patriarca F, Tacchetti P, Casulli AF, Volpe S, Perrone G, Ledda A, Ceccolini M, Califano C, Bigazzi C, Offidani M, Stefani P, Ballerini F, Fiacchini M, de Vivo A, Brioli A, Tosi P, Baccarani M.
The Bologna 2002 study utilized thalidomide 200 mg PO qhs from diagnosis until the second stem cell transplant. Results compared favorably with those of the Bologna 96 study, which used VAD in the induction therapy. RR: 68%, PFS at 4 years: 51%, OS at 5 years: 69% (53% in the control group, p= 0.07).

VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial.
Blood. 2016 May 26;127(21):2569-74.
Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, Garderet L, Royer B, Brechignac S, Tiab M, Puyade M, Escoffre M, Stoppa AM, Facon T, Pegourie B, Chaoui D, Jaccard A, Slama B, Marit G, Laribi K, Godmer P, Luycx O, Eisenmann JC, Allangba O, Dib M, Araujo C, Fontan J, Belhadj K, Wetterwald M, Dorvaux V, Fermand JP, Rodon P, Kolb B, Glaisner S, Malfuson JV, Lenain P, Biron L, Planche L, Caillon H, Avet-Loiseau H, Dejoie T, Attal M.
In this study, 340 patients with newly diagnosed myeloma were randomized to receive either VTD (bortezomib, thalidomide, and dexamethasone), or VCD (bortezomib, cyclophosphamide, and dexamethasone, also called CyBorD). After 4 cycles of induction therapy, before an autologous stem cell transplant, the results were better with VDT: response rate was 92% with VTD, and 83% with VCD (p=0.01).

 

THALIDOMIDE IN SMOLDERING MYELOMA

Thalidomide as initial therapy for early-stage myeloma.
Leukemia. 2003 Apr;17(4):775-9.
Rajkumar SV, Gertz MA, Lacy MQ, Dispenzieri A, Fonseca R, Geyer SM, Iturria N, Kumar S, Lust JA, Kyle RA, Greipp PR, Witzig TE.
This is a phase II trial of 31 patients with smoldering or indolent myeloma, treated with thalidomide at 200 mg PO qhs. Response rate was 34%, and 66% if minor responses (25-49% decrease in M protein) were included. Progression-free survival was 80% at 1 year and 63% at 2 years. Most important toxicities were somnolence, neuropathy, DVT, hearing loss, weakness, bradycardia, and edema.

Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease.
Blood. 2008 Oct 15;112(8):3122-5.
Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB.
This is a phase II trial of thalidomide in 76 patients with smoldering myeloma. Thalidomide was given at 200 mg PO qhs. Results:
  - Partial response: 25%
  - 4-year overall survival: 91%
  - 4-year event-free survival: 60%
  - 86% of patients required dose reduction, and 50% discontinuation of the drug

 

POST-TRANSPLANT MAINTENANCE

Consolidation therapy of multiple myeloma with thalidomide-dexamethasone after intensive chemotherapy.
Ann Oncol. 2002 Jul;13(7):1116-9.
Alexanian R, Weber D, Giralt S, Delasalle K.
21 patients with myeloma in partial remission after stem cell transplantation were given consolidation therapy with thalidomide + dexamethasone, in order to achieve a higher rate of complete remission. Thalidomide was given at a dose of 100-300 mg PO qhs, and dexamethasone at 20 mg/m2 on days 1-4, 9-12, and 17-20, with cycles repeated every 35 days. The combination was started within 15 months after transplant, and continued for at least 3 months. Reduction of myeloma paraprotein by at least 90% occurred in 57% of patients, and 19% of patients converted from partial remission to complete remission. Median duration of remission was 22 months.

Results of a multicenter randomized phase II trial of thalidomide and prednisone maintenance therapy for multiple myeloma after autologous stem cell transplant.
Clin Cancer Res. 2004 Dec 15;10(24):8170-6.
Stewart AK, Chen CI, Howson-Jan K, White D, Roy J, Kovacs MJ, Shustik C, Sadura A, Shepherd L, Ding K, Meyer RM, Belch AR.
This is a randomized phase II trial using thalidomide 200 or 400 mg PO qhs + prednisone 50 mg PO qod as post-transplant maintenance in 77 patients with multiple myeloma. After a median follow-up of 37 months, discontinuation rate for thalidomide was 88% (24% with 200 mg and 59% with 400 mg), even allowing dose reductions. Dose reduction for prednisone were needed in 72% of patients. Median progression-free survival was 32.3 months from the time of transplant, and 42.2 months from the time of diagnosis.

Maintenance thalidomide following single cycle autologous peripheral blood stem cell transplant in patients with multiple myeloma.
Bone Marrow Transplant. 2006 May;37(9):825-9.
Sahebi F, Spielberger R, Kogut NM, Fung H, Falk PM, Parker P, Krishnan A, Rodriguez R, Nakamura R, Nademanee A, Popplewell L, Frankel P, Ruel C, Tin R, Ilieva P, Forman SJ, Somlo G.
This is a phase II study of 29 myeloma patients treated with maintenance thalidomide after a single autologous stem cell transplant. Thalidomide was started at 50 mg PO qhs, and it was increased to max 400 mg a day, and continued for 6 months after achievement of CR for a maximum duration of 18 months. Results:
  - Median tolerated dose was 200 mg
  - CR or nCR rate at 6 months was 45%
  - Overall survival at 2 years was 83%
  - Progression-free survival at 2 years was 49%

Maintenance therapy with thalidomide improves overall survival after autologous hematopoietic progenitor cell transplantation for multiple myeloma.
Cancer. 2006 May 15;106(10):2171-80.
Brinker BT, Waller EK, Leong T, Heffner LT Jr, Redei I, Langston AA, Lonial S.
Among 112 myeloma patients treated with autologous stem cell transplant, 76 patients received no maintenance therapy, and 36 patients received thalidomide, either as maintenance or as salvage therapy. After a median follow-up of 58 months:
  - Median survival was 54 months
  - Median survival was better in patients who received thalidomide compared with those who did not (65.5 vs 44.5 months, p= 0.09)
  - Median survival was better in patients who received thalidomide as maintenance compared with those who received it as salvage therapy (65 vs 54 months, p= 0.05)

Maintenance therapy with thalidomide improves survival in patients with multiple myeloma.
Blood. 2006 Nov 15;108(10):3289-94.
Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub Agha I, Bourhis JH, Garderet L, Pegourie B, Dumontet C, Renaud M, Voillat L, Berthou C, Marit G, Monconduit M, Caillot D, Grobois B, Avet-Loiseau H, Moreau P, Facon T; Inter-Groupe Francophone du Myélome (IFM).
597 myeloma patients treated with a single autologous stem cell transplant were randomized into no maintenance (arm A), maintenance with pamidronate (arm B), and maintenance with thalidomide + pamidronate (arm C). Results:
  - CR or VGPR rate was 55% in arm A, 57% in arm B, and 67% in arm C (p= 0.03)
  - EFS at 3 years was 36% in arm A, 37% in arm B, and 52% in arm C (p <0.009)
  - OS at 4 year (post-diagnosis) was 77% in arm A, 74% in arm B, and 87% in arm C (p <0.04)
  - Rate of skeletal events was 24% in arm A, 21% in arm B, and 18% in arm C (p= 0.4)
Therefore, post-transplant maintenance with thalidomide improved overall survival. Maintenance with pamidronate did not decrease the incidence of bone events.

Thalidomide maintenance following high-dose therapy in multiple myeloma: a UK myeloma forum phase 2 study.
Br J Haematol. 2007 Nov;139(3):429-33.
Feyler S, Rawstron A, Jackson G, Snowden JA, Cocks K, Johnson RJ.
This is a phase II study of post-transplant maintenance with 5 different doses of thalidomide in 100 myeloma patients. After a median follow-up of 32 months:
  - 77% of patients stopped thalidomide, either because of disease progression (23%) or toxicity (54%)
  - 15% of patients converted from PR to CR (at a median of 13.5 months)
  - 3-year overall survival: 76%
  - 3-year progression-free survival: 41%
  - Doses >200 mg were too toxic. Main toxicity was peripheral neuropathy.
  - Increased dosage did not improve outcome but it increased toxicity.

[Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial.
Blood. 2008 Feb 15;111(4):1805-10.
Abdelkefi A, Ladeb S, Torjman L, Othman TB, Lakhal A, Romdhane NB, Omri HE, Elloumi M, Belaaj H, Jeddi R, Aissaouï L, Ksouri H, Hassen AB, Msadek F, Saad A, Hsaïri M, Boukef K, Amouri A, Louzir H, Dellagi K, Abdeladhim AB; Tunisian Multiple Myeloma Study Group.
This study has been retracted in June 2009]

Thalidomide maintenance following high-dose melphalan with autologous stem cell support in myeloma.
Clin Lymphoma Myeloma. 2008 Jun;8(3):153-8.
Chang JE, Juckett MB, Callander NS, Kahl BS, Gangnon RE, Mitchell TL, Longo WL.
31 patients with myeloma were treated with autologous stem cell transplant and then thalidomide 50 mg PO qhs, escalated to a maximum dose of 200 mg per day.
  - Treatment was poorly tolerated, mainly because of peripheral neuropathy.
  - Maintenance at the dose of 200 mg was not feasible (goal achieved in 55% of patients). The median tolerated dose was 100 mg.
  - No DVT was observed.
  - CR + VGPR: 65% at 1 year and 42% at 2 years.
  - Median OS: > 60 months. Median PFS: 20.8 months.

Long-term Follow-up of MRC Myeloma IX Trial: Survival Outcomes with Bisphosphonate and Thalidomide Treatment.
Clin Cancer Res. 2013 Nov 1;19(21):6030-8.
Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA.
The administration of zoledronic acid improved median overall survival in a study of 1,970 myeloma patients (compared to clodronic acid). Interestingly, maintenance therapy with thalidomide was associated with a shorter overall survival in patients with high-risk cytogenetics. In the overall group, it improved PFS but not OS.

 

 

SALVAGE THERAPY AFTER TRANSPLANT

Thalidomide salvage therapy following allogeneic stem cell transplantation for multiple myeloma: a retrospective study from the Intergroupe Francophone du Myélome (IFM) and the Société Française de Greffe de Moelle et Thérapie Cellulaire (SFGM-TC).
Bone Marrow Transplant. 2005 Jan;35(2):165-9.
Mohty M, Attal M, Marit G, Bulabois CE, Garban F, Gratecos N, Rio B, Vernant JP, Sotto JJ, Cahn JY, Blaise D, Jouet JP, Facon T, Yakoub-Agha I.
31 myeloma patients received salvage therapy with thalidomide after allogeneic stem cell ytransplant. RR was 29%.

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. 2004 Jul;79(7):875-82.
Richardson P, Schlossman R, Jagannath S, Alsina M, Desikan R, Blood E, Weller E, Mitsiades C, Hideshima T, Davies F, Doss D, Freeman A, Bosch J, Patin J, Knight R, Zeldis J, Dalton W, Anderson K.
This is a phase 2 study thalidomide 200-600 mg PO qhs, in 30 patients with MM in relapse after stem cell transplantation. Results:
  - Response rate was 43% (including partial response and minor response)
  - Median duration of response was 6 months
  - Progression-free survival at 3 months was 67%

Thalidomide plus dexamethasone is an effective salvage regimen for myeloma patients relapsing after autologous transplant.
Eur J Haematol. 2005 Nov;75(5):391-5.
Palumbo A, Falco P, Ambrosini MT, Petrucci MT, Musto P, Caravita T, Pregno P, Bertola A, Cavallo F, Ciccone G, Boccadoro M.
43 patients with MM in relapse after stem cell transplantation were treated with thalidomide + dexamethasone. Median progression-free survival was 20 months, and median overall survival was 55.5 months.

 

 


Giampaolo Talamo, MD