Dose-dependent effect of thalidomide on overall survival in relapsed multiple myeloma.
Clin Cancer Res. 2002 Nov;8(11):3377-82.
Neben K, Moehler T, Benner A, Kraemer A, Egerer G, Ho AD, Goldschmidt H.
This is a retrospective analysis of a phase II study in 83 patients with relapsed myeloma, treated with thalidomide at a maximum dose of 400 mg daily. Progression-free survival and overall survival at 1 year were 45% and 86%, respectively. The cumulative 3-month thalidomide dose was one of the most important prognostic factors for survival, supporting the hypothesis of a dose-dependent effect of thalidomide.

Response rate, durability of response, and survival after thalidomide therapy for relapsed multiple myeloma.
Mayo Clin Proc. 2003 Jan;78(1):34-9.
Kumar S, Gertz MA, Dispenzieri A, Lacy MQ, Geyer SM, Iturria NL, Fonseca R, Hayman SR, Lust JA, Kyle RA, Greipp PR, Witzig TE, Rajkumar SV.
32 patients with relapsed multiple myeloma were treated with thalidomide 200 mg/day for 2 weeks, increased to a maximum of 800 mg/d. Results:
  - Response rate: 31%. No complete responses were seen.
  - Median progression-free survival: 8.6 months
  - Median overall survival: 22 months

Thalidomide and dexamethasone for resistant multiple myeloma.
Br J Haematol. 2003 Jun;121(5):768-71.
Anagnostopoulos A, Weber D, Rankin K, Delasalle K, Alexanian R.
47 patients with resistant myeloma were treated with dexamethasone + thalidomide. Response rate was 47% (CR 13%). DVT occurred in 8% of patients.

Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age.
Blood. 2003 Jul 1;102(1):69-77.
Mileshkin L, Biagi JJ, Mitchell P, Underhill C, Grigg A, Bell R, McKendrick J, Briggs P, Seymour JF, Lillie K, Smith JG, Zeldis JB, Prince HM.
In this phase II study, 75 patients with relapsed/refractory myeloma were treated with thalidomide up to the maximum dose of 800 mg/day. Response rate was 28%, and stable disease was seen in 55% of patients. Median progression-free survival was 5.5 months, and median overall survival was 14.6 months. Patients older than 65 years had inferior outcomes.

Early response predicts thalidomide efficiency in patients with advanced multiple myeloma.
Br J Haematol. 2004 Apr;125(2):149-55.
Waage A, Gimsing P, Juliusson G, Turesson I, Gulbrandsen N, Eriksson T, Hjorth M, Nielsen JL, Lenhoff S, Westin J, Wislöff F; Nordic Myeloma Study Group.
65  patients with refractory myeloma were treated with thalidomide at a dose of 200 mg/day, escalated to 800 mg. Response: 14% PR, 6% CR, 14% minor response. Median survival was 12 months.

Extramedullary multiple myeloma escapes the effect of thalidomide.
Haematologica. 2004 Jul;89(7):832-6.
Rosiñol L, Cibeira MT, Bladé J, Esteve J, Aymerich M, Rozman M, Segarra M, Cid MC, Filella X, Montserrat E.
11 of 38 myeloma patients treated with thalidomide had extramedullary disease. The response rate was 59% in patients without extramedullary involvement, but extramedullary disease did not respond to thalidomide. Tumor markers reduced in 4 of 11 patients with extramedullary disease, but all patients had progression of the soft-tissue masses.

Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure.
Eur J Haematol. 2004 Aug;73(2):98-103.
Tosi P, Zamagni E, Cellini C, Cangini D, Tacchetti P, Tura S, Baccarani M, Cavo M.
Thalidomide was safely administered in 20 patients with relapsed/refractory myeloma and renal failure.

An evaluation of factors predicting long-term response to thalidomide in 234 patients with relapsed or resistant multiple myeloma.
Br J Cancer. 2004 Nov 29;91(11):1873-9.
Hus I, Dmoszynska A, Manko J, Hus M, Jawniak D, Soroka-Wojtaszko M, Hellmann A, Ciepluch H, Skotnicki A, Wolska-Smolen T, Sulek K, Robak T, Konopka L, Kloczko J.

Treatment of relapsed/refractory multiple myeloma with thalidomide-based regimens: identification of prognostic factors.
Leuk Lymphoma. 2004 Nov;45(11):2275-9.
Anagnostopoulos A, Gika D, Hamilos G, Zervas K, Zomas A, Pouli A, Zorzou M, Kastritis E, Anagnostopoulos N, Tassidou A, Anagnostou D, Dimopoulos MA.

A systematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma.
Br J Haematol. 2006 Mar;132(5):584-93.
Glasmacher A, Hahn C, Hoffmann F, Naumann R, Goldschmidt H, von Lilienfeld-Toal M, Orlopp K, Schmidt-Wolf I, Gorschlüter M.
This is a review of 42 trials including 1674 myeloma patients treated with thalidomide. Conclusions:
  - Clinical benefit: 54%
          Response rate (PR + CR): 29%
          Rate of minor responses: 14%
          Rate of stable disease: 11%
  - Median overall survival: 14 months
  - Severe adverse events (grade III-IV): constipation 16%, somnolence 11%, neuropathy 6%, rash 3%, VTE 3%.

Similar efficacy of thalidomide- and bortezomib-based regimens for first relapse of multiple myeloma.
Ann Hematol. 2011 Dec;90(12):1441-7.
Krejci M, Gregora E, Straub J, Minarik J, Scudla V, Adam Z, Krivanova A, Pour L, Zahradova L, Buchler T, Mayer J, Hajek R.
A retrospective comparison between 105 patients treated with thalidomide-based regimens and 106 patients treated with bortezomib-based regimens found no significantly different clinical outcomes:
  - Response rate: 51% in the thalidomide group, and 50% in the bortezomib group (p= 0.77)
  - Median time to progression: 13 months in the thalidomide group, and 17 months in the bortezomib group (p= 0.21)
  - Median overall survival: 30 months in the thalidomide group, and 37 months in the bortezomib group (p= 0.89)



Thalidomide after lenalidomide: a possible treatment regimen in relapse refractory multiple myeloma patients.
Br J Haematol. 2011 Jan;152(1):108-10.
Guglielmelli T, Petrucci MT, Saglio G, Palumbo A.
Among 14 patients treated with thalidomide + dexamethasone, after previous exposure to lenalidomide, response rate was 14% (2 patients). Progressive disease was seen in 3 patients, and minor responses/stable disease in 9 (64%).

Efficacy of thalidomide-based therapy following lenalidomide plus dexamethasone in patients with relapsed/refractory multiple myeloma.
Am J Hematol. 2013 Apr;88(4):337-8.
Kukreti V, Masih-Khan E, Young T, Chu CM, Jiang H, Trudel S, Chen C, Jimenez-Zepeda V, Reece DE.
This retrospective study of 24 patients with myeloma refractory to lenalidomide (or intolerant to lenalidomide) received salvage treatment with thalidomide. Response rate was 38% (all VGPR or PR, no CR), and median progression-free survival was only 3 months.



Thalidomide in combination with vincristine, epirubicin and dexamethasone (VED) for previously untreated patients with multiple myeloma.
Eur J Haematol. 2005 Jan;74(1):40-6.
Schütt P, Ebeling P, Buttkereit U, Brandhorst D, Opalka B, Hoiczyk M, Flasshove M, Hense J, Bojko P, Metz K, Moritz T, Seeber S, Nowrousian MR.
31 patients with newly diagnosed myeloma were treated with thalidomide 400 mg/day + VED (vincristine, epirubicin, dexamethasone) every 3 weeks. CR was 19%, PR 61%, and stable disease 16%. DVT occurred in 26% of patients, and polyneuropathy in 65%.

Combined thalidomide and cyclophosphamide treatment for refractory or relapsed multiple myeloma patients: a prospective phase II study.
Ann Hematol. 2005 May;84(5):311-6.
Hovenga S, Daenen SM, de Wolf JT, van Imhoff GW, Kluin-Nelemans HC, Sluiter WJ, Vellenga E.
38 patients with relapsed/refractory myeloma were treated with thalidomide and cyclophosphamide daily. Response rate was 84% (PR 64%). The median progression-free survival was 30 months, and the median overall survival was 20 months.

Primary treatment with pulsed melphalan, dexamethasone and thalidomide for elderly symptomatic patients with multiple myeloma.
Haematologica. 2006 Feb;91(2):252-4.
Dimopoulos MA, Anagnostopoulos A, Terpos E, Repoussis P, Zomas A, Katodritou E, Kyrtsonis MC, Delibasi S, Vassou A, Pouli A, Zervas K, Anagnostopoulos N, Maniatis A; Greek Myeloma Study Group.
50 patients with myeloma older than 75 were treated with MDT:
  - Melphalan 8 mg/m2 on days 1-4
  - Dexamethasone 12 mg/m2 on days 1-4 and 17-20
  - Thalidomide 300 mg qhs on days 1-4 and 17-20
Cycles were repeated every 5 weeks x3.
Results: partial response 62%, complete response 10%. Median time to response: 2 months. Median time to progression: 21 months. DVT was seen in 9% of patients.

Phase 2 study of pegylated liposomal doxorubicin, vincristine, decreased-frequency dexamethasone, and thalidomide in newly diagnosed and relapsed-refractory multiple myeloma.
Mayo Clin Proc. 2006 Jul;81(7):889-95.
Hussein MA, Baz R, Srkalovic G, Agrawal N, Suppiah R, Hsi E, Andresen S, Karam MA, Reed J, Faiman B, Kelly M, Walker E.
This is a phase II study of DVd (pegylated liposomal doxorubicin, vincristine, and decreased-frequency dexamethasone) + thalidomide in 102 patients with multiple myeloma (53 with newly diagnosed disease, and 49 with previously treated disease). Thalidomide was started at 50 mg/day and escalated up to 400 mg/day. At the time of best response, patients were started on maintenance with thalidomide + prednisone 50 mg PO qod. Results:
  - Response rate was 87% in patients with newly diagnosed myeloma and 90% in patients with previously treated myeloma
  - Rate of CR + VGPR was 49% in patients with newly diagnosed myeloma and 45% in patients with previously treated myeloma
  - Responders had longer progression-free and overall survival
  - Most common grade 3-4 toxicities: venous thromboembolism (25%), peripheral neuropathy (22%), and neutropenia (14%)

VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek Myeloma Study Group.
Ann Oncol. 2007 Aug;18(8):1369-75.
Zervas K, Mihou D, Katodritou E, Pouli A, Mitsouli CH, Anagnostopoulos A, Delibasi S, Kyrtsonis MC, Anagnostopoulos N, Terpos E, Zikos P, Maniatis A, Dimopoulos MA; Greek Myeloma Study Group.
232 patients with newly diagnosed myeloma were randomized to VAD-doxil (115 patients) vs VAD-doxil + thalidomide (117 patients). Results:
  - Response rate was 63% in the group treated with VAD and 81% in the group treated with VADT (p= 0.003)
  - Progression-free survival at 2 years was 45% in the group treated with VAD and 59% in the group treated witth VADT (p= 0.013)
  - Overall survival at 2 years was 65% in the group treated with VAD and 77% in the group treated with VADT (p= 0.037)
  - Adverse effects were more frequent in the group treated with VADT, but rate of grade 3-4 toxicities was similar in both groups



Oral melphalan, prednisone, and thalidomide for newly diagnosed patients with myeloma.
Cancer. 2005 Oct 1;104(7):1428-33.
Palumbo A, Bertola A, Musto P, Caravita T, Callea V, Nunzi M, Grasso M, Falco P, Cangialosi C, Boccadoro M.
49 patients with newly diagnosed myeloma were treated with melphalan, prednisone, and thalidomide (MPT). Response rates: PR 45%, VGPR 4%, nCR 6%, CR 18%. The median time to maximum response was 4 months. Event-free survival at 2 years was 64%, and overall survival at 2 years was 91%. VTE was observed in 20% of patients, and 1 patient died of pulmonary embolism.

Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomized controlled trial.
Lancet. 2006 Mar 11;367(9513):825-31.
Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, Cangialosi C, Grasso M, Rossini F, Galli M, Catalano L, Zamagni E, Petrucci MT, De Stefano V, Ceccarelli M, Ambrosini MT, Avonto I, Falco P, Ciccone G, Liberati AM, Musto P, Boccadoro M; Italian Multiple Myeloma Network, GIMEMA.
This trail randomized newly diagnosed myeloma patients aged 60-85 years between MP alone every 4 weeks x6 (126 patients) vs MPT with thalidomide 100 mg PO qhs (129 patients). MPT therapy was superior to MP:
  - Response rate was 48% with MP and 76% with MPT
  - CR + near-CR rate was 7% with MP and 28% with MPT
  - Event-free survival at 2 years was 27% with MP and 54% with MPT
  - Survival at 3 years was 64% with MP and 80% with MPT
  - Toxicity, defined as grade 3-4 adverse events rate, was 25% with MP and 48% with MPT
  - DVT was seen in 20% of patients without enoxaparin prophylaxis, and in 3% with enoxaparin prophylaxis

Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial.
Blood. 2008 Oct 15;112(8):3107-14.
Palumbo A, Bringhen S, Liberati AM, Caravita T, Falcone A, Callea V, Montanaro M, Ria R, Capaldi A, Zambello R, Benevolo G, Derudas D, Dore F, Cavallo F, Gay F, Falco P, Ciccone G, Musto P, Cavo M, Boccadoro M.
This is an updated analysis of efficacy and safety of MP vs MPT in multiple myeloma, after a median follow-up of 38.1 months.
  - The median PFS was 14.5 months with MP and 21.8 months with MPT (p= 0.004)
  - The median OS was 47.6 months with MP and 45.0 months with MPT (p= 0.79)
The results confirmed the activity of MPT for PFS but they failed to show a survival advantage. This is presumably due to the fact that salvage therapy with thalidomide or bortezomib improved survival after progression in the MP group, but not in the MPT group.

Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomized trial.
Lancet. 2007 Oct 6;370(9594):1209-18.
Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, Renaud M, Harousseau JL, Guillerm G, Chaleteix C, Dib M, Voillat L, Maisonneuve H, Troncy J, Dorvaux V, Monconduit M, Martin C, Casassus P, Jaubert J, Jardel H, Doyen C, Kolb B, Anglaret B, Grosbois B, Yakoub-Agha I, Mathiot C, Avet-Loiseau H; Intergroupe Francophone du Myélome.
At the time of this publication, the standard of care in the treatment of elderly patients (older than 65 years) with multiple myeloma was the combination of melphalan + prednisone. In this study, 447 patients with newly diagnosed myeloma, aged 65-75 years, were randomly assigned to receive:
  - MP: melphalan + prednisone (196 patients)
  - MPT: melphalan + prednisone + thalidomide (125 patients)
  - Mini-allogeneic stem cell transplant, using melphalan 100 mg/m2 (126 patients).
After a median follow-up of 51.5 months, median overall survival was:
  - 33.2 months for MP
  - 51.6 months for MPT
  - 38.3 months for mini-allogeneic SCT
No difference in survival was seen between for MP and mini-allogeneic SCT. The results of this trial established MPT as the new standard of care for the treatment of elderly patients with newly diagnosed multiple myeloma.

Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma.
Blood. 2010 Sep 2;116(9):1405-12.
Waage A, Gimsing P, Fayers P, Abildgaard N, Ahlberg L, Björkstrand B, Carlson K, Dahl IM, Forsberg K, Gulbrandsen N, Haukås E, Hjertner O, Hjorth M, Karlsson T, Knudsen LM, Nielsen JL, Linder O, Mellqvist UH, Nesthus I, Rolke J, Strandberg M, Sørbø JH, Wisløff F, Juliusson G, Turesson I; Nordic Myeloma Study Group.
This is a double-blind study of 363 patients with newly diagnosed myeloma, randomized to receive MPT (melphalan 0.25 mg/Kg + prednisone 100 mg days 1-4 every 6 weeks, and thalidomide 100-400 mg PO qhs) vs MP + placebo. Results:
  - Partial response was 34% with MPT and 33% with MP
  - VGPR or better was 23% with MPT and 7% with MP (p <0.001)
  - No difference in progression-free survival: 15 months with MPT and 14 months with MP (p= 0.16)
  - No difference in overall survival: 29 months with MPT and 32 months with MP (p= 0.16)



Low-dose thalidomide in combination with oral weekly cyclophosphamide and pulsed dexamethasone is a well tolerated and effective regimen in patients with relapsed and refractory multiple myeloma.
Br J Haematol. 2005 Jun;129(6):763-70.
Kyriakou C, Thomson K, D'Sa S, Flory A, Hanslip J, Goldstone AH, Yong KL.
52 patients with relapsed/refractory myeloma were treated with cyclophosphamide PO weekly, pulsed dexamethasone, and low-dose Thalidomide (CDT). Response rates: PR 62%, CR 17%.

The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma.
Leukemia. 2004 Apr;18(4):856-63.
García-Sanz R, González-Porras JR, Hernández JM, Polo-Zarzuela M, Sureda A, Barrenetxea C, Palomera L, López R, Grande-García C, Alegre A, Vargas-Pabón M, Gutiérrez ON, Rodríguez JA, San Miguel JF.
71 patients with relapsed or refractory myeloma were treated with  thalidomide 200-800 mg/day, cyclophosphamide 50 mg/day, and dexamethasone 40 mg/day, 4 days every 3 weeks. Response rate at 3 months was 83%: complete response 2%, partial response 55%, minor response 26%. CR rate was 10% at 6 months. Event free survival at 2 years was 57%. Venous thromboembolism was seen in 7% of patients.

Combination chemotherapy with cyclophosphamide, thalidomide and dexamethasone for patients with refractory, newly diagnosed or relapsed myeloma.
Haematologica. 2006 Jun;91(6):862-3.
Sidra G, Williams CD, Russell NH, Zaman S, Myers B, Byrne JL.
The combination of weekly cyclophosphamide, thalidomide, and pulsed dexamethasone (CTD) in patients with newly diagnosed or relapsed/refractory myeloma was highly effective, as it induced an overall response rate of 84%. CTD did not impair stem cell mobilization.

The combination of cyclophosphomide, thalidomide and dexamethasone is an effective alternative to cyclophosphamide - vincristine - doxorubicin - methylprednisolone as induction chemotherapy prior to autologous transplantation for multiple myeloma: a case-matched analysis.
Leuk Lymphoma. 2006 Nov;47(11):2335-8.
Wu P, Davies FE, Horton C, Jenner MW, Krishnan B, Alvares CL, Saso R, McCormack R, Dines S, Treleaven JG, Potter MN, Ethell ME, Morgan GJ.
This is a retrospective case-matched study comparing oral CTD (Cyclophosphamide, Thalidomide, Dexamethasone) vs IV CVAMP (Cyclophosphamide, Vincristine, doxorubicin, and MethylPrednisolone) as induction therapy before autologous stem cell transplantation in patients with newly diagnosed multiple myeloma. 27 patients received CTD, and 27 patients received CVAMP. After 3 cycles of treatment, response rate was higher in the group treated with CTD (89%) compared to the group treated with CVAMP (56%, p= 0.016). Neutropenia (grade 3-4) was more frequent in the group treated with CVAMP (60% vs 4%), and venous thromboemobolism was more frequent in the group treated with CTD (11% vs 4%).

Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation.
Blood. 2011 Aug 4;118(5):1231-8.
Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group.
The authors presented results from the MRC Myeloma IX trial, which randomized CTD (Cyclophosphamide, Thalidomide, and Dexamethasone, 426 patients) vs MP (Melphalan and Prednisolone, 423 patients) in non-transplant candidates having newly diagnosed disease. Response rate was higher with CTD (64% vs 33%). Rate of complete remission was also higher with CTD  (13% vs 2%), but progression-free survival and overall survival were similar between the two groups.



See the specific section on bortezomib.



Giampaolo Talamo, MD