Long-term outcome results of the first tandem autotransplant trial for multiple myeloma.
Br J Haematol. 2006 Oct;135(2):158-64.
Barlogie B, Tricot GJ, van Rhee F, Angtuaco E, Walker R, Epstein J, Shaughnessy JD, Jagannath S, Bolejack V, Gurley J, Hoering A, Vesole D, Desikan R, Siegel D, Mehta J, Singhal S, Munshi NC, Dhodapkar M, Jenkins B, Attal M, Harousseau JL, Crowley J.
Results after a median follow-up of 12 years:
  - 10-year OS 33%, 10-year EFS 15%
  - 15-year OS 17%, 15-year EFS 7%

NY-ESO-1 immunotherapy for multiple myeloma.
Leuk Lymphoma. 2006 Oct;47(10):2037-48.
Szmania S, Tricot G, van Rhee F.

Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma.
Blood. 2006 Oct 1;108(7):2159-64.
Offidani M, Corvatta L, Piersantelli MN, Visani G, Alesiani F, Brunori M, Galieni P, Catarini M, Burattini M, Centurioni R, Ferranti M, Rupoli S, Scortechini AR, Giuliodori L, Candela M, Capelli D, Montanari M, Olivieri A, Poloni A, Polloni C, Marconi M, Leoni P.
50 patients older than 65 years with newly diagnosed myeloma were treated with thalidomide 100 mg PO qhs, dexamethasone, and liposomal doxorubicin 40 mg/m2 every 28 days. Response rate was 98% (CR 34%, nCR 14%, VGPR 10%, PR 30%, and minor response 10%). 3-year OS was 74%, and 3-year EFS was 57%.

Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study.
Blood. 2006 Oct 1;108(7):2165-72.
Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Díaz-Mediavilla J, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, de Arriba F, Alegre A, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF.
At the time of this trial, the standard first-line treatment for elderly patients multiple myeloma was melphalan and prednisone (MP). In this phase I/II trial, 60 patients with multiple myeloma aged 65 years or older were treated with a combination of bortezomib, melphalan, and prednisone (VMP). Response rate was 89%, including 32% CR. When compared with historical controls from patients treated with MP, VMP produced better results:
  - Response rate: 89% with VMP vs 42% with MP
  - Event-free survival at 16 months: 83% with VMP vs 51% with MP
  - Overall survival at 16 months: 90% with VMP vs 62% with MP

A phase II trial with gemcitabine and paclitaxel for the treatment of refractory and relapsed multiple myeloma patients.
Oncol Rep. 2006 Oct;16(4):877-84.
Gazitt Y, Shaughnessy P, Rothenberg ML.
This is a phase II clinical trial of paclitaxel 150 mg/m2 IV + gemcitabine 2,000-3,000 mg/m2 IV q2weeks for 6 cycles in 12 patients with relapsed or refractory MM. Treatment with this combination was active, because among 8 evaluable patients there were 1 CR, 3 PR, 1 minor response, and 1 stable disease. The patient in CR remianed in remission for more than 6 months.



A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma.
Blood. 2006 Nov 15;108(10):3458-64.
Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC.
This is a randomized phase 2 study that evaluated 2 doses of lenalidomide in 70 patients with relapsed/refractory myeloma. Patients received lenalidomide either 30 mg once a day or 15 mg twice a day on days 1-21 every 28 days. Dexamethasone was added if no response was seen after 2 cycles. Toxicity was increased in the group receiving 15 mg twice a day, because the rate of grade 3-4 myelosuppression in patients was 41% (vs 13%). With 25 mg once a day, response rate (including minor responses) was 25%, median PFS was 7.7 months, and median overall survival was 28 months.

Multiple myeloma patients with CKS1B gene amplification have a shorter progression-free survival post-autologous stem cell transplantation.
Br J Haematol. 2006 Nov;135(4):486-91.
Chang H, Qi X, Trieu Y, Xu W, Reader JC, Ning Y, Reece D.
This study evaluated frequency and prognostic impact of CKS1B (chromosome 1q21 region) amplification by FISH in 99 myeloma patients treated with autologous stem cell transplantation. 3-8 CKS1B signals were found in 31 of 99 (31%) patients, and were associated with a worse outcome than in patients without CKS1B amplification: progression-free survival was 18.5 vs. 25.7 months (p= 0.035), and overall survival was 44.8 months vs not reached (p= 0.20, not statistically significant).

Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study.
Haematologica. 2006 Nov;91(11):1498-505.
Harousseau JL, Attal M, Leleu X, Troncy J, Pegourie B, Stoppa AM, Hulin C, Benboubker L, Fuzibet JG, Renaud M, Moreau P, Avet-Loiseau H.
This study used bortezomib (+ dexamethasone) as induction therapy of patients with newly diagnosed myeloma, in the attempt of increase the CR rate before autologous SCT. Among 48 patients, response rate was 66%, CR 21%, and very good partial remission 10%.

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%).

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).
This is a trial of 597 myeloma patients randomized to receive the following post-transplant maintenance, starting 2 months after stem cell transplant:
  - No maintenance (arm A)
  - Pamidronate (arm B)
  - Pamidronate + thalidomide (arm C) until relapse or toxicity (median 15 months)
  - Response rate: 55% in arm A, 57% in arm B, and 67% in arm C (p = 0.03).
  - The EFS at 3 years: 36% in arm A, 37% in arm B, and 52% in arm C (p <0.009)
  - 4-year survival (from the time of diagnosis): 77% in arm A, 74% in arm B, and 87% in arm C (p <0.04)
  - Rate of skeletal events: 24% in arm A, 21% in arm B, and 18% in arm C (p = 0.4).
Therefore, thalidomide maintenance was clinically effective, and pamidronate maintenance did not decrease the incidence of skeletal events.

A phase II study of ZD6474 (Zactima), a selective inhibitor of VEGFR and EGFR tyrosine kinase in patients with relapsed multiple myeloma - NCIC CTG IND.145.
Invest New Drugs. 2006 Nov;24(6):529-35.
Kovacs MJ, Reece DE, Marcellus D, Meyer RM, Mathews S, Dong RP, Eisenhauer E.
This is a phase II trial of ZD6474 (Zactima) given at 100 mg p.o. daily in 18 patients with relapsed multiple myeloma. There was no clinical benefit, because none of the patients had a reduction in the paraprotein level.

Pegfilgrastim compared with filgrastim after high-dose melphalan and autologous hematopoietic peripheral blood stem cell transplantation in multiple myeloma patients.
Eur J Haematol. 2006 Nov;77(5):410-5.
Martino M, Praticò G, Messina G, Irrera G, Massara E, Messina G, Console G, Iacopino P.
37 consecutive patients with myeloma treated with high-dose melphalan and autologous peripheral blood stem cell transplantation were randomly assigned to receive:
  - Filgrastim 5 mcg/kg SC qd starting on day +5 (19 patients)
  - Peg-filgrastim 6 mg SC x1 on day +1 (n = 18 patients)
The median duration of neutropenia in the Filgrastim and Pegfilgrastim groups was similar, but the incidence of febrile neutropenia (100% vs 61%) and the duration of febrile neutropenia (4 days vs 1.5 days) were lower in the Pegfilgrastim arm.

The outcome of autologous stem cell transplantation in patients with plasma cell disorders and dialysis-dependent renal failure.
Haematologica. 2006 Nov;91(11):1555-8.
Raab MS, Breitkreutz I, Hundemer M, Benner A, Klaus J, Hegenbart U, Moehler T, Ho AD, Zeier M, Goldschmidt H.
In this study, 34 myeloma patients on hemodialysis underwent autologous stem transplant with melphalan 100 mg/m2. The authors found no significant differences with other 34 myeloma patients with normal renal function who received melphalan 200 mg/m2, in terms of many parameters, including hematologic toxicity, transplant related mortality, disease response, EFS, and OS. Patients on dialysis required a longer IV antibiotic treatment and longer hospitalization. Therefore, the authors recommend the dose of melphalan of 100 mg/m2 for myeloma patients on dialysis undergoing autologous SCT.

Prospective evaluation of low-dose warfarin for prevention of thalidomide associated venous thromboembolism.
Leuk Lymphoma. 2006 Nov;47(11):2339-43.
Miller KC, Padmanabhan S, Dimicelli L, Depaolo D, Landrigan B, Yu J, Doran V, Marshal P, Chanan-Khan A.
This is a prospectively study of low-dose warfarin (1 or 2 mg) for the prevention of thalidomide-associated venous thromboembolism (VTE). The incidence of VTE was 6% (4 of 68 patients).



Immunotherapy of multiple myeloma: the start of a long and tortuous journey.
Expert Rev Anticancer Ther. 2006 Dec;6(12):1769-85.
Harrison SJ, Cook G, Nibbs RJ, Prince HM.

Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy.
Ann Oncol. 2006 Dec;17(12):1766-71.
Baz R, Walker E, Karam MA, Choueiri TK, Jawde RA, Bruening K, Reed J, Faiman B, Ellis Y, Brand C, Srkalovic G, Andresen S, Knight R, Zeldis J, Hussein MA.
62 patients with relapsed/refractory myeloma were treated with lenalidomide + DVd (liposomal doxorubicin 40 mg/m2 IV, vincristine 2 mg IV on day 1, dexamethasone 40 mg PO on days 1-4). Results:
  - Response rate: 75%, with CR/nCR 29%
  - Median progression-free survival: 12 months
  - Median overall survival: not reached, after a median f/u of 7.5 months

Pegylated liposomal doxorubicin, melphalan and prednisone therapy for elderly patients with multiple myeloma.
Hematol Oncol. 2006 Dec;24(4):205-11.
García-Sanz R, Hernández JM, Sureda A, García-Laraña J, Prósper F, Alegre A, Bárez A, Mateos MV, San Miguel JF.
This is a phase I/II study of 30 patients with newly diagnosed myeloma, age 70 years and older, treated with melphalan, prednisone, and liposomal doxorubicin x 6 cycles. The phase I of the study found that the maximum tolerated dose of liposomal doxorubicin was 30 mg/m2. Complete response was 14%, and partial response 52%. Median progression free survival was 24 months, 3-year OS 52%, and 3-year PFS 37%. No cases of hand-foot syndrome were observed.



Giampaolo Talamo, MD