OCTOBER 2007

Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma.
Mayo Clin Proc. 2007 Oct;82(10):1179-84.
Lacy MQ, Gertz MA, Dispenzieri A, Hayman SR, Geyer S, Kabat B, Zeldenrust SR, Kumar S, Greipp PR, Fonseca R, Lust JA, Russell SJ, Kyle RA, Witzig TE, Bergsagel PL, Stewart AK, Rajkumar SV.
This study reports the long-term results of the phase II study of 34 patients with newly diagnosed myeloma treated with lenalidomide + dexamethasone, previously published in Blood in December 2005. After 4 cycles of therapy, patients could either continue lenalidomide or proceed to autologous stem cell transplantation. 13 patients proceeded to transplant and they were censored at that time. Results:
  - The 2-year PFS was 83% in patients who had SCT and 59% in patients who remained on Rev-Dex
  - The 3-year OS was 92% in patients who had SCT and 85% in patients who remained on Rev-Dex

Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA - Italian Multiple Myeloma Network.
J Clin Oncol. 2007 Oct 1;25(28):4459-65.
Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N, Crippa C, Ciccone G, Omedè P, Ambrosini MT, Gay F, Bringhen S, Musto P, Foà R, Knight R, Zeldis JB, Boccadoro M, Petrucci MT; GIMEMA--Italian Multiple Myeloma Network.
54 elderly patients with newly diagnosed myeloma were treated with MPR:
  - Melphalan 0.18-0.25 mg/Kg PO on days 1-4
  - Prednisone 2 mg/Kg PO on days 1-4
  - Revlimid 5-10 mg PO on days 1-21
Cycles were repeated every 28 days, x9 cycles, followed by maintenance with lenalidomide alone.
Results:
  - The maximum tolerated dose was melphalan 0.18 mg/Kg and lenalidomide 10 mg
  - Response rate: 81%, with VGPR 48% and CR 24%
  - Event-free survival at 1 year: 92%
  - Overall survival at 11 year: 100%
  - Most common grade 3-4 adverse events: neutropenia, thrombocytopenia, vasculitis (9.5%), and venous thromboembolism (5%)

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 randomised 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.

Antigen-specific T-cell immunity in multiple myeloma patients is restored following high-dose therapy: implications for timing of vaccination.
Scand J Immunol. 2007 Oct;66(4):465-75.
Svane IM, Nikolajsen K, Johnsen HE.
This study evaluates the recovery of natural and vaccine induced immunity after autologous stem cell transplantation in patients with multiple myeloma. The authors serially measured the T-cell responses to CMV, VZV, and tetanus toxoid, and found that most patients regained specific T-cell immunity to those infections as early as 3 months after transplantation. After transplant, the CD4/CD8 ratio decreases, but antigen specific CD4+ T-cells recover prior to CD8+ T-cells.

New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells.
Blood. 2007 Oct 1;110(7):2586-92.
Pérez-Persona E, Vidriales MB, Mateo G, García-Sanz R, Mateos MV, de Coca AG, Galende J, Martín-Nuñez G, Alonso JM, de Las Heras N, Hernández JM, Martín A, López-Berges C, Orfao A, San Miguel JF.
This is a study of 407 patients with MGUS and 93 patients with smoldering myeloma. Normal and myelomatous plasma cells were differentiated by flow cytometry, based on the expression of 4 antigens (CD19, CD45, CD38, and and CD56). The authors showed that patients with predominance of aberrant plasma cells at diagnosis had a significantly higher risk of progressing to multiple myeloma. After multivariate analysis, the percentage of aberrant plasma cells in the bone marrow retained its prognostic significance.

Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma: efficacy and clinical implications of tumor response kinetics.
J Clin Oncol. 2007 Oct 1;25(28):4452-8.
Rosiñol L, Oriol A, Mateos MV, Sureda A, García-Sánchez P, Gutiérrez N, Alegre A, Lahuerta JJ, de la Rubia J, Herrero C, Liu X, Van de Velde H, San Miguel J, Bladé J.
40 patients with newly diagnosed myeloma received bortezomib and dexamethasone on an alternating basis as induction therapy before autologous SCT. Bortezomib was given at 1.3 mg/m2 IV on days 1, 4, 8, and 11 on cycles 1, 3, and 5, and dexamethasone was given at 40 mg PO on days 1-4, 9-12, and 17-20 on cycles 2, 4, and 6. Response rate was 65% (including 12.5% CR), and minor response 17.5%. Disease remission was achieved rapidly, usually within the first 2 cycles. Response rate after ASCT was 88%, with 33% CR and 22% VGPR.

Novel therapy with 2-methoxyestradiol for the treatment of relapsed and plateau phase multiple myeloma.
Clin Cancer Res. 2007 Oct 15;13(20):6162-7.
Rajkumar SV, Richardson PG, Lacy MQ, Dispenzieri A, Greipp PR, Witzig TE, Schlossman R, Sidor CF, Anderson KC, Gertz MA.
This is the first phase II trial of 2-methoxyestradiol in multiple myeloma. 60 patients were treated. PFS at 1, 2, and 3 years were 24%, 17%, and 11%, respectively. There were no partial responses, and minor response was observed in 2 patients.

Ideal body weight correlates better with engraftment after PBSC autograft than actual body weight, but is under-estimated in myeloma patients possibly due to disease-related height loss.
Bone Marrow Transplant. 2007 Oct;40(7):665-9.
Maclean PS, Parker AN, McQuaker IG, Clark AD, Farrell E, Douglas KW.

Myelodysplastic syndrome after autologous peripheral blood stem cell transplantation for multiple myeloma.
Bone Marrow Transplant. 2007 Oct;40(8):759-64.
Przepiorka D, Buadi F, McClune B, Franz G, Walsh W, White F.
Among 82 myeloma patients who underwent autologous stem cell transplantation, the rate of myelodysplastic syndrome was 12% (10 patients). High-dose melphalan was the conditioning regimen received by 83% of patients. Of note, most patients received other forms of chemotherapy, and 34% received radiation therapy as well. Median overall survival after the diagnosis of myelodysplastic syndrome was 18 months.

 

NOVEMBER 2007

Immunization with a recombinant MAGE-A3 protein after high-dose therapy for myeloma.
J Immunother. 2007 Nov-Dec;30(8):847-54.
Szmania S, Gnjatic S, Tricot G, et al.
A healthy donor was immunized with MAGE-A3 protein in order to transfer immunity to her identical twin with MAGE-A3+ myeloma. After a syngeneic stem cell transplant, patient received primed donor cells collected after immunizations, then repeated immmunizations. Patient remained in remission for at least 2.5 years.

Long-term effects of idiotype vaccination on the specific T-cell response in peripheral blood and bone marrow of multiple myeloma patients.
Eur J Haematol. 2007 Nov;79(5):371-81.
Abdalla AO, Hansson L, Eriksson I, Näsman-Glaser B, Mellstedt H, Osterborg A.

Immunoglobulin gene rearrangements and the pathogenesis of multiple myeloma.
Blood. 2007 Nov 1;110(9):3112-21.
González D, van der Burg M, García-Sanz R, Fenton JA, Langerak AW, González M, van Dongen JJ, San Miguel JF, Morgan GJ.
[Review]

Successful desensitization in a patient with lenalidomide hypersensitivity.
Am J Hematol. 2007 Nov;82(11):1030.
Phillips J, Kujawa J, Davis-Lorton M, Hindenburg A.

Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma.
Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foà R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD; Multiple Myeloma (010) Study Investigators.
N Engl J Med. 2007 Nov 22;357(21):2123-32.
This phase 3 trial investigated the use of lenalidomide + dexamethasone in 351 patients with relapsed/refractory myeloma. Patients received at least one previous antimyeloma therapy. Patients were randomized to receive lenalidomide (176 patients) or placebo (175 patients) on days 1-21 every 28 days, along with dexamethasone 40 mg PO on days 1-4, 9-12, and 17-20 in the first 4 cycles and on days 1-4 in the following cycles. Results:
  - Response rate (PR + CR) was 60% in the lenalidomide group and 24% in the placebo group (p <0.001)
  - CR rate was 16% in the lenalidomide group and 3% in the placebo group (p <0.001)
  - Time to progression was 11.3 months in the lenalidomide group and 4.7 months in the placebo group (p <0.001)
  - The most frequent grade 3-4 adverse events were neutropenia (29.5%), thrombocytopenia (11.4%), and venous thromboembolism (11.4% vs 4.6%)

Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America.
N Engl J Med. 2007 Nov 22;357(21):2133-42.
Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD; Multiple Myeloma (009) Study Investigators.
This phase 3 trial investigated the use of lenalidomide + dexamethasone in 353 patients with relapsed/refractory myeloma. Patients received at least one previous antimyeloma therapy. Patients were randomized to receive lenalidomide (177 patients) or placebo (176 patients) on days 1-21 every 28 days, along with dexamethasone 40 mg PO on days 1-4, 9-12, and 17-20 in the first 4 cycles and on days 1-4 in the following cycles. Results:
  - Response rate (PR + CR) was 61% in the lenalidomide group and 20% in the placebo group (p <0.001)
  - CR rate was 14% in the lenalidomide group and 1% in the placebo group (p <0.001)
  - Time to progression was 11.1 months in the lenalidomide group and 4.7 months in the placebo group (p <0.001)
  - Median overall survival was 29.6 months in the lenalidomide group and 20.2 months in the placebo group (p <0.001)
  - Rate of grade 3-4 adverse events was 85% in the lenalidomide group and 73% in the placebo group
  - Rate of venous thromboembolism was 15% in the lenalidomide group and 3% in the placebo group

Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial.
Blood. 2007 Nov 15;110(10):3557-60.
Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Miguel JS, Bladé J, Boccadoro M, Cavenagh J, Alsina M, Rajkumar SV, Lacy M, Jakubowiak A, Dalton W, Boral A, Esseltine DL, Schenkein D, Anderson KC.
This is an updated analysis of the APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial, a study that demonstrated an increased response rate and improved overall survival of bortezomib vs high-dose dexamethasone in patients with relapsed multiple myeloma. Response rate was 43% with bortezomib and 9% with dexamethasone. After a median follow-up of 22 months, the median survival was 30 months with  bortezomib and 24 months with dexamethasone. The survival advantage of 6 months was reached despite a significant crossover from the dexamethasone arm to tthe bortezomib arm.

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.

Peripheral blood or bone marrow cells in reduced-intensity or myeloablative conditioning allogeneic HLA identical sibling donor transplantation for multiple myeloma.
Haematologica. 2007 Nov;92(11):1513-8.
Gahrton G, Iacobelli S, Bandini G, Björkstrand B, Corradini P, Crawley C, Hegenbart U, Morgan G, Kröger N, Schattenberg A, Schönland SO, Verdonck LF, Volin L, de Witte T, Niederwieser D; Myeloma Subcommittee of the EBMT.
This study compared the use of peripheral blood stem cells (PBSC) vs bone marrow (BM) in 1,667 myeloma patients treated with allogeneic transplant from identical sibling, either myeloablative or RIC. Results:
  - The median engraftment was faster with PBSC (14 days for neutrophils and 15 days for platelets) than with BM (18 days for neutrophils and 25 days for platelets)
  - The incidence of acute GVHD was similar between the two groups, whereas chronic GVHD was more frequent with PBSC
  - Progression/relapse rate and non-relapse mortality were similar between the two groups
  - Overall survival and progression-free survival were similar between the two groups

 

DECEMBER 2007

Lack of CD56 expression on myeloma cells is not a marker for poor prognosis in patients treated by high-dose chemotherapy and is associated with translocation t(11;14).
Bone Marrow Transplant. 2007 Dec;40(11):1033-7.
Hundemer M, Klein U, Hose D, Raab MS, Cremer FW, Jauch A, Benner A, Heiss C, Moos M, Ho AD, Goldschmidt H.
Lack of CD56 expression in myeloma cells was believed to be associated with poor prognosis. This study in cells of 99 evaluated by flow cytometry the CD56 expression in cells of 99 patients prior to transplant. No statistically significant difference was found between the EFS of 28 patients with CD56- MM and the EFS of 71 patients with CD56+ MM. The lack of CD56 expression on malignant plasma cells correlated with the presence of the t(11;14) translocation.

Escalation therapy with bortezomib, dexamethasone and bendamustine for patients with relapsed or refractory multiple myeloma.
Leuk Lymphoma. 2007 Dec;48(12):2345-51.
Fenk R, Michael M, Zohren F, Graef T, Czibere A, Bruns I, Neumann F, Fenk B, Haas R, Kobbe G.
In this study, 50 patients with relapsed/refractory multiple myeloma were treated with an escalation therapy consisting of bortezomib, dexamethasone, and bendamustine (50-100 mg/m2 on days 1 + 8).
  - Bortezomib monotherapy was sufficient in 23 (46%) patients
  - Addition of dexamethasone was necessary in 20 (40%) patients
  - Triple combination therapy was necessary in 7 (14%) patients
Overall response rate was 84%. Median time to progression was 8 months, and overall survival was 20 months.

Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide or lenalidomide in myeloma.
Leuk Lymphoma. 2007 Dec;48(12):2330-7.
Niesvizky R, Martínez-Baños D, Jalbrzikowski J, Christos P, Furst J, De Sancho M, Mark T, Pearse R, Mazumdar M, Zafar F, Pekle K, Leonard J, Jayabalan D, Coleman M.
In this study, the prophylactic use of low-dose aspirin (81 mg) was effective in reducing the incidence of venous thromboembolism in patients with multiple myeloma treated with thalidomide or lenalidomide.

 

 


Giampaolo Talamo, MD