International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma.
J Clin Oncol. 2010 Oct 10;28(29):4521-30.
Lokhorst H, Einsele H, Vesole D, Bruno B, San Miguel J, Pérez-Simon JA, Kröger N, Moreau P, Gahrton G, Gasparetto C, Giralt S, Bensinger W.

Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial.
J Clin Oncol. 2010 Oct 20;28(30):4621-9.
Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, Lenain P, Hulin C, Facon T, Casassus P, Michallet M, Maisonneuve H, Benboubker L, Maloisel F, Petillon MO, Webb I, Mathiot C, Moreau P.

Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p).
J Clin Oncol. 2010 Oct 20;28(30):4630-4.
Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guerin-Charbonnel C, Caillot D, Marit G, Benboubker L, Voillat L, Mathiot C, Kolb B, Macro M, Campion L, Wetterwald M, Stoppa AM, Hulin C, Facon T, Attal M, Minvielle S, Harousseau JL.
This is a retrospective study of 507 patients with newly diagnosed myeloma who were treated with either bortezomib-dexamethasone x 4 cycles or VAD, as induction therapy before autologous stem cell transplantation. Results:
  - When compared with VAD chemotherapy, bortezomib improved both EFS and OS in patients with t(4;14), but not in patients with del(17p)
  - del(17p) was an adverse prognostic factor only if present in >60% plasma cells
  - t(4;14) and del(17p-) remained poor prognostic factors, and bortezomib did not overcome their prognostic impact (at least, when given for 4 cycles as induction therapy)

Light chain-induced acute renal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multiple myeloma: results of a phase II study.
J Clin Oncol. 2010 Oct 20;28(30):4635-41.
Ludwig H, Adam Z, Hajek R, Greil R, Tóthová E, Keil F, Autzinger EM, Thaler J, Gisslinger H, Lang A, Egyed M, Womastek I, Zojer N.
68 patients with light-chain myeloma and renal insufficiency (GFR <50 mL/min) received BDD therapy:
  - Bortezomib 1.0-1.3 mg/m2 IV on days 1, 4, 8, 11
  - Doxorubicin 9 mg/m2 IV on days 1, 4 or 1, 4, 8, 11
  - Dexamethasone 40 mg PO on days 1, 4, 8, 11
Renal response: 62%.
  - Renal CR: 31% (defined as GFR = or > 60)
  - Renal PR: 7% (defined as GFR increase >100%, from <15 to 30-60)
  - Renal MR: 24% (defined as GFR increase >50%, from <15 to <30, or from 15-30 to 30-60)

Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients.
Blood. 2010 Oct 7;116(14):2543-53.
Broyl A, Hose D, Lokhorst H, de Knegt Y, Peeters J, Jauch A, Bertsch U, Buijs A, Stevens-Kroef M, Beverloo HB, Vellenga E, Zweegman S, Kersten MJ, van der Holt B, el Jarari L, Mulligan G, Goldschmidt H, van Duin M, Sonneveld P.

Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial.
Lancet Oncol. 2010 Oct;11(10):934-41.
Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF.
260 patients of age 65 and older with newly diagnosed myeloma were randomized in to groups:
  - VMP (Velcade, Melphalan, Prednisone) (130 patients) x6 cycles
  - VTP (Velcade, Thalidomide, Prednisone) (130 patients) x6 cycles
then maintenance therapy with either VP (87 patients) or VT (91 patients).
Results after induction therapy:
  - Rate of partial response or better: 80% with VMP and 81% with VTP (p= 0.90)
  - Rate of complete response: 20% with VMP and 28% with VTP (p= 0.20)
  - Discontinuation of therapy due to toxicity was higher with VTP (17% vs 12%, p= 0.03)
  - Grade III/IV peripheral neuropathy: 9% with VMP and 7% with VTP
Results after maintenance therapy:
  - Rate of complete response: 39% with VP and 42% with VT
At the time of this publication, many myeloma experts believed that bortezomib was able to overcome the negative prognostic impact of adverse cytogenetic features. However, in this study, patients with high-risk disease had worse progression-free survival and overall survival despite bortezomib.

Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial.
Lancet Oncol. 2010 Oct;11(10):973-82.
Gimsing P, Carlson K, Turesson I, Fayers P, Waage A, Vangsted A, Mylin A, Gluud C, Juliusson G, Gregersen H, Hjorth-Hansen H, Nesthus I, Dahl IM, Westin J, Nielsen JL, Knudsen LM, Ahlberg L, Hjorth M, Abildgaard N, Andersen NF, Linder O, Wisløff F.
This is a double-blind randomised study of 504 myeloma patients, comparing two doses of pamidronate -30 mg or 90 mg- given IV monthly for at least 3 years. Results:
  - Median time to first skeletal-related event was 9.2 months with 90 mg and 10.2 months with 30 mg (p= 0.63)
  - Osteonecrosis of the jaw developed in 8 patients with 90 mg and 2 patients with 30 mg
The authors recommended that 30 mg is the optimal dose for prevention of bone disease in patients with multiple myeloma.



Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHEMA/GEM2000 study.
Haematologica. 2010 Nov;95(11):1913-20.
Lahuerta JJ, Mateos MV, Martínez-López J, Grande C, de la Rubia J, Rosiñol L, Sureda A, García-Laraña J, Díaz-Mediavilla J, Hernández-García MT, Carrera D, Besalduch J, de Arriba F, Oriol A, Escoda L, García-Frade J, Rivas-González C, Alegre A, Bladé J, San Miguel JF; Grupo Español de MM and Programa para el Estudio de la Terapéutica en Hemopatía Maligna Cooperative Study Groups.
225 patients who underwent transplant using busulfan 12 mg/Kg + melphalan 140 mg/m2 had a longer progression-free survival than 542 patients treated with melphalan 200 mg/m2. However, overall survival was not different, and there were deaths due to sinusoidal obstruction syndrome (veno-occlusive disease).

Interphase fluorescence in situ hybridization on selected plasma cells is superior in the detection of cytogenetic aberrations in plasma cell dyscrasia.
Genes Chromosomes Cancer. 2010 Nov;49(11):991-7.
Put N, Lemmens H, Wlodarska I, Konings P, Moreau Y, Hagemeijer A, Vandenberghe P, Michaux L.

In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2.
Blood. 2010 Nov 4;116(18):3635-44.
Maes K, Nemeth E, Roodman GD, Huston A, Esteve F, Freytes C, Callander N, Katodritou E, Tussing-Humphreys L, Rivera S, Vanderkerken K, Lichtenstein A, Ganz T.

Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM).
Leukemia. 2010 Nov;24(11):1934-9.
Lacy MQ, Hayman SR, Gertz MA, Short KD, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV, Buadi F.
34 patients with myeloma refractory to lenalidomide were treated with pomalidomide (2 mg PO daily, continuously, every 28 days) + dexamethasone (40 mg PO weekly). Results:
  - Response rate was 47%: stable disease 35%, PR 23%, VGPR 9%, and progressive disease 18%
  - Median time to response: 2 months
  - Median duration of response: 9 months
  - Median overall survival 14 months
  - Main  toxicity was myelosuppression, with grade 3-4 neutropenia in 26% of patients, and grade 3-4 thrombocytopenia in 9% of patients

Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series.
Am J Med. 2010 Nov;123(11):1060-4.
Fedele S, Porter SR, D'Aiuto F, Aljohani S, Vescovi P, Manfredi M, Arduino PG, Broccoletti R, Musciotto A, Di Fede O, Lazarovici TS, Campisi G, Yarom N.
This is a case series of 96 patients with the nonexposed variant of ONJ, i.e., osteonecrosis without bone exposure through an opening in the mucosa.
Clinical features were:
  - Jaw pain (92%)
  - Sinus tract (51%)
  - Bone enlargement (36%)
  - Gingival swelling (18%)
Nonexposed ONJ progressed to bone exposure in 53% of cases, after a mean period of 4.6 months.

IgM multiple myeloma: disease definition, prognosis, and differentiation from Waldenstrom's macroglobulinemia.
Am J Hematol. 2010 Nov;85(11):853-5.
Schuster SR, Rajkumar SV, Dispenzieri A, Morice W, Aspitia AM, Ansell S, Kyle R, Mikhael J.
At the time of its publication, this was the largest series of patients with IgM myeloma (21 patients). The translocation t(11;14) was present in 38% of cases.



Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial.
J Clin Oncol. 2010 Dec 1;28(34):5101-9.
Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T, Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Falcone AP, Gottardi D, Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M.
511 patients with newly diagnosed myeloma not eligible for stem cell transplantation were randomized in two groups:
  - VMP (bortezomib-melphalan-prednisone) x 9 cycles
  - VMPT (bortezomib-melphalan-prednisone-thalidomide) x 9 cycles, followed by maintenance with VT (bortezomib-thalidomide)
  - Complete response rate: 38% with VMP-VT, and 24% with VMP (p <0.001)
  - Progression-free survival at 3 years: 56% with VMP-VT, and 41% with VMP (p= 0.008)
  - Overall survival at 3 years: 89% with VMP-VT, and 87% with VMP (p= 0.008)
  - Thromboembolic events: 5% with VMP-VT, and 2% with VMP (p= 0.08)
  - Treatment-related mortality: 4% with VMP-VT, and 3% with VMP

Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study.
Lancet. 2010 Dec 18;376(9758):2075-85.
Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network.
480 patients with newly diagnosed multiple myeloma were treated with tandem autologous stem cell transplants, randomizing between two types of pre-transplant induction and post-transplant consolidation therapies: thalidomide + dexamethasone (TD, 241 patients) vs bortezomib + thalidomide + dexamethasone (VTD, 239 patients). Patients received maintenance therapy with dexamethasone 40 mg PO qd on days 1-4 every 28 days, until disease progression. Results (after a median follow-up of 36 months):
  - Rates of CR/nCR after induction therapy: 11% with TD, and 31% with VDT
  - Progression-free survival at 3 years was improved: 68% with VTD, and 56% with TD (p= 0.0057)
  - Overall survival was similar: 86% with VTD, and 84% with TD (p= 0.30)
The lack of survival advantage was possibly due to the relatively short follow-up, or maybe because of the use of effective salvage therapies.
This trial supported the use of triple therapy in the induction phase of myeloma treatment in transplant-eligible patients.

Beyond the CRAB symptoms: a study of presenting clinical manifestations of multiple myeloma.
Clin Lymphoma Myeloma Leuk. 2010 Dec 1;10(6):464-8.
Talamo G., Farooq U., Zangari M., Liao J., Dolloff N.G., Loughran T.P. Jr., Epner E.

Efficacy and safety of once-weekly bortezomib in multiple myeloma patients.
Blood. 2010 Dec 2;116(23):4745-53.
Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A.
372 patients received bortezomib once a week and 139 twice a week. Results:
  - Outcomes at 3 years were similar, including CR rate, progression-free survival, and overall survival
  - Grade 3/4 peripheral neuropathy was seen in 8% of patients with the once a week dosing and in 28% with twice a week dosing
  - Discontinuation of treatment was necessary in 5% of patients with the once a week dosing and in 15% with twice a week dosing
  - Grade 2 peripheral neuropathy improved or resolved in two-thirds of patients, after a median of 2-3 months

Efficacy and outcome of autologous transplantation in rare myelomas.
Haematologica. 2010 Dec;95(12):2126-33.
Morris C, Drake M, Apperley J, Iacobelli S, van Biezen A, Bjorkstrand B, Goldschmidt H, Harousseau JL, Morgan G, de Witte T, Niederwieser D, Gahrton G; Myeloma Subcommittee of Chronic Leukaemia Working Party of EBMT.
This is a retrospective analysis from the European Group for Blood and Marrow Transplantation Myeloma Database. The outcome of 976 patients with non-secretory myeloma was similar to that of patients with IgG, IgA, and light chain myeloma. Of note, the outcome of patients with other rare forms of myeloma was poor (the study included 379 patients with IgD, 13 patients with IgE, and 72 patients with IgM).

First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial.
Lancet. 2010 Dec 11;376(9757):1989-99.
Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group.
1970 patients with myeloma were randomized to zoledronic acid 4 mg IV every 3-4 weeks (981 patients) or clodronic acid 1600 mg PO qd (979 patients), continued at least until disease progression. After a median of 3.7 years of follow-up, skeletal-related events were lower in the group treated with zoledronic acid (27% vs 35%). ONJ was observed in 4% of patients treated with zoledronic acid, and <1% of patients treated with clodronic acid. Response rates were equivalent in the two groups, but median overall survival was longer in the group treated with zoledronic acid (50 vs 44.5 months, p= 0.04), regardless of the type of chemotherapy given. Improvement of overall survival with zoledronic acid was independent of its prevention of skeletal-related events. The median duration of zoledronic acid therapy in this study was only 1 year.

Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232).
Blood. 2010 Dec 23;116(26):5838-41.
Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore DF Sr, Whittenberger BF, Abidi MH, Durie BG, Barlogie B.
In this randomized trial, 97 patients received lenalidomide + dexamethasone, and 95 patients placebo + dexamethasone. Results:
  - Overall response rate: 78% with lenalidomide + dexamethasone, and 48% with dexamethasone
  - Progression-free survival at 1 year: 78% with lenalidomide + dexamethasone, and 52% with dexamethasone
  - Overall survival at 1 year: similar (94% with lenalidomide + dexamethasone, and 88% with dexamethasone, p= 0.25)
  - Thromboembolic events (despite aspirin prophylaxis): 23.5% with lenalidomide + dexamethasone, and 5% with dexamethasone



Giampaolo Talamo, MD