Survival effect of venous thromboembolism in patients with multiple myeloma treated with lenalidomide and high-dose dexamethasone.
J Clin Oncol. 2010 Jan 1;28(1):132-5.
Zangari M, Tricot G, Polavaram L, Zhan F, Finlayson A, Knight R, Fu T, Weber D, Dimopoulos MA, Niesvizky R, Fink L.
In this retrospective analysis of 353 patients treated with lenalidomide and high-dose dexamethasone, VTE occurred in 17% of patients.

Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase 2 study of the Intergroupe Francophone du Myelome (IFM).
Blood. 2010 Jan 7;115(1):32-7.
Roussel M, Moreau P, Huynh A, Mary JY, Danho C, Caillot D, Hulin C, Fruchart C, Marit G, Pégourié B, Lenain P, Araujo C, Kolb B, Randriamalala E, Royer B, Stoppa AM, Dib M, Dorvaux V, Garderet L, Mathiot C, Avet-Loiseau H, Harousseau JL, Attal M; Intergroupe Francophone du Myélome (IFM).
In this study, 54 patients with newly diagnosed MM underwent autologous stem cell transplantation with melphalan 200 mg/m2 (standard regimen) + bortezomib 1 mg/m2 x 4, on days -6, -3, +1, +4. Bortezomib did not delay hematologic recovery. At least VGPR was observed in 70% of patients, and CR rate was 32%. When comparing results with a matched group treated with only melphalan, CR was higher (35% vs 11%; p= 0.001).

Safety and preliminary efficacy of plerixafor (Mozobil) in combination with chemotherapy and G-CSF: an open-label, multicenter, exploratory trial in patients with multiple myeloma and non-Hodgkin's lymphoma undergoing stem cell mobilization.
Bone Marrow Transplant. 2010 Jan;45(1):39-47.
Dugan MJ, Maziarz RT, Bensinger WI, Nademanee A, Liesveld J, Badel K, Dehner C, Gibney C, Bridger G, Calandra G.

Safety and efficacy assessment of plerixafor in patients with multiple myeloma proven or predicted to be poor mobilizers, including assessment of tumor cell mobilization.
Bone Marrow Transplant. 2010 Jan;45(1):63-8.
Tricot G, Cottler-Fox MH, Calandra G.
20 patients with myeloma who were poor mobilizers received plerixafor for stem cell collection. Apheresis was successful (at least 2 million CD34+ cells/Kg) in 15 patients. Plerixafor did not mobilize myeloma cells.

The bisphosphonate zoledronic acid has antimyeloma activity in vivo by inhibition of protein prenylation.
Int J Cancer. 2010 Jan 1;126(1):239-46.
Guenther A, Gordon S, Tiemann M, Burger R, Bakker F, Green JR, Baum W, Roelofs AJ, Rogers MJ, Gramatzki M.

This study demonstrated that zoledronic acid has a direct antitumor effect, because its administration in a plasmacytoma xenograft model without skeletal lesions resulted in prolongation of survival in SCID mice.

Unrelated stem cell transplantation after reduced intensity conditioning for patients with multiple myeloma relapsing after autologous transplantation.
Br J Haematol. 2010 Jan;148(2):323-31.
Kröger N, Shimoni A, Schilling G, Schwerdtfeger R, Bornhäuser M, Nagler A, Zander AR, Heinzelmann M, Brand R, Gahrton G, Morris C, Niederwieser D, de Witte T.
49 patients with myeloma in relapse after autologous SCT were treated with:
  - Fludarabine 30 mg/m2 IV day -6, -5, -4
  - Melphalan 140 mg/m2 IV day -3
  - Acute GVHD, grade II-IV: 25%
  - Chronic GVHD: 35%
  - RR at day 100: 95%, including 46% CR
  - Non-relapse mortality at 1 year: 25%
  - 5-year progression-free survival: 20%
  - 5-year overall survival: 26%

Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial.
Lancet Oncol. 2010 Jan;11(1):29-37. Epub 2009 Oct 21.
Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR; Eastern Cooperative Oncology Group.
445 patients with newly diagnosed multiple myeloma were randomized to two groups:
  - Lenalidomide + high-dose dexamethasone: 40 mg on days 1-4, 9-12, and 17-20, every 28 days (223 patients)
  - Lenalidomide + low-dose dexamethasone: 40 mg on days 1, 8, 15, and 22, every 28 days (222 patients)
After 4 cycles, patients could continue with the same therapy or proceed with stem cell transplantation. After 4 cycles:
  - RR: 79% with high-dose dexamethasone and 68% with low-dose dexamethasone
  - Overall survival at 1 year: 87% with high-dose dexamethasone and 96% with low-dose dexamethasone (p= 0.0002)
  - Grade III-IV toxicity: 52% with high-dose dexamethasone and 35%with low-dose dexamethasone
  - Mortality in the first 4 months: 12 of 222 patients with high-dose dexamethasone and 1 of 220 with low-dose dexamethasone (p= 0.003)
The most common grade III-IV toxicities were DVT (26% vs 12%), infections (16% vs 9%), and fatigue (15% vs 9%).
In conclusion, lenalidomide + low-dose dexamethasone provides better survival and less toxicity than lenalidomide + high-dose dexamethasone.



Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients.
J Clin Oncol. 2010 Feb 10;28(5):800-7.
Palumbo A, Gay F, Falco P, Crippa C, Montefusco V, Patriarca F, Rossini F, Caltagirone S, Benevolo G, Pescosta N, Guglielmelli T, Bringhen S, Offidani M, Giuliani N, Petrucci MT, Musto P, Liberati AM, Rossi G, Corradini P, Boccadoro M.
In this study, 102 patients age 65-75 underwent the following treatment:
 1- Induction therapy with PAD (bortezomib, liposomal doxorubicin, dexamethasone) x 4 cycles
 2- Stem cell collection with cyclophosphamide 3 g/m2
 3- Tandem autologous stem cell transplantations with melphalan 100 mg/m2
 4- Consolidation therapy with Revlimid + Prednisone x 4 cycles
 5- Maintenance therapy with Revlimid until relapse
Results: the 2 year progression-free survival was 69%, and the 2-year overall survival was 86%.

Continuous administration of low-dose cyclophosphamide and prednisone as a salvage treatment for multiple myeloma.
Clin Lymphoma Myeloma Leuk. 2010 Feb;10(1):51-5.
Zhou F, Guo L, Shi H, Lin C, Hou J.
27 myeloma patients with severe comorbidities or history of recurrent infections wit conventional chemotherapy received salvage chemotherapy with prednisone 15 mg PO qd + cyclophosphamide 50 mg PO qd. The use of continuous low dose chemotherapy is called metronomic chemotherapy. Response rate was 67%. Median time to response was 2 months. Median OS was 22 months in the 18 responding patients, and 7 months in the 9 non-responding patients. The most common adverse events were infection and Cushing syndrome.

Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients.
Ann Oncol. 2010 Feb;21(2):325-30.
Varettoni M, Corso A, Pica G, Mangiacavalli S, Pascutto C, Lazzarino M.
In this study of 1003 consecutive myeloma patients, EMD was present in 13% of cases, 7% at the time of diagnosis, and 6% during the course of the disease. EMD was associated with worse prognosis (shorter OS and EFS). The use of stem cell transplant and novel agents did not seem to increase the risk of EMD.

A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myeloma.
Ann Hematol. 2010 Feb;89(2):185-90.
Galli M, Salmoiraghi S, Golay J, Gozzini A, Crippa C, Pescosta N, Rambaldi A.
ITF2357, an oral histone deacetylase inhibitor, was administered to 19 patients with advanced multiple myeloma in relapse or progression. 5 patients had stable disease, and 14 had disease progression.

Lenalidomide plus dexamethasone versus thalidomide plus dexamethasone in newly diagnosed multiple myeloma: a comparative analysis of 411 patients.
Blood. 2010 Feb 18;115(7):1343-50.
Gay F, Hayman SR, Lacy MQ, Buadi F, Gertz MA, Kumar S, Dispenzieri A, Mikhael JR, Bergsagel PL, Dingli D, Reeder CB, Lust JA, Russell SJ, Roy V, Zeldenrust SR, Witzig TE, Fonseca R, Kyle RA, Greipp PR, Stewart AK, Rajkumar SV.
This study compared efficacy and toxicity of RD (lenalidomide + dexamethasone) vs TD (thalidomide + dexamethasone) in 411 patients with newly diagnosed myeloma. 228 patients received RD and 183 TD. Results:
  - RR: 80% with RD and 61% with TD
  - VGPR: 34% with RD and 12% with TD
  - Median progression-free survival: 26.7 months with RD and 17.1 months with TD (p= 0.036)
  - Median overall survival: not reached with RD and 57.2 months with TD (p= 0.018)
  - At least 1 grade 3 or 4 adverse event: similar (57.5% vs 54.6%, p= 0.57)
  - Peripheral neuropathy: 0.9% with RD and 10.4% with TD
  - Venous thromboembolism: 9.2% with RD and 15.3% with TD (p= 0.058)
  - Main toxicity of RD was neutropenia (grade 3 or 4: 14.6% vs 0.6%)
The conclusion of this case-control study is that lenalidomide is more effective than thalidomide.


MARCH 2010

Melphalan 200 mg/m(2) versus melphalan 100 mg/m(2) in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study.
Blood. 2010 Mar 11;115(10):1873-9.
Palumbo A, Bringhen S, Bruno B, Falcone AP, Liberati AM, Grasso M, Ria R, Pisani F, Cangialosi C, Caravita T, Levi A, Meloni G, Nozza A, Pregno P, Gabbas A, Callea V, Rizzo M, Annino L, De Stefano V, Musto P, Baldi I, Cavallo F, Petrucci MT, Massaia M, Boccadoro M.
This is a randomized study of 298 myeloma patients treated with tandem autologous SCT and assigned to either melphalan 200 mg/m2 or melphalan 100 mg/m2. Results:
 - Treatment-related mortality: about 3% in both groups
  - RR was 79% with MEL200 and 72% with MEL100
  - CR was 15% with MEL200 and   8% with MEL100
  - Median PFS: 31 months with MEL200 and 26 months with MEL100
  - Median OS: not significantly different
The authors conclude that MEL200 should be considered the standard conditioning regimen, because it leads to longer remission duration.

Recurrent capillary leak syndrome following bortezomib therapy in a patient with relapsed myeloma.
Ann Pharmacother. 2010 Mar;44(3):587-9.
Hsiao SC, Wang MC, Chang H, Pei SN.

Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma.
J Clin Oncol. 2010 Mar 20;28(9):1606-10.
Hillengass J, Fechtner K, Weber MA, Bäuerle T, Ayyaz S, Heiss C, Hielscher T, Moehler TM, Egerer G, Neben K, Ho AD, Kauczor HU, Delorme S, Goldschmidt H.
149 patients with asymptomatic multiple myeloma underwent whole-body skeletal MRI. Focal lesions were detected in 28% of cases. The presence of focal lesions and a number >1 of focal lesions were strong prognostic factors for progression into symptomatic myeloma.

CR represents an early index of potential long survival in multiple myeloma.
Bone Marrow Transplant. 2010 Mar;45(3):498-504.
Wang M, Delasalle K, Feng L, Thomas S, Giralt S, Qazilbash M, Handy B, Lee JJ, Alexanian R.
A retrospective review of 758 myeloma patients showed that achievement of CR status was associated with long-term survival. Based on the disease status at 2 years from the beginning of the treatment, median survival was:
  - 2.7 years for patients with no response
  - 4.4 years for patients with partial response
  - 9.7 years for patients with complete response
Stem cell transplantation seemed more beneficial when done within 12 months from the diagnosis (395 patients), with a treatment-related mortality of 3%. Interestingly, no additional benefit was observed from stem cell transplantation if patients were already in CR after induction therapy. Median survival was:
  - 14.6 years in 29 patients in CR after induction therapy who received stem cell transplantation
  - 12.4 years in 23 patients in CR after induction therapy who did not receive stem cell transplantation
It seemed that the benefit of high-dose chemotherapy was due to its ability to convert patients in PR to CR. Achievement of CR was the most important prognostic factor for long-term survival, more relevant than stage and treatment modality. Only 9 patients remained in CR for >10 years, consistent with a very low cure fraction, estimated at 2%.

IL-6 and MYC collaborate in plasma cell tumor formation in mice.
Blood. 2010 Mar 4;115(9):1746-54.
Rutsch S, Neppalli VT, Shin DM, DuBois W, Morse HC 3rd, Goldschmidt H, Janz S.

Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease.
Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5124-9.
Vallet S, Mukherjee S, Vaghela N, Hideshima T, Fulciniti M, Pozzi S, Santo L, Cirstea D, Patel K, Sohani AR, Guimaraes A, Xie W, Chauhan D, Schoonmaker JA, Attar E, Churchill M, Weller E, Munshi N, Seehra JS, Weissleder R, Anderson KC, Scadden DT, Raje N.

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.



Giampaolo Talamo, MD