JULY 2011

A phase I safety study of enzastaurin plus bortezomib in the treatment of relapsed or refractory multiple myeloma.
Am J Hematol. 2011 Jul;86(7):573-8.
Ghobrial IM, Munshi NC, Harris BN, Shi P, Porter NM, Schlossman RL, Laubach JP, Anderson KC, Desaiah D, Myrand SP, Wooldridge JE, Richardson PG, Abonour R.
Enzastaurin is a serine/threonine kinase inhibitor that inhibits the protein kinase C and AKT pathways. 23 patients with relapsed/refractory myeloma were treated with enzastaurin in combination with bortezomib. In this phase I study, 4 patients showed response to therapy, and 9 additional patients had stable disease.

Guidelines for the diagnosis and management of multiple myeloma 2011.
Br J Haematol. 2011 Jul;154(1):32-75.
Bird JM, Owen RG, D'Sa S, Snowden JA, Pratt G, Ashcroft J, Yong K, Cook G, Feyler S, Davies F, Morgan G, Cavenagh J, Low E, Behrens J; Haemato-oncology Task Force of British Committee for Standards in Haematology (BCSH) and UK Myeloma Forum.

Body mass index and risk of multiple myeloma: A meta-analysis of prospective studies.
Eur J Cancer. 2011 Jul;47(11):1606-15.
Wallin A, Larsson SC.
This meta-analysis of 15 cohort studies on myeloma incidence and 5 studies on myeloma mortality concluded that excess body weight is a risk factor for multiple myeloma.

The impact of osteoporosis (as measured by lumbar spine quantitative computed tomography) on disease activity and survival in myeloma patients: A 13-year prospective study.
Am J Hematol. 2011 Jul;86(7):617-9.
Diamond T, Golombick T, Manoharan A, Kwan Y, Bryant C.
Data collected on 108 myeloma patients followed for 13 years showed that patients with severe osteoporosis (defined as a T-score > -3.5 at lumbar spine quantitative CT) had a median survival 18 months shorter than the rest of the patients. 



Effectiveness and safety of high-dose cyclophosphamide as salvage therapy for high-risk multiple myeloma and plasma cell leukemia refractory to new biological agents.
Am J Hematol. 2011 Aug;86(8):699-701.
Rivell GL, Brunson CY, Milligan L, Stuart RK, Costa LJ.
High-dose cyclophosphamide (1,500 mg/m2 IV for 2 consecutive days) is an effective salvage regimen for patients with myeloma refractory to the novel biologic agents. Among 17 patients with high-risk disease -6 with plasma cell leukemia-, response assessment at 6 weeks showed 9 pts in PR and 8 pts with stable disease. Circulating plasma cells disappeared in all 6 patients with plasma cell leukemia. Despite antibiotic prophylaxis and growth factor support with peg-filgrastim, most patients required hospitalization because of neutropenic fever, and 1 patient died from sepsis.

Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: Results from a phase 2 trial.
Am J Hematol. 2011 Aug;86(8):640-5.
Kumar SK, Lacy MQ, Hayman SR, Stewart K, Buadi FK, Allred J, Laumann K, Greipp PR, Lust JA, Gertz MA, Zeldenrust SR, Bergsagel PL, Reeder CB, Witzig TE, Fonseca R, Russell SJ, Mikhael JR, Dingli D, Rajkumar SV, Dispenzieri A.
This trial enrolled 53 patients with newly diagnosed myeloma. Treatment consisted of:
  - Cyclophosphamide 300 mg/m2 PO on days 1, 8, 15
  - Revlimid 25 mg PO on days 1-21
  - Dexamethasone 40 mg PO on days 1, 8, 15, 22 (= weekly)
Cycles were repeated every 28 days.
Response rate was 85%, and 47% of patients had VGPR or better. Median PFS was 28 months, and OS at 2 years 87%.

Diagnosis of smoldering multiple myeloma.
N Engl J Med. 2011 Aug 4;365(5):474-5.
Rajkumar SV, Larson D, Kyle RA.
After reviewing data from 655 patients with smoldering myeloma seen at the Mayo Clinic between 1996 and 2010, the authors noticed that patients with 60% of more plasma cells in the bone marrow had a very high rate of progression to symptomatic myeloma. This high percentage of plasma cells in the bone marrow was seen in 21 patients (3%), and their median progression to symptomatic myeloma was only 7 months. The authors propose immediate therapy of all myeloma patients having >60% plasma cells, regardless of the presence of symptoms.

Phase II randomized trial of bevacizumab versus bevacizumab and thalidomide for relapsed/refractory multiple myeloma: a California Cancer Consortium trial.
Br J Haematol. 2011 Aug;154(4):533-5.
Somlo G, Lashkari A, Bellamy W, Zimmerman TM, Tuscano JM, O'Donnell MR, Mohrbacher AF, Forman SJ, Frankel P, Chen HX, Doroshow JH, Gandara DR.
This is a phase II trial, which was closed prematurely due to poor accrual. Results were not encouraging, as median EFS among 12 evaluable patients was less than 2 months.

Predictive factors for successful salvage high-dose therapy in patients with multiple myeloma relapsing after autologous blood stem cell transplantation.
Leuk Lymphoma. 2011 Aug;52(8):1455-62.
Fenk R, Liese V, Neubauer F, Bruns I, Kondakci M, Balleisen S, Saure C, Schröder T, Haas R, Kobbe G.
55 patients with multiple myeloma previously treated with autologous stem cell transplantation underwent another stem cell transplant at relapse. Conditioning regimens consisted of melphalan, melphalan + busulfan, or melphalan + bortezomib. Transplant-related mortality was 5%. Median event-free survival was 14 months, and median overall survival was 52 months.

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.

Efficacy of retreatment with immunomodulatory drugs (IMiDs) in patients receiving IMiDs for initial therapy of newly diagnosed multiple myeloma.
Blood. 2011 Aug 18;118(7):1763-5.
Madan S, Lacy MQ, Dispenzieri A, Gertz MA, Buadi F, Hayman SR, Detweiler-Short K, Dingli D, Zeldenrust S, Lust J, Greipp PR, Rajkumar SV, Kumar S.
In this retrospective study, 81 patients initially treated with thalidomide and 59 patients initially treated with lenalidomide received again IMIDs as one of the salvages therapies at relapse or progression. Patients received a median of 2 lines of therapy, including stem cell transplantation in 75% of patients. Partial response was seen in 44% of patients after repeat exposure to the IMIDs, and response rate was higher with lenalidomide than thalidomide.

Surgical therapy of skeletal complications in multiple myeloma.
Int Orthop. 2011 Aug;35(8):1209-13.
Utzschneider S, Schmidt H, Weber P, Schmidt GP, Jansson V, Dürr HR.

Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up.
J Clin Oncol. 2011 Aug 1;29(22):3016-22.
Björkstrand B, Iacobelli S, Hegenbart U, Gruber A, Greinix H, Volin L, Narni F, Musto P, Beksac M, Bosi A, Milone G, Corradini P, Goldschmidt H, de Witte T, Morris C, Niederwieser D, Gahrton G.
357 patients with multiple myeloma were treated with:
  - Tandem auto-SCT and mini-allo-SCT (108 pts), if a matched sibling was available
  - Single autologous SCT (145 pts)
  - Tandem auto-STC (104 pts)
Median follow-up time was 61 months. Results:
  - Rate of complete remission was higher with auto-allo than with auto (51% vs 41%), p= 0.02
  - Progression-free survival at 5 years was better (35% vs 18%, p= 0.001)
  - Relapse incidence was lower (49% vs 78%)
  - Overall survival at 5 years was higher (65% vs 58%)
Of note, this study included only allo-SCT with HLA-matched sibling donors.

Trends in allogeneic stem cell transplantation for multiple myeloma: a CIBMTR analysis.
Blood. 2011 Aug 18;118(7):1979-88.
Kumar S, Zhang MJ, Li P, Dispenzieri A, Milone GA, Lonial S, Krishnan A, Maiolino A, Wirk B, Weiss B, Freytes CO, Vogl DT, Vesole DH, Lazarus HM, Meehan KR, Hamadani M, Lill M, Callander NS, Majhail NS, Wiernik PH, Nath R, Kamble RT, Vij R, Kyle RA, Gale RP, Hari PN.
The authors reviewed data from the Center for International Blood and Marrow Transplantation Research (CIBMTR). Outcomes of 1207 myeloma patients treated with allogeneic stem cell transplant were reviewed. Results in 488 patients transplanted in the period 2001-2005:
  - Relapse rate at 5 years: 58%
  - Progression-free survival at 5 years: 14%
  - Overall survival at 5 years: 29%
Survival was negatively affected by:
  - Older age
  - Unrelated donor
  - Longer interval between diagnosis and transplant



Lenalidomide maintenance after nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results of the HOVON 76 Trial.
Blood. 2011 Sep 1;118(9):2413-9.
Kneppers E, van der Holt B, Kersten MJ, Zweegman S, Meijer E, Huls G, Cornelissen JJ, Janssen JJ, Huisman C, Cornelisse PB, Bruijnen CP, Emmelot M, Sonneveld P, Lokhorst HM, Mutis T, Minnema MC.
30 patients treated with mini-allogeneic stem cell transplantation started post-transplant maintenance with low-dose lenalidomide (10 mg on days 1-21 every 28 days x 24 cycles). 87% of patients had to stop lenalidomide early, because of development of acute GVHD (43%), toxicities (17%), or disease progression (17%). Acute GVHD occurred at a median of 18 days after the start of lenalidomide. Lenalidomide induced acute GVHD, likely due to early activation of T cells. 1-year PFS from start of lenalidomide was 69%.

Lenalidomide is effective for extramedullary disease in relapsed or refractory multiple myeloma.
Eur J Haematol. 2011 Sep;87(3):281-4.
Calvo-Villas JM, Alegre A, Calle C, Hernández MT, García-Sánchez R, Ramírez G; GEM-PETHEMA/Spanish Myeloma Group, Spain.
18 patients with extramedullary disease in the setting of advanced myeloma were treated with lenalidomide. Results:
  - Response rate: 61%
  - Median progression-free survival: 10 months
  - Median overall survival: 15 months

Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease.
Blood. 2011 Sep 15;118(11):2970-5.
Lacy MQ, Allred JB, Gertz MA, Hayman SR, Short KD, Buadi F, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Stewart AK, Laumann K, Mandrekar SJ, Reeder C, Rajkumar SV, Mikhael JR.
Two trials of pomalidomide in 70 patients with myeloma refractory to both lenalidomide and bortezomib showed a clinical benefit of 43-49%. The most common toxicity was myelosuppression.



Giampaolo Talamo, MD