APRIL 2007

Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma.
Blood. 2007 Apr 1;109(7):2708-17.
Alsayed Y, Ngo H, Runnels J, Leleu X, Singha UK, Pitsillides CM, Spencer JA, Kimlinger T, Ghobrial JM, Jia X, Lu G, Timm M, Kumar A, Côté D, Veilleux I, Hedin KE, Roodman GD, Witzig TE, Kung AL, Hideshima T, Anderson KC, Lin CP, Ghobrial IM.
This study found that CXCR4 is expressed at high levels in the peripheral blood and is down-regulated in the bone marrow in response to high levels of SDF-1. The CXCR4 inhibitor AMD3100 and the anti-CXCR4 antibody MAB171 inhibited the migration of MM cells in vitro. AMD3100 inhibited the homing of MM cells to the bone marrow niches. Authors  demonstrates that SDF-1/CXCR4 is a critical regulator of MM homing.

The 15-Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry: estimates of radiation-related cancer risks.
Radiat Res. 2007 Apr;167(4):396-416.
Cardis E, Vrijheid M, Blettner M, Gilbert E, Hakama M, Hill C, Howe G, Kaldor J, Muirhead CR, Schubauer-Berigan M, Yoshimura T, Bermann F, Cowper G, Fix J, Hacker C, Heinmiller B, Marshall M, Thierry-Chef I, Utterback D, Ahn YO, Amoros E, Ashmore P, Auvinen A, Bae JM, Bernar J, Biau A, Combalot E, Deboodt P, Diez Sacristan A, Eklöf M, Engels H, Engholm G, Gulis G, Habib RR, Holan K, Hyvonen H, Kerekes A, Kurtinaitis J, Malker H, Martuzzi M, Mastauskas A, Monnet A, Moser M, Pearce MS, Richardson DB, Rodriguez-Artalejo F, Rogel A, Tardy H, Telle-Lamberton M, Turai I, Usel M, Veress K.
This 15-Country collaborative study analysed outcomes in 407,391 nuclear industry workers to estimate cancer risk following protracted low doses of ionizing radiation. A significant association was seen between radiation dose and increase in cancer mortality (5233 deaths). Among 31 specific types of cancer studied, they found a significant association for lung cancer and a borderline significant association for multiple myeloma (83 deaths, p=0.06).

The benefit of using whole-body, low-dose, nonenhanced, multidetector computed tomography for follow-up and therapy response monitoring in patients with multiple myeloma.
Cancer. 2007 Apr 15;109(8):1617-26.
Horger M, Kanz L, Denecke B, Vonthein R, Pereira P, Claussen CD, Driessen C.
This study evaluates the use of whole-body, low-dose, multidetector computed tomography (WBLD-MDCT) in 131 consecutive multiple myeloma patients. The authors found that WBLD-MDCT is a reliable imaging method for monitoring the course of MM.

Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma.
Blood. 2007 Apr 1;109(7):2767-72.
Palumbo A, Ambrosini MT, Benevolo G, Pregno P, Pescosta N, Callea V, Cangialosi C, Caravita T, Morabito F, Musto P, Bringhen S, Falco P, Avonto I, Cavallo F, Boccadoro M; Italian Multiple Myeloma Network; Gruppo Italiano Malattie Ematologiche dell'Adulto.
This is a multicenter phase I/II trial of 30 patients with relapsed/refractory myeloma treated with VMPT:
  - Velcade 1.0-1.6 mg/m2 IV on days 1, 4, 15, 22
  - Melphalan 6 mg/m2 PO on days 1-5
  - Prednisone 60 mg PO on days 1-5
  - Thalidomide 50 mg PO qhs on days 1-35
Cycles were repeated every 35 days.
  - Response rate: 67% (79% when used as second line therapy)
  - Progression-free survival at 1 year: 61%
  - Overall survival at 1 year: 84%
  - No grade 4 toxicities were observed, and grade 3 peripheral neuropathy was seen in only 2 patients

Thalidomide-dexamethasone plus pegylated liposomal doxorubicin vs. thalidomide-dexamethasone: a case-matched study in advanced multiple myeloma.
Eur J Haematol. 2007 Apr;78(4):297-302.
Offidani M, Bringhen S, Corvatta L, Falco P, Marconi M, Avonto I, Piersantelli MN, Polloni C, Boccadoro M, Leoni P, Palumbo A.
In this study, 47 patients with MM received ThaDD therapy: thalidomide 100 mg/d, dexamethasone 40 mg PO on days 1-4 and 9-12, and pegylated liposomal doxorubicin 40 mg/m2 on day 1 every 28 days. Their clinical outcome was compared with that of 47 matched patients treated at relapse with Thal-Dex (thalidomide (100 mg/d and dexamethasone 40 mg PO on days 1-4). Response rates were significantly higher in ThaDD group, including overall response rate (92% vs. 63.5%), partial response rate (75.5% vs. 59.5%), very good partial response (VGPR) rate (36% vs. 15%), and near complete remission (nCR) rate (30% vs. 10.5%). Patients in the ThaDD group had a longer median progression-free survival, event-free survival, and overall survival, than the group treated with Thal-Dex. Non-hematologic toxicity was similar in the 2 groups of patients, but hematologic toxicity and infections were significantly higher in the group of patieents treated with ThaDD.

Rituximab in CD20 positive multiple myeloma.
Leukemia. 2007 Apr;21(4):835-6.
Moreau P, Voillat L, Benboukher L, Mathiot C, Dumontet C, Robillard N, Hérault O, Garnache F, Garand R, Varoqueaux N, Avet-Loiseau H, Harousseau JL, Bataille R; IFM group.
This phase II study evaluated the efficacy of a single course of rituximab (375 mg/m2 IV for 4 weeks) in 14 MM patients expressing CD20 on at least 33% of tumor cells. 1 patient had minor response, 5 patients stable disease. Therefore, rituximab did not show a significant clinical activity even in a cohort of CD20+ MM.

Reduced intensity conditioning with thiotepa, fludarabine, and melphalan is effective in advanced multiple myeloma.
Leuk Lymphoma. 2007 Apr;48(4):759-66.
Majolino I, Davoli M, Carnevalli E, Locasciulli A, Di Bartolomeo P, Scimè R, Corradini P, Selleri C, Narni F, Musso M, Bregni M, Olivieri A, De Fabritiis P, Pogliani L, Arbelaez JE, Ruscio C, Bacigalupo A; Gitmo Institutions.
In this study, 53 patients with multiple myeloma underwent a RIC allogeneic stem cell transplant from HLA identical siblings using thiotepa 5 mg/kg + fludarabine 90 mg/m2 + melphalan 80 mg/m2. Results:
  - Transplant-related mortality: 13%
  - Acute GVHD of grade II-IV 45%, chronic GVHD 64%
  - Disease relapse: 32%
  - 3-year overall survival: 45%
  - 3-year progression free survival: 37%

Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning.
Blood. 2007 Apr 15;109(8):3588-94.
Crawley C, Iacobelli S, Björkstrand B, Apperley JF, Niederwieser D, Gahrton G.
This study compares outcomes of 196 patients treated with myeloablative allogeneic SCT vs 320 patients treated with RIC allogeneic SCT. The 2 groups had some imbalance: median age was 45 years in the myeloablative group and 51 in the RIC group, and patients who received a prior transplant were 11% in the myeloablative group and 76% in the RIC group. Results:
  - Nonrelapse mortality at 2 years: 37% in the myeloablative group and 24% in the RIC group (p= 0.002)
  - CR: 53% in the myeloablative group and 34% in the RIC group
  - Relapse at 3 years: 27% in the myeloablative group and 54% in the RIC group
  - Median PFS: 34.5% in the myeloablative group and 19% in the RIC group (p= 0.001)
  - Median OS: 51% in the myeloablative group and 38% in the RIC group (NS)

Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome.
Blood. 2007 Apr 15;109(8):3489-95.
Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, Leyvraz S, Michallet M, Yakoub-Agha I, Garderet L, Marit G, Michaux L, Voillat L, Renaud M, Grosbois B, Guillerm G, Benboubker L, Monconduit M, Thieblemont C, Casassus P, Caillot D, Stoppa AM, Sotto JJ, Wetterwald M, Dumontet C, Fuzibet JG, Azais I, Dorvaux V, Zandecki M, Bataille R, Minvielle S, Harousseau JL, Facon T, Mathiot C.
FISH was obtained in 1064 patients with newly diagnosed myeloma, screening for -13, -17p, t(11;14), t(4;14), hyperdiploidy, and MYC translocations. After multivariate analysis, only t(4;14) (14% of patients) and -17p (11% of patients) retained a negative prognostic value for both event-free survival and overall survival.


MAY 2007

Prognostic value of serum free light chain ratio at diagnosis in multiple myeloma.
Br J Haematol. 2007 May;137(3):240-3.
Kyrtsonis MC, Vassilakopoulos TP, Kafasi N, Sachanas S, Tzenou T, Papadogiannis A, Galanis Z, Kalpadakis C, Dimou M, Kyriakou E, Angelopoulou MK, Dimopoulou MN, Siakantaris MP, Dimitriadou EM, Kokoris SI, Panayiotidis P, Pangalis GA.
The serum free light chain ratio was obtained at baseline in 94 myeloma patients, and it was found to have prognostic value. Median FLC ratio at baseline was 3.6 in kappa-myeloma, and 45.1 in lambda-myeloma. A high level of FLC ratio, defined as a level higher than the median value for kappa-myeloma and lambda-myeloma, was associated with a worse outcome and it was an independent prognostic factor. The 5-year survival was 82% in patients with higher levels, and 30% in patients with lower levels.

Hyperammonemia and encephalopathy in patients with multiple myeloma.
Am J Hematol. 2007 May;82(5):414-5.
Talamo G, Cavallo F, Zangari M, Barlogie B, Lee CK, Pineda-Roman M, Kiwan E, Krishna S, Tricot G.

Critical review: updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients - May 2006.
Crit Rev Oncol Hematol. 2007 May;62(2):148-52.
Weitzman R, Sauter N, Eriksen EF, Tarassoff PG, Lacerna LV, Dias R, Altmeyer A, Csermak-Renner K, McGrath L, Lantwicki L, Hohneker JA.
An international advisory board of experts provided the following recommendations:
  - Encourage patients to practice good oral hygiene and minimize possible jaw trauma
  - Encourage patients to receive a dental examination prior to initiating bisphosphonate therapy
  - Complete any necessary dental procedures, such as tooth extractions, prior to initiating bisphosphonate therapy
  - Patients should avoid dental surgery during treatment with bisphosphonates
  - Patients should receive regular dental visits during bisphosphonate therapy
  - Refer patients to a dental professional immediately if ONJ is suspected (exposed bone in the oral cavity)

Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma.
Proc Natl Acad Sci U S A. 2007 May 1;104(18):7516-21.
Sukhdeo K, Mani M, Zhang Y, Dutta J, Yasui H, Rooney MD, Carrasco DE, Zheng M, He H, Tai YT, Mitsiades C, Anderson KC, Carrasco DR.
In this study, the use of PKF115-584, a small molecular compound that disrupt the interaction of the beta-catenin/TCF complex, resulted in inhibition of tumor growth and prolonged survival in xenograft models of human MM.


JUNE 2007

Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study.
J Clin Oncol. 2007 Jun 10;25(17):2434-41.
Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, Di Raimondo F, Volpe E, Ronconi S, Cangini D, Narni F, Carubelli A, Masini L, Catalano L, Fiacchini M, de Vivo A, Gozzetti A, Lazzaro A, Tura S, Baccarani M.
This is a prospective, randomized study of single vs double autologous stem-cell transplantation.
321 patients with newly diagnosed myeloma were treated with VAD x4, mobilization chemotherapy with high-dose cyclophosphamide 7 grams/m2, and randomized to receive:
  - 1 transplant: melphalan 200 mg/m2 (arm A, 163 patients)
  - 2 transplants: melphalan 200 mg/m2 followed, after 3-6 months, by melphalan 120 mg/m2 + busulfan 12 mg/Kg (arm B, 158 patients)
In comparison with a single autologous transplant, double autologous transplants showed:
  - Superior CR or nCR rate (47% vs 33%, p=0.008)
  - Similar transplant-related mortality (4% vs 3%, p=0.70)
  - Superior median event-free survival (35 vs 23 months, p=0.001)
  - Median OS was 71 months in arm A and 65 months in arm B
  - Similar 7-year survival (43% vs 46%, p=0.90)
Of note, the administration of a second transplant at relapse in patients assigned to receive a single transplant probably contributed to prolong the survival. Benefits offered by double transplantation were more evident among patients who failed to reach at least nCR after the first transplant.

Hypoglycemia due to an insulin binding antibody in a patient with an IgA-kappa myeloma.
J Clin Endocrinol Metab. 2007 Jun;92(6):2013-6.
Halsall DJ, Mangi M, Soos M, Fahie-Wilson MN, Wark G, Mainwaring-Burton R, O'Rahilly S.
This is the first report of a patient with an IgA-kappa myeloma with spontaneous hypoglycemia due to monoclonal anti-insulin antibodies. The authors used polyethylene glycol precipitation and gel filtration chromatography to demonstrate high-molecular weight insulin immunoreactivity in the patient's plasma. This was characterized as an insulin binding IgA-kappa paraprotein. The hypoglycemia was associated with high-plasma insulin levels, and it was probably due to delayed clearance of insulin.

American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma.
J Clin Oncol. 2007 Jun 10;25(17):2464-72.
Kyle RA, Yee GC, Somerfield MR, Flynn PJ, Halabi S, Jagannath S, Orlowski RZ, Roodman DG, Twilde P, Anderson K; American Society of Clinical Oncology.
These 2007 ASCO guidelines recommend the use of either zoledronic acid 4 mg IV over at least 15 minutes or pamidronate 90 mg IV over at least 2 hours every 3-4 weeks for patients with multiple myeloma who have lytic bone lesions or spine compression fractures from osteopenia. The guidelines indicate dose modifications for those patients with renal insufficiency. Bisphosphonate treatment should be continued for a period of 2 years. After 2 years, physicians should consider to discontinue the use of bisphosphonates, particularly in patients with responsive or stable disease.

Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma.
N Engl J Med. 2007 Jun 21;356(25):2582-90.
Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM, Larson DR, Plevak MF, Jelinek DF, Fonseca R, Melton LJ 3rd, Rajkumar SV.
This is a study of 276 patients with smoldering myeloma. The risk of progression to symptomatic myeloma was:
  - 10% per year for the first 5 years
  - 3% per year for the following 5 years
  - 1% per year for the following 10 years
The cumulative probability of progression to symptomatic myeloma was 73% at 15 years.

Testing standard and genetic parameters in 220 patients with multiple myeloma with complete data sets: superiority of molecular genetics.
Br J Haematol. 2007 Jun;137(6):530-6.
Shaughnessy JD Jr, Haessler J, van Rhee F, Anaissie E, Pineda-Roman M, Cottler-Fox M, Hollmig K, Zangari M, Mohiuddin A, Alsayed Y, Grazziutti M, Epstein J, Crowley J, Barlogie B



Giampaolo Talamo, MD