t(11;14) and t(4;14) translocations correlated with mature lymphoplasmacytoid and immature morphology, respectively, in multiple myeloma.
Leukemia. 2003 Oct;17(10):2032-5.
Garand R, Avet-Loiseau H, Accard F, Moreau P, Harousseau JL, Bataille R.
This study evaluates the bone marrow aspirates and FISH of 178 patients with newly diagnosed myeloma.
  - The plasma cells of patients with t(11;14) exhibited a lymphoplasmacytoid morphology in 25 of 48 cases (52%)
  - The plasma cells of patients with t(4;14) exhibited an immature morphology with diffuse chromatin pattern in 17 of 28 cases (61%)
t(4;14) translocation and immature morphology correlated with higher incidence of high tumor mass and chromosome 13 abnormality.

Vascular endothelial growth factor and its receptors in multiple myeloma.
Leukemia. 2003 Oct;17(10):1961-6.
Ria R, Roccaro AM, Merchionne F, Vacca A, Dammacco F, Ribatti D.

Expression of VEGF and its receptors by myeloma cells.
Leukemia. 2003 Oct;17(10):2025-31.
Kumar S, Witzig TE, Timm M, Haug J, Wellik L, Fonseca R, Greipp PR, Rajkumar SV.
These authors studied the expression of VEGF and its receptors (VEGFR1 or Flt-1 and VEGFR2 or Flk-1/KDR) in MM cell lines and plasma cells isolated from patients. By IHC, VEGF expression by plasma cells was found in 18 of 20 MM patients. ELISA found VEGF secretion in all 6 different MM cell lines tested. RT-PCR for VEGF mRNA was positive in all 5 patient marrow samples and all 7 MM cell lines tested. All MM cell lines expressed VEGFR1 and 3 cell lines expressed VEGFR2. VEGFR1 expression was detected in all and VEGFR2 in all but one of marrow samples.

Occurrence of dysregulated oncogenes in primary plasma cells representing consecutive stages of myeloma pathogenesis: indications for different disease entities.
Br J Haematol. 2003 Oct;123(2):253-62.
Rasmussen T, Theilgaard-Mönch K, Hudlebusch HR, Lodahl M, Johnsen HE, Dahl IM.
These authors studied the expression pattern in plasma cells of putative oncogenes in cDNA archives from 96 subjects, including healthy individuals, patients with MGUS, MM, and MM with extramedullary disease. Their data support a stepwise transformation model with the progressive accumulation of genetic alterations and proliferative capacity during the tumor progression of plasma cell dyscrasias.

Enhanced production of osteopontin in multiple myeloma: clinical and pathogenic implications.
Br J Haematol. 2003 Oct;123(2):263-70.
Saeki Y, Mima T, Ishii T, Ogata A, Kobayashi H, Ohshima S, Ishida T, Tabunoki Y, Kitayama H, Mizuki M, Katada Y, Asaoku H, Kitano M, Nishimoto N, Yoshizaki K, Maeda M, Kon S, Kinoshita N, Uede T, Kawase I.
This study examined the production of osteopontin (OPN) in MM cells and plasma OPN levels in 30 MM patients, 21 MGUS patients, and 30 healthy volunteers. OPN was produced in large amounts in MM cell lines and BM cells from MM patients, whereas no OPN was produced by BM cells from patients with MGUS. Plasma OPN levels of MM patients were significantly higher than those of MGUS patients and healthy volunteers. OPN levels correlated with progression and osteolysis of MM. Therefore, MM cells produce OPN, which may contribute to osteoclastic bone resorption.

Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial.
Cancer. 2003 Oct 15;98(8):1735-44.
Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, Apffelstaedt J, Hussein MA, Coleman RE, Reitsma DJ, Chen BL, Seaman JJ.
This study compared the safety and efficacy of long-term treatment (25 months) with zoledronic acid or pamidronate in 1648 patients with bone lesions secondary to multiple myeloma orr advanced breast cancer. Patients were randomized to receive zoledronic acid 4-8 mg IV over 15 minutes or pamidronate 90 mg IV over 2 hours every 3-4 weeks for 24 months. Endpoints were the proportion of patients with skeletal-related events and hypercalcemia of malignancy.
Skeletal related events (SREs) were defined as:
   - pathologic fracture
   - spinal cord compression
   - bone surgery
   - radiation therapy
After 25 months of follow-up, zoledronic acid reduced the proportion of patients with an SRE and skeletal morbidity similar to pamidronate. Compared with pamidronate, zoledronic acid reduced the risk of developing skeletal complications by an additional 16%. In patients with breast carcinoma, zoledronic acid appeared to be more effective than pamidronate, and it reduced the risk of SREs by an additional 20% compared with pamidronate. Zoledronic acid and pamidronate were tolerated equally well, and the most common toxicities were nausea, fatigue, and bone pain. The authors conclude that zoledronic acid and pamidronate have a similar efficacy in patients with multiple myeloma, and that zoledronic acid is more effective than pamidronate in reducing the risk of skeletal complications in patients with bone metastases from breast cancer.



Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation.
Hematol J. 2003;4(6):379-98.
Durie BG, Kyle RA, Belch A, Bensinger W, Blade J, Boccadoro M, Child JA, Comenzo R, Djulbegovic B, Fantl D, Gahrton G, Harousseau JL, Hungria V, Joshua D, Ludwig H, Mehta J, Morales AR, Morgan G, Nouel A, Oken M, Powles R, Roodman D, San Miguel J, Shimizu K, Singhal S, Sirohi B, Sonneveld P, Tricot G, Van Ness B; Scientific Advisors of the International Myeloma Foundation.

Long-term follow-up of IgM monoclonal gammopathy of undetermined significance.
Blood. 2003 Nov 15;102(10):3759-64.
Kyle RA, Therneau TM, Rajkumar SV, Remstein ED, Offord JR, Larson DR, Plevak MF, Melton LJ 3rd.
In this study, no cases of IgM myeloma were observed after following the evolution of IgM MGUS.
After a median follow-up of 6.3 years, 213 patients with IgM MGUS developed:
  - Lymphoma (17 patients)
  - Waldenström macroglobulinemia (6 patients)
  - Primary amyloidosis (3 patients)
  - CLL (3 patients)
Cumulative incidence of progression was:
  - 10% at 5 years
  - 18% at 10 years
  - 24% at 15 years
The average risk of progression was 1.5% per year.

Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma.
Blood. 2003 Nov 1;102(9):3447-54.
Maloney DG, Molina AJ, Sahebi F, Stockerl-Goldstein KE, Sandmaier BM, Bensinger W, Storer B, Hegenbart U, Somlo G, Chauncey T, Bruno B, Appelbaum FR, Blume KG, Forman SJ, McSweeney P, Storb R.
This is a study of 54 patients with multiple myeloma treated with an autologous stem cell transplant (using melphalan 200 mg/m2) followed by a mini-allogeneic stem cell transplant from HLA-matched siblings (using TBI). 52% of patients had refractory or relapsed disease. RR: 83% (CR 57%, PR 26%). At a median follow-up of about 1.5 years, overall survival was 78%.



Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis.
Blood. 2003 Dec 15;102(13):4504-11.
Davies FE, Dring AM, Li C, Rawstron AC, Shammas MA, O'Connor SM, Fenton JA, Hideshima T, Chauhan D, Tai IT, Robinson E, Auclair D, Rees K, Gonzalez D, Ashcroft AJ, Dasgupta R, Mitsiades C, Mitsiades N, Chen LB, Wong WH, Munshi NC, Morgan GJ, Anderson KC.
These authors used microarray analysis in PCs from 5 healthy donors, 7 patients with MGUS, and 24 patients with MM. They found 263 genes differentially expressed between normal and MGUS plasma cells, and 380 genes differentially expressed between normal and MM plasma cells, 197 of which also differentially expressed between normal and and MGUS plasma cells. Since only 74 genes were differentially expressed between MGUS and MM plasma cells, it appeared that the differences between MGUS and MM are smaller than those between normal and MGUS plasma cells. Differentially expressed genes included:
 - Oncogenes/tumor-suppressor genes (LAF4, RB1, and disabled homolog 2)
 - Cell-signaling genes (RAS family members, B-cell signaling and NF-kappaB genes)
 - DNA-binding and transcription-factor genes (XBP1, zinc finger proteins, forkhead box, and ring finger proteins)
 - Developmental genes (WNT and SHH pathways)

The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma.
N Engl J Med. 2003 Dec 25;349(26):2483-94.
Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD Jr.
In this study, purified plasma cells from the bone marrow of 36 patients with newly diagnosed MM were studied to identify molecules responsible for the osteolytic process. Dickkopf 1 (DKK1) was one of the genes differently expressed between MM patients with and those without focal bone lesions. A recombinant DKK1 protein was found to  inhibit the differentiation of osteoblast precursor cells in vitro.

Comparison of Technetium-99m-MIBI imaging with MRI for detection of spine involvement in patients with multiple myeloma.
BMC Nucl Med. 2003 Dec 11;3(1):2.
Mirzaei S, Filipits M, Keck A, Bergmayer W, Knoll P, Koehn H, Ludwig H, Pecherstorfer M.
This study compared Tc-99m-MIBI scan and MRI in the detection of myelomatous bone lesions. The authors found that the Tc-99m-MIBI scan underestimates the extent of myelomatous bone marrow infiltration in the spine, especially in patients with low disease stage. Among 21 patients with MM, the Tc-99m-MIBI scan missed bone marrow involvement in 43 of 87 vertebrae (50.5%) in which the MRI showed bone marrow infiltration. In patients with low disease stage (stage I and II), the Tc-99m-MIBI scan was negative in all of 24 vertebrae infiltrated according to the MRI findings.

A simplified approach to stem cell mobilization in multiple myeloma patients not previously treated with alkylating agents.
Bone Marrow Transplant. 2003 Dec;32(12):1113-7.
Lerro KA, Medoff E, Wu Y, Seropian SE, Snyder E, Krause D, Cooper DL.
This is a retrospective study of 50 consecutive myeloma patients who underwent the following mobilization regimen:
  - Cyclophosphamide 1.5 g/m2 IV in 500 mL NS, given as outpatient on a Friday (day -10)
  - Prehydration with 500 ml in 500 ml, posthydration with 1 L. Uroprophylaxis with MESNA was not administered
  - G-CSF 10 mcg/Kg SC qd was started on the following Monday (day -7)
  - Apheresis was scheduled to begin on Monday of the following week (day 0)
  - A peripheral blood CD34+ cell count >20/mcL was used to begin apheresis
  - Median stem cell collection was 4.88 million CD34+ cells/kg per apheresis
  - 44 patients (88%) collected >5 million CD34+ cells/kg within 2 days
  - 36 patients (72%) collected >10 million CD34+ cells/kg
  - The mobilizing program was highly predictable. 2 patients (4%) required weekend apheresis
  - This regimen was well tolerated. 1 patient required hospitalization for neutropenic fever

Single versus double autologous stem-cell transplantation for multiple myeloma.
N Engl J Med. 2003 Dec 25;349(26):2495-502.
Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, Monconduit M, Hulin C, Caillot D, Bouabdallah R, Voillat L, Sotto JJ, Grosbois B, Bataille R; InterGroupe Francophone du Myélome.
This is a randomized trial of 399 patients with newly diagnosed multiple myeloma, treated with high-dose chemotherapy followed by either 1 or 2 autologous stem-cell transplantations. Results favored the double transplant group:
  - Rate of complete or very good partial response was 42% with 1 transplant and 50% with 2 transplants
  - Event-free survival at 7 years was 10% with 1 transplant and 20% with 2 transplants
  - Overall survival at 7 years was 21% with 1 transplant and 42% with 2 transplants
The benefit of the second transplant was observed especially in those patients who did not have a very good partial response after the first transplant.

Outcome after autologous and allogeneic stem cell transplantation for patients with multiple myeloma: impact of graft-versus-myeloma effect.
Bone Marrow Transplant. 2003 Dec;32(12):1145-51.
Alyea E, Weller E, Schlossman R, Canning C, Mauch P, Ng A, Fisher D, Gribben J, Freeman A, Parikh B, Richardson P, Soiffer R, Ritz J, Anderson KC.
Among 228 myeloma patients, 166 patients received autologous transplant (124 from peripheral blood and 38 from bone marrow), and 66 patients receiving allogeneic transplant (T-cell depleted). Results at 2 years:
  - OS:   74% after autologous SCT and 51% after allogeneic SCT (p= 0.006)
  - PFS: 48% after autologous SCT and 28% after allogeneci SCT (p= 0.002)
However, 4 years after transplantation, outcome was similar:
  - OS:   41% after autologous SCT and 39% after allogeneic SCT
  - PFS: 23% after autologous SCT and 18% after allogeneic SCT
Risk of relapse at 4 years was 46% after allogeneic SCT vs 56% after autologous SCT (p= 0.02).



Giampaolo Talamo, M.D.