JULY 2002

Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis.
Clin Cancer Res. 2002 Jul;8(7):2210-6.
Rajkumar SV, Mesa RA, Fonseca R, Schroeder G, Plevak MF, Dispenzieri A, Lacy MQ, Lust JA, Witzig TE, Gertz MA, Kyle RA, Russell SJ, Greipp PR.

Using immunohistochemical staining for CD34 to identify microvessels, these authors analyzed BM angiogenesis in 76 patients with MGUS, 112 with smoldering myeloma, 99 newly diagnosed MM, 26 with advanced MM, 87 with primary amyloidosis, and 42 normal control BM samples. They found that BM angiogenesis was associated with disease progression, because it progressively increased along the spectrum of plasma cell dyscrasias, from MGUS to advanced myeloma. The median microvessel density (MVD) was significantly higher in MGUS, smoldering myeloma, newly diagnosed MM, and advanced MM compared with controls and amyloidosis. MVD was not significantly different between controls and AL. High-grade angiogenesis was present in 0% of controls, 0% of AL, 1% of MGUS, 3% of smoldering myeloma, 29% of newly diagnosed MM, and 42% of advanced MM. MVD correlated with the BM plasma cell labeling index and BM plasma cell percentage. Survival was shorter in MM patients with high-grade angiogenesis, compared with those with low-grade angiogenesis.

Absence of biologically important Kaposi sarcoma-associated herpesvirus gene products and virus-specific cellular immune responses in multiple myeloma.
Blood. 2002 Jul 15;100(2):698-700.
Brander C, Raje N, O'Connor PG, Davies F, Davis J, Chauhan D, Hideshima T, Martin J, Osmond D, Kedes DH, Walker BD, Scadden DT, Anderson KC.
The association between Kaposi sarcoma-associated herpesvirus (KSHV) and MM was controversial. This study assessed the presence of viral RNA transcripts as well as KSHV-specific cellular immune responses in MM patients, using highly sensitive reverse transcription-PCR for detection of viral transcripts of KSHV open reading frame (ORF) 26, ORF72, and ORF74. No viral gene transcripts in long-term cultures of bone marrow stromal cells from 23 patients with MM were detected. Assays for KSHV-specific cytotoxic T-lymphocyte (CTL) activity did not show any specific responses in 16 patients with MM. This study failed to show an important association between KSHV infection and MM.

Consolidation therapy of multiple myeloma with thalidomide-dexamethasone after intensive chemotherapy.
Ann Oncol. 2002 Jul;13(7):1116-9.
Alexanian R, Weber D, Giralt S, Delasalle K.
21 patients with myeloma in partial remission after stem cell transplantation were given consolidation therapy with thalidomide + dexamethasone, in order to achieve a higher rate of complete remission. Thalidomide was given at a dose of 100-300 mg PO qhs, and dexamethasone at 20 mg/m2 on days 1-4, 9-12, and 17-20, with cycles repeated every 35 days. The combination was started within 15 months after transplant, and continued for at least 3 months. Reduction of myeloma paraprotein by at least 90% occurred in 57% of patients, and 19% of patients converted from partial remission to complete remission. Median duration of remission was 22 months.

Pamidronate induces bone formation in patients with smouldering or indolent myeloma, with no significant anti-tumour effect.
Br J Haematol. 2002 Jul;118(1):239-42.
Martín A, García-Sanz R, Hernández J, Bladé J, Suquía B, Fernández-Calvo J, González M, Mateo G, Orfao A, San Miguel JF.
In this study, 12 patients with smoldering or indolent myeloma received 12 courses of IV pamidronate as a single agent to evaluate both the antitumour and bone metabolism effects.
Disease response among 12 patients:
 - 1 patient had minor response
 - 8 patients had stable disease
 - 3 patients had disease progression
Bone density significantly increased. The results of this study suggest that pamidronate treatment reduces bone turnover in smoldering or indolent MM, but it has no significant antitumor effect.

Repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma.
Blood. 2002 Jul 1;100(1):224-9.
Spanswick VJ, Craddock C, Sekhar M, Mahendra P, Shankaranarayana P, Hughes RG, Hochhauser D, Hartley JA.
The most important cytotoxic mechanism of melphalan is the formation of DNA adducts with the DNA interstrand crosslink. The authors utilized techniques of molecular biology to show that resistance to melphalan is associated with an impairment of DNA interstrand crosslink repair

Intermediate doses of melphalan and dexamethasone are better than vincristine, adriamycin, and dexamethasone (VAD) and polychemotherapy for the treatment of primary plasma cell leukemia.
Ann Hematol. 2002 Jul;81(7):362-7.
Vela-Ojeda J, García-Ruiz Esparza MA, Rosas-Cabral A, Padilla-González Y, García-Chávez J, Tripp-Villanueva F, Sánchez-Cortés E, Ayala-Sánchez M, García-León LD, Montiel-Cervantes L, Rubio-Borja ME.
In this study of 24 patients with primary plasma cell leukemia, 12 patients received treatment with VAD (vincristine, adriamycin, and dexamethasone), 8 with M-80 (melphalan 80 mg/m2 PO + dexamethasone), and 4 with VMCPA (vincristine, melphalan, cyclophosphamide, prednisone, and adriamycin). Median overall survival was 60 days.

Amyloid arthropathy in the course of multiple myeloma.
J Rheumatol. 2002 Jul;29(7):1473-81.
Fautrel B, Fermand JP, Sibilia J, Nochy D, Rousselin B, Ravaud P.



Interstitial deletions at the long arm of chromosome 13 may be as common as monosomies in multiple myeloma. A genotypic study.
Haematologica. 2002 Aug;87(8):828-35.
Nomdedéu JF, Lasa A, Ubeda J, Saglio G, Bellido M, Casas S, Carnicer MJ, Aventín A, Sureda A, Sierra J, Baiget M.
These authors performed a genotyping analysis on MM plasma cells was performed to identify the minimally deleted region at chromosome 13. 4 patients showed monosomy and 7 had interstitial deletions in the telomeric region. The minimal region with deletion was found at the centromeric 13q32.2 locus and at the telomeric 13q32.3 locus.

A molecular study of the t(4;14) in multiple myeloma.
Br J Haematol. 2002 Aug;118(2):514-20.
Sibley K, Fenton JA, Dring AM, Ashcroft AJ, Rawstron AC, Morgan GJ.
These authors analyzed 67 MM cases and 13 MGUS cases, using RT-PCR to detect IgH-MMSET fusions. They found the t(4;14) translocation in 7 of 67 (10%) MM cases, and all 7 expressed FGFR3, a phenomenon not seen in t(4;14)-negative MM cases. MGUS cases had a similar proportion of t(4;14) (2 of 13; 15%), but none of these expressed FGFR3. No mutations of the FGFR3 gene were found in the the MM or MGUS samples, except for a single case of relapsed MM, which was negative for mutations 13 months earlier, but it developed a K650E mutation in the kinase domain of FGFR3 at relapse.

Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications.
Oncogene. 2002 Aug 22;21(37):5673-83.
Mitsiades CS, Mitsiades N, Poulaki V, Schlossman R, Akiyama M, Chauhan D, Hideshima T, Treon SP, Munshi NC, Richardson PG, Anderson KC.
Authors demonstrate that insulin-like growth factor-1 (IGF-1) stimulates sustained activation of NF-kappaB and Akt. In contrast, IL-6 did not cause sustained NF-kappaB activation, and it induced less pronounced Akt activation.

Oral melphalan at diagnosis hampers adequate collection of peripheral blood progenitor cells in multiple myeloma.
Haematologica. 2002 Aug;87(8):846-50.
Boccadoro M, Palumbo A, Bringhen S, Merletti F, Ciccone G, Richiardi L, Rus C, Bertola A, Giaccone L, Omedè P, Musto P.
In this study, 89 patients with myeloma underwent mobilization with cyclophosphamide 3 g/m2 followed by G-CSF 10 mcg/kg from day 3 to the last day of the leukapheresis.
An adequate collection of stem cells (defined as a total of at least 2 million CD34+ cells/Kg) was obtained in 59 patients (66%):
 - 92% of patients treated with non-alkylating therapy (e.g., VAD)
 - 56% of patients treated with oral melphalan
 - 23% of patients treated with IV melphalan
Therefore, patients who are potential candidates for autologous steam cell transplant should not receive conventional alkylating therapy prior to collection of stem cells.

Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma.
Blood. 2002 Aug 1;100(3):755-60.
Kröger N, Schwerdtfeger R, Kiehl M, Sayer HG, Renges H, Zabelina T, Fehse B, Tögel F, Wittkowsky G, Kuse R, Zander AR.
In this study, 17 patients with myeloma underwent an autologous SCT with melphalan 200 mg/m2, followed by a mini-allogeneic SCT using fludarabine 180 mg/m2 + melphalan 100 mg/m2 + ATG. Transplant-related mortality at day 100 was 11%. CR increased from 18% after the autologous SCT to 73% after the mini-allogeneic SCT. After a median follow-up of 13 from the allogeneic SCT, 13 patients were alive and 12 of them were in remission.



Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy.
Blood. 2002 Sep 1;100(5):1579-83.
Moreau P, Facon T, Leleu X, Morineau N, Huyghe P, Harousseau JL, Bataille R, Avet-Loiseau H; Intergroupe Francophone du Myélome.
Analysis of chromosomal abnormalities in 168 myeloma patients at baseline showed poor outcome in patients with t(4;14), good outcome in patients with t(11;14), and intermediate outcome in patients with neither t(4;14) nor t(11;14).

Magnetic resonance imaging as a supplement for the clinical staging system of Durie and Salmon?
Cancer. 2002 Sep 15;95(6):1334-45.
Baur A, Stäbler A, Nagel D, Lamerz R, Bartl R, Hiller E, Wendtner C, Bachner F, Reiser M.
This study evaluated 77 MM patients with MRI of the thoracic and lumbar spine using a three-grade scale:
 - Stage I: no focal or diffuse infiltration
 - Stage II: 1-10 foci or mild diffuse infiltration
 - Stage III: more than 10 foci or strong diffuse infiltration
Of 77 patients, 25 would have been understaged using the Durie-Salmon staging system without the MRI findings, and 8 patients would have been understaged if the staging was based only on MRI. The authors proposed to combine the MRI findings in the Durie-Salmon staging system. The infiltration patterns had no significant effect on survival, but the combination of MRI and Durie-Salmon staging system was highly significant with respect to survival. The MRI staging I-III was independent of the staging system of Durie and Salmon.

Melphalan-prednisone versus alternating combination VAD/MP or VND/MP as primary therapy for multiple myeloma: final analysis of a randomized clinical study.
Haematologica. 2002 Sep;87(9):934-42.
Cavo M, Benni M, Ronconi S, Fiacchini M, Gozzetti A, Zamagni E, Cellini C, Tosi P, Baccarani M, Tura S; Writing Committee of the "Bologna 90" Clinical Trial.
527 patients with newly diagnosed myeloma were randomized to receive one of 3 induction regimens:
  - MP alone (Melphalan and Prednisone)
  - Alternating MP/VAD (Vincristine, Doxorubicin, Dexamethasone)
  - Alternating MP/VND (Vincristine, Mitoxantrone, Dexamethasone)
  - Response rate was 53% with MP, 47% with MP/VAD, and 49% with MP/VND
  - Median survival was 36.5 months with MP, 29 months with MP/VAD, and 32.5 months with MP/VND (difference not statistically significant)
Neuropenia and infections were more frequent with the MP/VND regimen. The conclusion of the study was that alternating MP/VAD and MP/VND did not improve clinical outcomes compared to MP alone.

Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma.
Oncogene. 2002 Sep 26;21(43):6587-97.
Pene F, Claessens YE, Muller O, Viguié F, Mayeux P, Dreyfus F, Lacombe C, Bouscary D.

Clinical activity of arsenic trioxide for the treatment of multiple myeloma.
Leukemia. 2002 Sep;16(9):1835-7.
Munshi NC, Tricot G, Desikan R, Badros A, Zangari M, Toor A, Morris C, Anaissie E, Barlogie B.
This is a phase II trial of arsenic trioxide in 14 patients with relapsed/refractory MM. Responses were seen in 3 patients, and prolonged stable disease in 1 patient. The longest response lasted 6 weeks.

2-Methoxyestradiol overcomes drug resistance in multiple myeloma cells.
Blood. 2002 Sep 15;100(6):2187-94.
Chauhan D, Catley L, Hideshima T, Li G, Leblanc R, Gupta D, Sattler M, Richardson P, Schlossman RL, Podar K, Weller E, Munshi N, Anderson KC.

Fludarabine/melphalan conditioning for allogeneic transplantation in patients with multiple myeloma.
Bone Marrow Transplant. 2002 Sep;30(6):367-73.
Giralt S, Aleman A, Anagnostopoulos A, Weber D, Khouri I, Anderlini P, Molldrem J, Ueno NT, Donato M, Korbling M, Gajewski J, Alexanian R, Champlin R.
In this study, 22 myeloma patients underwent a mini-allogeneic stem cell transplant using fludarabine + melphalan:
  - Fludarabine 30 mg/m2 for 4 days + melphalan 140 mg/m2 (18 pts)
  - Fludarabine 25 mg/m2 for 5 days + melphalan 90 mg/m2 for 2 days (4 pts)
After a median follow-up of 15 months (range, 10-47 months), 6 patients were alive. Transplant-related mortality at day 100 was 19%.

Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma.
Br J Haematol. 2002 Sep;118(4):1041-7.
Fassas AB, Spencer T, Sawyer J, Zangari M, Lee CK, Anaissie E, Muwalla F, Morris C, Barlogie B, Tricot G.



Giampaolo Talamo, MD