Response rate, durability of response, and survival after thalidomide therapy for relapsed multiple myeloma.
Mayo Clin Proc. 2003 Jan;78(1):34-9.
Kumar S, Gertz MA, Dispenzieri A, Lacy MQ, Geyer SM, Iturria NL, Fonseca R, Hayman SR, Lust JA, Kyle RA, Greipp PR, Witzig TE, Rajkumar SV.
32 patients with relapsed multiple myeloma were treated with thalidomide 200 mg/day for 2 weeks, increased to a maximum of 800 mg/d. Results:
  - Response rate: 31%. No complete responses were seen.
  - Median progression-free survival: 8.6 months
  - Median overall survival: 22 months

Thalidomide alone or with dexamethasone for previously untreated multiple myeloma.
J Clin Oncol. 2003 Jan 1;21(1):16-9.
Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R.
68 patients with newly diagnosed myeloma were treated with thalidomide 100-600 mg PO qhs with or without dexamethasone, for at least 3 months. Response rate was 36% with thalidomide alone and 72% with thalidomide + dexamethasone. CR was 16% with thalidomide + dexamethasone. Median time to remission was 4.2 months with thalidomide alone and 0.7 months with thalidomide + dexamethasone.

Hepatitis C virus, human herpesvirus 8, and the development of plasma-cell leukemia.
N Engl J Med. 2003 Jan 9;348(2):178-9.
Hermouet S, Corre I, Gassin M, Bigot-Corbel E, Sutton CA, Casey JW.
This study presents a case of plasma cell leukemia in which the monoclonal IgG-kappa antibody was directed against the HCV core protein. This was demonstrated by immunoblotting. Immunofluorescence studies showed that the malignant plasma cells were infected by HCV and produced HCV core protein.

Recombinant osteoprotegerin decreases tumor burden and increases survival in a murine model of multiple myeloma.
Cancer Res. 2003 Jan 15;63(2):287-9.
Vanderkerken K, De Leenheer E, Shipman C, Asosingh K, Willems A, Van Camp B, Croucher P.
In this study, recombinant osteoprotegerin decreased serum paraprotein and tumor burden, and it increased survival in mice injected with 5T33MM cells. Osteoclast number was decreased. This study provide a proof of concept that the inhibition of the interaction between RANKL and RANK with OPG not only inhibits the development of myeloma bone disease, but it also decreases tumor growth and prolongs survival.

Tandem transplants with different high-dose regimens improve the complete remission rates in multiple myeloma. Results of a Grupo Español de Síndromes Linfoproliferativos/Trasplante Autólogo de Médula Osea phase II trial.
Br J Haematol. 2003 Jan;120(2):296-303.
Lahuerta JJ, Grande C, Martínez-Lopez J, De La Serna J, Toscano R, Ortiz MC, Larregla S, Conde E, Insunza A, Gonzalez-San Miguel JD, Bargay J, Cabrera R, García-Ruiz JC, Albó C, García-Alonso L, Solano F, Vivancos P, León A, San Miguel J; Grupo Español de Síndromes Linfoproliferativos/Trasplante Autólogo de Médula Osea.
88 myeloma patients were treated with tandem autologous stem cell transplants, using melphalan 200 mg/m2 with the first transplant, and CBV (cyclophosphamide, BCNU, and etoposide) with the second transplant. Complete remission was achieved in 26 patients (30%) after the first transplant, and in 16 of the remaining 48 evaluable patients (33%) after the second transplant (final CR rate 48%). The 5-year event-free survival was 28%, and the 5-year overall survival was 55%. The outcome of the patients in CR after 2 transplants was not different from that of patients in CR after the first transplant. In this study, the benefit of the second transplant depended on the induction of CR for those patients who did not reach CR after the first transplant.



Translocation t(11;14)(q13;q32) is the hallmark of IgM, IgE, and nonsecretory multiple myeloma variants.
Blood. 2003 Feb 15;101(4):1570-1.
Avet-Loiseau H, Garand R, Lodé L, Harousseau JL, Bataille R; Intergroupe Francophone du Myélome.
These authors analyzed a series of 8 IgM, 9 IgD, 2 IgE, and 14 nonsecretory (NS) MM cases using FISH. A very high incidence (83%) of t(11;14) was detected in:
 - IgM MM cases (7 of 8)
 - IgE MM cases (2 of 2)
 - NS MM cases (11 of 14)
 - Not in IgD MM cases (2 of 9)
t(11;14) was associated with 2 features: "lymphoplasmacytic" presentation mainly in IgM MM and a lower secreting capacity in the others.
These authors showed that t(11;14) is the hallmark of IgM, IgE, and NS MM, (but not IgD MM).

Fluorescence in situ hybridization analysis of aneuploidization patterns in monoclonal gammopathy of undetermined significance versus multiple myeloma and plasma cell leukemia.
Cancer. 2003 Feb 1;97(3):601-9.
Rasillo A, Tabernero MD, Sánchez ML, Pérez de Andrés M, Martín Ayuso M, Hernández J, Moro MJ, Fernández-Calvo J, Sayagués JM, Bortoluci A, San Miguel JF, Orfao A.
This study assessed by interphase fluorescence in situ hybridization (FISH) the incidence of numerical abnormalities of chromosomes 6, 9, 13, and 17 in 30 patients with MGUS, and it compared the results with those found in 158 MM patients and 20 PCL patients. 57% of the MGUS patients displayed abnormalities for at least 1 of the 4 chromosomes analyzed, while 75% of MM and PCL cases had the same abnormalities. Compared with MM patients, MGUS patients had a lower incidence of +9 (23% vs. 54%) and 13q deletions (21% vs. 38%.

Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development.
Blood. 2003 Feb 1;101(3):1128-40.
Zhan F, Tian E, Bumm K, Smith R, Barlogie B, Shaughnessy J Jr.

In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression.
Blood. 2003 Feb 15;101(4):1520-9.
Keats JJ, Reiman T, Maxwell CA, Taylor BJ, Larratt LM, Mant MJ, Belch AR, Pilarski LM.
This study found the t(4;14) translocation in 31 of 208 (14.9%) patients with multiple myeloma, and 1 of 52 (1.9%) patients with MGUS. Breakpoint analysis of the IgH-MMSET showed that in 68% of cases, the protein produced by the t(4;14) was a hybrid transcript encoding full-length MMSET. The rest of cases lacked amino terminal exons. RT-PCR detected expression of FGFR3 in only 23 of 31 (74%) patients with t(4;14) MM. The presence of t(4;14) predicted a poor response to induction therapy, and poor prognosis: median survival was about 21 months (vs about 43 months), even in patients who did not have expression of FGFR.

Genomic characterization of the chromosomal breakpoints of t(4;14) of multiple myeloma suggests more than one possible etiological mechanism.
Oncogene. 2003 Feb 20;22(7):1103-13.
Fenton JA, Pratt G, Rawstron AC, Sibley K, Rothwell D, Yates Z, Dring A, Richards SJ, Ashcroft AJ, Davies FE, Owen RG, Child JA, Morgan GJ.
These authors characterized the genomic breakpoints of t(4;14) translocations from 7 MM patients. In 5 patients, chromosome 14q32 breakpoints were located in the IgH mu switch (S) region with deletion of intervening DNA from aberrant class switch recombination (CSR). However, in 2 patients the rearranged hybrid switch region sequence was joined to DNA from chromosome 4p16. Therefore, IgH translocations can occur in B cells that have already undergone legitimate CSR. These findings suggest that primary IgH translocations involve different mechanisms, and they may occur at different time points in the development of malignant plasma cells, either during the physiological CSR or at a later stage.

Bisphosphonates and osteoprotegerin as inhibitors of myeloma bone disease.
Cancer. 2003 Feb 1;97(3 Suppl):818-24.
Croucher PI, Shipman CM, Van Camp B, Vanderkerken K.
This study assesses the ability of recombinant osteoprotegerin (Fc.OPG) and bisphosphonates to inhibit the development of bone disease in the 5T2MM murine model of MM. Both bisphosphonates and Fc.OPG prevented the development of osteolytic bone lesions in 5T2MM mice.

RANK-Fc: a therapeutic antagonist for RANK-L in myeloma.
Cancer. 2003 Feb 1;97(3 Suppl):802-12.
Sordillo EM, Pearse RN.
RANK-Fc is a recombinant RANKL antagonist formed by fusing the extracellular domain of RANK to the Fc portion of human IgG1. In vitro, RANK-Fc suppresses the formation of osteoclasts in cocultures of MM with bone marrow and osteoblast/stromal cells. This study showed the ability of RANK-Fc to block the development of MM-induced bone disease in vivo. Administration of the RNAAKL antagonist RANK-Fc not only limited the osteoclastogenesis, but it also caused a reduction in tumor burden and serum paraprotein in SCID-hu-MM mice.

Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341.
Blood. 2003 Feb 15;101(4):1530-4.
Hideshima T, Mitsiades C, Akiyama M, Hayashi T, Chauhan D, Richardson P, Schlossman R, Podar K, Munshi NC, Mitsiades N, Anderson KC.

A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases.
Cancer. 2003 Feb 1;97(3 Suppl):887-92.
Body JJ, Greipp P, Coleman RE, Facon T, Geurs F, Fermand JP, Harousseau JL, Lipton A, Mariette X, Williams CD, Nakanishi A, Holloway D, Martin SW, Dunstan CR, Bekker PJ.
This is a randomized, double-blind study that evaluated safety and effect on bone resorption of AMGN-0007 in 28 patients with multiple myeloma and 26 patients with breast carcinoma and lytic bone lesions. AMGN-0007 is a recombinant OPG, developed as a potential therapeutic agent in the treatment of bone disease. Patients were randomized to receive a single dose of either AMGN-0007 SC or pamidronate 90 mg IV. AMGN-0007 suppressed bone resorption as indicated by a sustained, and profound decrease of urinary urinary N-telopeptide of collagen (NTX), surrogate marker of bone resorption. Changes were comparable to those observed with pamidronate.

Mobilization of CD34+ cells in elderly patients (>/= 70 years) with multiple myeloma: influence of age, prior therapy, platelet count and mobilization regimen.
Br J Haematol. 2003 Feb;120(3):413-23.
Morris CL, Siegel E, Barlogie B, Cottler-Fox M, Lin P, Fassas A, Zangari M, Anaissie E, Tricot G.
Among 984 myeloma patients who underwent mobilization of peripheral blood stem cells, 106 patients were aged 70 years or older. Older age correlated inversely with CD34+ yield, and it remained an adverse factor even after multivariate analysis. The effect of age was incremental, and there was no specific age threshold associated with collection failure.

Peripheral blood stem cell contamination evaluated by a highly sensitive molecular method fails to predict outcome of autotransplanted multiple myeloma patients.
Br J Haematol. 2003 Feb;120(3):405-12.
Galimberti S, Morabito F, Guerrini F, Palumbo GA, Azzará A, Martino M, Benedetti E, Di Raimondo F, Petrini M.
Apheresis products from 51 autotransplanted patients were tested by PCR. 69% of harvests were contaminated when evaluated for IgH rearrangement. Median overall survival was 33 months. The survival at 70 months was 72% in patients transplanted with PCR-negative stem cells, and 48% in patients transplanted with contaminated precursors, but the difference was not statistically significant. Purging reduced contamination of up to 3 logs, but 80% of purged harvests remained PCR-positive, and purging did not improve response or survival.


MARCH 2003

Cytogenetics of multiple myeloma: interpretation of fluorescence in situ hybridization results.
Br J Haematol. 2003 Mar;120(6):944-52.
Harrison CJ, Mazzullo H, Cheung KL, Gerrard G, Jalali GR, Mehta A, Osier DG, Orchard KH.
These authors studied cytogenetics and/or interphase FISH on bone marrow samples or purified plasma cells from 37 MM patients. Abnormal karyotypes by multiplex FISH were found in 11 patients, all of which were highly complex. Interphase FISH showed:
 - Translocations involving the IgH locus in 16 (43%) patients
 - The translocation t(11;14)(q13;q32), resulting in the IgH/cyclin D1 (CCND1) gene fusion, was seen in 12 (32%) of patients
 - Other rearrangements of IgH were seen in 4 (11%) patients
 - 14 patients had additional copies of chromosome 11
 - 20 patients (54%) had 13q14 deletions, 10 of whom also had t(11;14) or another IgH translocation.

A pooled analysis of karyotypic patterns, breakpoints and imbalances in 783 cytogenetically abnormal multiple myelomas reveals frequently involved chromosome segments as well as significant age- and sex-related differences.
Br J Haematol. 2003 Mar;120(6):960-9.
Nilsson T, Höglund M, Lenhoff S, Rylander L, Turesson I, Westin J, Mitelman F, Johansson B.
This study analyses the cytogenetic features of 783 abnormal multiple myeloma cases. Hyperdiploidy was most common, followed by hypodiploidy, pseudodiploidy and tri-/tetraploidy. Most cases had a complex karyotype, with a median of 8 abnormalities per patient. There were no sex- or age-related differences regarding the number of abnormalities. The most frequent genomic breakpoints were: 14q32, 11q13, 1q10, 8q24, 1p11, 1q21, 22q11, 1p13, 1q11, 19q13, 1p22, 6q21 and 17p11. The most frequent imbalances were +9, -13, +15, +19, +11, and -Y. -Y as the sole change was more common in elderly men.

Multiple myeloma with monosomy 13 developed in trisomy 13 acute myelocytic leukemia: numerical chromosome abnormality during chromosomal segregation process.
Sashida G, Ito Y, Nakajima A, Kawakubo K, Kuriyama Y, Yagasaki F, Bessho M, Ohyashiki K.
Cancer Genet Cytogenet. 2003 Mar;141(2):154-6.
This is a case report of a patient with acute myelocytic leukemia (AML-M2) who had trisomy 13 as the sole cytogenetic anomaly. At relapse of AML, this patient had a normal karyotype and developed multiple myeloma. FISH showed that the MM plasma cells had monosomy 13, whereas the relapsed blast cells of AML carried disomy of chromosome 13. Therefore, this case showed a clonal evolution of trisomy 13 AML and monosomy 13 MM, which probably derived from the leukemic clone at relapse.

A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript.
Blood. 2003 Mar 15;101(6):2374-6.
Santra M, Zhan F, Tian E, Barlogie B, Shaughnessy J Jr.

The reciprocal t(4;14)(p16;q32) translocation activates expression of FGFR3 and creates an IgH/MMSET fusion transcript. These authors analyzed 32 (18%) of 178 patients with newly diagnosed MM harboring the t(4;14)(p16;q32). They found that 32% of these cases lacked expression of FGFR3, but they still expressed MMSET and had the IgH/MMSET fusion transcript. Therefore, the oncogenic event of this recurrent translocation in MM is the activation of MMSET, not FGFR3.

Urinary N-telopeptide levels in multiple myeloma patients, correlation with Tc-99m-sestaMIBI scintigraphy and other biochemical markers of disease activity.
Hematol Oncol. 2003 Mar;21(1):17-24.
Alexandrakis MG, Kyriakou DS, Passam FH, Malliaraki N, Vlachonikolis IG, Karkavitsas N.
Urinary cross-linked N-telopeptide of type I collagen (NTx) has been reported to be a sensitive and specific marker of bone resorption in multiple myeloma (MM). These authors have measured the levels of cross-linked N-telopeptide of type I collagen (NTx) in the urine of 30 newly diagnosed MM patients and 25 controls and tehy correlated the levels with the degree of bone involvementt seen at the Tc-99m-MIBI scintigraphy, Durie-Salmon stage, and bone marrow infiltration by plasma cells. The NTx was found at significantly higher concentrations in patients with greater bone involvement at Tc-99m-sestaMIBI and higher bone marrow infiltration. The authors conclude that NTx is a useful marker for monitoring bone resorption in MM.

Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival.
J Bone Miner Res. 2003 Mar;18(3):482-92.
Croucher PI, De Hendrik R, Perry MJ, Hijzen A, Shipman CM, Lippitt J, Green J, Van Marck E, Van Camp B, Vanderkerken K.
This study investigated the effect of zoledronic acid on the development of bone disease, tumor burden, and disease-free survival in C57BL/KaLwRij mice injected with 5T2MM murine myeloma cells. After 8 weeks, a paraprotein was detected in all animals. All mice injected with tumor cells developed osteolytic lesions, a decrease in bone formation, and a decrease in bone mineral density. After treatment with zoledronic acid 120 mcg/kg subcutaneously twice a week, authors observed reduced development of osteolytic bone disease, decreased paraprotein concentration, decreased tumor burden, and reduced angiogenesis. Kaplan-Meier survival analysis demonstrated an increased survival after treatment with zoledronic acid when compared with controls. Therefore, zoledronic acid can prevent the development of osteolytic bone disease, decrease tumor burden, and increase survival in a murine model of multiple myeloma.

RANK ligand and osteoprotegerin in myeloma bone disease.
Blood. 2003 Mar 15;101(6):2094-8.
Sezer O, Heider U, Zavrski I, Kühne CA, Hofbauer LC.

Low-dose or intermediate-dose cyclophosphamide plus granulocyte colony-stimulating factor for progenitor cell mobilisation in patients with multiple myeloma.
Bone Marrow Transplant. 2003 Mar;31(5):347-51.
Jantunen E, Putkonen M, Nousiainen T, Pelliniemi TT, Mahlamäki E, Remes K.
Retrospective study of 57 patients with newly diagnosed myeloma previously treated with VAD. Mobilization regimen was:
  - Low-dose cyclophosphamide, 1.2-2 g/m2 + G-CSF (25 patients, Group 1)
  - Intermediate-dose cyclophosphamide, 4 g/m2 + G-CSF (32 patients, Group 2)
  - At least 2 million CD34+ cells/Kg were collected with a single apheresis from 88% of patients in Group 1 and 84% of patients in Group 2
  - Mobilization failure occurred in 1 patient (4%) in Group 1 and 0 patients in Group 2
  - Patients in Group 1 had less toxicity, including lower frequency of fever (20 vs 73%), and less need for platelet transfusions (0 vs 24%)



Giampaolo Talamo, M.D.