Comparison of gene expression profiling between malignant and normal plasma cells with oligonucleotide arrays.
Oncogene. 2002 Oct 3;21(44):6848-57.
De Vos J, Thykjaer T, Tarte K, Ensslen M, Raynaud P, Requirand G, Pellet F, Pantesco V, Rème T, Jourdan M, Rossi JF, Ørntoft T, Klein B.
These authors used the DNA microarray technology with Affymetrix microarrays to compared the gene expression profiles of MM cells from 9 patients with MM, 8 MM cell lines, and 8 samples of normal plasma cells. 250 genes were significantly up-regulated and 159 down-regulated in MM plasma cells compared to normal plasma cells.

Novel mutation and RNA splice variant of fibroblast growth factor receptor 3 in multiple myeloma patients at diagnosis.
Haematologica. 2002 Oct;87(10):1036-40.
Soverini S, Terragna C, Testoni N, Ruggeri D, Tosi P, Zamagni E, Cellini C, Cavo M, Baccarani M, Tura S, Martinelli G.
These authors investigated the presence of FGFR3 expression and activating mutations in a series of 78 newly diagnosed MM patients, using RT-PCR and gene sequence. RT-PCR revealed FGFR3 mRNA expression in 10 of 78 (13%) patients. In 2 cases, sequence analysis revealed FGFR3 mutations. Interestingly, a patient without the t(4;14) had 3 additional, abnormal-sized transcripts, corresponding to truncated transcripts originating from alternative splicing.

Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells.
Blood. 2002 Oct 15;100(8):3002-7.
Standal T, Seidel C, Hjertner Ø, Plesner T, Sanderson RD, Waage A, Borset M, Sundan A.
This study shows that MM cells can bind, internalize, and degrade OPG, thereby providing a possible explanation for the lower levels of OPG in the BM of patients with MM.

Molecular sequelae of proteasome inhibition in human multiple myeloma cells.
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14374-9.
Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Treon SP, Munshi NC, Richardson PG, Hideshima T, Anderson KC.

A combination of dexamethasone, cyclophosphamide, etoposide, and cisplatin is less toxic and more effective than high-dose cyclophosphamide for peripheral stem cell mobilization in multiple myeloma.
Haematologica. 2002 Oct;87(10):1041-5.
Corso A, Arcaini L, Caberlon S, Zappasodi P, Mangiacavalli S, Lorenzi A, Rusconi C, Troletti D, Maiocchi MA, Pascutto C, Morra E, Lazzarino M.
This study compares the efficacy of two mobilization regimens in 116 myeloma patients:
  - HD-Cy (high-dose cyclophosphamide, 4 g/m2) (61 patients)
  - DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) (55 patients)
G-CSF 5 mg/Kg/day was started 48 hours after chemotherapy.
DCEP was a better regimen than HD-Cy:
  - Median number of CD34+ cells harvested was similar (5.9 vs 5.8 million CD34+ cells/Kg)
  - The target of 4 million CD34+ cells/Kg was reached in 59% of HD-Cy patients and 75% of DCEP patients
  - Poor mobilizers (<2 million CD34+ cells/Kg) were 21% with HD-Cy and 13% with DCEP
  - Neutropenic fever: 18% with HD-Cy and 0% with DCEP
  - WHO grade >II extra-hematologic toxicities (microhematuria, cystitis, infections): 13% with HD-Cy and 0% with DCEP

Cytotoxic chemotherapy following tandem autotransplants in multiple myeloma patients.
Br J Haematol. 2002 Oct;119(1):164-8.
Fassas AB, Spencer T, Desikan R, Zangari M, Anaissie E, Barlogie B, Tricot G.
This study reviewed outcomes of consolidation chemotherapy after tandem transplants in 75 myeloma patients, and compared them with those of 75 matched controls who received dexamethasone and/or interferon. Consolidation chemotherapy provided no event-free nor overall survival advantage.

Neuropathies associated with IgG and IgA monoclonal gammopathy.
Rev Neurol (Paris). 2002 Oct;158(10 Pt 1):979-87.
Nobile-Orazio E, Casellato C, Di Troia A.



Intermediate-dose (25mg/m2) IV melphalan for multiple myeloma with renal failure.
J Nephrol. 2002 Nov-Dec;15(6):684-9.
Vigneau C, Ardiet C, Bret M, Laville M, Fiere D, Tranchand B, Fouque D.
These authors used a single dose of melphalan, 25 mg/m2 IV, in 45 patients with multiple myeloma. 79% patients had renal impairment, and some of them were on dialysis. Results:
  - Overall median survival was 45 +/- 43 months after diagnosis. Survival was no different whether renal insufficiency was present or not.
  - 25 of 34 patients had leukopenia, with a mean of 14 days
  - The most frequent adverse effect was infection

Dose-dependent effect of thalidomide on overall survival in relapsed multiple myeloma.
Clin Cancer Res. 2002 Nov;8(11):3377-82.
Neben K, Moehler T, Benner A, Kraemer A, Egerer G, Ho AD, Goldschmidt H.
This is a retrospective analysis of a phase II study in 83 patients with relapsed myeloma, treated with thalidomide at a maximum dose of 400 mg daily. Progression-free survival and overall survival at 1 year were 45% and 86%, respectively. The cumulative 3-month thalidomide dose was one of the most important prognostic factors for survival, supporting the hypothesis of a dose-dependent effect of thalidomide.

Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma.
J Clin Oncol. 2002 Nov 1;20(21):4319-23.
Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR, Geyer S, Iturria N, Fonseca R, Lust JA, Kyle RA, Witzig TE.
50 patients with newly diagnosed myeloma were treated with thalidomide 200 mg PO qhs + dexamethasone 40 mg PO on days 1-4, 9-12, and 17-20 in odd cycles and 40 mg PO on days 1-4 in even cycles. Cycles were repeated every 28 days. Response rate was 64%. The most frequent toxicities were DVT, constipation, and skin rash.

Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma.
Blood. 2002 Nov 1;100(9):3063-7.
Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, LeBlanc R, Catley LP, Doss D, Kelly K, McKenney M, Mechlowicz J, Freeman A, Deocampo R, Rich R, Ryoo JJ, Chauhan D, Balinski K, Zeldis J, Anderson KC.
In this phase I study of lenalidomide, 27 patients with relapsed/refractory myeloma received escalating doses of lenalidomide, from 5 mg to 50 mg daily. The most important toxicity was myelosuppression (grade 3 myelosuppression developed after 28 days in all of the 13 patients treated with 50 mg daily). The maximal tolerated dose was found to be 25 mg. Of note, the usual toxicities observed with thalidomide, i.e., somnolence, peripheral neuropathy, and constipation, were not observed. A response, defined as at least a 25% reduction in paraprotein level, was observed 17 of 24 (71%) patients, including 11 (46%) patients who received prior therapy with thalidomide.

Nephrotic proteinuria associated with high-dose pamidronate in multiple myeloma.
Br J Haematol. 2002 Nov;119(2):496-9.
Desikan R, Veksler Y, Raza S, Stokes B, Sabir T, Li ZJ, Jagannath S.
This study reports 5 cases of multiple myeloma who developed nephrotic proteinuria (range: 4-24 g/24 hours) after treatment with pamidronate at increased doses or frequency of administration. After dose reduction or discontinuation of pamidronate, proteinuria returned to normal levels (<1 g/24 hours) in 3 patients, and it decreased from 24 to to 4.5 g/24 hours in 1 patient. Renal biopsies, obtained in 2 patients, showed findings consistent with focal segmental glomerulosclerosis.

Pamidronate causes apoptosis of plasma cells in vivo in patients with multiple myeloma.
Br J Haematol. 2002 Nov;119(2):475-83.
Gordon S, Helfrich MH, Sati HI, Greaves M, Ralston SH, Culligan DJ, Soutar RL, Rogers MJ.
In this study, a single infusion of pamidronate induced apoptosis of human plasma cells in 16 patients with newly diagnosed multiple myeloma. The results suggest that pamidronate may have direct and/or indirect anti-tumour effects in patients with multiple myeloma.

Evaluation of bone disease in multiple myeloma: a correlation between biochemical markers of bone metabolism and other clinical parameters in untreated multiple myeloma patients.
Clin Chim Acta. 2002 Nov;325(1-2):51-7.
Alexandrakis MG, Passam FH, Malliaraki N, Katachanakis C, Kyriakou DS, Margioris AN.
These authors studied several biochemical markers in MM, including osteocalcin, bone-specific alkaline phosphatase, free urine pyridoline and deoxypyridinoline, and free urine NTx in 38 patients with newly diagnosed MM, and correlated their findings with the degree of bone involvement at the skeletal survey. They found that levels of NTx, free urine pyridoline, and free urine deoxypyridinoline increased with increasing degree of bone involvement. Instead, osteocalcin levels were increased in stages I and II of MM compared to stage III.

Whole-body (18)F-FDG PET identifies high-risk myeloma.
J Nucl Med. 2002 Nov;43(11):1457-63.
Durie BG, Waxman AD, D'Agnolo A, Williams CM.
This study evaluated the clinical utility of whole-body PET with (18)F-FDG in 52 patients with multiple myeloma at various disease stages and 14 patients with MGUS, and it compared the results with routine clinical and staging information, including CT and MRI scans. Negative PET reliably predicted MGUS. All 16 untreated patients with active myeloma had focal or diffusely positive PET scan findings, and 4 (25%) of them had positive PET and negative radiologic skeletal surveys. Another 4 (25%) of those 16 patients had focal extramedullary disease evident at PET. Extramedullary disease was also detected at PET in 6 of 26 (23%) patients with MM in relapse. Persistent positive PET after induction therapy predicted early relapse. PET was particularly helpful in identifying focal recurrent disease in patients with nonsecretory or hyposecretory disease.

Flow cytometric disease monitoring in multiple myeloma: the relationship between normal and neoplastic plasma cells predicts outcome after transplantation.
Blood. 2002 Nov 1;100(9):3095-100.
Rawstron AC, Davies FE, DasGupta R, Ashcroft AJ, Patmore R, Drayson MT, Owen RG, Jack AS, Child JA, Morgan GJ.
This study evaluates by flow cytometry both normal and neoplastic plasma cells in the bone marrow of 45 patients after stem cell transplant. Myeloma cells were detectable at 3 months after transplant in 42% of all patients, and in 9 of 33 (27%) of patients with IFE-negative CR . Flow cytometry was more sensitive than IFE for the assessment of CR in the post-transplant period. Flow cytometry had prognostic implications, because patients with positive flow cytometry had a median PFS of 20 months, whereas patients with negative flow cytometry had a median PFS of 35 months (p= 0.003).

A Phase II trial of pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone combination therapy in newly diagnosed multiple myeloma patients.
Cancer. 2002 Nov 15;95(10):2160-8.
Hussein MA, Wood L, Hsi E, Srkalovic G, Karam M, Elson P, Bukowski RM.
This is a phase II study of VAD incorporating pegylated liposomal doxorubicin (40 mg/m2) in 33 patients witth newly diagnosed multiple myeloma. Chemotherapy was given every 28 days for at least 6 cycles, and for 2 cycles after the best response. Results:
  - Response rate: 88% (complete response 12%, major response 55%, minor response 21%)
  - Stable disease: 9%
  - Progressive disease: 3%
  - Median time to progression: 23.1 months
  - Progression-free survival at 2 years: 42%
  - Progression-free survival at 3 years: 23%
  - Overall survival at 3 years: 67%
  - Most common toxicities: hand-foot syndrome, mucositis, and neutropenia. Only 1 patient had cardiac toxicity.
Compared with historical controls, VAD with liposomal doxorubicin has the same efficacy, and improved safety profile and patient convenience.

Response to induction chemotherapy is not essential to obtain survival benefit from high-dose melphalan and autotransplantation in myeloma.
Bone Marrow Transplant. 2002 Nov;30(10):673-9.
Singhal S, Powles R, Sirohi B, Treleaven J, Kulkarni S, Mehta J.
In this study, 222 myeloma underwent induction chemotherapy with C-VAMP (cyclophosphamide, vincristine, doxorubicin and methylprednisolone), followed by autologous SCT with melphalan 200 mg/m2. 43 patients did not respond to C-VAMP (<50% reduction in paraprotein). The 5-year survival was independent of response to the induction chemotherapy: 74% in the group who responded to C-VAMP, and 79% in the group with primary refractory disease.



Transplantation as salvage therapy for high-risk patients with myeloma in relapse.
Bone Marrow Transplant. 2002 Dec;30(12):873-8.
Lee CK, Barlogie B, Zangari M, Fassas A, Anaissie E, Morris C, Van Rhee F, Cottler-Fox M, Thertulien R, Muwalla F, Mazher S, Badros A, Tricot G.
76 consecutive patients with myeloma in relapse after tandem autologous stem cell transplants received a third transplant as salvage therapy. Transplant was autologous in 50 patients, sibling-matched allogeneic in 22 patients, and matched-unrelated allogeneic in 4 patients. Results:
  - Response rate: 59% (CR 11%, near-CR 18%, PR 30%)
  - Event-free survival at 2 years: 7%
  - Overall survival at 2 years: 19%

Human myeloma cells stimulate the receptor activator of nuclear factor-kappa B ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease.
Blood. 2002 Dec 15;100(13):4615-21.
Giuliani N, Colla S, Sala R, Moroni M, Lazzaretti M, La Monica S, Bonomini S, Hojden M, Sammarelli G, Barillè S, Bataille R, Rizzoli V.
T cells may regulate bone resorption through cross-talk between RANKL, and interferon gamma (IFN-gamma), which suppresses osteoclastogenesis. This study found that human myeloma cell lines (HMCLs) increased the expression and secretion of RANKL in activated T lymphocytes, and that the release of IFN-gamma by T lymphocytes was reduced in presence of MM cells. RANKL mRNA was up-regulated in T lymphocytes in the BM of MM patients. This suggests that T cells are probably involved in MM-induced osteolysis through overexpression of RANKL.

Diagnostic utility of FDG PET in multiple myeloma.
Skeletal Radiol. 2002 Dec;31(12):690-4.
Jadvar H, Conti PS.
In this study, PET scans showed development of new lesions or higher lesion glucose uptake in patients with progressive disease, while the other imaging studies showed no significant interval changes. Therefore, PET is very useful in assessing the extent of active disease and in evaluating treatment response.

Promising preclinical activity of 2-methoxyestradiol in multiple myeloma.
Clin Cancer Res. 2002 Dec;8(12):3948-54.
Dingli D, Timm M, Russell SJ, Witzig TE, Rajkumar SV.

High rate of monoclonal gammopathy among immunocompetent subjects with primary cytomegalovirus infection.
Clin Infect Dis. 2002 Dec 1;35(11):1430-3.
Bühler S, Laitinen K, Holthöfer H, Järvinen A, Schauman KO, Hedman K.



Giampaolo Talamo, MD