APRIL 2003

CD40 induces human multiple myeloma cell migration via phosphatidylinositol 3-kinase/AKT/NF-kappa B signaling.
Blood. 2003 Apr 1;101(7):2762-9.
Tai YT, Podar K, Mitsiades N, Lin B, Mitsiades C, Gupta D, Akiyama M, Catley L, Hideshima T, Munshi NC, Treon SP, Anderson KC.
CD40 activation is implicated in MM cell homing and migration. This study shows that  CD40-induced MM cell migration is primarily mediated by PI3K/AKT/NF-kappa-B signaling. Authors demonstrated that cross-linking CD40 (with either soluble CD40L or anti-CD40 monoclonal antibody) induces phosphatidyl-inositol 3-kinase (PI3K) activity and activates its downstream effector AKT in MM.1S cells. CD40 activation also activates the MAP kinase (MEK) pathway, but inhibition of ERK/MEK phosphorylation only partially (10%-15%) prevented migration, suggesting that MEK plays only a minor role in regulation of CD40-mediated MM migration. CD40 induced NF-kappa B activation as a downstream target of PI3K/AKT signaling.

The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma.
Leukemia. 2003 Apr;17(4):764-74.
Derksen PW, de Gorter DJ, Meijer HP, Bende RJ, van Dijk M, Lokhorst HM, Bloem AC, Spaargaren M, Pals ST.
The receptor for the hepatocyte growth factor/scatter factor (HGF) is Met, which is expressed on MM cells. HGF is produced by BM stromal cells and by some MM cell lines, enabling para- or autocrine interaction. Authors found that Met is expressed by the majority of MM cell lines and by approximately half of the primary plasma cell neoplasms tested. HGF is a potent myeloma growth and survival factor, by activating the RAS/mitogen-activated protein kinase and PI3K/PKB pathways. HGF had anti-apoptotic effects on both MM cell lines and primary MM cells.

The spectrum of cutaneous disease in multiple myeloma.
J Am Acad Dermatol. 2003 Apr;48(4):497-507.
Bayer-Garner IB, Smoller BR.
Dermatologic disorders associated with MM are:
 - Amyloidosis
 - Cryoglobulinemia
 - POEMS syndrome
 - Normolipemic plane xanthoma
 - Plasmacytoma
These authors reviewed 472 skin biopsy specimens form patients with MM. Diagnoses included: GVHD (120), neoplastic lesions (111; 73 malignant, 38 benign), nonspecific lesions (77), drug-related lesions (46), infectious lesions (41), papulosquamous lesions (18), bullous diseases (17), vasculitis (11), thrombocytopenia-related lesions (9), Sweet's syndrome (7), granulomatous dermatitis (6), cutaneous eruption of lymphocyte recovery (3), unrelated lesions (2), normolipemic plane xanthoma (1), amyloidosis (1), panniculitis (1), and alopecia cicatrisata (1).

Sweet syndrome in multiple myeloma: a series of six cases.
J Cutan Pathol. 2003 Apr;30(4):261-4.
Bayer-Garner IB, Cottler-Fox M, Smoller BR.
Sweet syndrome (SS) is a paraneoplastic syndrome characterized by fever, neutrophilia, erythematous painful plaques, and dermal neutrophilic infiltration. It is usually associated with acute myelogenous leukemia. These authors reviewed the pathology reports of 2357 patients with multiple myeloma, and they found 6 cases of SS. 5 of the 6 patients received G-SCF, and the sixth received GM-CSF. SS may be secondary to elevated levels of G-CSF.

Cutaneous involvement in multiple myeloma: a clinicopathologic, immunohistochemical, and cytogenetic study of 8 cases.
Arch Dermatol. 2003 Apr;139(4):475-86.
Requena L, Kutzner H, Palmedo G, Calonje E, Requena C, Pérez G, Pastor MA, Sangueza OP.
This is a case series of 8 patients with MM and cutaneous involvement. The cutaneous lesions consisted of multiple erythematous or violaceous nodules or plaques. 2 different histopathologic patterns were identified: nodular and diffuse interstitial. At IHC, neoplastic plasma cells were positive for CD79a, CD138, and epithelial membrane antigen, and variably positive for VS38c and CD43. 5 cases produced IgA-lambda proteins, 2 cases IgG-kappa; and 1 case IgA-kappa. Prognosis was poor, because all 8 patients died a few months after the development of cutaneous involvement, despite aggressive chemotherapy.

Thalidomide as initial therapy for early-stage myeloma.
Leukemia. 2003 Apr;17(4):775-9.
Rajkumar SV, Gertz MA, Lacy MQ, Dispenzieri A, Fonseca R, Geyer SM, Iturria N, Kumar S, Lust JA, Kyle RA, Greipp PR, Witzig TE.
This is a phase II trial of 31 patients with smoldering or indolent myeloma, treated with thalidomide at 200 mg PO qhs. Response rate was 34%, and 66% if minor responses (25-49% decrease in M protein) were included. Progression-free survival was 80% at 1 year and 63% at 2 years. Most important toxicities were somnolence, neuropathy, DVT, hearing loss, weakness, bradycardia, and edema.

Thalidomide dosing in patients with relapsed or refractory multiple myeloma.
Ann Pharmacother. 2003 Apr;37(4):571-6.
Thompson JL, Hansen LA.

Dermatologic side effects of thalidomide in patients with multiple myeloma.
J Am Acad Dermatol. 2003 Apr;48(4):548-52.
Hall VC, El-Azhary RA, Bouwhuis S, Rajkumar SV.
This is a report of the dermatologic side effects of thalidomide in 87 patients with multiple myeloma enrolled in a clinical trial with thalidomide either alone or in combination with dexamethasone. The prevalence of skin rash with thalidomide was high, because a minor-moderate skin rash was observed in 46% of patients (43% in patients taking thalidomide + dexamethasone). 3 patients taking thalidomide + dexamethasone developed a severe skin rash that required hospitalization and discontinuation of thalidomide.

14q32 Translocations discriminate IgM multiple myeloma from Waldenstrom's macroglobulinemia.
Semin Oncol. 2003 Apr;30(2):153-5.
Avet-Loiseau H, Garand R, Lodé L, Robillard N, Bataille R.
This study found the t(11;14) in 7 of 8 cases of IgM myeloma, whereas no case of t(11;14) was found in 17 cases of WM. Therefore, the presence of t(11;14) can be useful in the differential diagnosis of IgM myeloma vs Waldenstrom's macroglobulinemia.

POEMS syndrome: definitions and long-term outcome.
Blood. 2003 Apr 1;101(7):2496-506.
Dispenzieri A, Kyle RA, Lacy MQ, Rajkumar SV, Therneau TM, Larson DR, Greipp PR, Witzig TE, Basu R, Suarez GA, Fonseca R, Lust JA, Gertz MA.
This study describes 99 patients with POEMS syndrome. Clinical manifestations that appeared to be part of the syndrome included CHF, pulmonary hypertension, renal insufficiency, and thrombotic events. Median survival was 165 months.


MAY 2003

99mTc-MIBI scintigraphy in untreated stage III multiple myeloma: comparison with X-ray skeletal survey and bone scintigraphy.
Nucl Med Commun. 2003 May;24(5):537-42.
Alper E, Gurel M, Evrensel T, Ozkocaman V, Akbunar T, Demiray M.
This study evaluated the role of the 99mTc-MIBI scan, compared with skeletal survey and bone scintigraphy, in the disease assessment of 20 patients with advanced stage MM. The authors found that the 99mTc-MIBI scan is a very sensitive imaging modality for the identification of active disease in patients with advanced MM, and it can detect sites of disease that are sometimes missed by the skeletal survey and the bone scintigraphy.

Pilot study of recombinant human soluble tumor necrosis factor (TNF) receptor (p75) fusion protein (TNFR:Fc; Enbrel) in patients with refractory multiple myeloma: increase in plasma TNF alpha levels during treatment.
Leuk Res. 2003 May;27(5):375-80.
Tsimberidou AM, Waddelow T, Kantarjian HM, Albitar M, Giles FJ.
No responses were observed in 10 patients with refractory myeloma treated with Enbrel, a TNF antagonist fusion protein.

High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma.
N Engl J Med. 2003 May 8;348(19):1875-83.
Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ; Medical Research Council Adult Leukaemia Working Party.
407 patients with newly diagnosed myeloma were randomly assigned to standard chemotherapy or high-dose therapy + autologous stem-cell transplant. Results:
  - Complete response was 44% with transplant vs 8% without transplant
  - Overall survival was higher in the transplant group. Median survival was 54.1 months with transplant vs 42.3 months without transplant

Monoclonal gammopathy of undetermined significance in atomic bomb survivors: incidence and transformation to multiple myeloma.
Br J Haematol. 2003 May;121(3):405-10.
Neriishi K, Nakashima E, Suzuki G.
Among 6737 atomic bomb survivors, 112 developed MGUS, and 16 died with multiple myeloma. The authors found that the transformation from MGUS to MM was faster in exposed persons than in the control group, but the difference was not statistically significant.

Partially T-cell-depleted allogeneic stem-cell transplantation for first-line treatment of multiple myeloma: a prospective evaluation of patients treated in the phase III study HOVON 24 MM.
J Clin Oncol. 2003 May 1;21(9):1728-33.
Lokhorst HM, Segeren CM, Verdonck LF, van der Holt B, Raymakers R, van Oers MH, Barge RM, Schouten HC, Westveer PH, Steijaert MM, Cornelissen JJ, Sonneveld P; Dutch-Belgian Hemato-Oncology Cooperative Group.
This is a prospective phase III study of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON). 53 patients with MM were treated with up-front myeloablative allogeneic stem cell transplant, from HLA-identical sibling. Results: RR 89%. After a median follow-up of 38 months: 20 patients were alive, and 33 dead, because of transplant-related mortality (18 pts), progressive disease (14 pts), or other causes (1 pt). Median progression-free survival was 17 months, and median overall survival was 25 months. The results were overall disappointing, even because only 3 patients were alive and in CR, indicating that with an upfront myeloablative allogeneic SCT, the chance of presumed cure was only 6%.


JUNE 2003

Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group.
Br J Haematol. 2003 Jun;121(5):749-57
International Myeloma Working Group.
The IMWG has reviewed the criteria for diagnosis and classification of plasma cell dyscrasias, including:
 - MGUS, with M protein <3 g/dL and bone marrow clonal cells <10%
 - Smoldering myeloma, with M protein >3 g/dL and/or bone marrow clonal cells >10% but no clinical manifestations of CRAB
 - Symptomatic myeloma, with CRAB symptoms (hyperCalcemia, Renal insufficiency, Anemia, and Bone lesions)
 - Extramedullary plasmacytoma
 - Solitary plasmacytomas

Telomerase and telomere length in multiple myeloma: correlations with disease heterogeneity, cytogenetic status, and overall survival.
Blood. 2003 Jun 15;101(12):4982-9.
Wu KD, Orme LM, Shaughnessy J Jr, Jacobson J, Barlogie B, Moore MA.
Authors investigated the significance of telomerase activity (TA) and telomere length (TL) in multiple myeloma (MM) in MM cells isolated from the bone marrow of 183 MM patients either at diagnosis or in relapse. Findings included:
 - Heterogeneity in telomerase expression. 36% of the patients had normal TA levels.
 - The TL of MM cells was shorter than that of the patients' own leukocytes.
 - 7 patients had unusually long telomeres, and 5/7 patients had low TA, indicating the presence of a TA-independent pathway of telomere stabilization.
 - Negative correlation between TA and TL or platelet count.
 - Negative correlation between TL and age, IL-6 levels, or beta2-microglobulin levels.
 - Cytogenetic abnormalities strongly correlated with TA and with short TL.
 - High TA and short TL were associated with poor prognosis.

Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease.
Blood. 2003 Jun 15;101(12):4998-5006.
Magrangeas F, Nasser V, Avet-Loiseau H, Loriod B, Decaux O, Granjeaud S, Bertucci F, Birnbaum D, Nguyen C, Harousseau JL, Bataille R, Houlgatte R, Minvielle S.

Thalidomide and deep vein thrombosis in multiple myeloma: risk factors and effect on survival.
Clin Lymphoma. 2003 Jun;4(1):32-5.
Zangari M, Barlogie B, Thertulien R, Jacobson J, Eddleman P, Fink L, Fassas A, Van Rhee F, Talamo G, Lee CK, Tricot G.
Evaluation of 535 patients treated with thalidomide and corticosteroids or several types or chemotherapy found a total of 82 patients who developed DVT. The frequency of DVT was affected by several factors, including newly diagnosed disease and concomitant therapy with doxorubicin. The development of DVT did not adversely influence survival.

IgM myeloma and Waldenstrom's macroglobulinemia: a distinct clinical feature, histology, immunophenotype, and chromosomal abnormality.
Clin Lab Haematol. 2003 Jun;25(3):187-90.
Chehal A, Taher A, Shamseddine A.
Case report of a patient with IgM myeloma.

Detection of minimal residual disease in hematologic malignancies by real-time quantitative PCR: principles, approaches, and laboratory aspects.
Leukemia. 2003 Jun;17(6):1013-34.
van der Velden VH, Hochhaus A, Cazzaniga G, Szczepanski T, Gabert J, van Dongen JJ.

Thalidomide and dexamethasone for resistant multiple myeloma.
Br J Haematol. 2003 Jun;121(5):768-71.
Anagnostopoulos A, Weber D, Rankin K, Delasalle K, Alexanian R.
47 patients with resistant myeloma were treated with dexamethasone + thalidomide. Response rate was 47% (CR 13%). DVT occurred in 8% of patients.

A phase 2 study of bortezomib in relapsed, refractory myeloma.
N Engl J Med. 2003 Jun 26;348(26):2609-17.
Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC.
In this phase II trial, 202 patients with refractory myeloma received bortezomib for up to 8 cycles (6 months). Patients received dexamethasone 20 mg PO on the day of bortezomib and the day after, in case of no disease response. Results:
  - Response rate: 35%
  - Median duration of response: 12 months
  - Median overall survival: 16 months
Significant toxicities (grade III) included:
  - Thrombocytopenia (28%), neutropenia (11%)
  - Peripheral neuropathy (12%)
  - Fatigue (12%)

Idiotype vaccination in multiple myeloma induced a reduction of circulating clonal tumor B cells.
Blood. 2003 Jun 1;101(11):4607-10.
Rasmussen T, Hansson L, Osterborg A, Johnsen HE, Mellstedt H.
No significant reduction of the serum M component was noted in 6 patients with stage I IgG myeloma after idiotype vaccination.

Clinical and biologic implications of recurrent genomic aberrations in myeloma.
Blood. 2003 Jun 1;101(11):4569-75. Epub 2003 Feb 6.
Fonseca R, Blood E, Rue M, Harrington D, Oken MM, Kyle RA, Dewald GW, Van Ness B, Van Wier SA, Henderson KJ, Bailey RJ, Greipp PR.
FISH in 351 myeloma patients treated with conventional chemotherapy allowed to identify 3 risk categories:
 1 - High risk: median survival 24.7 months
         t(4; 14) (42 patients)
         t(14;16) (15 patients)
         -17p13 (37 patients)
  2 - Intermediate risk: median survival 42.3 months
         -13q14 (176 patients)
  3 - Good risk: median survival 50.5 months
         All others



Giampaolo Talamo, M.D.