JULY 2004

Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma.
Blood. 2004 Jul 1;104(1):40-2.
Ma CX, Lacy MQ, Rompala JF, Dispenzieri A, Rajkumar SV, Greipp PR, Fonseca R, Kyle RA, Gertz MA.
Fanconi syndrome (FS) is a rare complication of monoclonal gammopathy. These authors reviewed 32 patients with adult-acquired FS. At diagnosis, most patients had MGUS or smoldering myeloma. Their median serum creatinine was 2.0 mg/dL. Afteer a median follow-up of 65 months, 5 patients developed ESRD, and only 1 of 14 patients with MGUS progressed to MM. Therefore, FS associated with monoclonal gammopathy does not seem to increase the risk of progression to MM.

Extramedullary multiple myeloma escapes the effect of thalidomide.
Haematologica. 2004 Jul;89(7):832-6.
Rosiñol L, Cibeira MT, Bladé J, Esteve J, Aymerich M, Rozman M, Segarra M, Cid MC, Filella X, Montserrat E.
11 of 38 myeloma patients treated with thalidomide had extramedullary disease. The response rate was 59% in patients without extramedullary involvement, but extramedullary disease did not respond to thalidomide. Tumor markers reduced in 4 of 11 patients with extramedullary disease, but all patients had progression of the soft-tissue masses.

Thalidomide for patients with relapsed multiple myeloma after high-dose chemotherapy and stem cell transplantation: results of an open-label multicenter phase 2 study of efficacy, toxicity, and biological activity.
Mayo Clin Proc. 2004 Jul;79(7):875-82.
Richardson P, Schlossman R, Jagannath S, Alsina M, Desikan R, Blood E, Weller E, Mitsiades C, Hideshima T, Davies F, Doss D, Freeman A, Bosch J, Patin J, Knight R, Zeldis J, Dalton W, Anderson K.
This is a phase 2 study thalidomide 200-600 mg PO qhs, in 30 patients with MM that relapsed after stem cell transplantation. Results:
  - Response rate was 43% (including partial response and minor response)
  - Median duration of response was 6 months
  - Progression-free survival at 3 months was 67%

First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma.
Haematologica. 2004 Jul;89(7):826-31.
Cavo M, Zamagni E, Tosi P, Cellini C, Cangini D, Tacchetti P, Testoni N, Tonelli M, de Vivo A, Palareti G, Tura S, Baccarani M.
This is a phase II study of dexamethasone + thalidomide as first-line therapy in 71 patients with newly diagnosed myeloma. Thalidomide was given at a dose of 200 mg PO qhs, and dexamethasone at the dose of 40 mg PO on days 1-4, 9-12, and 17- 20 in odd cycles, and on days 1-4 in even cycles, for a total of 4 monthly cycles. Response rate was 66% (CR + VGPR 17%). DVT developed in 16% of patients.

High-dose cyclophosphamide with or without etoposide for mobilization of peripheral blood progenitor cells in patients with multiple myeloma: efficacy and toxicity.
Bone Marrow Transplant. 2004 Jul;34(1):69-76.
Gojo I, Guo C, Sarkodee-Adoo C, Meisenberg B, Fassas A, Rapoport AP, Cottler-Fox M, Heyman M, Takebe N, Tricot G.
77 myeloma patients underwent stem cell mobilization with:
  - Cyclophosphamide 4.5 g/m2 alone (28 patients, Group 1)
  - Cyclophosphamide 4.5 g/m2 + etoposide 2 g/m2 (49 patients, Group 2)
  - A median of 22.4 million CD34+ cells/kg were collected on the first day of leukapheresis (range 0.59-114.7)
  - The addition of etoposide resulted in similar stem cell yields but higher toxicity
  - RR including minimum response by EBMT criteria was 45% in Group 1 and 56% in Group 2.
  - Patients requiring hospitalization, mainly for neutropenic fever: 25% in Group 1 and 75% in Group 2.
  - Prior RT inhibited CD34+ cell yield

High-dose therapy and autologous stem cell transplantation for multiple myeloma poorly responsive to initial therapy.
Bone Marrow Transplant. 2004 Jul;34(2):161-7.
Kumar S, Lacy MQ, Dispenzieri A, Rajkumar SV, Fonseca R, Geyer S, Allmer C, Witzig TE, Lust JA, Greipp PR, Kyle RA, Litzow MR, Gertz MA.
This study evaluates the efficacy of autologous stem cell transplantation in patients with newly diagnosed MM who fail initial therapy, i.e., primary refractory disease. The authors compared outcomes of 50 patients with primary refractory MM to 101 patients with chemosensitive disease. Results:
  - Response (50% reduction in the M protein) was observed in 46 patients (92%) in the refractory group and 100 (99%) in the chemosensitive group
  - CR was observed in 10 patients (20%) in the refractory group and 35 (35%) in the chemosensitive group (p=0.06)
  - The 1-year estimated PFS from the time of transplant was 70% in the refractory group and 83% in the chemosensitive group (p=0.65)
The authors concluded that lack of response to initial induction therapy does not preclude a good response to autologous transplant.

Graft-versus-myeloma effect following antithymocyte globulin-based reduced intensity conditioning allogeneic stem cell transplantation.
Bone Marrow Transplant. 2004 Jul;34(1):77-84.
Mohty M, Boiron JM, Damaj G, Michallet AS, Bay JO, Faucher C, Perreau V, Bilger K, Coso D, Stoppa AM, Tabrizi R, Gastaut JA, Michallet M, Maraninchi D, Blaise D.
In this study, 41 patients with myeloma received a RIC allogeneic stem cell transplant  from HLA-identical siblings, using ATG, fludarabine, and busulfan. Transplant-related mortality was 17%. At 2 years, OS was 62% and PFS was 41%.



A molecular basis for nonsecretory myeloma.
Blood. 2004 Aug 1;104(3):829-31.
Coriu D, Weaver K, Schell M, Eulitz M, Murphy CL, Weiss DT, Solomon A.
This is the first study which proved that the pathogenesis of non-secretory myeloma is related to the synthesis of of an aberrant immunoglobulin polypeptide. In a patient with non-secretory myeloma, the kappa light chain sequence was altered by a frameshift mutation in nucleotides encoding the constant region of the peptide. Because of a 2-base deletion in codon 187 and loss of the normal stop codon, the kappa chain was composed of 128 amino acids instead of the expected 106. The amino acid sequence was completely altered, and the cysteines required for intrachain and interchain disulfide bonds were absent.

Serum free light chains for monitoring multiple myeloma.
Br J Haematol. 2004 Aug;126(3):348-54.
Mead GP, Carr-Smith HD, Drayson MT, Morgan GJ, Child JA, Bradwell AR.

Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure.
Eur J Haematol. 2004 Aug;73(2):98-103.
Tosi P, Zamagni E, Cellini C, Cangini D, Tacchetti P, Tura S, Baccarani M, Cavo M.
Thalidomide was safely administered in 20 patients with relapsed/refractory myeloma and renal failure.

Clinical outcomes with intensive therapy for patients with primary resistant multiple myeloma.
Bone Marrow Transplant. 2004 Aug;34(3):229-34.
Alexanian R, Weber D, Delasalle K, Handy B, Champlin R, Giralt S.
This study evaluates outcomes of autologous SCT in 89 myeloma patients who did not respond to dexamethasone-based induction therapy.
Response rate: 69%, including 16% CR. CR occurred in 43% of patients with serum M component <1.5 g/dL, and 7% of patients with higher values.
Median survival was:
  - >7.0 years in 14 patients with CR
  - 4.5 years in 47 patients with PR
  - 2.2 years in 28 patients with NR



Cell proliferation of myeloma plasma cells: comparison of the blood and marrow compartments.
Am J Hematol. 2004 Sep;77(1):7-11.
Kumar S, Rajkumar SV, Greipp PR, Witzig TE.
These authors compared the plasma cell labeling index (PCLI) of the bone marrow plasma cells with the PCLI of circulating plasma cells in 117 myeloma patients. The PCLI in the peripheral blood correlated with the PCLI in the bone marrow, and it was usually lower (median difference: 0.4), suggesting that myeloma cells find a more favorable microenvironment in the marrow. 27 of 117 patients had a PCLI higher in the peripheral blood than in the bone marrow, and these patients had a worse prognosis (median survival from the time of the test was 2 months, vs 12 months for the other 90 patients, p= 0.01).

Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation.
Br J Haematol. 2004 Sep;126(5):715-21.
Zangari M, Barlogie B, Anaissie E, Saghafifar F, Eddlemon P, Jacobson J, Lee CK, Thertulien R, Talamo G, Thomas T, Van Rhee F, Fassas A, Fink L, Tricot G.

Among 256 newly diagnosed myeloma patients randomized to thalidomide vs no thalidomide, DVT was observed more frequently in the thalidomide group (hazard ratio: 4.5). Low dose coumadin (1 mg/day) did not prevent venous thromboembolism, whereas LMWH (enoxaparin 40 mg SC qd) effectively prevented it.

Single agent dexamethasone for pre-stem cell transplant induction therapy for multiple myeloma.
Bone Marrow Transplant. 2004 Sep;34(6):485-90.
Kumar S, Lacy MQ, Dispenzieri A, Rajkumar SV, Fonseca R, Geyer S, Allmer C, Witzig TE, Lust JA, Greipp PR, Kyle RA, Litzow MR, Gertz MA.
This is a retrospective study evaluating the effectiveness of single agent dexamethasone as induction therapy for myeloma before stem cell transplantation. A group of 35 patients treated with dexamethasone alone was compared to a group of 72 patients treated with VAD. Results:
  - Response rate before transplant was 63% with dexamethasone and 74% with VAD (p= 0.25)
  - Response rate after transplant was 97% with dexamethasone and 100% with VAD (p= 0.33)
  - Complete response rate after transplant was 26% with dexamethasone and 39% with VAD (p= 0.18)
  - Progression-free survival and overall survival at 1 year after transplant were similar between the two groups
These results showed that single agent dexamethasone had an efficacy similar to VAD for the induction therapy of myeloma before stem cell transplantation.

A clinical and pharmacological study of arsenic trioxide in advanced multiple myeloma patients.
Leukemia. 2004 Sep;18(9):1518-21.
Rousselot P, Larghero J, Arnulf B, Poupon J, Royer B, Tibi A, Madelaine-Chambrin I, Cimerman P, Chevret S, Hermine O, Dombret H, Claude Brouet J, Paul Fermand J.
In this study, 12 patients with relapsing or refractory MM patients were treated with arsenic - 10 patients with arsenic trioxide (ATO), and 2 with melarsoprol, an organic compound of arsenic. The melarsoprol arm was prematurely closed due to toxicity. In the ATO arm, median duration of treatment was 38 days (9-54). Results:
  - No complete or partial remission was observed
  - 3 patients had a minor response, i.e., a 25-49% reduction of serum M protein
  - 4 patients had a stabilization of the serum M protein level
Responses were of short duration in all cases.



Giampaolo Talamo, M.D.