Possible roles for activating RAS mutations in the MGUS to MM transition and in the intramedullary to extramedullary transition in some plasma cell tumors.
Blood. 2005 Jan 1;105(1):317-23.
Rasmussen T, Kuehl M, Lodahl M, Johnsen HE, Dahl IM.
This study assessed the possible role of RAS mutations in tumor progression of MM. Authors evaluated the occurrence and type of K- and N-RAS mutations in plasma cells from patients with MGUS, MM, and extramedullary PC tumors. Only 1 RAS mutation was identified in 20 MGUS samples (5%), in contrast to 31% in MM. Surprisingly, RAS mutations were absent in bone marrow plasma cells from all patients with extramedullary disease. From 3 of 6 patients with both intramedullary and extramedullary PCs, RAS mutations were identified only in extramedullary PCs. These data suggest that RAS mutations may have a role in the transition from intramedullary to extramedullary disease.

Severe tremors associated with use of thalidomide.
Am J Hematol. 2005 Jan;78(1):81-2.
Chiruka S, Chapman CS.

Familiality of benign and malignant paraproteinemias. A population-based cancer-registry study of multiple myeloma families.
Haematologica. 2005 Jan;90(1):66-71.
Ogmundsdóttir HM, Haraldsdóttirm V, Jóhannesson GM, Olafsdóttir G, Bjarnadóttir K, Sigvaldason H, Tulinius H.
Although inheritance does not seem to be a major risk factor for the development of paraproteinemias, the occurrence of multiple cases of benign and malignant paraproteinemias in a few families does suggest a hereditary contribution. This survey investigated the familiality of MM, using a family registry of 218 MM cases and the records of the Icelandic Cancer Registry. First-degree relatives of MM patients did not have an increased relative risk of developing MGUS, but they had a significantly increased risk of developing MM (RR = 2.33, CI 1.12-4.26), especially for female relatives. In 3 families, both myeloid and lymphoid malignancies occurred.

Hyperammonemia: an unusual presenting feature of multiple myeloma.
Indian J Med Sci. 2005 Jan;59(1):24-7.
Shah AS, Shetty N, Jaiswal S, Mehta BC.
This is a case report of a 76 year old lady with altered mental status due to hyperammonemia. She had no evidence of liver disease, and work-up showed multiple myeloma. Treatment of myeloma resulted in a reduction of serum ammonia levels and improvement in her mental status. Hyperammonemia should be included in the differential diagnosis of altered mental status in multiple myeloma, along with the other more common causes, such as hypercalcemia and hyperviscosity.

Primary extramedullary plasmacytoma and multiple myeloma: phenotypic differences revealed by immunohistochemical analysis.
J Pathol. 2005 Jan;205(1):92-101.
Kremer M, Ott G, Nathrath M, Specht K, Stecker K, Alexiou C, Quintanilla-Martinez L, Fend F.
This study compares the IHC phenotype of 28 cases of primary extramedullary plasmacytoma with 17 cases of myeloma and 9 cases of extramedullary myeloma. Among the patients with primary extramedullary plasmacytoma, none of them progressed to multiple myeloma, 1 progressed to NHL, and 9 experienced local relapse. In comparison to extramedullary myeloma, primary extramedullary plasmacytoma was associated with a more mature morphology, lower proliferation indices, infrequent expression of CD56, and absence of cyclin D1.

Ophthalmic manifestations of multiple myeloma.
Ophthalmologica. 2005 Jan-Feb;219(1):43-8.
Fung S, Selva D, Leibovitch I, Hsuan J, Crompton J.
Ophthalmic manifestations of MM are very rare. These authors describe 8 MM patients with ophthalmic manifestations: 4 patients had neuro-ophthalmic symptoms resulting in diplopia or visual disturbances, 3 patients had orbital involvement, and 1 patient had hyperviscosity retinopathy.

Thalidomide salvage therapy following allogeneic stem cell transplantation for multiple myeloma: a retrospective study from the Intergroupe Francophone du Myélome (IFM) and the Société Française de Greffe de Moelle et Thérapie Cellulaire (SFGM-TC).
Bone Marrow Transplant. 2005 Jan;35(2):165-9.
Mohty M, Attal M, Marit G, Bulabois CE, Garban F, Gratecos N, Rio B, Vernant JP, Sotto JJ, Cahn JY, Blaise D, Jouet JP, Facon T, Yakoub-Agha I.
31 myeloma patients received salvage therapy with thalidomide after allogeneic stem cell ytransplant. RR was 29%.

Thalidomide in combination with vincristine, epirubicin and dexamethasone (VED) for previously untreated patients with multiple myeloma.
Eur J Haematol. 2005 Jan;74(1):40-6.
Schütt P, Ebeling P, Buttkereit U, Brandhorst D, Opalka B, Hoiczyk M, Flasshove M, Hense J, Bojko P, Metz K, Moritz T, Seeber S, Nowrousian MR.
31 patients with newly diagnosed myeloma were treated with thalidomide 400 mg/day + VED (vincristine, epirubicin, dexamethasone) every 3 weeks. CR was 19%, PR 61%, and stable disease 16%. DVT occurred in 26% of patients, and polyneuropathy in 65%.

Prognostic value of urinary pyridinium crosslinks and their derivatives in multiple myeloma.
Ann Hematol. 2005 Jan;84(1):19-24.
Samani KK, Brazier M, Mathiot C, Kamel S, Jamart J, Jaubert J, Blanc M, Azaïs I, Facon T, Leleu X.



IgD multiple myeloma - a clinical profile and outcome with chemotherapy and autologous stem cell transplantation.
Ann Hematol. 2005 Feb;84(2):115-7.
Wechalekar A, Amato D, Chen C, Keith Stewart A, Reece D.
This study evaluates the clinical features and outcomes of 25 patients with IgD multiple myeloma.
Associated disorders: 1 patient has B-CLL and another patient had hairy cell leukemia.
Cytogenetics: 3 of 9 patients had monosomy 13 (1 by cytogenetics and 2 by FISH), and 2 patients had a complex karyotype.
Outcome was worse than that observed in historical controls with other myeloma types.

Cure of myeloma: hype or reality?
Bone Marrow Transplant. 2005 Feb;35(3):215-24.
Fassas A, Shaughnessy J, Barlogie B.

Arterial thrombosis in four patients treated with thalidomide.
Leuk Lymphoma. 2005 Feb;46(2):239-42.
Scarpace SL, Hahn T, Roy H, Brown K, Paplham P, Chanan-Khan A, van Besien K, McCarthy PL Jr.
This is a report of 7 cases of arterial thrombotic events during therapy with thalidomide. 3 cases occurred in patients with other risk factors.

Analysis of outcome following allogeneic haemopoietic stem cell transplantation for myeloma using myeloablative conditioning--evidence for a superior outcome using melphalan combined with total body irradiation.
Br J Haematol. 2005 Feb;128(4):496-502.
Hunter HM, Peggs K, Powles R, Rahemtulla A, Mahendra P, Cavenagh J, Littlewood T, Potter M, Hunter A, Pagliuca A, Williams CD, Cook G, Towlson K, Marks David I, Russell NH; Clinical Trials Committee of the British Society of Blood and Marrow Transplantation (BSBMT).
This is a retrospective analysis of 139 myeloma patients treated with myeloablative sibling allogeneic stem cell transplant, using either cyclophosphamide/TBI or melphalan/TBI. Results:
  - Transplant-related mortality at 1 year was 38% (no difference between cyclophosphamide/TBI and melphalan/TBI)
  - CR was 47% with cyclophosphamide/TBI and 65% with melphalan/TBI (p= 0.085)
  - Risk of relapse/progression at 5 years was 81% with cyclophosphamide/TBI and 37% with cyclophosphamide/TBI (p < 0.0001)
  - Overall survival at 5 years was 28% with cyclophosphamide/TBI and of 44% with melphalan/TBI (p= 0.059)
Therefore, melphalan/TBI was a better regimen than cyclophosphamide/TBI.


MARCH 2005

Non-Hodgkin's lymphoma and other nonhepatic malignancies in Swedish patients with hepatitis C virus infection.
Hepatology. 2005 Mar;41(3):652-9.
Duberg AS, Nordström M, Törner A, Reichard O, Strauss R, Janzon R, Bäck E, Ekdahl K.
These authors evaluated the association between hepatitis C virus (HCV) infection and several hematologic malignancies, including MM, HL, NHL, CLL, and ALL in a Swedish cohort of 27,150 HCV+ persons. The relative risk of malignancy was expressed as a standardized incidence ratio (SIR)-the observed number compared to the expected number. During 1990-2000 there were 15 cases of MM. It was found that the risk of MM was significantly increased in persons with more than 15 years of infection, with a relative risk of 2.54 (95% CI, 1.11-5.69).

Minimal residual disease monitoring in multiple myeloma: flow cytometry is the method of choice.
Br J Haematol. 2005 Mar;128(5):732-3.
Owen RG, Rawstron AC.

Toxicity in standard melphalan-prednisone therapy among myeloma patients with renal failure: a retrospective analysis and recommendations for dose adjustment.
Br J Haematol. 2005 Mar;128(5):631-5.
Carlson K, Hjorth M, Knudsen LM; Nordic Myeloma Study Group.
272 patients with newly diagnosed myeloma were treated with melphalan + prednisone (MP) without dose adjustment for renal function. The hematological toxicity of melphalan was related to the degree of renal insufficiency. Grade 3-4 hematologic toxicity was:
  - 18% with GFR >50
  - 28% with GFR 30-50
  - 36% with GFR <30
Grades 3-4 infections developed in 6% of patients, and they were not related to the renal function. The authors recommend to decrease the dose of melphalan if the GFR is <30. No recommendations could be made for GFR <10 because only 2% of patients had such a degree of renal insufficiency.

Neurological toxicity of long-term (>1 yr) thalidomide therapy in patients with multiple myeloma.
Eur J Haematol. 2005 Mar;74(3):212-6.
Tosi P, Zamagni E, Cellini C, Plasmati R, Cangini D, Tacchetti P, Perrone G, Pastorelli F, Tura S, Baccarani M, Cavo M.
40 myeloma patients treated with thalidomide for longer than 12 months were assessed for neurotoxicity. Neurotoxicity was the most important and frequent (75%) toxicity of thalidomide. Symptoms included paresthesias, tremors, and dizziness.
  - Grade 1: 15%
  - Grade 2: 32.5%
  - Grade 3: 27.5% (patients with grade 3 neurotoxicity had to interrupt the therapy)
EMG showed a symmetrical, mainly sensory peripheral neuropathy.

Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impaired renal function.
Cancer. 2005 Mar 15;103(6):1195-200.
Jagannath S, Barlogie B, Berenson JR, Singhal S, Alexanian R, Srkalovic G, Orlowski RZ, Richardson PG, Anderson J, Nix D, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators.

Hematopoietic stem cell mobilization with intravenous melphalan and G-CSF in patients with chemoresponsive multiple myeloma: report of a phase II trial.
Bone Marrow Transplant. 2005 Mar;35(5):441-7.
Gupta S, Zhou P, Hassoun H, Kewalramani T, Reich L, Costello S, Drake L, Klimek V, Dhodapkar M, Teruya-Feldstein J, Hedvat C, Kalakonda N, Fleisher M, Filippa D, Qin J, Nimer SD, Comenzo RL.
32 patients with multiple myeloma underwent stem cell mobilization with melphalan 60 mg/m2 IV, followed by G-CSF 10 mcg/kg/day.
  - Median mobilization days: 16 (12-30)
  - Median CD34+ cells/kg: 12.1 million (2.6-52.8) in 2 days (1-5)
  - 4 patients (12.5 %) failed to achieve the target of 4 million CD34+ cells/kg in 5 leukaphereses
  - RR: 34%, with  CR 9%
  - 14 patients (44%) required hospitalization for neutropenic fever

The impact of donor gender on outcome of allogeneic hematopoietic stem cell transplantation for multiple myeloma: reduced relapse risk in female to male transplants.
Bone Marrow Transplant. 2005 Mar;35(6):609-17.
Gahrton G, Iacobelli S, Apperley J, Bandini G, Björkstrand B, Bladé J, Boiron JM, Cavo M, Cornelissen J, Corradini P, Kröger N, Ljungman P, Michallet M, Russell NH, Samson D, Schattenberg A, Sirohi B, Verdonck LF, Volin L, Zander A, Niederwieser D.
This is a retrospective study of 1312 myeloma patients who underwent allogeneic stem cell transplant from HLA-identical siblings. It suggested that the donor gender influences the outcome: for female patients, the use of a male donor was a negative factor for outcome.
  - Male to male (476): median OS 25 months
  - Female to male (334): median OS 18 months
  - Male to female (258): median OS 19 months
  - Female to female (244): median OS 41 months



Giampaolo Talamo, MD