Accurate identification of paraprotein antigen targets by epitope reconstruction.
Blood. 2008 Jan 1;111(1):302-8.
Sompuram SR, Bastas G, Vani K, Bogen SA.
Authors applied a technology called "epitope-mediated antigen prediction" (E-MAP) to try to systematically identify the protein targets of paraproteins. They first reconstructed the paraproteins' epitope by analyzing the peptides binding to them, then they interrogated the protein database, searching for a match. E-MAP analysis of 2 MM paraproteins identified human cytomegalovirus (CMV) as a target in both, one binding to the AD-2S1 epitope of CMV glycoprotein B, and the other one binding to the amino terminus of the CMV UL-48 protein.

The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity.
Blood. 2008 Jan 15;111(2):856-64.
Lauring J, Abukhdeir AM, Konishi H, Garay JP, Gustin JP, Wang Q, Arceci RJ, Matsui W, Park BH.
These authors provided evidence that MMSET plays a significant role in t(4;14) MM cells.
 - Down-regulation of MMSET expression in MM cell lines reduced colony formation in methylcellulose
 - The effect in liquid culture was modest
 - MMSET knockdown led to cell-cycle arrest of adherent MM cells and reduced the ability of MM cells to adhere to extracellular matrix.
 - MMSET knockdown and knockout reduced tumor formation by MM xenografts

Pulmonary interstitial amyloidosis complicating multiple myeloma.
J Clin Oncol. 2008 Jan 20;26(3):504-6.
Chim CS, Wong M, Fan Y.



Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma.
Blood. 2008 Feb 1;111(3):1309-17.
Shi J, Tricot GJ, Garg TK, Malaviarachchi PA, Szmania SM, Kellum RE, Storrie B, Mulder A, Shaughnessy JD Jr, Barlogie B, van Rhee F

RHAMM-R3 peptide vaccination in patients with acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma elicits immunologic and clinical responses.
Blood. 2008 Feb 1;111(3):1357-65.
Schmitt M, Schmitt A, Rojewski MT, Chen J, Giannopoulos K, Fei F, Yu Y, G÷tz M, Heyduk M, Ritter G, Speiser DE, Gnjatic S, Guillaume P, Ringhoffer M, Schlenk RF, Liebisch P, Bunjes D, Shiku H, Dohner H, Greiner J.
RHAMM-R3 peptide vaccination induced a reduction of serum free light chains levels in 2 of 4 myeloma patients. RHAMM (receptor for hyaluronic acid-mediated motility) is an antigen that elicits both humoral and cellular immune responses in multiple myeloma and other malignancies.

Prognostic impact of cancer/testis antigen expression in advanced stage multiple myeloma patients.
Cancer Immun. 2008 Feb 1;8:2.
Andrade VC, Vettore AL, Felix RS, Almeida MS, Carvalho F, Oliveira JS, Chauffaille ML, Andriolo A, Caballero OL, Zago MA, Colleoni GW.

Bone marrow trephine combined with immunohistochemistry is superior to bone marrow aspirate in follow-up of myeloma patients.
J Clin Pathol. 2008 Feb;61(2):213-6.
Joshi R, Horncastle D, Elderfield K, Lampert I, Rahemtulla A, Naresh KN.
This is a study of 106 bone marrow samples, comparing conventional 500-cell differential count in the bone marrow aspirate vs the IHC of the bone marrow biopsy. The mean plasma cell number was 13% in the bone marrow aspirate and 32% in the bone marrow biopsy with IHC. While the positive predictive value was 100% with both tests, the negative predictive value was higher with the biopsy + IHC than the aspirate (57% vs 22%).

18F-FDG PET/CT, 99mTc-MIBI, and MRI in evaluation of patients with multiple myeloma.
J Nucl Med. 2008 Feb;49(2):195-200.
Fonti R, Salvatore B, Quarantelli M, Sirignano C, Segreto S, Petruzziello F, Catalano L, Liuzzi R, Rotoli B, Del Vecchio S, Pace L, Salvatore M.
This is a prospective study comparing imaging findings in 33 newly diagnosed patients with MM, who underwent whole-body (18)F-FDG PET/CT, whole-body (99m)Tc-MIBI, and MRI of the spine and pelvis within 10 days.
 - FDG PET/CT was positive in 32 patients (16 with focal uptake, 3 with diffuse uptake, and 13 with both focal and diffuse uptake)
   Total: 196 focal lesions (178 in bones and 18 in soft tissues), of which 121 in areas other than the spine and pelvis
 - (99m)Tc-MIBI was positive in 30 patients (6 focal, 11 diffuse, 13 focal and diffuse uptake)
   Total: 63 focal lesions (60 in bones and 3 in soft tissues), of which 53 in areas other than the spine and pelvis
 - MRI of the spine and pelvis was positive in 27 patients (6 focal, 13 diffuse, 8 focal and diffuse uptake)
   Total: 51 focal lesions (40 in spine and 11 in pelvis)
PET/CT performed better than (99m)Tc-MIBI in the detection of focal lesions, whereas (99m)Tc-MIBI was superior in the visualization of diffuse disease. In the spine and pelvis, MRI was comparable to FDG PET/CT and (99m)Tc-MIBI. Since myelomatous lesions often develop out of spinal and pelvic areas, MRI should be reserved to the evaluation of bone marrow involvement of these regions.

Flow cytometric minimal residual disease monitoring in patients with multiple myeloma undergoing autologous stem cell transplantation: a retrospective study.
Leuk Lymphoma. 2008 Feb;49(2):306-14.
Liu H, Yuan C, Heinerich J, Braylan R, Chang M, Wingard J, Moreb J.
Flow cytometry of the bone marrow before and after autologous stem cell transplant was obtained in 39 patients with multiple myeloma. Normal plasma cells were distinguished from aberrant plasma cells based on the expression of CD38, CD45, CD56, and CD19. A detectable population of aberrant plasma cells was found in all patients before the transplant, and in 52% of cases after the transplant. Survival analysis showed a correlation between the detection of aberrant plasma cells in the flow cytometry of the bone marrow aspirates after the transplant, and a poorer progression-free survival.

BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma.
Blood. 2008 Feb 1;111(3):1101-9.
Niesvizky R, Jayabalan DS, Christos PJ, Furst JR, Naib T, Ely S, Jalbrzikowski J, Pearse RN, Zafar F, Pekle K, Larow A, Lent R, Mark T, Cho HJ, Shore T, Tepler J, Harpel J, Schuster MW, Mathew S, Leonard JP, Mazumdar M, Chen-Kiang S, Coleman M.
The BiRD regimen was used as first-line therapy in 72 myeloma patients. RR= 90.3%, CR= 38.9%.
The BiRD regimen consists of:
  - Clarithromycin (Biaxin«) 500 mg PO bid
  - Revlimid 25 mg PO days 1-21
  - Dexamethasone 40 mg PO once weekly
Cycles are repeated every 28 days.
Supportive therapy: ASA 81 mg PO qd, omeprazole 20 mg PO qd, Bactrim DS 1 tab PO bid 3 times/week.
Clarithromycin potentiates the effects of corticosteroids.

[Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial.
Blood. 2008 Feb 15;111(4):1805-10.
Abdelkefi A, Ladeb S, Torjman L, Othman TB, Lakhal A, Romdhane NB, Omri HE, Elloumi M, Belaaj H, Jeddi R, Aissaou´ L, Ksouri H, Hassen AB, Msadek F, Saad A, Hsa´ri M, Boukef K, Amouri A, Louzir H, Dellagi K, Abdeladhim AB; Tunisian Multiple Myeloma Study Group.
This study has been retracted in June 2009]

AMD3100 plus G-CSF can successfully mobilize CD34+ cells from non-Hodgkin's lymphoma, Hodgkin's disease and multiple myeloma patients previously failing mobilization with chemotherapy and/or cytokine treatment: compassionate use data.
Bone Marrow Transplant. 2008 Feb;41(4):331-8.
Calandra G, McCarty J, McGuirk J, Tricot G, Crocker SA, Badel K, Grove B, Dye A, Bridger G.
AMD3100 given with G-CSF mobilized CD34+ cells in approximately 71% of myeloma patients who failed stem cell collection. The most common toxicities of AMD3100 were gastrointestinal reactions, injection site reactions, and paresthesias. No serious adverse events were observed.


MARCH 2008

Autologous antitumor activity by NK cells expanded from myeloma patients using GMP-compliant components.
Blood. 2008 Mar 15;111(6):3155-62.
Alici E, Sutlu T, Bj÷rkstrand B, Gilljam M, Stellan B, Nahi H, Quezada HC, Gahrton G, Ljunggren HG, Dilber MS.

Multiple myeloma.
Blood. 2008 Mar 15;111(6):2962-72.
Kyle RA, Rajkumar SV.
Historically focused review of MM, since the description of the first case in 1844.

The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor.
Blood. 2008 Mar 15;111(6):3145-54.
Marango J, Shimoyama M, Nishio H, Meyer JA, Min DJ, Sirulnik A, Martinez-Martinez Y, Chesi M, Bergsagel PL, Zhou MM, Waxman S, Leibovitch BA, Walsh MJ, Licht JD.
MMSET possesses domains found within chromatin regulators, including the SET domain
 - MMSET possesses methyltransferase activity for core histone H3 lysine 4 and histone 4 lysine 20
 - MMSET-mediated repression was associated with increased H4K20 methylation gene and loss of histone acetylation
 - MMSET formed a complex with HDAC1 and HDAC2, mSin3a, and the histone demethylase LSD1
 - MMSET coexpression enhanced HDAC1- and HDAC2-mediated repression
 - Knockdown of MMSET compromised viability of a myeloma cell line
This study indicate that MMSET influences gene expression as a direct modifier of chromatin and through binding with other chromatin-modifying enzymes.

IgM myeloma: a rare entity characterized by a CD20-CD56-CD117- immunophenotype and the t(11;14).
Br J Haematol. 2008 Mar;140(5):547-51.
Feyler S, O'Connor SJ, Rawstron AC, Subash C, Ross FM, Pratt G, Drayson MT, Ashcroft J, Cook G, Owen RG.
These authors report 10 cases of IgM myeloma. They conclude that IgM myeloma is characterized by a CD20-, CD56-, CD117- phenotype and the t(11;14) translocation.
Phenotype: 70% had an aberrant phenotype CD19+, CD45+, CD27+ and Cyclin D1+, but all cases were CD56- and CD117-.
FISH: 50% had deletion 13, and 5/8 cases had the t(11;14) translocation. Despite the high incidence of the t(11;14) translocation, CD20 was positive in only 1 of 9 cases.

Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders.
Haematologica. 2008 Mar;93(3):431-8.
Rawstron AC, Orfao A, Beksac M, Bezdickova L, Brooimans RA, Bumbea H, Dalva K, Fuhler G, Gratama J, Hose D, Kovarova L, Lioznov M, Mateo G, Morilla R, Mylin AK, OmedÚ P, Pellat-Deceunynck C, Perez Andres M, Petrucci M, Ruggeri M, Rymkiewicz G, Schmitz A, Schreder M, Seynaeve C, Spacek M, de Tute RM, Van Valckenborgh E, Weston-Bell N, Owen RG, San Miguel JF, Sonneveld P, Johnsen HE; European Myeloma Network.
This report indicates several technical recommendations for the correct identification of malignant plasma cells by flow cytometry. Recommendations included:
  1 - The primary gating strategy should be based on CD38 vs CD138 expression, to ensure that CD45+ plasma cells are not excluded
  2 - Plasma cells should be identified and counted by simultaneous expression of CD38, CD138 and CD45
  3 - The panel for abnormal plasma cells should include at least CD19 and CD56 (essential), and also CD20, CD27, CD28, and CD117 (recommended)

Improved survival in multiple myeloma and the impact of novel therapies.
Blood. 2008 Mar 1;111(5):2516-20.
Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR, Dingli D, Russell SJ, Lust JA, Greipp PR, Kyle RA, Gertz MA.
This study evaluated demonstrated the impact of the new agents (i.e., thalidomide, lenalidomide, or bortezomib) on the clinical outcomes of myeloma patients. In 387 myeloma patients who relapsed after stem cell transplant, patients who relapsed before 2000 had a median overall survival of 12 months, whereas patients who relapsed after 2000 had a median overall survival of 24 months. Patients who were treated with at least one of the new agents had a median survival after relapse longer than those patients who did not receive the new agents (31 vs 15 months). Survival was prolonged not only in relapsed disease, but also in patients with newly diagnosed myeloma: overall survival in 2981 patients with newly diagnosed myeloma diagnosed treated in the last decade was 45 months, whereas it was 30 months in those diagnosed before the last decade.

Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma.
Leuk Lymphoma. 2008 Mar;49(3):502-7.
Richardson P, Mitsiades C, Colson K, Reilly E, McBride L, Chiao J, Sun L, Ricker J, Rizvi S, Oerth C, Atkins B, Fearen I, Anderson K, Siegel D.

13 patients with relapsed/refractory myeloma were enrolled in a phase I trial of vorinostat 200, 250 or 300 mg PO bid for 5 days/week every 28 days or for 14 days every 21 days, continued until progressive disease or intolerable toxicity. MTD was not determined due to early study termination. Of 10 evaluable patients, there were 1 minimal response and 9 stable disease.

Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2.
Br J Haematol. 2008 Mar;140(6):625-34.
Pineda-Roman M, Zangari M, Haessler J, Anaissie E, Tricot G, van Rhee F, Crowley J, Shaughnessy JD Jr, Barlogie B.
After a median follow-up of 2 years and among 303 patients enrolled in TT3, 92% of patients who reached CR sustained their remission at 2 years. Superior outcomes of TT3 compared with TT2 are presumably due to the addition of bortezomib.



Giampaolo Talamo, M.D.