Differential pattern of CD4+ and CD8+ T-cell immunity to MAGE-A1/A2/A3 in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma.
Blood. 2008 Oct 15;112(8):3362-72.
Goodyear OC, Pratt G, McLarnon A, Cook M, Piper K, Moss P.

Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: a study of the Intergroupe Francophone du Myélome.
J Clin Oncol. 2008 Oct 10;26(29):4798-805.
Decaux O, Lodé L, Magrangeas F, Charbonnel C, Gouraud W, Jézéquel P, Attal M, Harousseau JL, Moreau P, Bataille R, Campion L, Avet-Loiseau H, Minvielle S; Intergroupe Francophone du Myélome.
These authors used gene expression profiles of plasma cells from 182 MM patients obtained at diagnosis to identify prognostic markers. The validity of our model was assessed in in three independent cohorts of 853 MM patients. High-risk patients had overexpression of genes involved in cell cycle progression and its surveillance, whereas low-risk patients had hyperdiploid signatures.

Combined functional and molecular analysis of tumor cell signaling defines 2 distinct myeloma subgroups: Akt-dependent and Akt-independent multiple myeloma.
Blood. 2008 Oct 15;112(8):3403-11.
Zöllinger A, Stühmer T, Chatterjee M, Gattenlöhner S, Haralambieva E, Müller-Hermelink HK, Andrulis M, Greiner A, Wesemeier C, Rath JC, Einsele H, Bargou RC.
This study tried to assess the importance of Akt phosphatidylinositide 3-kinase (PI3K)/Akt pathway both in primary MM samples and MM cell lines. With various techniques of molecular biology, authors demonstrated that there are 2 MM subgroups: Akt-dependent and Akt-independent MM.

Prognostic value of the serum free light chain ratio in newly diagnosed myeloma: proposed incorporation into the international staging system.
Leukemia. 2008 Oct;22(10):1933-7.
Snozek CL, Katzmann JA, Kyle RA, Dispenzieri A, Larson DR, Therneau TM, Melton LJ 3rd, Kumar S, Greipp PR, Clark RJ, Rajkumar SV.
Serum levels of free light chains were obtained at the time of diagnosis in 790 patients with multiple myeloma. The levels had prognostic significance, with inferior survival in 479 patients with a kappa/lambda ratio >32 (kappa myeloma) or <0.03 (lambda myeloma) compared with 311 patients with a kappa/lambda ratio between 0.03 and 32 ( 30 vs 39 months). The authors incorporated the abnormal kappa/lambda ratio with the ISS, for improved risk stratification.

Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial.
Blood. 2008 Oct 15;112(8):3107-14.
Palumbo A, Bringhen S, Liberati AM, Caravita T, Falcone A, Callea V, Montanaro M, Ria R, Capaldi A, Zambello R, Benevolo G, Derudas D, Dore F, Cavallo F, Gay F, Falco P, Ciccone G, Musto P, Cavo M, Boccadoro M.
This is an updated analysis of efficacy and safety of MP vs MPT in multiple myeloma, after a median follow-up of 38.1 months.
  - The median PFS was 14.5 months with MP and 21.8 months with MPT (p= 0.004)
  - The median OS was 47.6 months with MP and 45.0 months with MPT (p= 0.79)
The results confirmed the activity of MPT for PFS but they failed to show a survival advantage. This is presumably due to the fact that salvage therapy with thalidomide or bortezomib improved survival after progression in the MP group, but not in the MPT group.

Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study.
J Clin Oncol. 2008 Oct 10;26(29):4784-90.
Chanan-Khan A, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Neuwirth R, Anderson KC, Richardson PG.
The authors evaluated the incidence of VZV reactivation in 663 patients with relapsed myeloma enrolled in the APEX trial (phase III trial comparing bortezomib vs dexamethasone). They found that bortezomib treatment was associated with a significantly higher incidence of VZV reactivation compared with dexamethasone treatment (13% vs 5%, p =0.0002). Time to onset of VZV reactivation and absolute lymphocyte counts at baseline were similar between the two arms. The incidence of other (non-VZV) herpes viral infections was similar between the two arms. The authors concluded that the use of antiviral prophylaxis considered in all patients treated with bortezomib.

Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma.
J Clin Oncol. 2008 Oct 10;26(29):4777-83.
Reece DE, Rodriguez GP, Chen C, Trudel S, Kukreti V, Mikhael J, Pantoja M, Xu W, Stewart AK.
This is a phase I-II trial that evaluated the combination of bortezomib, cyclophosphamide, and prednisone in 37 patients with relapsed/refractory MM. Regimen:
  - Bortezomib 1.3-1.5 mg/m2 IV on days 1, 4, 8, 11
  - Cyclophosphamide 300 mg/m2 PO once a week
  - Prednisone PO on alternate days
  - Response rate was 95%, when including minor responses. CR was reached in >50% of patients.
  - 1-year progression-free survival: 83%
  - 1-year overall survival 100%

Poor outcomes for IgD multiple myeloma patients following high-dose melphalan and autologous stem cell transplantation: a single center experience.
J Korean Med Sci. 2008 Oct;23(5):819-24.
Chong YP, Kim S, Ko OB, Koo JE, Lee D, Park SH, Park SJ, Lee D, Kim SW, Suh C.
This is a small study comparing outcomes of 8 patients with IgD myeloma vs 69 patients with other types of myeloma. Outcomes after autologous stem cell transplant were inferior among patients with IgD MM:
  - The median  event-free survival was 6.9 months in IgD MM vs 11.5 months in other types of MM
  - The median overall survival was 12 months vs 55.5 months in other types of MM

A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma.
Cancer. 2008 Oct 1;113(7):1588-95.
Musto P, Petrucci MT, Bringhen S, Guglielmelli T, Caravita T, Bongarzoni V, Andriani A, D'Arena G, Balleari E, Pietrantuono G, Boccadoro M, Palumbo A; GIMEMA (Italian Group for Adult Hematologic Diseases)/Multiple Myeloma Working Party and the Italian Myeloma Network.
163 patients with asymptomatic myeloma were randomized to receive either zoledronic acid 4 mg IV monthly x12 (81 patients) or observation (82 patients). Progression to symptomatic myeloma was similar in the two groups: 44.4% of patients in the zoledronic acid group and 45.1% of the patients in the control group. The median time to progression was also similar (67 vs 59 months, p= 0.8312). At progression, the skeletal complications were reduced in the zoledronic acid group (55.5% vs 78.3%, p= 0.041)ONJ was seen in 1 patient. This study demonstrated that zoledronic acid reduced the development of skeletal complications, but it did not reduce/delay the progression of the disease. The results do not support the notion that bisphosphonate may have a direct antineoplastic activity.

Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease.
Blood. 2008 Oct 15;112(8):3122-5.
Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB.
This is a phase II trial of thalidomide in 76 patients with smoldering myeloma. Thalidomide was given at 200 mg PO qhs. Results:
  - Partial response: 25%
  - 4-year overall survival: 91%
  - 4-year event-free survival: 60%
  - 86% of patients required dose reduction, and 50% discontinuation of the drug

Comparison of twin and autologous transplants for multiple myeloma.
Bashey A, Pérez WS, Zhang MJ, Anderson KC, Ballen K, Berenson JR, To LB, Fonseca R, Freytes CO, Gale RP, Gibson J, Giralt SA, Kyle RA, Lazarus HM, Maharaj D, McCarthy PL, Milone GA, Nimer S, Pavlovsky S, Reece DE, Schiller G, Vesole DH, Hari P; Plasma Cell Disorders Working Committee.
Biol Blood Marrow Transplant. 2008 Oct;14(10):1118-24.
This is a study of 43 patients treated with syngeneic transplant. When compared with a matched group of patients treated with autologous transplant, these patients had a lower relapse/progression rate, and longer progression-free survival.

Treatment of myeloma: cure vs control.
Mayo Clin Proc. 2008 Oct;83(10):1142-5.
Rajkumar SV.



Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation.
Blood. 2008 Nov 15;112(10):4017-23.
Paiva B, Vidriales MB, Cerveró J, Mateo G, Pérez JJ, Montalbán MA, Sureda A, Montejano L, Gutiérrez NC, García de Coca A, de Las Heras N, Mateos MV, López-Berges MC, García-Boyero R, Galende J, Hernández J, Palomera L, Carrera D, Martínez R, de la Rubia J, Martín A, Bladé J, Lahuerta JJ, Orfao A, San Miguel JF; GEM (Grupo Español de MM)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) Cooperative Study Groups.
This is a prospective study which evaluates the prognostic significance of flow cytometry in detecting minimal residual disease after stem cell transplant. 295 patients with newly diagnosed myeloma underwent autologous stem cell transplant, and disease remission was evaluated at day 100 after transplant. In the group of patients with minimal residual disease by flow cytometry, the median progression-free survival was 37 months, whereas in the group of patients with negative flow cytometry (two-thirds of patients), the median PFS was 71 months. Overall survival was also different between the two groups (89 months vs not reached. The authors demonstrated a prognostic significance even when they defined CR by immunofixation status, but at multivariate analysis the presence of minimal residual disease detected by flow cytometry was the most important independent prognostic factor.

Practical blood dendritic cell vaccination for immunotherapy of multiple myeloma.
Br J Haematol. 2008 Nov;143(3):374-7.
Vari F, Munster DJ, Hsu JL, Rossetti TR, Mahler SM, Gray PP, Turtle CJ, Prue RL, Hart DN.

Hepatitis C virus (HCV) infection, monoclonal immunoglobulin specific for HCV core protein, and plasma-cell malignancy.
Blood. 2008 Nov 15;112(10):4357-8.
Bigot-Corbel E, Gassin M, Corre I, Le Carrer D, Delaroche O, Hermouet S.
Among 700 patients with monoclonal immunoglobulins, 10 (1.4%) were found to be HCV+. The monoclonal component was purified in 7 cases. The monoclonal Ig reacted against:
  - The C22-3 fragment of the HCV-core protein (4 cases: 2 IgG, 1 IgA, and 1 IgM)
  - The NS-4 of HCV (2 cases: 2 IgG)
  - Did not recognize HCV (1 case)
Interestingly, 1 of 4 patients with monoclonal antibodies against the HCV-core protein developed multiple myeloma.

Antibiotic prophylaxis before dental procedures may reduce the incidence of osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates.
Leuk Lymphoma. 2008 Nov;49(11):2156-62.
Montefusco V, Gay F, Spina F, Miceli R, Maniezzo M, Teresa Ambrosini M, Farina L, Piva S, Palumbo A, Boccadoro M, Corradini P.
This retrospective analysis of 178 patients with MM showed that antibiotic prophylaxis before dental procedures may prevent ONJ. 75 patients received at least one dental procedure, and 43 patients received antibiotic prophylaxis. 9 patients developed ONJ. Only 1 case of ONJ was not correlated with dental procedures. Interestingly, all 8 cases of ONJ observed with dental procedures occurred in the group of patients without antibiotic prophylaxis.

Mobilization of peripheral blood stem cells in myeloma with either pegfilgrastim or filgrastim following chemotherapy.
Haematologica. 2008 Nov;93(11):1739-42.
Tricot G, Barlogie B, Zangari M, van Rhee F, Hoering A, Szymonifka J, Cottler-Fox M.
After mobilization chemotherapy with DT-PACE, patients received either filgrastim bid or peg-filgrastim 6 mg SC on days +6 and +13 (the second dose was held if WBC were >100,000 by day +13). The authors considered peg-filgrastim the standard of care for stem cell mobilization because of its advantages:
  - Lower median number of growth factor injections (2 vs 26)
  - Higher median number of CD34+ cells/kg collected on day 1
  - Higher percentage of patients who collected 15 million CD34+ cells/Kg in 3 days
  - Faster neutrophil recovery after transplant

A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma.
Blood. 2008 Nov 1;112(9):3591-3.
Rosiñol L, Pérez-Simón JA, Sureda A, de la Rubia J, de Arriba F, Lahuerta JJ, González JD, Díaz-Mediavilla J, Hernández B, García-Frade J, Carrera D, León A, Hernández M, Abellán PF, Bergua JM, San Miguel J, Bladé J; Programa para el Estudio y la Terapéutica de las Hemopatías Malignas y Grupo Español de Mieloma (PETHEMA/GEM).
110 patients with multiple myeloma not in CR/nCR after a first autologous transplant received a second transplant, either second autologous transplant (85 patients) or a RIC allogeneic transplant (25 patients), depending on the availability of a matched sibling donor. Results:
  - Transplantation-related mortality: 16% in the auto-allo group and 5% in the auto-auto group (p= 0.07)
  - CR: 40% in the auto-allo group and 11% in the auto-allo group (p =0.001)
  - Median PFS: not reached in the auto-allo group and 31 months in the auto-auto group (trend: p= 0.08)
  - Median EFS and OS: no statistical difference
  - Chronic GVHD: 66%
The auto-allo group reached an encouraging plateu of PFS, but the allogeneic transplant was associated with high morbidity and mortality, as expected.



Oncolytic virotherapy for multiple myeloma using a tumour-specific double-deleted vaccinia virus.
Leukemia. 2008 Dec;22(12):2261-4.
Deng H, Tang N, Stief AE, et al.

Natural history of osteonecrosis of the jaw in patients with multiple myeloma.
J Clin Oncol. 2008 Dec 20;26(36):5904-9.
Badros A, Terpos E, Katodritou E, Goloubeva O, Kastritis E, Verrou E, Zervas K, Baer MR, Meiller T, Dimopoulos MA.
In this study, 97 MM patients with ONJ were observed prospectively for at least 3 years after ONJ. Results:
 - ONJ resolved in 60 patients (62%)
 - ONJ resolved and recurred in 12 patients (12%)
 - ONJ did not heal in 25 patients (26%)
Recurrent ONJ followed reinitiation of bisphosphonates in 6 of 12 patients.

Influence of pre- and post-transplantation responses on outcome of patients with multiple myeloma: sequential improvement of response and achievement of complete response are associated with longer survival.
J Clin Oncol. 2008 Dec 10;26(35):5775-82.
Lahuerta JJ, Mateos MV, Martínez-López J, Rosiñol L, Sureda A, de la Rubia J, García-Laraña J, Martínez-Martínez R, Hernández-García MT, Carrera D, Besalduch J, de Arriba F, Ribera JM, Escoda L, Hernández-Ruiz B, García-Frade J, Rivas-González C, Alegre A, Bladé J, San Miguel JF.
This study analyzed 632 MM patients treated with induction chemotherapy followed by autologous stem-cell transplantation, and found that post-SCT response markedly influenced outcomes: patients who achieved CR had better median EFS (61 v 40 months) and OS (not reached) than patients who achieved nCR. Similarly, patients who achieved nCR had better median EFS (40 vs 34 months) and OS (not reached vs 61 months) than patients who achieved PR. Trends in the same direction were observed with the pre-SCT response. Therefore, improvements in response were associated with prolonged survival.

Prospective comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple myeloma.
Haematologica. 2008 Dec;93(12):1908-11.
Moreau P, Coiteux V, Hulin C, Leleu X, van de Velde H, Acharya M, Harousseau JL.
This is a phase I study of 24 patients with multiple myeloma randomized to receive bortezomib by standard IV bolus (12 patients) or SC injection (12 patients). Injection concentration was 1 mg/mL. SC administration resulted in similar systemic availability, pharmacodynamic activity, response rate, and toxicity profile to those seen with IV administration.



Giampaolo Talamo, M.D.