APRIL 2006

Flow cytometric detection of circulating myeloma cells before transplantation in patients with multiple myeloma: a simple risk stratification system.
Blood. 2006 Apr 15;107(8):3384-8.
Dingli D, Nowakowski GS, Dispenzieri A, Lacy MQ, Hayman SR, Rajkumar SV, Greipp PR, Litzow MR, Gastineau DA, Witzig TE, Gertz MA.
This study evaluated circulating myeloma cells in 246 patients undergoing autologous stem cell transplantation. Circulating tumor cells were detected by flow cytometry at the time of stem cell collection. 95 patients were found to have circulating cells. No difference in CR rate was found between the group with circulating cells (32%) and the group without circulating cells (36%), but the group with circulating cells had a shorter time to progression (14 vs 22 months, p= 0.001) and a shorter overall survival (33 vs 59 months, p= 0.01). The presence of circulating tumor cells was a prognostic factor independent of cytogenetics and disease status at the time of transplant.

Treatment of bendamustine and prednisone in patients with newly diagnosed multiple myeloma results in superior complete response rate, prolonged time to treatment failure and improved quality of life compared to treatment with melphalan and prednisone - a randomized phase III study of the East German Study Group of Hematology and Oncology (OSHO).
J Cancer Res Clin Oncol. 2006 Apr;132(4):205-12.
Pönisch W, Mitrou PS, Merkle K, Herold M, Assmann M, Wilhelm G, Dachselt K, Richter P, Schirmer V, Schulze A, Subert R, Harksel B, Grobe N, Stelzer E, Schulze M, Bittrich A, Freund M, Pasold R, Friedrich T, Helbig W, Niederwieser D; East German Study Group of Hematology and Oncology (OSHO).
This randomized phase III study compared bendamustine and prednisone (BP) (68 patients) to melphalan and prednisone (MP) (63 patients) in the treatment of newly diagnosed multiple myeloma.
  BP: bendamustine 150 mg /m2 on days 1-2 + prednisone 60 mg/m2 on days 1-4, cycles repeated every 28 days
  MP: melphalan 15 mg/m2 on day 1+ prednisone 60 mg/m2 on days 1-4, cycles repeated every 28 days
BP proved to be superior to MP:
  - Response rate was 75% with BP and 70% with MP
  - Complete remission was 32% with BP and 13% with MP (p=0.007)
  - The maximum response was achieved in about 7 cycles with BP and 9 cycles with MP
  - Duration  of remission was longer with BP group


MAY 2006

Severe pulmonary complications in Japanese patients after bortezomib treatment for refractory multiple myeloma.
Blood. 2006 May 1;107(9):3492-4.
Miyakoshi S, Kami M, Yuji K, Matsumura T, Takatoku M, Sasaki M, Narimatsu H, Fujii T, Kawabata M, Taniguchi S, Ozawa K, Oshimi K.
The authors report the occurrence of severe lung toxicity in 13 patients with multiple myeloma treated with bortezomib. Two patients died of respiratory failure.

Role of 18F-FDG PET/CT in the assessment of bone involvement in newly diagnosed multiple myeloma: preliminary results.
Eur J Nucl Med Mol Imaging. 2006 May;33(5):525-31.
Nanni C, Zamagni E, Farsad M, Castellucci P, Tosi P, Cangini D, Salizzoni E, Canini R, Cavo M, Fanti S.
In this study, (18)F-FDG PET/CT detected more lesions in 16 of 28 (57%) MM patients. Of these 16 patients, 9 had a completely negative skeletal survey. In 12 of 28 43%) patients, the two methods yielded equivalent findings. When comparing (18)F-FDG PET/CT and MRI, 7 of 28 (25%) patients were found to have more lytic bone lesions, all of which were located outside the field included in the MRI. In 7 of 28 (25%) patients, skeletal MRI detected an infiltrative pattern in the spine whereas the (18)F-FDG PET/CT was negative. In conclusion, PET scans are more sensitive than skeletal survey in detecting lytic bone lesions, and skeletal MRI may be superior to PET in diagnosing an infiltrative pattern in the spine. MM bone disease should be evaluated with both MRI of the spine and PET/CT.

Maintenance thalidomide following single cycle autologous peripheral blood stem cell transplant in patients with multiple myeloma.
Bone Marrow Transplant. 2006 May;37(9):825-9.
Sahebi F, Spielberger R, Kogut NM, Fung H, Falk PM, Parker P, Krishnan A, Rodriguez R, Nakamura R, Nademanee A, Popplewell L, Frankel P, Ruel C, Tin R, Ilieva P, Forman SJ, Somlo G.
This is a phase II study of 29 myeloma patients treated with maintenance thalidomide after a single autologous stem cell transplant. Thalidomide was started at 50 mg PO qhs, and it was increased to max 400 mg a day. It was continued for 6 months after achievement of CR for a maximum duration of 18 months. Results:
  - Median tolerated dose was 200 mg
  - CR or nCR rate at 6 months was 45%
  - Overall survival at 2 years was 83%
  - Progression-free survival at 2 years was 49%

Maintenance therapy with thalidomide improves overall survival after autologous hematopoietic progenitor cell transplantation for multiple myeloma.
Cancer. 2006 May 15;106(10):2171-80.
Brinker BT, Waller EK, Leong T, Heffner LT Jr, Redei I, Langston AA, Lonial S.
Among 112 myeloma patients treated with autologous stem cell transplant, 76 patients received no maintenance therapy, and 36 patients received thalidomide, either as maintenance or as salvage therapy. After a median follow-up of 58 months:
  - Median survival was 54 months
  - Median survival was better in patients who received thalidomide compared with those who did not (65.5 vs 44.5 months, p= 0.09)
  - Median survival was better in patients who received thalidomide as maintenance compared with those who received it as salvage therapy (65 vs 54 months, p= 0.05)

Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma.
Blood. 2006 May 1;107(9):3474-80.
Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I, Lamy T, Marit G, Maloisel F, Berthou C, Dib M, Caillot D, Deprijck B, Ketterer N, Harousseau JL, Sotto JJ, Moreau P.
In 1999, the Intergroupe Francophone du Myélome (IFM) initiated 2 trials in patients with high-risk myeloma:
  - IFM99-03: autologous stem cell transplant with melphalan 200 mg/m2 followed by RIC allogeneic stem cell transplant, in patients with HLA-identical sibling donor
  - IFM99-04: tandem autologous stem cell transplant with melphalan 200 mg/m2, in patients without HLA-identical sibling donor
This study included 264 patients, 65 in the IFM-03 trial and 219 patients in the IFM99-04 trial.
On an intent-to-treat analysis, overall survival and event-free survival were similar:
  - In IFM99-03, median OS was 35 months, and median EFS was 25 months
  - In IFM99-04, median OS was 41 months, and median EFS was 30 months
In this study, autologous SCT followed by allogeneic SCT was not superior to tandem autologous SCT in patients with high-risk MM.


JUNE 2006

Familial characteristics of autoimmune and hematologic disorders in 8,406 multiple myeloma patients: a population-based case-control study.
Int J Cancer. 2006 Jun 15;118(12):3095-8.
Landgren O, Linet MS, McMaster ML, Gridley G, Hemminki K, Goldin LR.
Authors conducted a population-based case-control study to evaluate risk of MM associated with personal history of autoimmune diseases and occurrence of autoimmune and several hematologic disorders in first-degree relatives. Data were obtained for 8,406 MM cases diagnosed in Sweden in 1958-1998, compared with 16,543 matched controls, 22,490 first-degree relatives of cases, and 44,436 first-degree relatives of controls. The risk for MM was significantly increased among subjects with a personal history of pernicious anemia (OR = 3.27; 2.22-4.83) and family history of SLE (OR = 2.66; 1.12-6.32). Compared with controls, relative risk of MM was significantly increased (RR = 1.67; 1.02-2.73) in relatives of cases. MM cases had more cases of MGUS among their relatives than controls. Risk of MM was not increased in persons whose relatives had hematologic malignancies other than MM. Authors found no significant association between personal/familial autoimmune diseases and MM.

Prolonged overall survival with second on-demand autologous transplant in multiple myeloma.
Am J Hematol. 2006 Jun;81(6):426-31.
Elice F, Raimondi R, Tosetto A, D'Emilio A, Di Bona E, Piccin A, Rodeghiero F.
In this study, 130 patients with multiple myeloma were treated with an up-front autologous stem cell transplant, followed by a second autologous transplant at the time of disease relapse/progression. 107 (82%) patients completed the first transplant. Median EFS was 27.7 months, and median OS was 65.4 months. 26 of 70 patients with disease relapsed or progression received a second transplant, at a median time of 20.4 months from the first transplant. RR was 69%. After the second autologous transplant, median event-free survival was 14.8 months, and median overall survival was 38.1 months. Transplant-related mortality was 1.9% after the first transplant, and 0% after the second transplant.

Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells.
Blood. 2006 Jun 15;107(12):4907-16.
Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH.

Bortezomib with or without dexamethasone in relapsed multiple myeloma following allogeneic hematopoietic cell transplantation.
Haematologica. 2006 Jun;91(6):837-9.
Bruno B, Patriarca F, Sorasio R, Mattei D, Montefusco V, Peccatori J, Bonifazi F, Petrucci MT, Milone G, Guidi S, Giaccone L, Rotta M, Fanin R, Boccadoro M, Corradini P; Gruppo Italiano Trapianti di Midollo.
23 patients with myeloma in relapse after allogeneic stem cell transplant received bortezomib. Response rate was 61%, CR 22%, and progression free survival 6 months.

Diverse niches within multiple myeloma bone marrow aspirates affect plasma cell enumeration.
Br J Haematol. 2006 Jun;133(5):530-2.
Nadav L, Katz BZ, Baron S, Yossipov L, Polliack A, Deutsch V, Geiger B, Naparstek E.
This study demonstrated that flow cytometry underestimates the number of plasma cells in BM aspirates by an average of 60%, when compared with morphological analysis. This discrepancy may be explained by the fact that bone marrow smears contain plasma cells associated with lipid-enriched spicules, whereas flow cytometry counts plasma cells in the fluid of the bone marrow aspirate, which is depleted of the lipid-adhesive plasma cells.

Combination chemotherapy with cyclophosphamide, thalidomide and dexamethasone for patients with refractory, newly diagnosed or relapsed myeloma.
Haematologica. 2006 Jun;91(6):862-3.
Sidra G, Williams CD, Russell NH, Zaman S, Myers B, Byrne JL.
The combination of weekly cyclophosphamide, thalidomide, and pulsed dexamethasone (CTD) in patients with newly diagnosed or relapsed/refractory myeloma was highly effective, as it induced an overall response rate of 84%. CTD did not impair stem cell mobilization.

Bortezomib after dose-reduced allogeneic stem cell transplantation for multiple myeloma to enhance or maintain remission status.
Exp Hematol. 2006 Jun;34(6):770-5.
Kröger N, Zabelina T, Ayuk F, Atanackovic D, Schieder H, Renges H, Zander A.
18 myeloma patients treated with mini-allogeneic stem cell transplantation received at least two cycles of bortezomib. Treatment with bortezomib was effective (CR was seen in 30% of patients with measurable disease), but it was followed by several complications, including:
  - development or worsening of GVHD (4 patients)
  - neurotoxicity requiring discontinuation of the drug (3 patients)
  - complicated by infections (herpes zoster in 3 patients)

Rituximab treatment provides no clinical benefit in patients with pretreated advanced multiple myeloma.
Leuk Lymphoma. 2006 Jun;47(6):1103-9.
Zojer N, Kirchbacher K, Vesely M, Hübl W, Ludwig H.
This phase II study evaluated the efficacy of a single course of rituximab (375 mg/m2 IV for 4 weeks) in 10 patients with relapsed myeloma. None of the patients achieved an objective response. CD20 was expressed on 10% and 50% of bone marrow plasma cells in 2 patients.

Fixed-dose single agent pegfilgrastim for peripheral blood progenitor cell mobilisation in patients with multiple myeloma.
Br J Haematol. 2006 Jun;133(5):533-7.
Hosing C, Qazilbash MH, Kebriaei P, Giralt S, Davis MS, Popat U, Anderlini P, Shpall EJ, McMannis J, Körbling M, Champlin RE.
In this phase II study, pegfilgrastim 12 mg SC x1 was administered in 19 patients with multiple myeloma for stem cell mobilization. The median number of stem cells collected was 8.4 million CD34+ cells/kg (range: 4.1-15.8), and the median number of apheresis procedures was 2 (range: 1-5). Toxicities were similar to those seen with filgrastim, i.e., mainly bone pain/myalgias.

Myeloablative allogeneic stem cell transplantation for advanced stage multiple myeloma: very long-term follow up of a single center experience.
Clin Lab Haematol. 2006 Jun;28(3):189-97.
Kennedy GA, Butler J, Morton J, Hill G, Western R, Cummings J, Allison R, Durrant S.
This is a retrospective study of 37 patients with heavily pretreated myeloma who underwent myeloablative allogeneic SCT. After a median follow-up of 108 months (range: 33-148):
  - TRM at day 100: 32%
  - Median OS: 28 months
  - Median EFS: 13 months
  - Median PFS: 66 months
The authors conclude that allogeneic SCT can result in long-term survival in a minority of patients with heavily pretreated myeloma.

Prognostic factors for donor lymphocyte infusions following non-myeloablative allogeneic stem cell transplantation in multiple myeloma.
Bone Marrow Transplant. 2006 Jun;37(12):1135-41.
van de Donk NW, Kröger N, Hegenbart U, Corradini P, San Miguel JF, Goldschmidt H, Perez-Simon JA, Zijlmans M, Raymakers RA, Montefusco V, Ayuk FA, van Oers MH, Nagler A, Verdonck LF, Lokhorst HM.
At the time of its publication, this was the largest study of DLI in myeloma. Among 63 patients who relapsed after allogeneic transplant , 48 patients had relapsed disease, and 15 patients persistent disease. Results after DLI:
  - Response rate: 38% (CR 19%)
  - Treatment-related mortality: 11%
  - Median OS: 24 months
  - In non-responders: median OS 24 months
  - In responders: median OS not reached, median PFS 28 months
  - Prognostic factors for response were acute and chronic GVHD
  - Efficacy of DLI decreased in patients who received DLI after 12 months post transplant



Giampaolo Talamo, MD