JULY 2007

Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3.
Br J Haematol. 2007 Jul;138(2):176-85.
Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K, Pineda-Roman M, Cottler-Fox M, Mohiuddin A, Alsayed Y, Tricot G, Bolejack V, Zangari M, Epstein J, Petty N, Steward D, Jenkins B, Gurley J, Sullivan E, Crowley J, Shaughnessy JD Jr.
303 patients with newly diagnosed patients received induction chemotherapy, tandem autologous transplants, consolidation chemotherapy, and maintenance therapy, integrating bortezomib during the various phases of the protocol. Results:
  - Treatment-related mortality was 5%
  - At 2 years, 83% of patients achieved at least a near-complete remission
  - 2-year estimate of event-free survival was 84%
  - 2-year estimate of overall survival was 86%

Identification of antigenic targets of paraproteins by expression cloning does not support a causal role of chronic antigenic stimulation in the pathogenesis of multiple myeloma and MGUS.
Int J Cancer. 2007 Jul 15;121(2):459-61.
Preuss KD, Held G, Kubuschok B, Hung CZ, Malatsidze N, Wagner M, Pfreundschuh M.
Antigenic targets of paraproteins in both MGUS and MM could have a role as growth stimulators in the pathogenesis of these neoplasms. These authors tried to identify such targets, and they screened cDNA libraries from several tissues, for reactivity with paraproteins in the sera from 115 patients with MGUS and MM. Since these authors did not find a consistent reactivity to auto-, allo- and heteroantigens, they concluded that a causal role of the antigenic stimulus in the pathogenesis of MGUS and MM is unlikely.

A different schedule of zoledronic acid can reduce the risk of the osteonecrosis of the jaw in patients with multiple myeloma.
Leukemia. 2007 Jul;21(7):1545-8.
Corso A, Varettoni M, Zappasodi P, Klersy C, Mangiacavalli S, Pica G, Lazzarino M.
This study evaluated the incidences of ONJ and skeletal-related events (SREs) in 106 patients with multiple myeloma divided in two groups:
  - Group A (standard schedule of administration): 51 patients who received monthly administrations of bisphosphonates until tolerated
  - Group B (reduced schedule of administration): 55 patients who received monthly administrations of bisphosphonates during the first year, and then every 3 months
  - The incidence of SREs was similar: 15.1 per 100 person years in group A and 17.7 in group B.
  - The risk of ONJ was lower with the reduced schedule: ONJ developed in 7 patients: 6 in group A and 1 in group B (P=0.049).
  - ONJ developed in patients treated with zoledronic acid, and no ONJ was seen in patients treated only with pamidronate.
These authors conclude that a reduced schedule of zoledronic acid is safer than the standard schedule and, at the same time, it maintains its efficacy in preventing SREs.

Intermediate-dose melphalan compared with myeloablative treatment in multiple myeloma: long-term follow-up of the Dutch Cooperative Group HOVON 24 trial.
Haematologica. 2007 Jul;92(7):928-35.
Sonneveld P, van der Holt B, Segeren CM, Vellenga E, Croockewit AJ, Verhoe GE, Cornelissen JJ, Schaafsma MR, van Oers MH, Wijermans PW, Westveer PH, Lokhorst HM; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON).
The Dutch-Belgian HOVON group performed a randomized trial in 303 patients with newly diagnosed MM. After induction chemotherapy with VAD, patients received either:
  - 2 cycles of non-myeloablative intermediate-dose melphalan (70 mg/m2) (group A)
  - Same regimen followed by cyclophosphamide 120 mg/kg  + TBI 9 Gy and autologous stem cell transplantation (group B)
Patient were given maintenance with interferon alpha-IIa until relapse or progression.
  - CR was higher in group B (32% vs 13%, p<0.001)
  - Group B had similar median EFS (22 vs 21 months) and better EFS at 6 years (15% vs 7% at 6 years)
  - Median overall survival was similar (55 months in group A vs 50 months in group B)
  - OS at 6 years was similar (36% in group A vs 39% in group B)
Achievement of CR had a favorable prognostic impact.



High serum-free light chain levels and their rapid reduction in response to therapy define an aggressive multiple myeloma subtype with poor prognosis.
Blood. 2007 Aug 1;110(3):827-32.
van Rhee F, Bolejack V, Hollmig K, Pineda-Roman M, Anaissie E, Epstein J, Shaughnessy JD Jr, Zangari M, Tricot G, Mohiuddin A, Alsayed Y, Woods G, Crowley J, Barlogie B.
Serum FLC were measured at baseline and at several time points during induction therapy in myeloma 301 patients. FLC levels were >75 mg/dL were found at baseline in 33% of patients, and they had a negative prognostic impact. A rapid and deeper reduction of FLC seen during induction therapy was associated with aggressive disease and inferior outcome.

Demonstration of changes in plasma cell subsets in multiple myeloma.
Haematologica. 2007 Aug;92(8):1135-8.
Ayliffe MJ, Davies FE, de Castro D, Morgan GJ.
Using a double immunofluorescence staining method, these authors demonstrated that bone marrow plasma cells express intact monoclonal immunoglobulins in 74% of case, free light chains in 8% of cases, and a mixture of both cell population in 18% of cases. In a few patients, myeloma cells changed during the course of the disease from producing intact immunoglobulins to cells producing free light chains. The presence of cells expressing free light chains only was associated with worse prognosis.

Hematopoietic stem cell transplantation in multiple myeloma.
Biol Blood Marrow Transplant. 2007 Aug;13(8):877-85.
Pant S, Copelan EA.

Rapid response to high-dose steroids of severe bortezomib-related pulmonary complication in multiple myeloma.
J Clin Oncol. 2007 Aug 1;25(22):3380-1.
Zappasodi P, Dore R, Castagnola C, Astori C, Varettoni M, Mangiacavalli S, Lazzarino M, Corso A.
A 66-year-old man with myeloma treated with bortezomib developed severe acute respiratory failure after the second cycle. CT of the chest showed bilateral pulmonary lesions and consolidation, and pleural effusions, with a pattern suggesting bronchiolitis obliterans organizing pneumonia. A rapid improvement was achieved with corticosteroids, starting with methylprednisolone 500 mg/24 hours for 2 days.

VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek Myeloma Study Group.
Ann Oncol. 2007 Aug;18(8):1369-75.
Zervas K, Mihou D, Katodritou E, Pouli A, Mitsouli CH, Anagnostopoulos A, Delibasi S, Kyrtsonis MC, Anagnostopoulos N, Terpos E, Zikos P, Maniatis A, Dimopoulos MA; Greek Myeloma Study Group.
232 patients with newly diagnosed myeloma were randomized to VAD-doxil (115 patients) vs VAD-doxil + thalidomide (117 patients). Results:
  - Response rate was 63% in the group treated with VAD and 81% in the group treated with VADT (p= 0.003)
  - Progression-free survival at 2 years was 45% in the group treated with VAD and 59% in the group treated witth VADT (p= 0.013)
  - Overall survival at 2 years was 65% in the group treated with VAD and 77% in the group treated with VADT (p= 0.037)
  - Adverse effects were more frequent in the group treated with VADT, but rate of grade 3-4 toxicities was similar in both groups

The combination of cyclophosphamide, velcade and dexamethasone induces high response rates with comparable toxicity to velcade alone and velcade plus dexamethasone.
Haematologica. 2007 Aug;92(8):1149-50.
Davies FE, Wu P, Jenner M, Srikanth M, Saso R, Morgan GJ.
These authors studied the effects of the CVD combination in 47 patients with relapsed/refractory multiple myeloma.
  - Cyclophosphamide 500 mg PO on days 1, 8, 15
  - Velcade 1.3 mg/m2 IV on days 1, 4, 8, 11 of a 21 day cycle
  - Dexamethasone 40 mg PO on the day of Velcade and the day after
CVD induced high overall response rate (75%) and complete response rate (31%) compared to velcade/dexamethasone (overall response rate 47%, CR rate 5%) and velcade alone (overall response rate 27%, CR rate 0%). Toxicities, including cytopenias and neuropathy, were comparable between the groups.

Efficacy of single-agent bortezomib vs. single-agent thalidomide in patients with relapsed or refractory multiple myeloma: a systematic comparison.
Eur J Haematol. 2007 Aug;79(2):93-9.
Prince HM, Adena M, Smith DK, Hertel J.

This systematic review evaluates the efficacy of single-agent bortezomib vs single-agent thalidomide in patients with relapsed/refractory multiple myeloma. Authors included 1 bortezomib study with 333 patients and 15 thalidomide studies with 1007 patients). Authors conclude that bortezomib, when compared with thalidomide, induces a significantly higher response rate (41-53% vs 22-32%) and complete remission rate.

Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma.
Br J Haematol. 2007 Aug;138(3):330-7.
Kropff M, Bisping G, Schuck E, Liebisch P, Lang N, Hentrich M, Dechow T, Kröger N, Salwender H, Metzner B, Sezer O, Engelhardt M, Wolf HH, Einsele H, Volpert S, Heinecke A, Berdel WE, Kienast J; Deutsche Studiengruppe Multiples Myelom.
This phase 2 trial studied the combination of bortezomib, intermediate-dose dexamethasone (on the day of bortezomib injection and the day thereafter), and continuous low-dose oral cyclophosphamide (50 mg PO once daily) in 54 patients with relapsed multiple myeloma. Overall response rate was 90%, with CR 16%, PR 66%, and minor responses 8%. Median overall survival was 22 months, and median event-free survival was 12 months.

High-dose melphalan versus busulfan, cyclophosphamide, and etoposide as preparative regimens for autologous stem cell transplantation in patients with multiple myeloma.
Leuk Res. 2007 Aug;31(8):1069-75.
Benson DM Jr, Elder PJ, Lin TS, Blum W, Penza S, Avalos B, Copelan E, Farag SS.

Relapse risk after autologous transplantation in patients with newly diagnosed myeloma is not related with infused tumor cell load and the outcome is not improved by CD34+ cell selection: long term follow-up of an EBMT phase III randomized study.
Haematologica. 2007 Aug;92(8):1083-90.
Bourhis JH, Bouko Y, Koscielny S, Bakkus M, Greinix H, Derigs G, Salles G, Feremans W, Apperley J, Samson D, Björkstrand B, Niederwieser D, Gahrton G, Pico JL, Goldschmidt H; European Group for Blood and Marrow Transplantation.
This multicentre randomized phase III study evaluated the efficacy of CD34+ selection in 111 patients with newly diagnosed myeloma undergoing autologous stem cell transplantation. One group underwent CD34+ selection, which depleted tumor cells by a median of 2.2 logs. No significant difference in terms of 5-year survival, event free survival, and relapse rate was observed between the two groups. Reinfused tumor cells were probably not the cause of relapse after autologous transplant, because of a similar relapse rate between patients who received grafts with detectable tumor cells and those who received grafts with no detectable tumor cells.

Multiple myeloma patients receiving pre-emptive donor lymphocyte infusion after partial T-cell-depleted allogeneic stem cell transplantation show a long progression-free survival.
Bone Marrow Transplant. 2007 Aug;40(4):355-9.
Levenga H, Levison-Keating S, Schattenberg AV, Dolstra H, Schaap N, Raymakers RA.
In this study, 24 MM patients received partial T-cell-depleted myeloablative SCT, followed by pre-emptive DLI. Transplant-related mortality within 1 year was 29%. With a median follow-up of 67 months, 7 patients (29%) were in persistent CR.

Long-term outcome of myeloablative allogeneic stem cell transplantation for multiple myeloma.
Biol Blood Marrow Transplant. 2007 Aug;13(8):925-31.
Kuruvilla J, Shepherd JD, Sutherland HJ, Nevill TJ, Nitta J, Le A, Forrest DL, Hogge DE, Lavoie JC, Nantel SH, Toze CL, Smith CA, Barnett MJ, Song KW.
This study retrospective compares outcomes of myeloma treated with myeloablative allogeneic SCT (72 patients) vs autologous SCT (86 patients).58 patients had related allogeneic SCT, and 14 unrelated allogeneic SCT. Results (median follow-up 7.4 years):
  - Treatment-related mortality at 1 year: 22% in the allogeneic group and 14% in the autologous group (p= 0.21)
  - Acute GVHD, grade II-IV: 72%. Chronic GVHD: 68%
  - 5-year survival: 48% in the allogeneic group and 46% in the autologous group
  - 10-year survival: 40% in the allogeneic group and 31% in the autologous group (p= 0.94)
  - EFS survival at 10 years: 31% in the allogeneic group and 32% in the autologous group (p= 0.64)



Lenalidomide-induced myelosuppression is associated with renal dysfunction: adverse events evaluation of treatment-naďve patients undergoing front-line lenalidomide and dexamethasone therapy.
Br J Haematol. 2007 Sep;138(5):640-3.
Niesvizky R, Naib T, Christos PJ, Jayabalan D, Furst JR, Jalbrzikowski J, Zafar F, Mark T, Lent R, Pearse RN, Ely S, Leonard JP, Mazumdar M, Chen-Kiang S, Coleman M.

Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials.
Leukemia. 2007 Sep;21(9):2020-4.
Moreau P, Attal M, Garban F, Hulin C, Facon T, Marit G, Michallet M, Doyen C, Leyvraz S, Mohty M, Wetterwald M, Mathiot C, Caillot D, Berthou C, Benboubker L, Garderet L, Chaleteix C, Traullé C, Fuzibet JG, Jaubert J, Lamy T, Casassus P, Dib M, Kolb B, Dorvaux V, Grosbois B, Yakoub-Agha I, Harousseau JL, Avet-Loiseau H; SAKK; IFM Group.
Among 100 myeloma patients treated with tandem transplants, patients with t(4;14) had worse outcomes than patients without t(4:14): median event-free survival was 21 vs 37 months, and median overall survival was 41.4 vs 65 months.

A single-tube six-colour flow cytometry screening assay for the detection of minimal residual disease in myeloma.
Leukemia. 2007 Sep;21(9):2046-9.
de Tute RM, Jack AS, Child JA, Morgan GJ, Owen RG, Rawstron AC.

Polymorphisms of CYP2C19 gene are associated with the efficacy of thalidomide based regimens in multiple myeloma.
Haematologica. 2007 Sep;92(9):1246-9.
Li Y, Hou J, Jiang H, Wang D, Fu W, Yuan Z, Chen Y, Zhou L.
This study showed that polymorphisms of CYP2C19 gene influence the efficacy of thalidomide. Among 92 myeloma patients, the response rate to thalidomide was 63% in extensive metabolizers and 33% in poor metabolizers.

Leukocytoclastic vasculitis due to thalidomide in multiple myeloma.
Jpn J Clin Oncol. 2007 Sep;37(9):704-7.
Yildirim ND, Ayer M, Küçükkaya RD, Alpay N, Mete O, Yenerel MN, Yavuz AS, Nalçaci M.

Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression.
J Clin Oncol. 2007 Sep 1;25(25):3892-901.
Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL.
This is a phase III international study which randomized 646 patients with relapsed or refractory myeloma to either bortezomib or the combination bortezomib + pegylated liposomal doxorubicin (30 mg/m2 IV on day 4). Results:
  - Response rate was 41% with bortezomib vs 44% with bortezomib + liposomal doxorubicin (not statistically significant)
  - Median time to progression was 6.5 months with bortezomib vs 9.3 months with bortezomib + liposomal doxorubicin (p= 0.000004)
  - The 15-month survival rate was 65% with bortezomib and 76% with bortezomib + liposomal doxorubicin (p= 0.03)
The group receiving the combination regimen experienced more frequent toxicities, especially cytopenias, diarrhea, and hand-foot syndrome.

Phase II study of CLAD (cyclophosphamide, liposomal doxorubicin and dexamethasone) in patients with advanced multiple myeloma and historical comparison to CAD (cyclophosphamide, doxorubicin and dexamethasone).
Hematol Oncol. 2007 Sep;25(3):132-9.
Hütter G, Szélenyi H, Schmittel A, Siehl JM, Thiel E, Keilholz U.
This study evaluates the CLAD regimen in 60 patients with advanced multiple myeloma.
  - Cyclophosphamide 200 mg/m2 IV days 1-4
  - Pegylated liposomal doxorubicin 20 mg/m2 IV day 1
  - Dexamethasone 40 mg PO days 1-4
Efficacy and toxicity was compared to a historical cohort of 46 patients treated with CAD (cyclophosphamide, dexamethasone and conventional doxorubicin). The response rate was similar: 71% with CLAD and 74% with CAD. CLAD showed an advantage in hematological toxicity and lower infectious complications, and presumably lower cardiotoxicity.



Giampaolo Talamo, MD