Clinical outcomes in t(4;14) multiple myeloma: a chemotherapy-sensitive disease characterized by rapid relapse and alkylating agent resistance.
J Clin Oncol. 2005 Oct 1;23(28):7069-73.
Jaksic W, Trudel S, Chang H, Trieu Y, Qi X, Mikhael J, Reece D, Chen C, Stewart AK.
This study clarified that the poor prognosis associated with the t(4;14) translocation is not due to primary drug resistance, but instead to a rapid relapse of the disease. t(4;14) was present in 19 of 131 (14.5%) myeloma patients treated with stem cell transplantation. Patients with t(4;14) had a predominance of IgA isotype (53%). After induction chemotherapy, 90% of the 19 patients achieved a partial response, but disease progression occurred rapidly, as 26% of patients progressed before the stem cell transplant, and median progression-free survival after transplant was only 14 months. Median overall survival after stem cell transplantation was 24 months. Duration of response to salvage therapy was short (median: 4.7 months).

Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy.
Blood. 2005 Oct 15;106(8):2837-40.
Gertz MA, Lacy MQ, Dispenzieri A, Greipp PR, Litzow MR, Henderson KJ, Van Wier SA, Ahmann GJ, Fonseca R.
This study evaluated the prognostic impact of FISH in 238 myeloma patients treated with stem cell transplantation. The t(11;14) translocation did not influence prognosis, but patients with the t(4;14) translocation or -17p had a shorter progression-free survival (only 8.2 months with t4;14) and shorter overall survival. The risk ratio for t(4;14) was greater than for Del13. Patients with both t(4;14) and Del13 had a shorter overall survival than patients with Del13 alone (19 vs 27 months).

Circulating plasma cells detected by flow cytometry as a predictor of survival in 302 patients with newly diagnosed multiple myeloma.
Blood. 2005 Oct 1;106(7):2276-9.
Nowakowski GS, Witzig TE, Dingli D, Tracz MJ, Gertz MA, Lacy MQ, Lust JA, Dispenzieri A, Greipp PR, Kyle RA, Rajkumar SV.
This study evaluated prognosis according to the number of circulating plasma cells tested by flow cytometry of peripheral blood in 302 myeloma patients.
Circulating plasma cells per 50,000 mononuclear cells were:
  - 0 circulating plasma cells in 80 (27%) patients
  - 1-10 circulating plasma cells in 106 (35%) patients
  - >10 circulating plasma cells in 115 (38%) patients
Median overall survival was:
  - 47 months for the whole group
  - 59 months for patients with 10 or fewer circulating plasma cells
  - 37 months for patients with >10 circulating PCs
Multivariate analysis showed that the number of circulating plasma cells was an independent predictor of survival. Its prognostic value was independent of other known prognostic factors, such as albumin and b2m.

Minimal residual disease monitoring in multiple myeloma: a comparison between allelic-specific oligonucleoide real-time quantitative polymerase chain reaction and flow-cytometry.
Haematologica. 2005 Oct;90(10):1365-72.
Sarasquete ME, García-Sanz R, González D, Martínez J, Mateo G, Martínez P, Ribera JM, Hernández JM, Lahuerta JJ, Orfão A, González M, San Miguel JF.
This study compared quantitative PCR and flow cytometry (FCM) for the detection of minimal residual disease in multiple myeloma. The authors analyzed 32 bone marrow samples of patients in complete remission after stem cell transplant both by PCR and flow cytometry. Because of technical reasons, PCR was feasible in 75% of patients, while flow cytometry was feasible in up to 90% of patients. Therefore, both tests were obtained simultaneously in only 24 patients. PCR was more sensitive than flow cytometry, because it detected residual myeloma cells in 17 patients, whereas floww cytometry detected residual cells in 11 patients. The authors concluded that both PCR and flow cytometry are acceptable methods and provide equivalent prognostic information. PCR was more sensitive, but it was time-consuming and technically feasible in a lower proportion of patients.

Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma.
Br J Haematol. 2005 Oct;131(1):71-3.
Zangari M, Esseltine D, Lee CK, Barlogie B, Elice F, Burns MJ, Kang SH, Yaccoby S, Najarian K, Richardson P, Sonneveld P, Tricot G.
Response to bortezomib is associated with a significant increase in alkaline phosphatase.

Oral melphalan, prednisone, and thalidomide for newly diagnosed patients with myeloma.
Cancer. 2005 Oct 1;104(7):1428-33.
Palumbo A, Bertola A, Musto P, Caravita T, Callea V, Nunzi M, Grasso M, Falco P, Cangialosi C, Boccadoro M.
49 patients with newly diagnosed myeloma were treated with melphalan, prednisone, and thalidomide (MPT). Response rates: PR 45%, VGPR 4%, nCR 6%, CR 18%. The median time to maximum response was 4 months. Event-free survival at 2 years was 64%, and overall survival at 2 years was 91%. VTE was observed in 20% of patients, and 1 patient died of pulmonary embolism.

Phase II study of topotecan and cyclophosphamide in patients with relapsed and refractory multiple myeloma.
Leuk Res. 2005 Oct;29(10):1233-4.
Kraut EH, Young D, Farag S, James AG, Solove RJ.
The combination of cyclophosphamide and topotecan did not show antitumor activity in 11 patients with relapsed or refractory myeloma.

Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade.
Mol Cancer Ther. 2005 Oct;4(10):1533-40.
Shi Y, Yan H, Frost P, Gera J, Lichtenstein A.

IgA multiple myeloma responding to erythropoietin monotherapy.
Am J Hematol. 2005 Oct;80(2):165-6.
Barrios M, Alliot C.



Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2.
Blood. 2005 Nov 1;106(9):3160-5.
Oshima T, Abe M, Asano J, Hara T, Kitazoe K, Sekimoto E, Tanaka Y, Shibata H, Hashimoto T, Ozaki S, Kido S, Inoue D, Matsumoto T.
This study showed that MM cells in vitro produce a soluble Wnt inhibitor, secreted Frizzled-related protein 2 (sFRP-2), but not other Wnt inhibitors including sFRP-1, sFRP-3, and dickkopf 1 (DKK-1) at the protein level. Most MM cells from patients with advanced osteolytic lesions also expressed sFRP-2. Secretion of sFRP-2 inhibits bone formation by  inhibiting the canonical Wnt pathway.

CD33 is expressed on plasma cells of a significant number of myeloma patients, and may represent a therapeutic target.
Leukemia. 2005 Nov;19(11):2021-2.
Robillard N, Wuillème S, Lodé L, Magrangeas F, Minvielle S, Avet-Loiseau H.
This study of 63 patients with MM detected the expression of CD33 in 35% of cases. When detected, the expression was found in 11-100% of the myeloma cells.

Liposomal daunorubicin and dexamethasone as a treatment for multiple myeloma: the DD Protocol.
Sao Paulo Med J. 2005 Nov 3;123(6):266-70.
Dulley FL, Saboya R, Hungria VT, Bueno ND, Mello FG, Frota MT, Chiattone CS, Barros JC, Mori NS, Sturaro D, Macedo MC, Silva RL, Melo LM, Souza CA.
Liposomal daunorubicin + dexamethasone (DD) was administered to 20 patients with myeloma. Response rate was 30%.

Thalidomide plus dexamethasone is an effective salvage regimen for myeloma patients relapsing after autologous transplant.
Eur J Haematol. 2005 Nov;75(5):391-5.
Palumbo A, Falco P, Ambrosini MT, Petrucci MT, Musto P, Caravita T, Pregno P, Bertola A, Cavallo F, Ciccone G, Boccadoro M.
43 patients with MM in relapse after stem cell transplantation were treated with thalidomide + dexamethasone. Median progression-free survival was 20 months, and median overall survival was 55.5 months.

Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma.
Blood. 2005 Nov 1;106(9):2977-81.
Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Hideshima T, Xiao H, Esseltine D, Schenkein D, Anderson KC; SUMMIT Investigators.
Data review fro 202 myeloma patients enrolled in a phase II trial showed that response to bortezomib was not associated with sex, race, performance status, myeloma isotype, number of previous therapies, and type of previous therapies. Even beta2-microglobulin level and monosomy 13, two poor prognostic factors, were not predictive of poor response to bortezomib. After multivariate analysis, age >65 and degree of plasma cell infiltration in the bone marrow >50% were associated with lower response to bortezomib. Response to bortezomib was 19% in patients older than 65 vs 32% in patients younger than 65, and it was 20% in patients with >50% plasma cells in the bone marrow vs 35% in patients with >50% plasma cells in the bone marrow.

Continuous prednisolone versus conventional prednisolone with VMCP-interferon-alpha2b as first-line chemotherapy in elderly patients with multiple myeloma.
Br J Haematol. 2005 Nov;131(3):329-37.
Ludwig H, Spicka I, Klener P, Greil R, Adam Z, Gisslinger H, Tarkovács G, Linkesch W, Maniatis A, Morant R, Drach J, Kuhn I, Schuster J, Hinke A.
299 elderly patients with newly diagnosed multiple myeloma were randomized to induction therapy with either prednisolone daily conttinuously or prednisolone for 2 weeks/cycle + VMCP (vincristine, melphalan, cyclophosphamide, and prednisolone) and interferon-alpha 2b. Prednisolone given continuously during the induction therapy did not improve outcome:
  - Response rate: 62% in the continuous arm and 60% in the control arm
  - Median progression-free survival: 20 months in the continuous arm vs 19 months in the control (p= 0.97)
  - Median overall survival: 34 months in the continuous arm vs 37 months in the control arm (p= 0.35)
Continuous prednisolone was more toxic, because it was associated with more frequent dyspnea, cardiac impairment, and hyperglycaemia.

Prognostic significance of magnetic resonance imaging of bone marrow in previously untreated patients with multiple myeloma.
Ann Oncol. 2005 Nov;16(11):1824-8.
Moulopoulos LA, Gika D, Anagnostopoulos A, Delasalle K, Weber D, Alexanian R, Dimopoulos MA.



Incidence of haematopoietic malignancies in US radiologic technologists.
Occup Environ Med. 2005 Dec;62(12):861-7.
Linet MS, Freedman DM, Mohan AK, Doody MM, Ron E, Mabuchi K, Alexander BH, Sigurdson A, Hauptmann M.
The investigators followed 71,894 US radiology technologists, collecting data on risks of hematopoietic malignancies associated with protracted exposure to radiation. Only 28 cases of MM developed, and authors concluded that working as a radiology technologist did not increase the risk of multiple myeloma. Risk was increased for non-CLL leukaemias.

Plasma exchange when myeloma presents as acute renal failure: a randomized, controlled trial.
Ann Intern Med. 2005 Dec 6;143(11):777-84.
Clark WF, Stewart AK, Rock GA, Sternbach M, Sutton DM, Barrett BJ, Heidenheim AP, Garg AX, Churchill DN; Canadian Apheresis Group.
This is a randomized trial conducted from 1998 to 2004 in 14 Canadian medical centers. 104 patients with acute renal failure at the onset of myeloma were randomly assigned to conventional therapy + 5-7 plasma exchanges for 10 days or conventional therapy alone. The primary outcome was a composite measure of death, dialysis dependence, or glomerular filtration rate <30 mL/min/1.73 m2. This end point occurred in 33 of 57 (57.9%) patients in the plasma exchange group and in 27 of 39 (69.2%) patients in the control group (P = 0.36). Therefore, there was no conclusive evidence that 5-7 plasma exchanges improve clinical results at 6 months in patients with acute renal failure at the onset of multiple myeloma. This study failed to demonstrate a benefit of the addition of plasma exchange therapy

Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors.
J Clin Oncol. 2005 Dec 1;23(34):8580-7.
Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, Koutsoukou V, Gika D, Anagnostopoulos A, Papadimitriou C, Terpos E, Dimopoulos MA.
This is a prospective study of ONJ in 252 patients who received bisphosphonates. 17 patients (7%) developed ONJ: 11 of 111 (10%) with multiple myeloma, 2 of 70 (3%) with breast cancer, 3 of 46 (6.5%) with prostate cancer, and 1 of 25 (4%) with other neoplasms. The median number of treatment cycles and time of exposure to bisphosphonates were:
  - 35 infusions and 39 months for patients with ONJ
  - 15 infusions and 19 months for patients with no ONJ (p<0.001)
The incidence of ONJ increased with time to exposure:
  - 1.5% among patients treated for 4-12 months
  - 7.7% among patients treated for 37-48 months.
The cumulative hazard was significantly higher with zoledronic acid compared with pamidronate. All but 2 patients with ONJ had a history of dental procedures within the last year or use of dentures. Based on the results, the authors conclude that the length of exposure is the most important risk factor for ONJ, that the type of bisphosphonate plays a role, and that previous dental procedures are a precipitating factor.

Serum free light chain analysis and urine immunofixation electrophoresis in patients with multiple myeloma.
Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8706-14.
Nowrousian MR, Brandhorst D, Sammet C, Kellert M, Daniels R, Schuett P, Poser M, Mueller S, Ebeling P, Welt A, Bradwell AR, Buttkereit U, Opalka B, Flasshove M, Moritz T, Seeber S.

Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma.
Blood. 2005 Dec 15;106(13):4050-3.
Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, Zeldenrust SR, Kumar S, Greipp PR, Fonseca R, Lust JA, Russell SJ, Kyle RA, Witzig TE, Gertz MA.
This is a phase 2 trial of lenalidomide + dexamethasone in 34 patients with newly diagnosed myeloma. Lenalidomide was given at a dose of 25 mg daily on days 1-21, and dexamethasone was given at a dose of 40 mg daily on days 1-4, 9-12, and 17-20, with cycles repeated every 28 days. Response rate was 91%, including 6% CR and 32% VGPR + nCR.

Weekly cyclophosphamide and alternate-day prednisone: an effective, convenient, and well-tolerated oral treatment for relapsed multiple myeloma after autologous stem cell transplantation.
Mayo Clin Proc. 2005 Dec;80(12):1578-82.
Trieu Y, Trudel S, Pond GR, Mikhael J, Jaksic W, Reece DE, Chen CI, Stewart AK.

This is a retrospective study of 66 patients with myeloma in relapse after stem cell transplantation. Patients were treated with cyclophosphamide 500 mg PO once weekly + alternate-day prednisone 100 mg PO on alternate days. Among 59 evaluable patients, response rate was 61% (PR 41%), 1-year PFS 66%, median PFS 18.6 months, and median overall survival from the time of initiation of salvage therapy 28.6 months.

Long-term outcome of nonmyeloablative allogeneic transplantation in patients with high-risk multiple myeloma.
Bone Marrow Transplant. 2005 Dec;36(11):963-9.
Gerull S, Goerner M, Benner A, Hegenbart U, Klein U, Schaefer H, Goldschmidt H, Ho AD.
This is a retrospective study of 52 patients with high-risk myeloma, treated with nonmyeloablative allogeneic stem cell transplant. The conditioning regimen was TBI + fludarabine (49 patients) or TBI alone (2 patients). Patient were heavily pretreated and with relapsed disease after a median of 8 cycles of conventional chemotherapy and autologous transplant. Median follow-up was about 19 months. Results:
  - Transplant-related mortality: 17%
  - Acute GVHD, grade II-IV: 37%
  - Chronic GVHD: 70%
  - Overall survival at 18 months: 41%
  - Progression-free survival at 18 months: 29%



Giampaolo Talamo, MD