JANUARY 2006

The tumor kinetics of multiple myeloma following autologous stem cell transplantation as assessed by measuring serum-free light chains.
Leuk Lymphoma. 2006 Jan;47(1):21-8.
Pratt G, Mead GP, Godfrey KR, Hu Y, Evans ND, Chappell MJ, Lovell R, Bradwell AR.

Amylase: a disease activity index in multiple myeloma?
Leuk Lymphoma. 2006 Jan;47(1):151-4.
Pinelli M, Bindi M, Rosada J, Scatena P, Castiglioni M.
This is a case report of a patient with lambda-light chain multiple myeloma who had hyperamylasaemia of the salivary type. The authors review the literature of ectopic production of amylase by myeloma cells, and they conclude that these cases are associated with high tumor mass, extensive bone destruction, extra-medullary disease,  and poor prognosis.

Cure of multiple myeloma - more hype, less reality.
Bone Marrow Transplant. 2006 Jan;37(1):1-18.
Hari P, Pasquini MC, Vesole DH.

[Review]

Vitamin C inactivates the proteasome inhibitor PS-341 in human cancer cells.
Clin Cancer Res. 2006 Jan 1;12(1):273-80.
Zou W, Yue P, Lin N, He M, Zhou Z, Lonial S, Khuri FR, Wang B, Sun SY.
These authors studied the interaction between vitamin C and bortezomib in human cancer cell lines. They found that vitamin C abrogated the ability of bortezomib to inhibit the proteasome activity and induce apoptosis. There was a direct chemical interaction between vitamin C and bortezomib. Vitamin C directly binds to bortezomib and it may suppress the anticancer activity of bortezomib. These findings are relevant because many cancer patients routinely take multivitamins.

Doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective well tolerated initial therapy for multiple myeloma.
Br J Haematol. 2006 Jan;132(2):155-61.
Hassoun H, Reich L, Klimek VM, Dhodapkar M, Cohen A, Kewalramani T, Zimman R, Drake L, Riedel ER, Hedvat CV, Teruya-Feldstein J, Filippa DA, Fleisher M, Nimer SD, Comenzo RL.
This is a phase II clinical trial of 45 myeloma patients treated with the AD-TD regimen: doxorubicin + dexamethasone for 2-3 months, followed by thalidomide + dexamethasone for 2 months. Response rate was 90.5% (CR 15.5%, nCR 20%, PR 49%). Venous thromboembolism was observed in 11% of cases (prophylaxis consisted of aspirin 81 mg/day).

Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group.
J Clin Oncol. 2006 Jan 20;24(3):431-6.
Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR; Eastern Cooperative Oncology Group.
This study demonstrated that dexamethasone + thalidomide (DT) induces superior response rates compared with single-agent dexamethasone (D) in 207 patients with newly diagnosed multiple myeloma. Patients were randomized to:
  - Dexamethasone (40 mg PO on days 1-4, 9-12, and 17-20) + thalidomide (200 mg PO qhs) (103 patients) or
  - Single-agent dexamethasone (104 patients)
Each cycle was 28 days.
Response rate was 63% in the DT group and 41% in the D group (p= 0.0017)
Toxicities were more frequent in the DT group, especially DVT (17% vs 3%), rash, bradycardia, and peripheral neuropathy.
This study established the combination of dexamethasone and thalidomide as the new (as of 2006) standard of care for the induction therapy of multiple myeloma.

Autologous stem cell transplantation followed by consolidation chemotherapy for patients with multiple myeloma.
Bone Marrow Transplant. 2006 Jan;37(1):65-72.
Gojo I, Meisenberg B, Guo C, Fassas A, Murthy A, Fenton R, Takebe N, Heyman M, Philips GL, Cottler-Fox M, Sarkodee-Adoo C, Ruehle K, French T, Tan M, Tricot G, Rapoport AP.
103 patients with myeloma patients received autologous stem cell transplantation followed by 2 cycles of DCEP (Dexamethasone, Cyclophosphamide, Etoposide, cisPlatin) +/- gemcitabine) at 3 and 9 months after transplant, and 2 cycles of DPP (Dexamethasone, cisPlatin, Paclitaxel) at 6 and 12 months after transplant. Results:
  - Median event-free survival was 26 months
  - Median overall survival was 54.1 months
  - Event-free survival at 5 years was 23.1%
  - Overall survival at 5 years was 42.5%
Of note, only 50% of patients completed the planned chemotherapy courses.

Sequential, cycling maintenance therapy for post transplant multiple myeloma.
Bone Marrow Transplant. 2006 Jan;37(1):89-94.
Chen CI, Nanji S, Prabhu A, Beheshti R, Yi QL, Sutton D, Stewart AK.
28 patients with myeloma were treated with autologous stem cell transplantation followed by consolidation therapy with a sequential approach:
  - Dexamethasone (months 1-3)
  - Melphalan and prednisone (months 4-5)
  - Cyclophosphamide and prednisone (months 6-7)
  - Alpha-interferon (months 8-10)
  - Drug holiday (months 11-12)
Median event-free survival (from transplant) was 36.9 months.

Low-dose thalidomide with pegylated liposomal doxorubicin and high-dose dexamethasone for relapsed/refractory multiple myeloma: a prospective, multicenter, phase II study.
Haematologica. 2006 Jan;91(1):133-6.
Offidani M, Corvatta L, Marconi M, Visani G, Alesiani F, Brunori M, Galieni P, Catarini M, Burattini M, Centurioni R, Rupoli S, Scortechini AR, Giuliodori L, Candela M, Capelli D, Montanari M, Olivieri A, Piersantelli MN, Leoni P.
This is a phase II study of thalidomide 100 mg PO qhs, dexamethasone, and liposomal doxorubicin 40 mg/m2 every 28 days in 50 patients with advanced myeloma. Response rate was 92% (CR 26%, nCR 6%, VGPR 6%, PR 38%, and minor response 16%), median event-free survival was 17 months, and median overall survival was not reached.

Low dose Velcade, thalidomide and dexamethasone (LD-VTD): an effective regimen for relapsed and refractory multiple myeloma patients.
Leuk Lymphoma. 2006 Jan;47(1):171-3.
Ciolli S, Leoni F, Gigli F, Rigacci L, Bosi A.
18 patients with relapsed/refractory myeloma were treated with VTD:
  - Velcade 1.0 mg/m2 IV on days 1, 4, 8, 11
  - Thalidomide 100 mg PO qhs
  - Dexamethasone 24 mg PO on the same day and the day after Velcade
Cycles were repeated every 28 days x6.
Response rate was 53%, despite the fact that patients had previously received a median of 4 lines of therapy.

A phase II trial of imatinib in patients with refractory/relapsed myeloma.
Leuk Lymphoma. 2006 Jan;47(1):39-42.
Dispenzieri A, Gertz MA, Lacy MQ, Geyer SM, Greipp PR, Rajkumar SV, Kimlinger T, Lust JA, Fonseca R, Allred J, Witzig TE.
Imatinib inhibits not only the bcr-abl protein, but also other receptor tyrosine kinases, such as c-kit. In this study, 23 patients with relapsed/refractory myeloma were treated with imatinib 400 mg daily for a median duration of 48 days (range: 12-349). 52% of cases had positive c-kit staining. Imatinib was inactive, because there were no responses.

Local irradiation prior to stem cell harvest has no influence on CD34+ yield: a quantitative analysis.
Ann Hematol. 2006 Jan;85(1):38-44.
Rinn JP, Schwella N, Wollmer E, Jaques G, Heinzel-Gutenbrunner M, Strassmann G, Gross MW, Movassaghi K, Neubauer A, Ritter M.
Among 114 patients with multiple myeloma, 53 (47%) patients received RT prior to mobilization chemotherapy. 84% of them received high-dose cyclophosphamide followed by G-CSF. The study found no difference of CD34+ cell counts between irradiated and non-irradiated patients. Dose of RT did not influence the yield of CD34+ cells, but RT decreased the number of mobilized stem cells when the time elapsed since the last irradiation was short.

The role of second autografts in the management of myeloma at first relapse.
Haematologica. 2006 Jan;91(1):141-2.
Alvares CL, Davies FE, Horton C, Patel G, Powles R, Morgan GJ.
These authors performed an intention-to-treat analysis on 383 patients with newly diagnosed myeloma,  and reviewed the outcomes of a second autologous stem cell transplant with high dose melphalan done at relapse. SCT at relapse did not improve overall survival, and therefore data did not support the use of salvage SCT. One of the most important prognostic factor was a relapse-free survival after the first transplant >18 months.

 

FEBRUARY 2006

Guidelines on the diagnosis and management of multiple myeloma 2005.
Br J Haematol. 2006 Feb;132(4):410-51.
Smith A, Wisloff F, Samson D; UK Myeloma Forum; Nordic Myeloma Study Group; British Committee for Standards in Haematology.

Incidence of monoclonal B-cell disease in siblings of patients with multiple myeloma.
Haematologica. 2006 Feb;91(2):274-6.
Engelhardt M, Ihorst G, Behringer D, Finke J, Roth B.
Authors observed clustering of monoclonal B-cell disease in siblings screened as donors for MM patients who needed an allogeneic stem cell transplantation (SCT). Of 134 donors, the incidence of monoclonal B-cell disease was 8/84 in siblings and 1/50 in matched unrelated donors. In 5 MM families scheduled for allogeneic SCT, monoclonal B-cell disease was detected in 8 of 27 siblings.

Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors.
J Clin Oncol. 2006 Feb 20;24(6):945-52.
Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, Fenton R, Gahres N, Sausville E, Ord R, Meiller T.
This is a retrospective review of 90 MM patients who had dental assessments, including 22 patients with ONJ. 27 patients had recent dental extraction, including 12 patients in the ONJ group. Median time from MM diagnosis to ONJ was 8.4 years. ONJ usually presented with pain, and it occurred posterior to the cuspids (n = 20) mostly in the mandible. 4 patients had recurrent ONJ. Bone histology revealed necrosis and osteomyelitis. Microbiology showed actinomycetes (n = 7) and mixed bacteria (n = 9). Risk factors for ONJ were dental extractions, long-term treatment with bisphosphonates, prolonged survival, and older age.

Percutaneous vertebroplasty and kyphoplasty in patients with multiple myeloma.
Eur J Haematol. 2006 Feb;76(2):180-1.
Bartolozzi B, Nozzoli C, Pandolfo C, Antonioli E, Guizzardi G, Morichi R, Bosi A.

Primary treatment with pulsed melphalan, dexamethasone and thalidomide for elderly symptomatic patients with multiple myeloma.
Haematologica. 2006 Feb;91(2):252-4.
Dimopoulos MA, Anagnostopoulos A, Terpos E, Repoussis P, Zomas A, Katodritou E, Kyrtsonis MC, Delibasi S, Vassou A, Pouli A, Zervas K, Anagnostopoulos N, Maniatis A; Greek Myeloma Study Group.
50 patients with myeloma older than 75 were treated with MDT:
  - Melphalan 8 mg/m2 on days 1-4
  - Dexamethasone 12 mg/m2 on days 1-4 and 17-20
  - Thalidomide 300 mg qhs on days 1-4 and 17-20
Cycles were repeated every 5 weeks x3.
Results: partial response 62%, complete response 10%. Median time to response: 2 months. Median time to progression: 21 months. DVT was seen in 9% of patients.

Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy.
Blood. 2006 Feb 15;107(4):1292-8.
Facon T, Mary JY, Pégourie B, Attal M, Renaud M, Sadoun A, Voillat L, Dorvaux V, Hulin C, Lepeu G, Harousseau JL, Eschard JP, Ferrant A, Blanc M, Maloisel F, Orfeuvre H, Rossi JF, Azaïs I, Monconduit M, Collet P, Anglaret B, Yakoub-Agha I, Wetterwald M, Eghbali H, Vekemans MC, Maisonneuve H, Troncy J, Grosbois B, Doyen C, Thyss A, Jaubert J, Casassus P, Thielemans B, Bataille R; Intergroupe Francophone du Myélome (IFM) group.
In the IFM 95-01 trial, 488 myeloma patients aged 65-75 years were randomized between 4 different regimens of treatment:
  - MP (melphalan + prednisone)
  - Dexamethasone alone
  - Melphalan + dexamethasone
  - Dexamethasone + interferon alpha
The standard MP remained the best regimen, in terms of efficacy and toxicity. The response rate at 6 months was higher in the group receiving melphalan + dexamethasone. The progression-free survival was longer in the groups receiving melphalan. However, overall survival was similar among the 4 treatment groups. The toxicity of dexamethasone-containing regimens was higher than with MP, particularly because of pyogenic infections, hemorrhage, diabetes, GI, and psychiatric complications.

Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a Phase III multicenter randomized trial.
Cancer. 2006 Feb 15;106(4):848-58.
Rifkin RM, Gregory SA, Mohrbacher A, Hussein MA.
This is a noninferiority trial of 192 patients with newly diagnosed myeloma, randomized to receive:
1) VAd (95 patients): conventional doxorubicin 9 mg/m2/day, vincristine 0.4 mg per day as continuous IV infusion on Days 1-4 + dexamethasone
2) DVd (97 patients): liposomal doxorubicin 40 mg/m2, vincristine 1.4 mg/m2 IV on Day 1 + dexamethasone 40 mg PO on Days 1-4 (DVd)
Treatment was given every 4 weeks, for at least 4 cycles.
Results:
  - Clinical efficacy was similar:
       RR: 41% with VAd and 44% with DVd
       CR: 0% with VAd and 3% with DVd
       Progressive disease: 0% with VAd and 2% with DVd
       Need for hospitalization: 36% with VAd and 37% with DVd
       PFS and OS were similar
  - Toxicity was less with DVd:
       Lower incidence of neutropenia and sepsis, reduced need for central venous access and growh factors
       Alopecia: 44% with VAd and 20% with DVd
       Mean changes from baseline LVEF: -4.5 with VAd and -2.3 with DVd
       Hand-foot syndrome was observed in 25% of patients treated with DVd (Grade 1 and 2 in 84% of cases)

Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma.
J Clin Oncol. 2006 Feb 20;24(6):937-44.
Berenson JR, Yang HH, Sadler K, Jarutirasarn SG, Vescio RA, Mapes R, Purner M, Lee SP, Wilson J, Morrison B, Adams J, Schenkein D, Swift R.
35 patients with relapsed or refractory multiple myeloma received melphalan in escalating doses from 0.025 to 0.25 mg/kg PO on days 1-4 + bortezomib 0.7-1.0 mg/m2 on days 1, 4, 8, and 11 of a 28-day cycle for up to 8 cycles. The maximum-tolerated dose (MTD) was melphalan 0.10 mg/kg + bortezomib 1.0 mg/m2. Results:
  - RR was 83%, CR was 6%
  - Median progression-free survival was 8 months (range, 2-18 months)
  - The most important toxicity was myelosuppression

Results of a phase I/II trial adding carmustine (300 mg/m2) to melphalan (200 mg/m2) in multiple myeloma patients undergoing autologous stem cell transplantation.
Leukemia. 2006 Feb;20(2):345-9.
Comenzo RL, Hassoun H, Kewalramani T, Klimek V, Dhodapkar M, Reich L, Teruya-Feldstein J, Fleisher M, Filippa D, Nimer SD.
In this study, 49 patients with myeloma underwent autologous stem cell transplant using melphalan 200 mg/m2 + carmustine 300 mg/m2. The transplant-related mortality was 2% and the pulmonary toxicity 10%. The rate of CR + nCR was 49%.

 

MARCH 2006

Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomized controlled trial.
Lancet. 2006 Mar 11;367(9513):825-31.
Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, Cangialosi C, Grasso M, Rossini F, Galli M, Catalano L, Zamagni E, Petrucci MT, De Stefano V, Ceccarelli M, Ambrosini MT, Avonto I, Falco P, Ciccone G, Liberati AM, Musto P, Boccadoro M; Italian Multiple Myeloma Network, GIMEMA.
This trail randomized newly diagnosed myeloma patients aged 60-85 years between MP alone every 4 weeks x6 (126 patients) vs MPT with thalidomide 100 mg PO qhs (129 patients). MPT therapy was superior to MP:
  - Response rate was 48% with MP and 76% with MPT
  - CR + near-CR rate was 7% with MP and 28% with MPT
  - Event-free survival at 2 years was 27% with MP and 54% with MPT
  - Survival at 3 years was 64% with MP and 80% with MPT
  - Toxicity, defined as grade 3-4 adverse events rate, was 25% with MP and 48% with MPT
  - DVT was seen in 20% of patients without enoxaparin prophylaxis, and in 3% with enoxaparin prophylaxis

Thalidomide and hematopoietic-cell transplantation for multiple myeloma.
N Engl J Med. 2006 Mar 9;354(10):1021-30.
Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F, Fassas A, Zangari M, Hollmig K, Pineda-Roman M, Lee C, Talamo G, Thertulien R, Kiwan E, Krishna S, Fox M, Crowley J.

Total Therapy 2 (1998-2004) is one of the largest trials conducted in multiple myeloma. 668 patients with newly diagnosed myeloma were treated with induction therapy, tandem autologous transplants using melphalan, consolidation chemotherapy, and maintenance therapy. Patients were randomized to receive thalidomide continuously, until disease progression or unacceptable toxicity (323 patients), or no thalidomide (345 patients). Results:
  - Rate of complete response was 62% in the thalidomide group, and 43% in the control group (p<0.001)
  - 5-year event-free survival was 56% in the thalidomide group, and 44% in the control group (p=0.01)
  - 5-year overall survival was 65% in both groups (P=0.90)
  - Median survival after relapse was inferior in the thalidomide group (1.1 vs 2.7 years, p=0.001)
As expected, toxicities were more frequent in the thalidomide group, particularly severe peripheral neuropathy and deep venous thrombosis.
In conclusion, after a median follow-up of 42 months, thalidomide increased response rate and event-free survival, but did not improve overall survival.

Clonal cytogenetic changes and myeloma relapse after reduced intensity conditioning allogeneic transplantation.
Bone Marrow Transplant. 2006 Mar;37(5):511-5.
Lee CK, Zangari M, Fassas A, Thertulien R, Talamo G, Badros A, Cottler-Fox M, van Rhee F, Barlogie B, Tricot G.

Osteonecrosis of the jaws in patients treated with bisphosphonates - histomorphologic analysis in comparison with infected osteoradionecrosis.
J Oral Pathol Med. 2006 Mar;35(3):155-60.
Hansen T, Kunkel M, Weber A, James Kirkpatrick C.
This study examined the histologic findings of 8 cases (5 patients with MM) of ONJ after bisphosphonate treatment. 5 patients had mandibular involvement, and 3 patients had maxillar involvement. Histological analysis revealed diffuse and patchy areas of necrosis of the bone, and all cases were found to have Actinomyces attached to the necrotic bone tissue. In 5 cases, numerous osteoclasts were found close to vital bone, exhibiting signs of bone resorption. Pseudoepitheliomatous hyperplasia was revealed in 5 patients. The authors conclude that Actinomyces are involved in the chronic, non-healing inflammatory process, and believe that both Actinomyces infection and increased osteoclast numbersare involved in the osteolysis of ONJ.

A systematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma.
Br J Haematol. 2006 Mar;132(5):584-93.
Glasmacher A, Hahn C, Hoffmann F, Naumann R, Goldschmidt H, von Lilienfeld-Toal M, Orlopp K, Schmidt-Wolf I, Gorschlüter M.
[Review]
This is a review of 42 trials including 1674 myeloma patients treated with thalidomide. Conclusions:
  - Clinical benefit: 54%
          Response rate (PR + CR): 29%
          Rate of minor responses: 14%
          Rate of stable disease: 11%
  - Median overall survival: 14 months
  - Severe adverse events (grade III-IV): constipation 16%, somnolence 11%, neuropathy 6%, rash 3%, VTE 3%.

Extended follow-up of a phase II trial in relapsed, refractory multiple myeloma: final time-to-event results from the SUMMIT trial.
Cancer. 2006 Mar 15;106(6):1316-9.
Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin DH, Rajkumar SV, Srkalovic G, Alsina M, Anderson KC.
202 patients with relapsed/refractory myeloma were treated with bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 every 21 days, for up to 8 cycles (in case of suboptimal response, they also received dexamethasone 20 mg PO on the day of and the day after bortezomib). Results:
  - Response rate was 28%: PR 18%, nCR 6%, CR 4%. Minimal response 7%
  - Median time to progression: 7 months (14 months in responding patients vs 1.3 months in non-responding patients)
  - Median overall survival: 17 months (not reached at 23 months of follow-up in responding patients vs 8 months in non-responding patients)

Flavopiridol in patients with relapsed or refractory multiple myeloma: a phase 2 trial with clinical and pharmacodynamic end-points.
Haematologica. 2006 Mar;91(3):390-3.
Dispenzieri A, Gertz MA, Lacy MQ, Geyer SM, Fitch TR, Fenton RG, Fonseca R, Isham CR, Ziesmer SC, Erlichman C, Bible KC.
No responses were observed in 18 myeloma patients treated with flavopiridol, given as IV infusion over 1 hour on days 1-3 every 21 days.

Second autologous or allogeneic transplantation after the failure of first autograft in patients with multiple myeloma.
Cancer. 2006 Mar 1;106(5):1084-9.
Qazilbash MH, Saliba R, De Lima M, Hosing C, Couriel D, Aleman A, Roden L, Champlin R, Giralt SA.
This study analyzes the outcomes of salvage autologous or mini-allogeneic transplants in myeloma patients who relapsed after an autologous transplant.
  - In 14 pts treated with salvage autologous SCT: median PFS 6.8 months, median OS 29 months (median f/u 18 months)
  - In 26 pts treated with salvage mini-allogeneic SCT: median PFS 7.3 months, median OS 13 months (median f/u 30 months)

 

 


Giampaolo Talamo, MD