JULY 2006

Phase 2 study of pegylated liposomal doxorubicin, vincristine, decreased-frequency dexamethasone, and thalidomide in newly diagnosed and relapsed-refractory multiple myeloma.
Mayo Clin Proc. 2006 Jul;81(7):889-95.
Hussein MA, Baz R, Srkalovic G, Agrawal N, Suppiah R, Hsi E, Andresen S, Karam MA, Reed J, Faiman B, Kelly M, Walker E.
This is a phase II study of DVd (pegylated liposomal doxorubicin, vincristine, and decreased-frequency dexamethasone) + thalidomide in 102 patients with multiple myeloma (53 with newly diagnosed disease, and 49 with previously treated disease). Thalidomide was started at 50 mg/day and escalated up to 400 mg/day. At the time of best response, patients were started on maintenance with thalidomide + prednisone 50 mg PO qod. Results:
  - Response rate was 87% in patients with newly diagnosed myeloma and 90% in patients with previously treated myeloma
  - Rate of CR + VGPR was 49% in patients with newly diagnosed myeloma and 45% in patients with previously treated myeloma
  - Responders had longer progression-free and overall survival
  - Most common grade 3-4 toxicities: venous thromboembolism (25%), peripheral neuropathy (22%), and neutropenia (14%)

Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib.
J Clin Oncol. 2006 Jul 1;24(19):3113-20.
Richardson PG, Briemberg H, Jagannath S, Wen PY, Barlogie B, Berenson J, Singhal S, Siegel DS, Irwin D, Schuster M, Srkalovic G, Alexanian R, Rajkumar SV, Limentani S, Alsina M, Orlowski RZ, Najarian K, Esseltine D, Anderson KC, Amato AA.
In this study of 256 myeloma patients enrolled in 2 phase II studies, bortezomib-induced peripheral neuropathy developed in 35% of patients. The rate of neuropathy was 37% (84 of 228 patients) when bortezomib was given at 1.3 mg/m2, and 21% (6 of 28 patients) when bortezomib was given at 1.0 mg/m2.
Severity of peripheral neuropathy:
  - Grade 1-2: 22%
  - Grade 3: 13%
  - Grade 4: 0.4%
Neuropathy required dose reductions of bortezomib in 12% of patients, and discontinuation of it in 5% of patients. After dose reduction or discontinuation of bortezomib, neuropathy of grade 3 or 4 improved or completely resolved in 71% of patients.

Clinical and biological features of multiple myeloma involving the gastrointestinal system.
Haematologica. 2006 Jul;91(7):964-7.
Talamo G, Cavallo F, Zangari M, Barlogie B, Lee CK, Pineda-Roman M, Kiwan E, Krishna S, Tricot G.

This study describes 24 cases of MM with involvement of the gastrointestinal system. MM involving the GI tract was associated with adverse biological features (high LDH levels, plasmablastic morphology, and unfavorable karyotype) and with short-lasting remissions, even after aggressive treatment. GI involvement at the time of initial diagnosis was much rarer than later in the course of the disease. The median survival after diagnosis of GI involvement was 7 months. Among 13 patients treated with stem cell transplantation, the response rate was 92%, but the median progression-free survival was only 4 months.

Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone.
Haematologica. 2006 Jul;91(7):929-34.
Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators.
This study reviews data from 202 patients enrolled in the SUMMIT trial and 54 patients enrolled in the CREST trial. In those two trials, patients with refractory myeloma received bortezomib, and dexamethasone (20 mg PO on the day of and the day after bortezomib) was added in case of no response, i.e., presence of progressive disease after 2 cycles or stable disease after 4 cycles. The addition of dexamethasone produced an improvement of disease response in 13/74 (18%) patients in the SUMMIT trial, and 9/27 (33%) in the CREST trial. Combining the data, 22 of  101 (22%) patients with no response to bortezomib single agent had a therapeutic response when dexamethasone was added to bortezomib.

International prognostic index (IPI) - a critical comparison with five multiple myeloma staging systems in the group of 270 patients treated by conventional chemotherapy.
Neoplasma. 2006;53(4):277-84.
Scudla V, Zemanova M, Minarik J, Bacovsky J, Ordeltova M, Indrak K, Budikova M, Dusek L, Farbiakova V.

Conventional diagnostics in multiple myeloma.
Eur J Cancer. 2006 Jul;42(11):1510-9.
San Miguel JF, Gutiérrez NC, Mateo G, Orfao A.



Nonsecretory plasma cell myeloma - becoming even more rare with serum free light-chain assay: a brief review.
Arch Pathol Lab Med. 2006 Aug;130(8):1212-5.
Shaw GR.

Evaluation of five staging systems in 470 patients with multiple myeloma.
Haematologica. 2006 Aug;91(8):1149-50.
Mihou D, Katodritou I, Zervas K.
This study evaluates and compares 5 different staging systems in 470 patients with newly diagnosed multiple myeloma:
  - ISS (International Staging System)
  - Durie-Salmon
  - SWOG (South West Oncology Group)
  - Bataille et al.
  - Weber et al.
The ISS was the best one, because of its simplicity and high prognostic power.

Does low-dose aspirin have antineoplastic effects in multiple myeloma?
Baz R, Hussein MA.
Br J Haematol. 2006 Aug;134(3):349-50.
These authors suspected that low-dose aspirin may have antineoplastic properties in MM. They retrospectively reviewed the outcomes of 84 MM patients who received aspirin and 19 who did not receive it. RR was 81% in the aspirin group and 63% in the no-aspirin group. The 1-year survival was 89% in the aspirin group and 68% in the no-aspirin group.

The clinical outcome and toxicity of high-dose chemotherapy and autologous stem cell transplantation in patients with myeloma or amyloid and severe renal impairment: a British Society of Blood and Marrow Transplantation study.
Br J Haematol. 2006 Aug;134(4):385-90.
Bird JM, Fuge R, Sirohi B, Apperley JF, Hunter A, Snowden J, Mahendra P, Milligan D, Byrne J, Littlewood T, Fegan C, McQuaker G, Pagliuca A, Johnson P, Rahemtulla A, Morris C, Marks DI; British Society of Blood and Marrow Transplantation.
27 myeloma patients and 4 amyloidosis patients with severe renal insufficiency (23 on dialysis) underwent autologous stem cell transplantation using high-dose melphalan (median 140 mg/m2, range: 60-200 mg/m2). Results:
  - Response rate: 70%
  - 24% (4 of 17) patients became dialysis-independent at a median of 5 months after SCT
  - Transplant-related mortality at day 100: 19% (5 of 27 patients)
  - Median time to disease progression: 32 months (range: 6-54 months)
  - At a median follow-up of about 6 years, 7 of 23 (30%) myeloma patients were alive, 4 (17%) with disease remission



International uniform response criteria for multiple myeloma.
Leukemia. 2006 Sep;20(9):1467-73.
Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadoro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV; International Myeloma Working Group.
These International uniform response criteria added 2 categories of response, i.e., "stringent complete response" and "very good partial response".

Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation.
Blood. 2006 Sep 1;108(5):1724-32.
Hanamura I, Stewart JP, Huang Y, Zhan F, Santra M, Sawyer JR, Hollmig K, Zangari M, Pineda-Roman M, van Rhee F, Cavallo F, Burington B, Crowley J, Tricot G, Barlogie B, Shaughnessy JD Jr.
These authors used FISH to investigate the amplification of chromosome band 1q21 (Amp1q21) in more than 500 untreated patients with plasma cell dyscrasias. They found that Amp1q21 is associated with both disease progression and poor prognosis. The frequency of Amp1q21 was 0% in MGUS, 45% in smoldering MM, 43% in newly diagnosed MM, and 72% in relapsed MM. Amp1q21 was an independent poor prognostic factor at multivariate analysis. Patients with newly diagnosed MM with Amp1q21 had a 5-year EFS of 38% and OS of 52%, while patients lacking Amp1q21 had a 5-year EFS of 62% and OS of 78%. 5-year post-relapse survival was 15% in patients with relapsed MM who had Amp1q21, and 53% in patients lacking Amp1q21 at relapse. At relapse, both proportion of cells with Amp1q21 and copy number of 1q21 were higher than those at diagnosis.

Significant increase of CKS1B amplification from monoclonal gammopathy of undetermined significance to multiple myeloma and plasma cell leukaemia as demonstrated by interphase fluorescence in situ hybridisation.
Br J Haematol. 2006 Sep;134(6):613-5.
Chang H, Yeung J, Xu W, Ning Y, Patterson B.
Authors investigated the CKS1B amplification status at 1q21 in clonal plasma cells from 123 patients: 23 MGUS, 75 MM and 26 plasma cell leukemia (PCL). While CKS1B amplification was absent in MGUS patients, such amplification (3-8 copies) was detected in 36% of newly diagnosed MM, 52% relapsed MM and 62% PCL (P < 0.001). The results suggest that CKS1B amplification is associated with progression from MGUS to MM, and from MM to PCL.

The molecular classification of multiple myeloma.
Blood. 2006 Sep 15;108(6):2020-8.
Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S, Epstein J, Yaccoby S, Sawyer J, Burington B, Anaissie E, Hollmig K, Pineda-Roman M, Tricot G, van Rhee F, Walker R, Zangari M, Crowley J, Barlogie B, Shaughnessy JD Jr.

Authors performed mRNA expression profiles in plasma cells from 414 newly diagnosed MM patients. They validated 7 disease subtypes, characterized by known genetic lesions: c-MAF- and MAFB-, CCND1- and CCND3-, MMSET-activating translocations, and hyperdiploidy.

Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients.
Br J Haematol. 2006 Sep;134(6):620-3.
Zervas K, Verrou E, Teleioudis Z, Vahtsevanos K, Banti A, Mihou D, Krikelis D, Terpos E.
This study  evaluated ONJ in 303 myeloma patients. Only patients who received bisphosphonates developed ONJ (28/254; 11%). Number of bisphosphonate infusions increased the risk for ONJ. Zoledronic acid was 10 times more likely to induce ONJ than pamidronate, and ONJ developed earlier with the use of zoledronic acid. Based on the data, the authors conclude that administration of zoledronic acid for more than 2 years requires caution.



Giampaolo Talamo, MD