JULY 2003

Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age.
Blood. 2003 Jul 1;102(1):69-77.
Mileshkin L, Biagi JJ, Mitchell P, Underhill C, Grigg A, Bell R, McKendrick J, Briggs P, Seymour JF, Lillie K, Smith JG, Zeldis JB, Prince HM.
In this phase II study, 75 patients with relapsed/refractory myeloma were treated with thalidomide up to the maximum dose of 800 mg/day. Response rate was 28%, and stable disease was seen in 55% of patients. Median progression-free survival was 5.5 months, and median overall survival was 14.6 months. Patients older than 65 years had inferior outcomes.

Heterogeneous pattern of chromosomal breakpoints involving the MYC locus in multiple myeloma.
Genes Chromosomes Cancer. 2003 Jul;37(3):261-9.
Fabris S, Storlazzi CT, Baldini L, Nobili L, Lombardi L, Maiolo AT, Rocchi M, Neri A.
MM and plasma cell leukemia (PCL) can harbor c
hromosomal rearrangements of MYC (8q24), which may involve the Ig loci. Author used dual-color FISH to characterize the breakpoint locations of chromosomal rearrangements of the MYC locus in 14 MM cell lines, 66 cases of MM and 4 cases of PCL. They found MYC locus alterations in 21 cases: MYC/Ig (mainly IgH) fusions in 11 cell lines, 2 MM patients, and 1 PCL patient, and extra signals and/or abnormal MYC localizations in 5 MM patients and 2 PCL patients. These data document the dispersion of 8q24 breakpoints in MM.

Monoclonal gammopathy: significance and possible causality in renal disease.
Am J Kidney Dis. 2003 Jul;42(1):87-95.
Paueksakon P, Revelo MP, Horn RG, Shappell S, Fogo AB.
This study reviews data from 121 patients who had monoclonal gammopathy on serum and/or urine electrophoresis and underwent a renal biopsy.
Among 66 cases of renal disease related to monoclonal gammopathy, diagnoses were:
 - Cryoglobulinemic glomerulonephritis (CG) (30.3%)
 - Monoclonal immunoglobulin deposition disease (MIDD) (28.8%)
 - Light chain cast nephropathy (CN) (19.7%)
 - Light chain amyloidosis (AL) (19.7%)
 - CN + MIDD (1.5%)
Among 55 patients with renal disease unrelated to monoclonal gammopathy (63.2% of all patients with monoclonal gammopathy), diagnoses were:
 - Diabetic nephropathy (18.1%)
 - Focal segmental glomerulosclerosis (18.1%)
 - Arterionephrosclerosis (12.7%)
 - Membranous glomerulonephritis (9.0%)
 - Minimal change disease (7.3%)
 - Various immune complex diseases, interstitial nephritis, or nonspecific changes
Authors conclude that most patients with monoclonal gammopathy who undergo renal biopsy have findings unrelated to the monoclonal gammopathy, probably because of the high frequency of MGUS in older patients.

Toxic acute tubular necrosis following treatment with zoledronate (Zometa).
Kidney Int. 2003 Jul;64(1):281-9.
Markowitz GS, Fine PL, Stack JI, Kunis CL, Radhakrishnan J, Palecki W, Park J, Nasr SH, Hoh S, Siegel DS, D'Agati VD.
This study is the first clinical-pathologic report of nephrotoxicity associated with zoledronic acid. Authors report 6 patients (5 patients with multiple myeloma and 1 patient with Paget's disease) who received zoledronate at a dose of 4 mg intravenously over at least 15 minutes once a month for 3-9 months (mean 4.7 months). These patients developed acute renal failure with a serum creatinine increased from a mean baseline level of 1.4 mg/dL to 3.4 mg/dL. Renal biopsy revealed acute tubular necrosis (ATN), and the pathology showed tubular cell degeneration, loss of brush border, and apoptosis. After discontinuation of zoledronic acid, all 6 patients had an improvement in renal function (mean final serum creatinine, 2.3 mg/dL), after 1-4 months of follow-up.

DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma.
J Clin Oncol. 2003 Jul 15;21(14):2732-9.
Lee CK, Barlogie B, Munshi N, Zangari M, Fassas A, Jacobson J, van Rhee F, Cottler-Fox M, Muwalla F, Tricot G.
DT-PACE is a 4-day chemotherapy regimen which consists of Dexamethasone, Thalidomide, cisPlatin, doxorubicin (Adriamycin), Cyclophosphamide, and Etoposide. 236 patients with previously treated myeloma (at least 2 cycles of prior therapy) received DT-PACE. 63% of them had refractory disease. Results after 2 cycles of DT-PACE:
  - PR: 32%
  - CR or near-CR: 16%

Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma.
Ann Oncol. 2003 Jul;14(7):1039-44.
Dimopoulos MA, Pouli A, Zervas K, Grigoraki V, Symeonidis A, Repoussis P, Mitsouli C, Papanastasiou C, Margaritis D, Tokmaktsis A, Katodritou I, Kokkini G, Terpos E, Vyniou N, Tzilianos M, Chatzivassili A, Kyrtsonis MC, Panayiotidis P, Maniatis A; Greek Myeloma Study Group.
This study randomized 259 patients with newly diagnosed myeloma into two groups: 127 patients treated with standard VAD (VAD bolus), and 132 patients treated with VAD containing liposomal doxorubicin 40 mg/m2 (VAD Doxil). The chemotherapy was given every 28 days x 4. Results:
  - Response rate was 61% in both arms
  - Toxicities were similar between the two arms, except for alopecia (more common with VAD bolus), and hand-foot syndrome (more common with VAD Doxil)

A Phase I-II trial of polyethylene glycol-conjugated L-asparaginase in patients with multiple myeloma.
Cancer. 2003 Jul 1;98(1):94-9.
Agrawal NR, Bukowski RM, Rybicki LA, Kurtzberg J, Cohen LJ, Hussein MA.
This is a phase I/II trial with PEG-L-asparaginase as a single agent in 22 patients with relapsing or refractory myeloma. Maximal tolerated dose was found to be 1000 mg/m2 every 4 weeks. 53% of patients had response or stable disease: among 17 evaluable patients, 1 patient reached CR, 8 patients had stable disease, and 8 patients progressive disease. Median survival was 31.7 months.

Busulfan, cyclophosphamide, and etoposide as conditioning for autologous stem cell transplantation in multiple myeloma.
Am J Hematol. 2003 Jul;73(3):169-75.
Cogle CR, Moreb JS, Leather HL, Finiewicz KJ, Khan SA, Reddy VS, Wingard JR.
26 patients treated with Bu-Cy-Etoposide. After SCT, median EFS was 24 months, and median OS 43 months.



Interpreting the molecular biology and clinical behavior of multiple myeloma in the context of global gene expression profiling.
Immunol Rev. 2003 Aug;194:140-63.
Shaughnessy JD Jr, Barlogie B.

CD20 is associated with a small mature plasma cell morphology and t(11;14) in multiple myeloma.
Blood. 2003 Aug 1;102(3):1070-1.
Robillard N, Avet-Loiseau H, Garand R, Moreau P, Pineau D, Rapp MJ, Harousseau JL, Bataille R.
Results of the study:
  - CD20 was found to be expressed in 12 of 66 (18%) myeloma patients.
  - In 5 of 50 (10%) patients, CD20+ cells represented 100% of myeloma cells at the time of diagnosis.
  - A small mature plasma cell morphology was found in 58% of patients with CD20+ plasma cells and 7% of patients with CD20 negative plasma cells.
  - 80% of patients with 100% CD20+ plasma cells had a small mature plasma cell morphology.
  - The translocation t(11;14) was more frequently found in patients with CD20+ plasma cells than in those with CD20 negative plasma cells (83% vs 9%, p <0.001).
  - All patients with 100% CD20+ plasma cells had the translocation t(11;14)
  - 66% of patients with t(11;14) had CD20+ plasma cells
  - Only 4% of patients without the translocation t(11;14) had CD20+ plasma cells
 In conclusion, CD20 expression was associated with small mature plasma cell morphology and t(11;14).

Pamidronate for early-stage, untreated myeloma.
J Clin Oncol. 2003 Aug 15;21(16):3177-8.
Musto P, Falcone A, Sanpaolo G, Bodenizza C, Carella AM.
43 patients with asymptomatic myeloma, either smoldering or stage IA, were treated with pamidronate 60-90 mg IV monthly for 1 year and every 3 months thereafter, until progression. No responses were seen. Progression-free survival was not improved, because time to progression was similar to that in a control group (19 months in both the pamidronate group and control group).

Practical considerations for the measurement of free light chains in serum.
Clin Chem. 2003 Aug;49(8):1252-7.
Tate JR, Gill D, Cobcroft R, Hickman PE.

The treatment of multiple myeloma with docetaxel (an ECOG study).
Leuk Res. 2003 Aug;27(8):751-4.
Friedenberg WR, Graham D, Greipp P, Blood E, Winston RD.
31 patients with relapsing or refractory multiple myeloma were treated with docetaxel 75 mg/m2 IV every 3 weeks. Docetaxel was inactive: no responses (PR or CR) were found. Median survival was 9.9 months.

MDS-type abnormalities within myeloma signature karyotype (MM-MDS): only 13% 1-year survival despite tandem transplants.
Br J Haematol. 2003 Aug;122(3):430-40.
Jacobson J, Barlogie B, Shaughnessy J, Drach J, Tricot G, Fassas A, Zangari M, Giroux D, Crowley J, Hough A, Sawyer J.

A new staging system for multiple myeloma patients based on the Southwest Oncology Group (SWOG) experience.
Br J Haematol. 2003 Aug;122(3):441-50.
Jacobson JL, Hussein MA, Barlogie B, Durie BG, Crowley JJ; Southwest Oncology Group.



Insights into extramedullary tumour cell growth revealed by expression profiling of human plasmacytomas and multiple myeloma.
Br J Haematol. 2003 Sep;122(5):728-44.
Hedvat CV, Comenzo RL, Teruya-Feldstein J, Olshen AB, Ely SA, Osman K, Zhang Y, Kalakonda N, Nimer SD.
These authors analysed the gene expression profiles of MM), plasma cell leukaemia (PCL), and extramedullary plasmacytoma (EPC), to identify tumour-specific alterations required for grow outside the normal bone marrow environment. They found 156 genes significantly upregulated and 85 genes significantly downregulated in the EPCs. Several of the upregulated genes were involved in angiogenesis (such as CD31 and endoglin) and adhesion.

Immunoglobulin A multiple myeloma presenting with Henoch-Schönlein purpura associated with reduced sialylation of IgA1.
Br J Haematol. 2003 Sep;122(6):915-7.
Van Der Helm-Van Mil AH, Smith AC, Pouria S, Tarelli E, Brunskill NJ, Eikenboom HC.
Henoch-Schönlein purpura is characterized by IgA1 depositions in blood vessels of the skin or in renal glomeruli. Serum IgA levels may be very high. These authors report 2 patients with IgA1 myeloma presenting with Henoch-Schönlein purpura.

Leukocytoclastic (small vessel) vasculitis in multiple myeloma.
Clin Exp Dermatol. 2003 Sep;28(5):521-4.
Bayer-Garner IB, Smoller BR.
The hallmark of leukocytoclastic vasculitis is palpable purpura. Its association with MM is rare. These authors reviewed the pathology reports of 2357 patients with MM, and they found 8 cases of leukocytoclastic vasculitis.

Reduction of leukocyte count is associated with thalidomide response in treatment of multiple myeloma.
Ann Hematol. 2003 Sep;82(9):558-64.
Huang SY, Tang JL, Yao M, Ko BS, Hong RL, Tsai W, Wang CH, Tien HF, Shen MC, Chen YC.
50 patients with relapsed or refractory myeloma were treated with thalidomide, at escalating doses 100-800 mg PO qhs. Results:
  - Response rate was 44%, when including both PR (45.5%) and minor response (54.5%). No CR were seen.
  - The median tolerated dose of thalidomide was 400 mg, and only 2 patients (4%) were able to tolerate 800 mg daily
  - The median time to response was 29 days (range, 8-155 days)
Interestingly, leukopenia was a clinical predictor of response to thalidomide: 18 of the 22 (82%) responders had  a transient reduction of WBC before the the response, whereas this was seen in only 4 of the 28 (14%) non-responders (p<0.001). Leukopenia was generally transient, and it quickly resolved despite the continuation of thalidomide.

Effect of thalidomide on stem cell collection and engraftment in patients with multiple myeloma.
Bone Marrow Transplant. 2003 Sep;32(6):587-92.
Ghobrial IM, Dispenzieri A, Bundy KL, Gastineau DA, Rajkumar SV, Therneau TM, Lacy MQ, Witzig TE, Litzow MR, Christensen BR, Hayman S, Pribula CG, Gertz MA.
This is a retrospective study of 24 patients with newly diagnosed myeloma who received thalidomide, 200 mg PO qhs + dexamethasone as induction therapy before stem cell collection. Median exposure to thalidomide was 4 cycles (range: 2-7 cycles). When the thalidomide group was compared with a control group, there was no significant difference in number of stem cells collected, time to collection, and time to hematologic engraftment, and therefore the authors concluded that thalidomide does not affect peripheral cell mobilization or engraftment.



Giampaolo Talamo, M.D.