APRIL 2005

Value of FDG PET in the assessment of patients with multiple myeloma.
AJR Am J Roentgenol. 2005 Apr; 184(4):1199-204.
Bredella MA, Steinbach L, Caputo G, Segall G, Hawkins R.
In this study of 17 FDG PET scans in 13 MM patients, sensitivity of FDG PET in detecting myelomatous involvement was 85% and specificity was 92%.

Side effects and good effects from new chemotherapeutic agents. Case 2. Thalidomide-induced interstitial pneumonitis.
J Clin Oncol. 2005 Apr 1;23(10):2425-6.
Onozawa M, Hashino S, Sogabe S, Haneda M, Horimoto H, Izumiyama K, Kondo T, Aldana LP, Hamada K, Asaka M.

Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies.
Blood. 2005 Apr 15;105(8):3058-65.
Orlowski RZ, Voorhees PM, Garcia RA, Hall MD, Kudrik FJ, Allred T, Johri AR, Jones PE, Ivanova A, Van Deventer HW, Gabriel DA, Shea TC, Mitchell BS, Adams J, Esseltine DL, Trehu EG, Green M, Lehman MJ, Natoli S, Collins JM, Lindley CM, Dees EC.
The maximum tolerated dose of bortezomib and pegylated liposomal doxorubicin in combination was found to be bortezomib 1.3 mg/m2 and liposomal doxorubicin 30 mg/m2.

CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma.
Blood. 2005 Apr 1;105(7):2941-8.
Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C, Reece D, Heise C, Stewart AK.
This study describes the therapeutic efficacy of CHIR-258, an inhibitor of FGFR3, in a xenograft mouse model of FGFR3+ MM.

Primary plasma cell leukemia: report of 17 new cases treated with autologous or allogeneic stem-cell transplantation and review of the literature.
Am J Hematol. 2005 Apr;78(4):288-94.
Saccaro S, Fonseca R, Veillon DM, Cotelingam J, Nordberg ML, Bredeson C, Glass J, Munker R.


MAY 2005

International staging system for multiple myeloma.
J Clin Oncol. 2005 May 20;23(15):3412-20.
Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, Boccadoro M, Child JA, Avet-Loiseau H, Kyle RA, Lahuerta JJ, Ludwig H, Morgan G, Powles R, Shimizu K, Shustik C, Sonneveld P, Tosi P, Turesson I, Westin J.
This study analyzed clinical and laboratory data from 10,750 myeloma patients, and found a reliable staging system, simpler than the old Durie-Salmon system. Patients had newly diagnosed symptomatic multiple myeloma, and they were followed at 17 institutions from several sites, including North America, Europe, and Asia. Important prognostic factors were beta-2-microglobulin, albumin, platelet count, creatinine, and age, but the combination of beta-2-microglobulin and albumin provided the simplest and most powerful risk stratification. Median survival was 62 months in stage I (b2m <3.5 and albumin > or = 3.5), 44 months in stage II (neither stage I nor III), and 29 months in stage III (b2m > or = 5.5).

Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients.
Blood. 2005 May 15;105(10):4060-9.
Keats JJ, Maxwell CA, Taylor BJ, Hendzel MJ, Chesi M, Bergsagel PL, Larratt LM, Mant MJ, Reiman T, Belch AR, Pilarski LM.
Only transcripts originating from the WHSC1/MMSET/NSD2 gene are uniformly dysregulated in MM patients with the t(4;14) translocation. The transcripts detected were:
 - Multiple myeloma SET domain containing protein (MMSET I)
 - Exon 4a/MMSET III
 - Response element II binding protein (RE-IIBP)
These are produced by alternative transcription initiation events and alternative splicing.
The Exon 4a/MMSET III splice variant contains a protein domain that prevents nucleolar localization.
RE-IIBP is universally dysregulated and also potentially functional in all t(4;14) patients, regardless of FGFR3 expression or breakpoint type.

NY-ESO-1 is highly expressed in poor-prognosis multiple myeloma and induces spontaneous humoral and cellular immune responses.
Blood. 2005 May 15;105(10):3939-44.
van Rhee F, Szmania SM, Zhan F, Gupta SK, Pomtree M, Lin P, Batchu RB, Moreno A, Spagnoli G, Shaughnessy J, Tricot G.
This study shows that NY-ESO-1 is frequently expressed in MM with cytogenetic abnormalities, and it is capable of eliciting spontaneous humoral and T-cell immunity. MM patients with cytogenetic abnormality have increased expression of NY-ESO-1 compared to patients with normal cytogenetics (60% vs 31%). NY-ESO-1 is highly expressed in patients with relapsing disease (61%), especially when they have cytogenetic abnormalities (100%). Spontaneous NY-ESO-1-specific antibodies were detected in 33% of patients with NY-ESO-1+ MM, but not in NY-ESO-1-negative MM. Spontaneous NY-ESO-1-specific T cells were also found, and, when expanded, they were able to kill primary MM cells.

Characterization of a myeloma patient with a life-threatening hemorrhagic diathesis: presence of a lambda dimer protein inhibiting shear-induced platelet aggregation by binding to the A1 domain of von Willebrand factor.
Thromb Haemost. 2005 May;93(5):889-96.
Shinagawa A, Kojima H, Berndt MC, Kaneko S, Suzukawa K, Hasegawa Y, Shigeta O, Nagasawa T.
This study describes a patient with IgD-lambda MM who had a significant bleeding tendency. Both bleeding time and APTT were prolonged. Thee purified protein responsible for the aPTT prolongation was found to be a homodimer of the lambda light chain. The lambda dimer protein bound to the region of the A1 domain of vWF and interfered with the vWF-GPIb-alpha interaction.

Severe irreversible bilateral hearing loss after bortezomib (VELCADE) therapy in a multiple myeloma (MM) patient.
Leukemia. 2005 May;19(5):869-70.
Engelhardt M, Müller AM, Maier W, Wäsch R.

Pilot study of 13cis-retinoic acid+dexamethasone+alpha interferon as maintenance therapy following high-dose chemotherapy and autologous stem cell transplant for multiple myeloma.
Bone Marrow Transplant. 2005 May;35(10):979-84.
Friedman J, Khoury H, Adkins D, Devine S, Nervi B, Edwards T, Dipersio J, Vij R.
33 patients with multiple myeloma treated with autologous stem cell transplantation were given maintenance therapy with 13-cis-retinoic acid, dexamethasone, and interferon alpha. After a median follow-up of 35 months, only 34% of patients were in remission, and 33% died. The median progression-free survival from diagnosis was 35 months.

Combined thalidomide and cyclophosphamide treatment for refractory or relapsed multiple myeloma patients: a prospective phase II study.
Ann Hematol. 2005 May;84(5):311-6.
Hovenga S, Daenen SM, de Wolf JT, van Imhoff GW, Kluin-Nelemans HC, Sluiter WJ, Vellenga E.
38 patients with relapsed/refractory myeloma were treated with thalidomide and cyclophosphamide daily. Response rate was 84% (PR 64%). The median progression-free survival was 30 months, and the median overall survival was 20 months.


JUNE 2005

Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma.
Br J Haematol. 2005 Jun;129(6):776-83.
Jagannath S, Durie BG, Wolf J, Camacho E, Irwin D, Lutzky J, McKinley M, Gabayan E, Mazumder A, Schenkein D, Crowley J.
32  patients with newly diagnosed myeloma were treated with bortezomib for a maximum of 6 cycles. Dexamethasone was added if less than PR was achieved after 2 cycles or less than CR was achieved after 4 cycles. Response rate was 88%, CR 6%, and near-CR (IFE positive) 19%. The most common significant (grade 2 or higher) adverse events were:
  - Peripheral neuropathy (31%), reversible in 50% of cases within a median of 3 months
  - Myalgia (28%)
  - Constipation (28%)
  - Fatigue (25%)

The enigmatic role of cyclin D1 in multiple myeloma.
Int J Cancer. 2005 Jun 10;115(2):171-6.
Lesage D, Troussard X, Sola B.

t(11;14) does not predict long-term survival in myeloma.
Leukemia. 2005 Jun;19(6):1078-9.
Chang H, Qi XY, Stewart AK.

The bisphosphonate zoledronic acid inhibits the development of plasmacytoma induced in BALB/c mice by intraperitoneal injection of pristane.
Eur J Haematol. 2005 Jun;74(6):496-500.
Avcu F, Ural AU, Yilmaz MI, Ozcan A, Ide T, Kurt B, Yalcin A.
This study investigated the effect of zoledronic acid on the development of pristane-induced plasmacytoma in BALB/c mice. Authors found a a significant difference in survival between the group of mice treated with pristane alone and the group receiving pristane + xoledronic acid. The increased survival indicates a direct anti-tumor effect of zoledronic acid in the development of pristane-induced plasmacytomas in BALB/c mice. This hypothesis should now be further investigated in clinical trials.

Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles.
Mod Pathol. 2005 Jun;18(6):806-15.
Vega F, Chang CC, Medeiros LJ, Udden MM, Cho-Vega JH, Lau CC, Finch CJ, Vilchez RA, McGregor D, Jorgensen JL.
According to the WHO classification of lymphomas, plasmablastic lymphoma is a variant of diffuse large B-cell lymphoma (DLBCL). These authors performed IHC on 9 cases of plasmablastic lymphoma and 7 cases of plasmablastic myeloma, and they found that all cases of plasmablastic NHL and plasmablastic myeloma were negative for CD20, and positive for CD38, CD138, and MUM1/IRF4. i.e., they had a profile seen in myeloma plasma cells but not in DLBCL cells. Therefore, these results did not support the notion that plasmablastic lymphoma is a variant of DLBCL. After testing for several antigens, the authors found that the only significant difference between plasmablastic NHL and plasmablastic myeloma was the presence of EBV RNA, which was negative in all cases of plasmablastic myeloma, and positive in all cases of plasmablastic NHL.

Bortezomib or high-dose dexamethasone for relapsed multiple myeloma.
N Engl J Med. 2005 Jun 16;352(24):2487-98.
Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Bladé J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators.
In this study, 669 patients with relapsed myeloma were randomized to bortezomib (1.3 mg/m2 IV on days 1, 8, 15, 22 every 5 weeks for 3 cycles) vs high-dose dexamethasone (40 mg PO on days 1-4, 9-12, 17-20 every 5 weeks for 4 cycles, then on days 1-4 every 4 weeks for 5 cycles). Patients assigned to the dexamethasone arm were allowed to cross over to the bortezomib arm in case of disease progression. Patients had received 1-3 previous therapies. Results:
  - Response rate was higher in the bortezomib arm (38% vs 18%)
  - Rate of CR was 6% in the bortezomib arm and <1% in the dexamethasone arm
  - Time to progression was longer in the bortezomib arm (6.2 months vs 3.5 months)
  - Overall survival was longer in the bortezomib arm. 1-year OS was 80% in the bortezomib arm and 66% in the dexamethasone arm.
  - Grade 3-4 toxicities were seen in 75% of patients in the bortezomib arm vs 60% of patients in the dexamethasone arm.

Low-dose thalidomide in combination with oral weekly cyclophosphamide and pulsed dexamethasone is a well tolerated and effective regimen in patients with relapsed and refractory multiple myeloma.
Br J Haematol. 2005 Jun;129(6):763-70.
Kyriakou C, Thomson K, D'Sa S, Flory A, Hanslip J, Goldstone AH, Yong KL.
52 patients with relapsed/refractory myeloma were treated with cyclophosphamide PO weekly, pulsed dexamethasone, and low-dose Thalidomide (CDT). Response rates: PR 62%, CR 17%.

Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients.
J Clin Oncol. 2005 Jun 20;23(18):4089-99.
Badros AZ, Goloubeva O, Rapoport AP, Ratterree B, Gahres N, Meisenberg B, Takebe N, Heyman M, Zwiebel J, Streicher H, Gocke CD, Tomic D, Flaws JA, Zhang B, Fenton RG.
In this study, 33 patients with MM received G3139, a Bcl-2 antisense oligonucleotide targeting the Bcl-2 mRNA. G3139 was administered as continuous IV infusion for 7 days. Thalidomide and dexamethasone were added on day 4, with 21-day cycles. RR: 55%. There were 6 minimal responses, 12 PR, 4 near CR (positive immunofixation), and 2 CR. The median duration of response was 13 months. PFS: 12 months. OS: 17.4 months.

Long-term outcomes of previously untreated myeloma patients: responses to induction chemotherapy and high-dose melphalan incorporated within a risk stratification model can help to direct the use of novel treatments.
Br J Haematol. 2005 Jun;129(5):607-14.
Alvares CL, Davies FE, Horton C, Patel G, Powles R, Sirohi B, Zuha R, Gatt A, Saso R, Treleaven JG, Dearden CE, Potter MN, Ethell ME, Morgan GJ.
This study analyzed outcomes of 383 patients with newly diagnosed myeloma who underwent autologous stem cell transplant. The authors found that survival was predicted by response to induction therapy and also by the response after transplant.
 - Median overall survival was 7.5 years in patients who had early response (PR and CR) after induction therapy, and 4.9 years in non-responders (p= 0.035)
 - Attainment of CR at 3 months after SCT was prognostically important: median PFS was 7.4 years in CR group and 5.3 years in non-CR group (p= 0.023)
This data suggests that complete remission should be the goal of myeloma therapy at every stage of treatment, both pre-SCT and post-SCT.

Results of autologous and allogeneic hematopoietic cell transplant therapy for multiple myeloma.
Bone Marrow Transplant. 2005 Jun;35(12):1133-40.
Arora M, McGlave PB, Burns LJ, Miller JS, Barke JN, Defor TE, Weisdorf DJ.
This study compared outcomes of autologous (70 patients) and myeloablative allogeneic stem cell transplant (17 patients) in multiple myeloma. Results:
  - Transplant-related mortality was lower with autologous transplant (4% vs 18%)
  - Complete responses were higher with allogeneic transplant (64% vs 34%)
  - After autologous transplant, survival at 1 year was 86%, but it fell to 50% at 4 years, mainly because of disease relapse
  - After allogeneic transplant, survival at 1 year was 64%, and it remained the same at 4 years
Therefore, although autologous transplant was associated with a lower mortality and superior short-term outcomes, allogeneic transplant produced superior long-term responses.

Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT.
Blood. 2005 Jun 1;105(11):4532-9.
Crawley C, Lalancette M, Szydlo R, Gilleece M, Peggs K, Mackinnon S, Juliusson G, Ahlberg L, Nagler A, Shimoni A, Sureda A, Boiron JM, Einsele H, Chopra R, Carella A, Cavenagh J, Gratwohl A, Garban F, Zander A, Björkstrand B, Niederwieser D, Gahrton G, Apperley JF; Chromic Leukaemia Working Party of the EBMT.

This is a retrospective study of 229 myeloma patients who underwent a RIC allogeneic stem cell transplant in 33 European centers. Results:
  - Transplant-related mortality at 1 year: 22%
  - Progression-free survival at 3 years: 21%
  - Overall survival at 3 years: 41%
  - No significant benefit was observed in heavily pretreated patients and patients with progressive disease

Evaluation and prognostic value of serum osteoprotegerin in multiple myeloma.
Br J Haematol. 2005 Jun;129(5):706-7.
Depil S, Mathiot C, Leleu X, Moreau AS, Faucompré JL, Hennache B, Bauters F, Bataille R, Facon T.
This study of serum levels of OPG in 140 patients with newly diagnosed MM found that OPG >2.4 ng/mL is an adverse independent prognostic factor for overall survival.



Giampaolo Talamo, MD