APRIL 2009

Comparison of high-dose CY and growth factor with growth factor alone for mobilization of stem cells for transplantation in patients with multiple myeloma.
Bone Marrow Transplant. 2009 Apr;43(8):619-25.
Gertz MA, Kumar SK, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK, Dingli D, Gastineau DA, Winters JL, Litzow MR.
370 MM patients were mobilized using CY and growth factors, and 346 using growth factors alone. Patients receiving CY had higher stem cell yields than those receiving the growth factors only (2 vs 4 median number of apheresis sessions). Patients treated with CY required more time for engraftment of platelets and neutrophils. Platelet engraftment, defined as a level >50,000, in 75% of patients was obtained at day +39 in the group mobilized with CY, and at day +18 in the group mobilized with growth factors only. Results for neutrophil engraftment were similar. These authors suggested to lengthen the period between the completion of apheresis and the stem cell reinfusion in patients mobilized with CY, because they believe that CY damages the bone marrow microenvironment.

Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo.
Blood. 2009 Apr 2;113(14):3375-82.
Bruno B, Rotta M, Patriarca F, Mattei D, Allione B, Carnevale-Schianca F, Sorasio R, Rambaldi A, Casini M, Parma M, Bavaro P, Onida F, Busca A, Castagna L, Benedetti E, Iori AP, Giaccone L, Palumbo A, Corradini P, Fanin R, Maloney D, Storb R, Baldi I, Ricardi U, Boccadoro M.
These authors enrolled 100 newly diagnosed patients younger than 65 years in a prospective multicenter study. They used induction therapy with VAD-based chemotherapy and an autologous SCT with melphalan 200 mg/m2, followed by an allogeneic SCT from an HLA-matched sibling with a single dose of nonmyeloablative total body irradiation. CR rate was 53%. After a median follow-up of 5 years, OS was not reached, and EFS was 37 months. Acute GVHD was observed in 38% of patients, and chronic GVHD in 50% of them.

Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting.
Blood. 2009 Apr 2;113(14):3383-91.
Rotta M, Storer BE, Sahebi F, Shizuru JA, Bruno B, Lange T, Agura ED, McSweeney PA, Pulsipher MA, Hari P, Maziarz RT, Chauncey TR, Appelbaum FR, Sorror ML, Bensinger W, Sandmaier BM, Storb RF, Maloney DG.
102 MM patients received auto SCT with high-dose melphalan and allogeneic SCT from HLA-matched siblings, using 2-Gy total body irradiation. 42% of patients developed grade 2-4 acute GVHD, and 74% chronic GVHD. After a median follow-up of 6.3 years, the 5-year nonrelapse mortality was 18%, mostly due to GVHD or infections. CR was observed in 59 of 95 patients. Median OS was not reached, and median progression-free survival (PFS) was 3 years. Five-year OS was 64%, and 5-year PFS was 36%. Overall, these results do not compare favorably with tandem autologous transplants, due to nonrelapse mortality, frequent GVHD, and relatively inadequate long-term disease control.

Varicella-zoster virus prophylaxis with low-dose acyclovir in patients with multiple myeloma treated with bortezomib.
Clin Lymphoma Myeloma. 2009 Apr;9(2):151-3.
Pour L, Adam Z, Buresova L, Krejci M, Krivanova A, Sandecka V, Zahradova L, Buchler T, Vorlicek J, Hajek R.
This study analyzed the effect of acyclovir prophylaxis in 98 consecutive patients with relapsed MM treated with bortezomib. Herpes zoster was seen in:
 - 4 of 11 (36%) patients without VZV prophylaxis
 - 0 of 32 patients who received acyclovir 400 mg 3 times daily
 - 0 of 55 patients who received acyclovir 400 mg once daily
Therefore, acyclovir 400 mg once daily is sufficient to protect from VZV reactivation in patients with MM treated with bortezomib.

Phase III randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma.
Leuk Lymphoma. 2009 Apr;50(4):559-65.
Chanan-Khan AA, Niesvizky R, Hohl RJ, Zimmerman TM, Christiansen NP, Schiller GJ, Callander N, Lister J, Oken M, Jagannath S.
Oblimersen sodium is a bcl-2 antisense oligonucleotide which decreases the transcription of the bcl-2 protein. 224 patients with relapsed/refractory myeloma were randomized to receive either dexamethasone (114 pts) or the combination dexamethasone + oblimersen (110 pts). No significant differences between the two groups were seen in RR or TTP.

Complete remission status before autologous stem cell transplantation is an important prognostic factor in patients with multiple myeloma undergoing upfront single autologous transplantation.
Biol Blood Marrow Transplant. 2009 Apr;15(4):463-70.
Kim JS, Kim K, Cheong JW, Min YH, Suh C, Kim H, Jo DY, Ryoo HM, Yoon SS, Lee JH; Korean Multiple Myeloma Working Party.
This study evaluated the prognostic effect of disease status before ASCT. 197 MM patients were treated with induction chemotherapy followed by a single ASCT. CR was defined as the absence of detectable M protein regardless of the result of immunofixation. The median follow-up was 29.2 months from the day of diagnosis. Before ASCT, 63 patients (32%) were in CR, and 134 (68%) were in partial remission (PR). The patients in CR had significantly longer OS compared with those in PR. Patients with CR pre-ASCT and CR post-ASCT had better OS compared with patient with PR pre-ASCT and CR post-ASCT. CR pre-ASCT maintained its prognostic significance in multivariate analysis. These results suggest that patients undergoing ASCT should receive effective induction regimens, aiming at CR.

Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure.
J Clin Oncol. 2009 Apr 10;27(11):1788-93.
Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, Gill DS, Horvath N, Reynolds J, Kennedy N.
In this study, patients with newly diagnosed MM who received a single ASCT with high-dose melphalan were randomized to receive maintenance therapy with prednisolone, indefinitely (control group, 129 patients), or the same + 12 months of thalidomide (thalidomide group, 114 patients). After a median follow-up of 3 years, the 3-year PFS rates were 42% and 23%, and the OS rates were 86% and 75%, in the thalidomide and control groups, respectively. There was no difference between groups for thromboembolic events.

Contamination of autologous peripheral blood progenitor cell grafts predicts overall survival after high-dose chemotherapy in multiple myeloma.
J Cancer Res Clin Oncol. 2009 Apr;135(4):637-42.
Kopp HG, Yildirim S, Weisel KC, Kanz L, Vogel W.
This study evaluates the outcomes of 60 patients with multiple myeloma who underwent mobilization chemotherapy + G-CSF, followed by autologous stem cell transplantation. The number of CD38+/CD138+ cells/kg in the apheresis products was determined by flow cytometry. Levels >4.5 x 10,000 plasma cells/kg were defined as "high plasma cell contamination" (16 patients), while lower levels were defined as "low or absent plasma cell contamination" (44 patients). Results:
  - Median PFS was 33.5 months (range: 11-99 months) in the high-contamination group and 47 months (range: 8-148 months) in the low-contamination group (p=0.15)
  - Median overall survival was 53 months (range: 11-119 months) in the high-contamination group and 114 months (range: 8-158 months) in the low-contamination group (p=0.012)
The authors conclude that patients with apheresis products containing >4.5 x 10,000 plasma cells/kg have a significantly reduced overall survival. It was unclear whether the reduced survival in the high contamination group was directly due to the reinfused plasma cells, or instead the high contamination of grafts reflected a higher residual tumor mass or a more aggressive behavior of myeloma cells prior to the stem cell transplant.


MAY 2009

The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor.
Blood. 2009 May 7;113(19):4614-26.
Sprynski AC, Hose D, Caillot L, Réme T, Shaughnessy JD Jr, Barlogie B, Seckinger A, Moreaux J, Hundemer M, Jourdan M, Meissner T, Jauch A, Mahtouk K, Kassambara A, Bertsch U, Rossi JF, Goldschmidt H, Klein B.
These authors investigated 5 myeloma growth factors (IL-6, IGF-1, HGF, HB-EGF, and APRIL) in serum-free cultures of MM cell lines. IGF-1 was the major one.

Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study.
Blood. 2009 May 28;113(22):5412-7.
Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, Dispenzieri A, Kumar S, Clark RJ, Baris D, Hoover R, Rajkumar SV.
Among 77,469 healthy persons enrolled in the nationwide prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, 71 persons developed MM. Serum samples were available from 2-9.8 years prior to the diagnosis of MM. MGUS was present in 82% of cases at 8+ years prior to MM diagnosis. Therefore, an asymptomatic MGUS stage preceded MM.

Vascular endothelial growth factor inhibition is not an effective therapeutic strategy for relapsed or refractory multiple myeloma: a phase 2 study of pazopanib (GW786034).
Blood. 2009 May 7;113(19):4819-20
Prince HM, Hönemann D, Spencer A, Rizzieri DA, Stadtmauer EA, Roberts AW, Bahlis N, Tricot G, Bell B, Demarini DJ, Benjamin Suttle A, Baker KL, Pandite LN.

Bortezomib administered pre-auto-SCT and as maintenance therapy post transplant for multiple myeloma: a single institution phase II study.
Bone Marrow Transplant. 2009 May;43(10):793-800.
Uy GL, Goyal SD, Fisher NM, Oza AY, Tomasson MH, Stockerl-Goldstein K, DiPersio JF, Vij R.
In this study, 40 patients with MM were given bortezomib pre-ASCT for 2 cycles, and post-ASCT, as maintenance therapy, weekly for 5 out of 6 weeks for 6 cycles. RR was 83% and CR + VGPR was 50%. At 3 years, disease-free survival and overall survival were 38.2 and 63.1%, respectively.

Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure.
J Clin Oncol. 2009 Apr 10;27(11):1788-93.
Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, Gill DS, Horvath N, Reynolds J, Kennedy N.
This study evaluated the results of post-transplant maintenance with thalidomide in 269 patients with newly diagnosed myeloma treated with a single autologous stem cell transplant. Patients were randomized to either prednisolone maintenance, indefinitely (control group, 129 patients) or the same + thalidomide for 12 months (thalidomide group, 114 patients). Results:
  - 3-year PFS: 42% in the thalidomide group and 23% in the control group (p <0.001)
  - 3-year OS: 86% in the thalidomide group and 75% in the control group (p= 0.004)
  - No difference in survival 12 months after disease progression (79% vs 77%, p= 0.24)


JUNE 2009

A possible link between Trousseau's syndrome and tissue factor producing plasma cells.
Am J Hematol. 2009 Jun;84(6):382-5.
Shimizu K, Itoh J.
These authors described a patient with Trousseau's syndrome (recurrent, migratory superficial thrombophlebitis), and demonstrated elevated plasma tissue factor antigen levels and tissue factor production by the bone marrow clonal plasma cells.

Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors.
Golden EB, Lam PY, Kardosh A, Gaffney KJ, Cadenas E, Louie SG, Petasis NA, Chen TC, Schönthal AH.
Blood. 2009 Jun 4;113(23):5927-37.
This study explores the interactions between bortezomib and some components of green tea in myeloma cell lines. Surprisingly, the authors found that several constituents of green tea, such as epigallocatechin gallate (EGCG) and other polyphenols prevented tumor cell death induced by bortezomib. These findings are important, because some cancer patients self-medicate with herbs, hoping to increase the anticancer effect of chemotherapy. Since green tea polyphenols may negate the therapeutic efficacy of bortezomib, the authors suggest that patients receiving bortezomib should avoid a large consumption of green tea products.

Pesticide exposure and risk of monoclonal gammopathy of undetermined significance in the Agricultural Health Study.
Blood. 2009 Jun 18;113(25):6386-91.
Landgren O, Kyle RA, Hoppin JA, Beane Freeman LE, Cerhan JR, Katzmann JA, Rajkumar SV, Alavanja MC.
This study evaluates 678 men with a clear exposure to pesticides (restricted-use pesticide applicators)  to compared the risk of MGUS with that of 9,469 controls. Among 555 male pesticide applicators older than 50 years, 38 (6.8%) were found to have MGUS, a rate 1.9-fold higher than controls. Risk was higher among users of the chlorinated insecticide dieldrin, the fumigant mixture carbon-tetrachloride/carbon disulfide, and the fungicide chlorothalonil. Since the prevalence of MGUS among pesticide applicators was twice that in controls, the data support the hypothesis that specific pesticides can promote the development of multiple myeloma.

Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma.
DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff PJ, Kaufman JL, Maziarz RT, Hosing C, Früehauf S, Horwitz M, Cooper D, Bridger G, Calandra G; 3102 Investigators.
Blood. 2009 Jun 4;113(23):5720-6.
This is an international double-blind randomized phase III study comparing G-CSF + placebo vs G-CSF + plerixafor for stem cell collection in multiple myeloma. G-CSF was given at the dose of 10 mcg/Kg SC qd for 4 days, and plerixafor 240 mcg/Kg SC was started on day 4, with the plan of apheresis on day 5. The primary endpoint was to collect at least 6 million CD34+ cells/Kg within 2 days of apheresis. Results:
  - 53 of 154 (34%) patients in the placebo group reached the endpoint (and 56% in 4 days)
  - 106 of 148 (72%) patients in the plerixafor group reached the endpoint (and 54% in 1 day)
Plerixafor was well tolerated. Most common adverse events of plerixafor: injection site reactions and GI disturbances.



Giampaolo Talamo, MD