JULY 2009

The relationship between the serum free light chain assay and serum immunofixation electrophoresis, and the definition of concordant and discordant free light chain ratios.
Blood. 2009 Jul 2;114(1):38-9.
Singhal S, Vickrey E, Krishnamurthy J, Singh V, Allen S, Mehta J.
This study explores the relationship between serum free light chain assay (FL) and serum immunofixation electrophoresis (IFE) in 2648 serial samples from 122 patients with IgG or IgA multiple myeloma. Surprisingly, the results were often discordant, as FL was normal in 34% of cases with positive IFE, and abnormal in 31% of cases with negative IFE.

Infections in patients with multiple myeloma.
Semin Hematol. 2009 Jul;46(3):277-88.
Nucci M, Anaissie E.

Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma.
Blood. 2009 Jul 23;114(4):772-8.
Richardson P, Jagannath S, Hussein M, Berenson J, Singhal S, Irwin D, Williams SF, Bensinger W, Badros AZ, Vescio R, Kenvin L, Yu Z, Olesnyckyj M, Zeldis J, Knight R, Anderson KC.
This study evaluated the efficacy and safety of lenalidomide monotherapy (30 mg/day on days 1-21 every 28 days) in 222 patients with relapsed/refractory MM. PR or better was observed in 26% of patients, minimal response in 18%. Median PFS was 4.9 months, and median OS was 23.2 months.

Hypercoagulable states in patients with multiple myeloma can affect the thalidomide-associated venous thromboembolism.
Blood Coagul Fibrinolysis. 2009 Jul;20(5):337-9.
Talamo G, Ibrahim S, Claxton D, Tricot GJ, Fink LM, Zangari M.

Post-transplant immunotherapy with donor-lymphocyte infusion and novel agents to upgrade partial into complete and molecular remission in allografted patients with multiple myeloma.
Exp Hematol. 2009 Jul;37(7):791-8.
Kröger N, Badbaran A, Lioznov M, Schwarz S, Zeschke S, Hildebrand Y, Ayuk F, Atanackovic D, Schilling G, Zabelina T, Bacher U, Klyuchnikov E, Shimoni A, Nagler A, Corradini P, Fehse B, Zander A.
This study investigates the use of DLIs in combination with novel agents (thalidomide, bortezomib, and lenalidomide) in 32 patients with myeloma in partial remission after allogeneic stem cell transplant, aiming at CR. If no CR was achieved with DLIs, one of the novel agents was added. CR was obtained in 50-63% of patients, depending on the criteria used to define CR. Achievement of CR resulted in improved 5-year progressive-free survival and overall survival.

Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance.
Blood. 2009 Jul 23;114(4):785-90.
Vachon CM, Kyle RA, Therneau TM, Foreman BJ, Larson DR, Colby CL, Phelps TK, Dispenzieri A, Kumar SK, Katzmann JA, Rajkumar SV.
This study examined whether MGUS is increased in first-degree relatives of patients with MM or MGUS. The authors collected serum samples from 911 first-degree relatives of 232 patients with MM and 97 patients with MGUS. MGUS was detected in 8.1% (95% CI, 6.3-9.8) of first-degree relatives, a higher rate than in the control population. The prevalence of MGUS in relatives increased with age. These findings support the role for genetic susceptibility, shared environmental influences, or an interaction between both.

Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden.
Blood. 2009 Jul 23;114(4):791-5.
Landgren O, Kristinsson SY, Goldin LR, Caporaso NE, Blimark C, Mellqvist UH, Wahlin A, Bjorkholm M, Turesson I.
This study examined whether MGUS is increased in first-degree relatives of patients with MGUS. The authors evaluated 4,458 patients with MGUS, 17,505 normal controls, 14,621 first-degree relatives of patients, and 58,387 first-degree relatives of normal controls (n = 58387). The relatives of patients with MGUS had an increased risk of MGUS (relative risk = 2.8), multiple myeloma (RR = 2.9), lymphoplasmacytic lymphoma (RR = 4.0), and chronic lymphocytic leukemia (RR = 2.0). These findings support the role for genetic susceptibility, shared environmental influences, or an interaction between both.

Impact of vitamin D deficiency on the clinical presentation and prognosis of patients with newly diagnosed multiple myeloma.
Am J Hematol. 2009 Jul;84(7):397-400.
Ng AC, Kumar SK, Rajkumar SV, Drake MT.
These authors evaluated serum levels of 25-hydroxyvitamin D in 148 consecutive patients at baseline, within 14 days of diagnosis. Vitamin D deficiency was found in 16% of patients in stage I, 20% in stage II, and 37% in stage III ISS. Patients with vitamin D deficiency (defined as a level <50 nmol/L or <20 ng/mL) had higher serum creatinine, higher ISS stage at time of diagnosis, and poorer prognosis.



Serum free light chain ratio, total kappa/lambda ratio, and immunofixation results are not prognostic factors after stem cell transplantation for newly diagnosed multiple myeloma.
Clin Chem. 2009 Aug;55(8):1510-6.
Giarin MM, Giaccone L, Sorasio R, Sfiligoi C, Amoroso B, Cavallo F, Cipriani A, Palumbo A, Boccadoro M.
These authors evaluated the disease response 3 months after stem cell transplant (both autologous and allogeneic) in 203 patients with multiple myeloma, analyzing serum immunofixation, the total kappa/lambda ratio, and the serum free light chain ratio. Serum IFE was negative in 51 patients (25%), and serum free light chain ratio was normal in 92 patients (45%). None of the tests was associated with overall survival, therefore, in this study, achievement of a stringent CR did not have an impact on patient survival.

Serum free light chain analysis may miss monoclonal light chains that urine immunofixation electrophoreses would detect.
Shaheen SP, Levinson SS.
Clin Chim Acta. 2009 Aug;406(1-2):162-6.

A frequent target of paraproteins in the sera of patients with multiple myeloma and MGUS.
Int J Cancer. 2009 Aug 1;125(3):656-61.
Preuss KD, Pfreundschuh M, Ahlgrimm M, Fadle N, Regitz E, Murawski N, Grass S.
The authors screened a human fetal brain-derived macroarray with Ig from 192 patients with MGUS or MM. 29 (15.1%) paraproteins reacted with paratarg-7, a protein of unknown function (as of 2009), expressed in all human tissues.

Arterial thrombosis with immunomodulatory derivatives in the treatment of multiple myeloma: a single-center case series and review of the literature.
Clin Lymphoma Myeloma. 2009 Aug;9(4):320-3.
Martin MG, Vij R.
The authors describe 5 cases of arterial thrombosis in patients with MM treated with thalidomide.

Reversibility of renal impairment in patients with multiple myeloma treated with bortezomib-based regimens: identification of predictive factors.
Clin Lymphoma Myeloma. 2009 Aug;9(4):302-6.
Dimopoulos MA, Roussou M, Gavriatopoulou M, Zagouri F, Migkou M, Matsouka C, Barbarousi D, Christoulas D, Primenou E, Grapsa I, Terpos E, Kastritis E.
This study describes the outcomes of renal response in 46 myeloma patients with renal insufficiency treated with bortezomib + dexamethasone. Improvement of the renal function was observed in 59% of patients within a short period (median: 11 days, range: 8-41 days). Normalization of the renal function was seen in 30% of cases. 2 of 9 patients who required hemodialysis became dialysis independent.

The efficacy of arsenic trioxide for the treatment of relapsed and refractory multiple myeloma: a systematic review.
Cancer Treat Rev. 2009 Aug;35(5):425-30.
Röllig C, Illmer T.

Is the International Staging System superior to the Durie-Salmon staging system? A comparison in multiple myeloma patients undergoing autologous transplant.
Leukemia. 2009 Aug;23(8):1528-34.
Hari PN, Zhang MJ, Roy V, Pérez WS, Bashey A, To LB, Elfenbein G, Freytes CO, Gale RP, Gibson J, Kyle RA, Lazarus HM, McCarthy PL, Milone GA, Pavlovsky S, Reece DE, Schiller G, Vela-Ojeda J, Weisdorf D, Vesole D.
This study compared the DSS and ISS staging systems for predicting outcomes 729 myeloma patients treated with upfront ASCT (1995-2002). After a median follow-up of 56 months, the median overall survival was:
  - Stage I: 82 months by DSS and 64 months by ISS
  - Stage II: 68 months by DSS and 68 months by ISS
  - Stage III: 50 months by DSS and 45 months by ISS
The concordance between DSS and ISS was only 36%.

Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens.
Blood. 2009 Aug 27;114(9):1729-35.
Kumar S, Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W, Comenzo RL, Lentzsch S, Munshi N, Niesvizky R, San Miguel J, Ludwig H, Bergsagel L, Blade J, Lonial S, Anderson KC, Tosi P, Sonneveld P, Sezer O, Vesole D, Cavo M, Einsele H, Richardson PG, Durie BG, Rajkumar SV; International Myeloma Working Group.
These authors gave the following suggestions for stem cell mobilization:
  - Collect the stem cells after 3-4 cycles of induction therapy
  - In patients <65 years old and <4 cycles of induction therapy - use G-CSF alone
  - In patients <65 years old and >4 cycles of lenalidomide - use G-CSF + Cyclophosphamide
  - In patients >65 years old - use G-CSF + reduced-dose cyclophosphamide
    or G-CSF + plerixafor before the second leukapheresis if <2 million CD34+ cells/Kg collected with the first leukapheresis
For second attempt after collection failure with G-CSF, 3 options are suggested:
 1) G-CSF + cyclophosphamide
 2) G-CSF + plerixafor
 3) GM-CSF 10 mcg/Kg/day SC x 2 days, followed by G-CSF 16 mcg/Kg/day SC until completion of stem cell collection

BU and CY as conditioning regimen for autologous transplant in patients with multiple myeloma.
Bone Marrow Transplant. 2009 Aug;44(3):157-61.
Talamo G, Claxton DF, Dougherty DW, Ehmann CW, Sivik J, Drabick JJ, Rybka W.
Clinical outcomes of  busulfan and cyclophosphamide used as conditioning regimen before stem cell transplantation in 79 myeloma patients were not superior to those obtained in historical controls treated with high-dose melphalan.



Long-term outcomes following myeloablative allogeneic transplantation for multiple myeloma compared to autologous transplantation and the impact of graft-versus-myeloma effect.
Bone Marrow Transplant. 2009 Sep;44(5):325-6.
Khaled Y, Mellacheruvu S, Reddy P, Peres E, Mineishi S.
In this retrospective study, 28 patients with multiple myeloma underwent myeloablative allogeneic stem cell transplantation using TBI, busulfan PO, and cyclophosphamide IV. The transplant-related mortality at day 100 was 22%. Acute GVHD (grade II-IV) was seen in 46% of patients, and chronic GVHD was seen in 73% of patients. With a median follow-up of 10 years, the median progression-free survival was 3.8 years, which compared favorably with that of a control group of 46 patients treated with an autologous stem cell transplant (1.7 years). Overall survival was similar (5.8 years in the autologous group and 5.7 years in the allogeneic group).

Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma.
Mol Cancer Ther. 2009 Sep;8(9):2616-24.
van Rhee F, Szmania SM, Dillon M, van Abbema AM, Li X, Stone MK, Garg TK, Shi J, Moreno-Bost AM, Yun R, Balasa B, Ganguly B, Chao D, Rice AG, Zhan F, Shaughnessy JD Jr, Barlogie B, Yaccoby S, Afar DE.
Elotuzumab is a humanized monoclonal antibody directed against CS1, a cell surface glycoprotein (CD2 subset 1, CD319) highly expressed on myeloma cells. This study showed that bortezomib enhanced the anti-myeloma activity of elotuzumab, both in vitro and in vivo, in a myeloma xenograft model.

International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple Myeloma.
Leukemia. 2009 Sep;23(9):1545-56.
Dimopoulos M, Terpos E, Comenzo RL, Tosi P, Beksac M, Sezer O, Siegel D, Lokhorst H, Kumar S, Rajkumar SV, Niesvizky R, Moulopoulos LA, Durie BG; IMWG.

The importance of bone marrow examination in determining complete response to therapy in patients with multiple myeloma.
Blood. 2009 Sep 24;114(13):2617-8.
Chee CE, Kumar S, Larson DR, Kyle RA, Dispenzieri A, Gertz MA, Colby CL, Rajkumar SV.
This study evaluated the role of bone marrow biopsy in 92 myeloma patients in good remission after therapy, i.e., with negative immunofixation in both serum and urine. Bone marrow was found to contain residual disease (defined as presence of 5% or more plasma cells) in 14% of cases. Even after including a normal serum free light chain ratio to negative IFE and UIFE, the BM biopsy retained its importance, as it was positive in 10% of cases. Therefore, the bone marrow biopsy should not be eliminated from the criteria used to define complete remission in MM. Bone marrow involvement with 5% or more plasma cells was found to have a prognostic impact for overall survival.

Multiple myeloma presenting with acquired factor VIII inhibitor.
Int J Hematol. 2009 Sep;90(2):166-9.
Sari I, Erkurt MA, Ifran A, Kaptan K, Beyan C.

Long-term outcomes following myeloablative allogeneic transplantation for multiple myeloma compared to autologous transplantation and the impact of graft-versus-myeloma effect.
Bone Marrow Transplant. 2009 Sep;44(5):325-6.
Khaled Y, Mellacheruvu S, Reddy P, Peres E, Mineishi S.
28 myeloma patients underwent myeloablative related allogeneic SCT with Bu/Cy + TBI:
  - TBI 3 Gy/day days -10 to -8
  - Busulfan 2.4 mg/Kg/day PO days -7 to -4
  - Cyclophosphamide 60 mg/Kg/day IV days -3 and -2
After a median follow-up of 10 years:
  - TRM at day 100: 22%
  - Median PFS: 3.8 years
  - Median OS: 5.7 years 

F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma.
Blood. 2009 Sep 3;114(10):2068-76.
Bartel TB, Haessler J, Brown TL, Shaughnessy JD Jr, van Rhee F, Anaissie E, Alpe T, Angtuaco E, Walker R, Epstein J, Crowley J, Barlogie B.
This study evaluates the use of PET scans in 239 patients with newly diagnosed myeloma. The presence of >3 active focal lesions was associated with inferior prognosis, including overall survival. Normalization of the PET scan before the first stem cell transplant was associated with better prognosis.



Giampaolo Talamo, MD