Management of multiple myeloma in the era of novel drugs

Gordan Srkalovic, Ines Srkalovic


Multiple Myeloma (MM) is a malignancy of terminally differentiatedplasma cells and is the second most common hematologicalneoplasm to Non-Hodgkin’s Lymphoma. Generally,it is disease of older patients. Our knowledge about theunderlying biological and cytogenetic abnormalities leadingto MM is rapidly increasing. Similarly our ability is improvingto treat this complex disease. A number of new treatmentshave been introduced into our armamentarium in the past10-15 years. Until recently, high rates of complete responses(CR) and other major responses were seen only in patientsundergoing treatment with high dose chemotherapy with autologousstem cell support (HD+ASCT). However new regimens,incorporating new agents (thalidomide, lenalidomide,bortezomib) are now offering similar response rates and lowertoxicity than HD+ASCT. The new agents seem to combinewell with classical chemotherapy agents (melphalan, cyclophosphamide),modern chemotherapy (pegylated liposomaldoxorubicin) and steroids (dexamethasone, prednisone).In addition, the novel agents show significant activity whencombined with each other in patients with newly diagnosedas well as relapsed/refractory MM patients. Although this isstill considered an incurable disease, the life expectancy andquality of life of MM patients is continuously improving. Ourhope is that progress in this area of research will continuewith the advent of new treatment options and will lead to theultimate goal: a cure.


Multiple myeloma; Novel agents; Bortezomib; IMiDs; Chemotherapy

Full Text:



Katzel JA, Hari P, Vesole DH. Multiple myeloma: charging toward a bright future CA. Cancer J Clin. 2007;57(5):301-18.

American Cancer Society. Cancer Facts and Figures 2008. Atlanta, GA: American Cancer Society, 2008.

Richardson PG, Mitsiades C, Schlossman R, Munshi N, Anderson K. New drugs for myeloma. Oncologist. 2007;12(6):664-89.

Kyle RA. Multiple myeloma, review of 869 cases. Mayo Clin Proc. 1975;50:29-40.

Blade J, Kyle RA, Greipp PR. Presenting features and prognosis in 72 patients with multiple myeloma who were younger than 40 years. Br J Haematol. 1996;93(2):345-51.

McKean-Cowdin R, Feigelson HS, Ross RK, Pike MC, Henderson BE. Declining cancer rates in the 1990’s. J Clin Oncol. 2000;18(11):2258-68.

Longo D. Plasma cell disorders. In: Fauci A, et al, ed. Harrison’s Principles of Internal Medicine. 14th ed. New York, New York: McGraw-Hill. 1998. p. 712-18.

Anderson KC. Plasma cell tumors. In: Holland JF, Bast RC, Weichselbau, Pollock RE, Jufe DW, eds. Cancer Medicine. 5th ed. Lewiston, NY; BC Decker Inc. 2000.

Durie BGM, Salmon SE. A clinical staging system for multiple myeloma - correlation of measured myeloma cell mass with presenting clinical features, response to treatment and survival. Cancer. 1998;36:842-54.

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

Greipp PR, San Miguel JF, Durie BG, Crowley JJ, Barlogie B, Blade J et al. International staging system for multiple myeloma. J Clin Oncol. 2005; 23:3412-20.

Zhan F, Barlogie B, Shaughnessy J Jr. Toward the identification of distinct molecular and clinical entities of multiple myeloma using global gene expression profiling. Semin Hematol. 2003;40(4): 308-20.

Shaughnessy JD Jr, Barlogie B. Integrating cytogenetics and gene expression profiling in the molecular analysis of multiple myeloma. Int J Hematol (Suppl 2). 2002;59-64.

Zhan F, Tian E, Bumm K, Smith R, Barlogie B, Shaughnessy J Jr.. Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development.

Blood. 2003;101(3):1128-40.

Kyle RA, Rajkumar SV. Multiple Myeloma. Blood. 2008;1008:2962-72.

Attal M, Harrousseau JL, Stopa AM, Sotto JJ, Fuzibet JG,. Rossi JF et al. A prospective randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma: Intergroupe Francais du Myelome. N Engl J Med. 1996; 335(23):91-97.

Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K et al. High-dose chemotherapy with hematopoetic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875-83.

Alexanian R, Weber D, Giralt S, Dimoupulos S, Delasalle K, Smith T. et al. Impact of complete remission with intensive therapy in patients with responsive multiple myeloma. Bone Marrow Transplant. 2001;27:1037-43.

Wang M, Delasalle K, Thomas S, Giralt S, Alexanian R. Complete remission represents the major surrogate marker of long survival in multiple myeloma. Blood. 2006;108:123a-24a.

Kyle RA, Leong T, Li S, Oken MM, Kay NE, Van Ness B et al. Complete response in multiple myeloma: Clinical Trial E9486, an Eastern Cooperative Oncology Group study not involving stem cell transplantation. Cancer. 2006;106:1958-66.

Durie BGM, Jacobson J, Barlogie B, Crowley JJ. Magnitude of response with myeloma frontline therapy does not predict outcome: Importance of time to progression in Southwest Oncology Group chemotherapy trials. J Clin Oncol. 2004;22:1857-63.

Dispenzieri A, Rajkumar SV, Gertz MA, Lacy MQ, Kyle RA, Greipp PR et al. Treatment of newly diagnosed multiple myeloma based on Mayo stratification of myeloma and risk-adapted therapy (mSMART): Consensus Statement. Mayo Clin

Proc. 2007;82:323-41.

Landgren O, Katzmann JA, Hsing AW, Pfeiffer RM, Kyle RA, Yeboah ED et al. Prevalence of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in

the United States. Blood. 2006;107(3):904-6.

Hussein, M. Role of high-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. Leukemia. 2004;18(4):893.

Bladé, J., Rosiñol, L., Sureda, A., Ribera, J.M., Díaz- Mediavilla, J., García-Laraña, J., et al.; Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA). High-dose therapy intensification versus continued standard chemotherapy in multiple myeloma patients responding

to the initial chemotherapy: long term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005;106(12):3755-59.

Koreth J., Cutler CS., Djulbegovic B, Behl R, Schlossman RL, Munshi NC et al. High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: A systemic review and meta-analysis of

randomized controlled trials. Biol Blood Marrow Transplant. 2007;13:183-96.

Monconduit M, Le Loet X, Bernard JF, Michaux JL. Combination chemotherapy with vincristine, doxorubicin, dexamethasone for refractory or relapsing multiple myeloma. Br J Haematol. 1986; 63(3):599-601.

Barlogie B, Smith L, Alexanian R. Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med.1984;310(21): 1353-56.

Rajkumar SV. Treatment of myeloma: cure vs. control. Mayo Clin Proc. 2008;83(10):1142-45.

Alexanian R. Dimoupulos MA, Delasalle K. Barlogie B. Primary dexamethasone treatment of multiple myeloma. Blood. 1992;80(4):887-90.

Kumar S, Lacy MQ, Dispenzieri A, Rajkumar SV, Fonseca R, Geyer S et al. Single agent dexamethasone for pre-stem cell transplant induction therapy for multiple myeloma. Bone Marrow Transpl. 2004;34(6):485-90.

Kumar S., Mikhael JR, Buadi FK, Dingli D, Dispenzieri A, Fonseca R et al. Management of newly diagnosed symptomatic multiple myeloma: Updated Mayo stratification of myeloma and riskadapted therapy (mSMART) consensus guidelines. Mayo Clin Proc. 2009;84(12):1095-110 .

Cavo M, Zamagni E, Tosi P, Tacchetti R, Cellini C, Cangini D et al. Writing Committee of the Bologna 2002 Study. Superiority of thalidomide and dexamethasone over vincristine-doxoxrubicindexamethasone (VAD as a primary therapy in

preparation for autologous transplantation for multiple myeloma. Blood. 2005;106(1):35-39.

Harousseau JL, Mathoit C, Attal M, Marit G, Caillot D, Mohamad MM et al. Velcade/Dexamethasone (Vel/D) versus VAD as induction treatment prior to autologous stem cell transplant

(ASCT) in newly diagnosed multiple myeloma (MM): updated results of the IFM 2005/01 trial. Blood. 2007;110(11):450.

Cavo M., Patriarca F., Tacchetti P, Galli M, Perrone G, Petrucci MT et al. Bortezomib-thalidomidedexamethasone (VTD) vs thalidomide-dexamethasone (TD) in preparation for autologous stem-cell (SC) transplantation (ASCT) in newly diagnosed multiple myeloma (MM). Blood. 2007;10:30a.

Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Peqourie B et al. InterGroupe Francophone du Myelome. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation

in elderly patients with multiple myeloma (IFM 99-06). Lancet. 2007;370(9594):1209-18.

Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD et al. Proteasome inhibitors: A novel class of potent and effective antitumor agents. Canc Res. 1999;59:2615-22.

Myung J, Kim KB, Crews CM. The ubiquitin-proteasome

pathway and proteasome inhibitors. Med Res Rev. 2001;21(4):245-73.

DeMartino G.N, Slaughter C. The Proteosome, a novel protease regulated by multiple mechanisms. J Biol Chem. 1999;274(32):22123-26.

Elliott PJ, Adams J. Recent advances in understanding proteasome function. Curr Opin Drug Discov. 1999;2:484-90.

Koepp DM, Harper JW, Elledge SJ. How the cyclin became a cyclin: regulated proteolysis in the cell cycle. Cell. 1997;97(4):431-4.

Sherr CJ. Cancer cell cycles. Science. 1996;274 (5293):1672-77.

Galmarini CM, Clarke ML, Falette N, Puisieux A, Mackey JR, Dumontet C. Expression of a nonfunctional p53 affects the sensitivity of cancer cells to gemcitabine. Intern J Canc. 2000;97(4):439-45.

Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994;78 (5):773-85.

Read MA, Neish AS, Luscinskas FW, Palombella VJ, Maniatis T, Collins T. The proteasome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression. Immunity. 1995;2(5):493-506.

Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nature Rev Cancer. 2002;2(4):301-10.

Zetter BR. Adhesion molecules in tumor metastasis. Semin Canc Biol. 1193;4(4):219-29.

Beg AA, Baltimore D. An essential role for NFkappaB in preventing TNF-alpha-induced cell death. Science. 1996;274(5288):782-84.

Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NFkappaB. J Clin Invest. 2001;107(3):241-46.

Adams J., Palombella V.J., Elliot P.J. Proteosome inhibition: a new strategy in cancer treatment. Investig New Drugs. 2000;18:109-21.

Russo SM, Tepper JE, Baldwin AS Jr, Liu R, Adams J, Elliot P et al.. Enhancement of radiosensitivity by proteasome inhibition: implications for a role of NF-kappaB. Intern J Rad Onc Biol Phys. 2001;50(1):183-93.

Shah SA, Potter MW, McDade TP, Ricciardi R, Perugini RA, Elliot PJ et al. 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J Cel Biochem. 2001; 82(1):110-22.

Bold RJ, Virudachalam S, McConkey DJ. Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome. J Surg Res. 2001;100(1):11-7.

Cusack JC, Jr., Liu R, Houston M, Abendroth, Elliott PJ, Adams J et al. Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Canc Res. 2001;61(9):3535-40.

Sunwoo JB, Chen Z, Dong G, Yeh N, Crowl BC, Sausville E et al. Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Canc Res. 2001;7(5):1419-28.

Ma MH, Yang HH, Parker K, Manyak S, Friedman JM, Altamirano C et al. The Proteasome Inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Canc Res. 2003;9(3):1136-44.

Hideshima T, Chauhan D, Schlossman R, Richardson P, Anderson KC. The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications. Oncogene. 2001;20(33):4519-27.

Kudo Y, Takata T, Ogawa I, Kaneda T, Sato S, Takekashi T et al. p27Kip1 accumulation by inhibition of proteasome function induces apoptosis in oral squamous cell carcinoma cells. Clin Canc Res. 2000;6(3):916-23.

Orlowski RZ, Eswara JR, Lafond-Walker A, Grever MR, Orlowski M, Chi V. Tumor growth inhibition induced in a murine model of human Burkitt’s lymphoma by a proteasome inhibitor. Canc Res. 1998;58(19):4342-48.

Masdehors P, Merle-Beral H, Maloum K, Omura S, Magdelenat H, Delic J. Deregulation of the ubiquitin system and p53 proteolysis modify the apoptotic response in B-CLL lymphocytes. Blood. 2000;96(1):269-74.

Delic J, Masdehors P, Omura S, Cosset JM, Dumont J, Binet JL. The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemoand radioresistant human chronic lymphocytic

leukaemia lymphocytes to TNF-alpha-initiated apoptosis. Brit J Canc. 1998;77(7):1103-7.

Soengas MS, Capodieci P, Polsky D, Mora J, Estellar M, Opitz-Araya X et al. Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature. 2001;409(6817):207-11.

Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Canc Res. 2001;61(7):3071-76.

Richardson P.G, Barlogie B., Berenson J., Singhal S, Jagannath S, Irwin D et al. A Phase 2 study of Bortezomib in relapsed, refractory myeloma. New Engl J Med. 2003;348:2609-17.

Jagannath S, Richardson P, Barlogie B, Berenson J, Singhal S, Irwin D et al. Phase II trials of bortezomib in combination with dexamethasone in multiple myeloma (MM): Assessment of additional benefits to combination in patients with sub-optimal responses to bortezomib alone. Proc ASCO. 2003;22:582.

Richardson PG, Sonneveld P., Schuster MW. Irwin D, Stadtmauer EA, Facon T et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487-98.

Richardson PG, Sonneveld P., Schuster MW. Irwin D, Stadtmauer EA, Facon T et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007;110:3557-60.

Orlowski RZ., Nagler A., Sonneveld P. Blade J, Hajek R, Spencer A et al. Randomized Phase III study of pegylated liposomal doxorubicin plus bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25:3892-901.

San Miguel JF., Schlag R., Khagueva NK. Dimopoulos MA, Shpilberg O, Kropff M et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-17.

Rosignol L., Oriol A., Mateos MV. Sureda A, Garcia- Sanchez P, Gutierrez N et al. Phase II Pethema trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with

multiple myeloma: Efficacy and clinical implications of tumor response kinetics. J Clin Oncol. 2007;25:4452-58.

Palumbo A., Gay F, Falco P. Crippa C, Montefusco V, Patriarca F et al. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol. 2010;28(5):800-7.

Roussel M, Moreau P, Huynh A, Mary JY, Danho C, Caillot D et al. Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: A phase 2 study of Intergroupe Francophone du Myelome (IFM). Blood. 2010;115:32-37.

Bartlett, J.B., Dredge, K., Dalgleish, A.G. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer. 2004;4(4):314-22.

Muller GW, Chen R, Huang SY, Corral LG, Wong LM, Patterson RT et al. Amino-substituted thalidomide analogs: potent inhibitors of TNF-alpha production. Bioorg Med Chem Lett. 1999;9:1625-30.

Marriott JB, Clarke IA, Dredge K, Muller G, Stirling D, Dalgleish AG et al. Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) T cells. Clin Exp Immunol. 2002;130(1):75-84.

Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple

myeloma cells: therapeutic implications. Blood. 2002;99(12):4525-30.

Teo, S.K. Properties of thalidomide and its analogues: implications for anticancer therapy. AAPS J. 2005;22(7):E14-E19.

Anderson, K.C. Multiple Myeloma. Advances in disease biology: therapeutic implications. Semin Hematol. 2001;38(2 Suppl 3):6-10.

Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai YT et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood.


Gupta D, Treon SP, Shima Y, Hideshima T, Podar K, Tai YT et al. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia. 2001;15(12):1950-61.

Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001;98(1):210-16.

Treon SP, Mitsiades C, Mitsiades N, Young G, Doss D, Schlossman R et al. Tumor cell expression of CD59 is associated with resistance to CD20 serotherapy in patients with B-cell malignancies. J Immunother. 2001;24(3):263-71.

Lentzsch S, LeBlanc R, Podar K, Davies F, Lin B, Hideshima T et al. Immunomodulatory analogs of thalidomide inhibit growth of Hs Sultan cells and angiogenesis in vivo. Leukemia. 2003;17(1):41-4.

Hideshima, T., Anderson, K.C. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer 2002;2(12):927-37.

Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA et al.; Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357(21):2133-42.

Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A et al.; Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed

or refractory multiple myeloma. N Engl J Med. 2007;357(21):2123-32.

Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore DF, Whittenberger, BF, et al. Superiority of lenalidomide (Len) plus high-dose dexamethasone (HD) compared to HD alone as treatment of newly-diagnosed multiple myeloma (NDMM): results of the randomized, double-blinded, placebo-controlled

SWOG trial S0232. Blood. 2007;110(11):77.

Rajkumar SV, Jacobus S, Callander N, Fonseca R, Vesole D, Williams M et al. Randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed myeloma (E4A03), a trial coordinated by the Eastern Cooperative Oncology Group: Analysis of response, survival, and outcome. J Clin Oncol. 2008;26(15S):8504.

Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, Ottman E, Czuczman MS. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin

Cancer Res. 2005;11(16):5984-92.

Xu W., Celeridad M, Sankar S, Webb DR, Bennett BL. CC-4047 promotes Th1 cell differentiation and reprograms polarized human Th2 cells by enhancing transcription factor T-bet. Clin Immunol. 2008;128(3):392-99.

Schey SA, Fields P, Bartlett JB, Clarke IA, Ashan G, Knight RD et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol. 2004;22(16):3269-76.

Lacy MQ, Hayman SR, Gertz MA, Dispenzieri A, Buadi F, Kumar S et al. Pomalidomide (CC4047) plus low-dose dexamethasone (Pom/dex) is highly effective therapy in relapsed multiple myeloma. Blood. 2008;112(11):866[abstract].

D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA. 1994;91(9):4082-85.

Haslett PA, Corral LG, Albert M, Kaplan G. Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset. J Exp Med. 1998;187(11):1885-92.

Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341(21):1565-71.

Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol.


Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R.. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003;21(1):16-9.

Lokhorst H, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MHJ et al. Final analysis of HOVON-50 randomized phase III study on the effect of thalidomide combined with adriamycine, dexamethasone (AD) and high dose melphalan (HDM) in patients with multiple myeloma

(MM). Blood. 2008;112(11):157.

Palumbo A, Bringhen S, Rossi D, Magarotto V, Di Raimondo F, Ria R et al. A prospective, randomized, phase III study of bortezomib, melphalan, prednisone and thalidomide (VMPT) versus bortezomib, melphalan and prednisone (VMP) in elderly

newly diagnosed myeloma pateints. Blood. 2008;112(11):652.

Wijermans P, Schaafsma M, van Norden Y, Ammerlaan R, Wittebol S, Sinnige H et al. Melphalan + prednisone versus melphalan + prednisone + thalidomide in induction therapy for multiple myeloma in elderly patients: final analysis of the

Dutch cooperative Group HOVON 49 study. Blood. 2008;112(11):649.

Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Ceccolini M et al. Superior complete response rate and progression-free survival after autologous transplantation with up-front velcade-thalidomide-dexamethasone compared with

thalidomide-dexamethasone in newly diagnosed multiple myeloma. Blood. 2008;112(11):158.

Raza A, Meyer P, Dutt D, Zorat F, Lisak L, Nascimben F et al. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood. 2001;98(4):958-65.

Mileshkin L, Stark R, Day B, Seymour JF, Zeldis JB, Prince HM et al. Development of neuropathy in patients with myeloma treated with thalidomide: patterns of occurrence and the role of electrophysiologic monitoring. J Clin Oncol. 2006; 24(27):4507-14.

Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005; 106(13):4050-53.

Richardson PG., Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108(10):3458-64.

Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002;100(9): 3063-67.

Zangari M, Tricot G, Zeldis J, Eddlemon P,; Saghafifar F, Barlogie B et al. Results of a phase I study of CC-5013 for the treatment of multiple myeloma (MM) patients who relapse after high dose chemotherapy (HDCT). Blood. 2001;98(11):3226.

Stadtmauer EA, Weber DM, Niesvizky R, Belch A, Prince MH, San Miguel JF et al. Lenalidomide in combination with dexamethasone at first relapse in comparison with its use as later salvage therapy in relapse or refractory multiple myeloma. Eur J Haematol. 2009;82(6):426-32.

Srkalovic G, Cameron MG, Rybicki L, Deitcher SR,; Kottke-Marchant K, Hussein MA. Monoclonal gammopathy of undetermined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease. Cancer. 2004;101(3):558-66.

Baz R, Li L, Kottke-Marchant K, Srkalovic G, McGowan B, Yiannaki E et al. The role of aspirin in the prevention of thrombotic complications thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc. 2005;80(12):1568-74.

FitzGerald GA, Brash AR, Oates JA, Pedersen, AK. Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthase in man. J Clin Invest.


FitzGerald GA, Oates JA, Hawiger J, Maas RL, Roberts LJ 2nd, Lawson JA et al. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest. 1983;71(3):676-88.

Rajkumar SV, Jacobus S, Callander N, Fonseca R, Vesole D, Williams M et al. A randomized trial of lenalidomide plus high-dose dexamethasone (RD) versus lenalidomide plus low-dose dexamethasone (Rd) in newly diagnosed multiple myeloma

(E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. Blood. 2007; 110(11):74.

Baz R, Walker E, Karam MA, Choueiri TK, Jawde RA, Bruening K et al. Lenalidomide and pegylated doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Ann. Oncol. 2006;17(12):1766-71.

Wu KL, van Wieringen W, Vellenga E, Zweegman S, Lokhorst. HM, Sonneveld P. Analysis of the efficacy and toxicity of bortezomib for treatment of relapsed or refractory multiple myeloma in community practice. Haematologica. 2005;90(7):996-97.

Tong Y, Qian J, Li Y, Meng H, Jin J. The high incidence of varicella herpes zoster with the use of bortezomib in 10 patients. Am J Hematol. 2007;82(5):403-4.

Mateos M-V, Oriol A, Martinez J, Cibeira T, Gutierrez NC, Terol MJ et al. A prospective , multicenter, randomized, trial of bortezomib/melphalan/prednisone (VMP) versus bortezomib/thalidomide/prednisone (VTP) as induction therapy

followed by maintenance treatment with bortezomib/thalidomide (VT) versus bortezomib/prednisone

(VP) in elderly untreated patients with multiple myeloma older than 65 years. Blood. 2009;114(22):3 (Abstract 3).

Palumbo A, Bringhen S, Rossi D, Ria R, Offidani M, Patriarca F et al. Bortezomib, melphalan, prednisone and thalidomide (VMPT) followed by maintenance with bortezomib and thalidomide for initial treatment of elderly multiple myeloma

patients. Blood. 2009;114(22):58 (Abstract 128).

Einsele H., Liebisch P.,Langer C., et al. Velcade, intravenous cyclophosphamide and dexamethasone (VCD) induction for previously untreated multiple myeloma (German DSMM XIa trial). Blood. 2009;114(22):58 (Abstract 131).

Mikhael JR, Belch AR, Prince HM, Kropff M, Wandt H, Jung W et al. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of global phase 3b expanded access program. Brit J Haematol. 2008;144(2):169-75.

Ghobrial IM, Vij R, Munshi N, Schlossman RL, Laubach J, Campagnero EL et al. Phase II trial of weekly bortezomib in combination with CCI-779 (temsorilimus) in relapsed/refractory multiple myeloma. Blood. 2009;114(22):311 (Abstract 748).

Kropff M, Bisping G, Schuck E, Liebisch P, Lang N, Hentrich M et al. Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Brit J Haematol. 2007;138(3):330-37.

Niesvizky R, Jayabalan DS, Christos PJ, Furst JR, Naib T, Ely S et al. BiRD (Biaxin {clarithromycin]/Revlimid [lenalidomide]/ dexamethasone) combination therapy results in high complete-and overall-response rates in treatmentnaïve

symptomatic multiple myeloma. Blood. 2008;111(3):1101-9.

Palumbo A, Dimopoulos MA, Delforge M, Kropff M, Foa M, Yu Z et al. A Phase III study to determine the efficacy and safety of lenalidomide in combination with melphalan and prednisone (MPR) in elderly patients with newly diagnosed multiple myeloma. Blood. 2009;114(22):253 (Abstract 613).

Palumbo A, Falco P, Sanpaolo G, Falcone A, Ferderico V, Canepa L et al. Lenalidomide, melphalan, prednisone and thalidomide (RMPT) for relapsed/refractory multiple myeloma. Haematologica. 2008;93(s1):256 (Abstract 0636).


  • There are currently no refbacks.

2019 Department of Medical Sciences, Academy of Sciences and Arts of Bosnia and Herzegovina, Sarajevo, Bosnia and Herzegovina. All rights reserved.
The full text of articles published in this journal can be used free of charge for personal and educational purposes while respecting authors and publishers’ copyrights. For commercial purposes no part of this journal may be reproduced without the written permission of the publisher.