DePaul University From the SelectedWorks of Joseph D Tariman PhD, RN, ANP-BC, FAAN Fall September 1, 2003 Understanding novel therapeutic agents for multiple myeloma Joseph D Tariman, PhD, DePaul University Available at: https://works.bepress.com/jdtariman/12/ This material is protected by U.S. copyright law. Unauthorized reproduction is prohibited. To purchase reprints or request permission to reproduce, e-mail [email protected]. FEATURE ARTICLE Understanding Novel Therapeutic Agents for Multiple Myeloma Joseph D. Tariman, RN, APN, MN, APRN, BC, OCN ® ultiple myeloma (MM) At least one-third of patients is a B cell malignancy Multiple myeloma, a B cell malignancy of the plasma with MM do not respond to in- M of the plasma cells. It cells, remains incurable. Advances in high-dose chemo- duction chemotherapy, and is the second most common he- therapy and stem cell transplantation have improved those who initially achieve re- matologic malignancy; only overall survival and event-free disease periods, but re- mission (even with HDC) even- non-Hodgkin’s lymphoma is tually relapse and require addi- more common. About 14,600 lapses are inevitable. New therapeutic agents have tional treatment (Kyle, 1999). cases of MM will be diagnosed shown promising clinical use in patients with relapsed Because MM remains incurable in 2003, and approximately or refractory multiple myeloma. This article discusses and relapse is inevitable, a great 10,900 people will die of the need exists for novel therapeutic disease (Jemal et al., 2003). Re- the therapeutic applications of these novel agents with agents that can prolong life and cently published data on cancer a focus on immunomodulatory drugs, proteasome in- improve overall survival rates for incidence and mortality indicate hibitors, and arsenic compounds. patients with MM. a consistent decline in mortality rates for most cancers from Key Words: multiple myeloma, stem cell transplanta- Immunomodulatory 1991–1995. However, MM is tion, antineoplastic protocols one of three cancers that Drugs showed increased mortality Thalidomide (Thalomid®, rates for men and women, with increases of An oral regimen of melphalan and pred- Celgene Corporation, Warren, NJ), used em- 5.6% and 3.6%, respectively (McKean- nisone was the most frequently used treat- pirically to treat MM based on its antiangio- Cowdin, Feigelson, Ross, Pike, & Hender- ment for newly diagnosed MM from 1970– genic activity and the increased angiogenesis son, 2000). 2000. The mean survival rate with this observed in MM bone marrow, achieves re- People affected by MM often are elderly, regimen is about 72 months (Trippoli, sponses even in refractory, relapsed disease with a median age at diagnosis of 65 years. Messori, Becagli, Alterini, & Tendi, 1998). (Singhal et al., 1999). However, thalidomide Eighty percent of patients are older than 60 Clinical trials have tested numerous regimens has significant and dose-limiting side effects years, and less than 3% are younger than 40 to improve mean survival from time of diag- (Tariman, 2003), including somnolence, con- years. African Americans are affected by the nosis, but, until recently, none was found to stipation, and neuropathy, which have disease twice as often as Caucasian Ameri- be superior to melphalan and prednisone prompted the search for more potent and less cans. MM is one of the leading causes of can- (Hjorth et al., 1999; Myeloma Trialists’ Col- toxic thalidomide derivatives (Richardson, cer death among African Americans (Blade, laborative Group, 1998). Schlossman, et al., 2002). Kyle, & Greipp, 1996). Recent articles have reviewed the main MM results from clonal proliferation of therapeutic regimens for managing patients plasma cells, which produce a homoge- with MM (Campbell, 2002; Rajkumar, Gertz, Preclinical Studies neous immunoglobulin fraction detectable Kyle, & Greipp, 2002; Weber, 2002). The ef- in the serum or urine, called myeloma pro- ficacy and safety of high-dose chemotherapy Immunomodulatory Drugs (IMiDs™) are tein or M-spike. Bone destruction caused by (HDC) and autologous stem cell transplanta- potent thalidomide derivatives or analogs that the production of osteoclastic factors by ma- tion is well established in myeloma and con- markedly stimulate T cell proliferation, as well lignant plasma cells is the most characteris- sidered standard therapy (Goldschmidt et al., Submitted February 2003. Accepted for pub- tic feature of MM, and bone pain is the pre- 1997; Singhal, 2002). HDC has been used for lication March 28, 2003. (Mention of specific dominant presenting symptom. Other more than 10 years as treatment for MM, ei- products and opinions related to those prod- presenting symptoms include anemia, ure- ther alone or with autologous hematopoietic ucts do not indicate or imply endorsement by mia, recurrent infections, and, less com- stem cell rescue. It has improved remission, the Clinical Journal of Oncology Nursing or monly, hypercalcemia, hyperviscosity, event-free survival, and overall survival rates the Oncology Nursing Society.) polyneuropathy, and spinal cord compres- in patients with MM (Attal & Harousseau, sion (Lokhorst, 2002). 1997; Harousseau & Attal, 1997). Digital Object Identifier: 10.1188/03.CJON.521-528 CLINICAL JOURNAL OF ONCOLOGY NURSING • VOLUME 7, NUMBER 5 • UNDERSTANDING NOVEL THERAPEUTIC AGENTS FOR MULTIPLE MYELOMA 521 as interleukin (IL)-2 and inter- concomitant marrow response oc- feron-gamma (IFN-g) production curred in three patients (20%). C. CC-5013 (Corral et al., 1999). CC-5013, However, in contrast to the study also known as IMiD-1 (Re- D. CC-5013 findings of Richardson et al. ® MM cells ▲ ▲ ▲ ▲ ▲ ▲ vimid , Celgene Corporation), a ▲ IL-6 (2001), responses were observed lead IMiD, is 50–2,000 times only at the 25 and 50 mg dose lev- ▲ more potent than thalidomide in TNF-a els. Significant myelosuppression stimulating T cell proliferation was observed, even in patients B. CC-5013 ▲ ▲ ▲ ▲ ▲ triggered via the T cell receptor ▲ IL-1b with adequate platelet counts and ▲ Bone Marrow and 50–100 times more potent A. CC-5013 ▲ marrow cellularity. Furthermore, ICAM-1 Stromal Cells ▲ ▲ ▲ ▲ than thalidomide in augmenting ▲ . this particular study suggested that IL-2 and IFN-g (Richardson, . CC-5013 has the potential to cause Schlossman, et al., 2002). In ad- ▲ cardiovascular problems such as ▲ ▲ ▲ ▲ ▲ Bone Marrow dition, CC-5013 triggers dose-de- ▲ Vessels ▲ thromboembolism (two patients) pendent decreased secretion of tu- VEGF IL-2 and syncope (one patient) (Zangari ▲ mor necrosis factor-alpha bFGF et al., 2001). ▲ ▲ ▲ ▲ ▲ ▲ PBMC ▲ (TNF-a), IL-1b, and IL-6 and IFNg Promising results from these triggers increased secretion of IL- ▲ phase I studies led to a multicenter 10. It also decreases MM cell pro- E. CC-5013 phase II trial; its findings were pre- liferation by decreasing binding CD8+ cells F. CC-5013 sented at the American Society of of MM cells to bone marrow NK cells Hematology conference in Decem- stromal cells (BMSCs); inhibits ber 2002. The trial enrolled 34 pa- A. MM cell g1 growth arrest and apoptosis the production in the bone mar- tients in three months, with a target B. Decreased MM cell to bone marrow stromal cell binding row milieu of cytokines (IL-6, C. Decreased cytokine activity accrual of 60 evaluable patients. vascular endothelial growth fac- D. Decreased cytokine production in bone marrow Preliminary findings of the study tor [VEGF], TNF-a), which me- E. Decreased angiogenesis were presented. Two cohorts of diates the growth and survival of F. Induced host anti-MM immune response patients participated; the first co- MM cells; blocks angiogenesis; bFGF— basic fibroblast growth factor; ICAM-1— intercellular adhesion hort received CC-5013 15 mg and stimulates host anti-MM molecule 1; IL— interleukin; MM— multiple myeloma; NK—natural killer; twice a day and the second cohort natural killer-cell immunity PBMC— peripheral blood mononuclear cells; TNF-a— tumor necrosis fac- received 30 mg once a day for three (Davies et al., 2001; Gupta et al., tor-alpha; VEGF— vascular endothelial growth factor weeks, followed by a one-week 2001; Hideshima et al., 2000; rest period. Nineteen patients were Richardson, Schlossman, et al., FIGURE 1. MECHANISMS OF ACTION OF CC-5013 TARGETING evaluable for paraprotein response 2002) (see Figure 1). MULTIPLE MYELOMA CELLS AND BONE MARROW MICROENVIRONMENT with a median follow-up of one MM cells secrete a number of Note. From “Immunomodulatory Drug CC-5013 Overcomes Drug Resis- month. Best paraprotein reductions cytokines that act on BMSCs, tance and Is Well Tolerated in Patients With Relapsed Multiple Myeloma,” across both dose schedules were which, in turn, secrete factors that by P.G. Richardson, R.L. Schlossman, E. Weller, T. Hideshima, C.S. as follows: 75%–99% in 2 patients contribute to the growth and pro- Mitsiades, F. Davies, et al., 2002, Blood, 100, p. 3064. Copyright 2002 by (11%), greater than or equal to liferation of MM cells. Abnor- American Society of Hematology. Reprinted with permission. 50%–75% reduction in 2 patients mal IL-1b expression is believed (11%), greater then or equal to to stimulate that transition from a clinical con- relapsed MM. More importantly, no signifi- 25%–49% reduction in 2 patients (11%), dition known as monoclonal gammopathy of cant somnolence, constipation, or neuropa- stable disease (less than a 25% reduction) in 10 undetermined significance to frank MM. IL- thy occurred among four cohorts of patients patients (52%), and progression (25% increase 1b is a