Understanding Novel Therapeutic Agents for Multiple Myeloma Joseph D Tariman, Phd, Depaul University

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

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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 remission (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 key activator of osteoclasts, increases who received the drug at different doses of 5, in paraprotein) in 3 patients (15%). Grade three the expression of adhesion molecules, and 10, 25, or 50 mg per day. The best responses thrombocytopenia and neutropenia were ob- induces the production of IL-6, which is the in myeloma proteins (also called served in 4 patients (13%), prompting dose central regulatory cytokine in the pathogen- paraproteins) were reductions of greater than reduction and cytokine support. Somnolence, esis of MM (Hussein, 2002). VEGF, on the or equal to 25% in 12 of 19 evaluable pa- constipation, neuropathy, or other toxicities other hand, plays a pivotal role not only in tients (63%) and less than 25% in an addi- were not reported. This study suggests that neoangiogenesis in MM bone marrow but tional 3 patients (16%). Study findings sup- CC-5013 has an acceptable toxicity profile and also in proliferation and migration of tumor ported the antitumor activity and acceptable the convenience of daily oral dosing cells (Hideshima, Chauhan, Podar, et al., toxicity of CC-5013 and provided the frame- (Richardson, Jagannath, et al., 2002). 2001). In preclinical studies, CC-5013 has work for subsequent studies. Dose-limiting been found to have strong activity in these toxicities, including grade three and four leu- Ongoing Clinical Trials multiple pathways of myeloma pathogenesis kopenia, neutropenia, and thrombocytope- (Hideshima et al., 2000; Richardson, Schloss- nia, were found in all groups except the 5 mg With the completion of phase I and phase II man, et al., 2002). per day cohort of patients (Richardson et al., trials, CC-5013 currently is being studied in 2001). phase III trials in more than 50 U.S. and inter- In a similar phase I study of 15 patients (all national clinical trial sites. This final phase aims Clinical Studies patients had chemorefractory disease, having to enroll 302 patients with relapsed or refrac- Researchers conducting a phase I study of relapsed after at least one HDC treatment with tory MM. Its primary objective is comparing CC-5013 found that it overcame drug resis- a median of 10 prior cycles of chemotherapy), the efficacy of oral CC-5013 in combination tance and was well tolerated in patients with a more than 50% paraprotein reduction with a with oral high-dose pulse dexamethasone to

522 SEPTEMBER/OCTOBER 2003 • VOLUME 7, NUMBER 5 • CLINICAL JOURNAL OF ONCOLOGY NURSING with oral high-dose pulse dexamethasone to MM cells, overcame drug resistance, added m2, followed by a two-week rest period. that of placebo and oral high-dose pulse dex- to the anti-MM activity of dexamethasone, Among nine fully assessable patients with amethasone (Weber, 2003). and overcame the resistance to apoptosis in heavily pretreated plasma cell dyscrasias CC-5013 has the potential to cause myelo- MM cells conferred by IL-6 (Hideshima, completing one cycle of therapy, the re- suppression; therefore, weekly complete Richardson, et al., 2001). It also inhibited the searchers found one complete response (CR) blood count with differential is suggested paracrine growth of human MM cells by de- and a reduction in myeloma protein levels while patients are on therapy. Dose modifi- creasing their adherence to BMSCs and re- or decreased marrow plasmacytosis in eight cations may be needed based on the degree lated nuclear factor kB-dependent induction others. In addition, one patient with mantle of myelotoxicity. New Drug Application of IL-6 secretion in BMSCs, as well as in- cell lymphoma and another with follicular (NDA) filing for CC-5013 to the U.S. Food hibiting proliferation and growth signaling lymphoma had shrinkage of nodal disease. and Drug Administration (FDA) is expected of residual adherent MM cells (Hideshima et Pharmacodynamic studies (direct measure- after completion of the phase III study. al., 2002; Hideshima, Chauhan, Schlossman, ment of whole blood 20S proteasome activ- Richardson, & Anderson, 2001; Hideshima, ity) revealed that bortezomib induced 20S Richardson, et al., 2001; Mitsiades et al., proteasome inhibition in a time-dependent Bortezomib 2002) (see Figure 3). Leblanc et al. (2002) manner, and this inhibition also was related Proteasome inhibitor bortezomib, for- also recently reported that bortezomib inhib- to both the dose in mg/m2 and the absolute merly known as PS-341 (VelcadeTM, Millen- its growth, induces apoptosis, and overcomes dose of bortezomib. Dose-limiting toxicities nium Pharmaceuticals, Inc., Cambridge, drug resistance in human myeloma cells in attributed to bortezomib above the 1.04 mg/ MA) is a novel, first-in-class agent that in- vitro, supporting the clinical potential of m2 maximum tolerated dose include throm- hibits the 26S proteasome (simply called “the bortezomib to improve patient outcomes. bocytopenia, hyponatremia, hypokalemia, proteasome”). The proteasome is a Bortezomib also has been tested in phase I fatigue, and malaise. Researchers concluded multicatalytic enzyme present in the nucleus trials in a variety of tumor types. In these that bortezomib was well tolerated at 1.04 and cytoplasm of all eukaryotic cells (cells early clinical trials, bortezomib was well tol- mg/m2 but patients must be monitored for with nuclei and other internal organelles). It erated, and preliminary evidence of biologic electrolyte abnormalities and late toxicities. is a ubiquitous and essential intracellular en- activity was observed in some patients. Phase The study also showed that careful assess- zyme that degrades many proteins that regu- II trials in several hematologic malignancies ment and monitoring of patients during late cell cycle, apoptosis, transcription, cell and solid tumor types are in progress therapy are critical, particularly because of adhesion, angiogenesis, and antigen presen- (Adams, 2002b). bortezomib’s potential myelosuppressive tation (Adams, 2002a). It consists of the 20S adverse effects. Very importantly, the study proteasome (the proteolytic core), which is Clinical Studies showed that bortezomib has a promising ac- capped on each end by a 19S regulatory com- tivity against refractory MM and possibly plex. The 19S regulatory complexes recog- In a phase I study of bortezomib con- non-Hodgkin’s lymphoma (Orlowski et al.). nize ubiquinated proteins and help funnel the ducted by Orlowski et al. (2002), 27 patients A phase II study in patients with MM was protein into the proteolytic core. The received bortezomib twice weekly for four initiated immediately; results were published proteasome plays a critical role in the coordi- weeks at either 0.40, 1.04, 1.20, or 1.38 mg/ recently (Richardson, Barlogie, et al., 2002). nated degradation of proteins (or their inhibitors), which regulates cell cycle and cell survival. By degrading regulatory proteins or their inhibitors, the proteasome serves as a central conduit for many cellular regulatory signals and, thus, is a novel target for therapeutic drugs. Proteolysis by the 26S proteasome is a fundamental metabolic process, and complete blockage of the proteasome activity with an inhibitor such as bortezomib results in death for cells and or- ganisms (Adams, 2002a) (see Figure 2).

Preclinical Studies Bortezomib was tested against a broad range of human tumor cells, including pros- tate cancer cell lines, and demonstrated that it is able to inhibit intracellular proteasome Prior to degradation, doomed proteins first are marked on specific lysine residues with a polyubiquitin activity and reduce tumor growth in murine chain. Marking the protein is a three-step process in which ubiquitin is activated by a ubiquitin-activat- tumor models (Adams et al., 1999). In MM ing enzyme (E1), then transferred to a ubiquitin-conjugating enzyme (E2). E3s (the ubiquitin-protein li- cell lines, bortezomib demonstrated the fol- gases) recognize degradation motifs on specific substrates and catalyze the transfer of ubiquitin from lowing activities: It directly inhibited prolif- the E2 to the target. These polyubiquitinated substrates then are recognized and degraded by the 26S eration and induced apoptosis of human MM proteasome. cell lines and freshly isolated patient MM cells, inhibited mitogen-activated protein ki- FIGURE 2. UBIQUITIN-PROTEASOME PROTEIN DEGRADATION nase growth signaling in MM cells, induced Note. From “Development of the Proteasome Inhibitor PS-341,” by J. Adams, 2002, Oncologist, 7, p. apoptosis despite induction of some mutant 10. Copyright 2002 by AlphaMed Press. Reprinted with permission.

CLINICAL JOURNAL OF ONCOLOGY NURSING • VOLUME 7, NUMBER 5 • UNDERSTANDING NOVEL THERAPEUTIC AGENTS FOR MULTIPLE MYELOMA 523 efficacy of bortezomib with that of high-dose dexamethasone, a treatment commonly used by clinicians to treat patients with MM (Mil- lennium Pharmaceuticals, Inc., 2002a). An extension phase II clinical trial also is enrolling patients with the primary objective of determining the time to progression among patients treated with bortezomib 1.3 mg/m2. This is an open-label study of bortezomib administered to patients with MM who experienced relapsed or progressive disease after receiving at least four previous treatment regimens or experienced progressive disease after receiving dexamethasone in the phase III study (Millennium Pharmaceuticals, Inc., 2002b). On May 13, 2003, Millennium Pharma- ceuticals, Inc., received approval from the FDA to market Velcade for the treatment of Bortezomib (formerly called PS-341) targets multiple myeloma in the bone marrow microenvironment. patients with multiple myeloma who have received at least two prior therapies and have FIGURE 3. BORTEZOMIB (FORMERLY CALLED PS-341) MECHANISMS OF ACTION demonstrated disease progression on the last Note. From “Challenging Cases in Myeloma and Plasma Cell Dyscracias” [Monograph], by K.C. Anderson, therapy (Millennium Pharmaceuticals, Inc., 2002, p. 58. Reprinted with permission. Based on information from Hideshima et al., 2002; Hideshima, 2003). Chauhan, Schlossman, et al., 2001; Hideshima, Richardson, et al., 2001; Mitsiades et al., 2002.

In the phase II trial, bortezomib demon- The adverse effects reported usually were strated promising activity in relapsed and re- minor and well tolerated by patients Arsenic Trioxide fractory MM; clinical benefits included im- (Richardson, 2002). These adverse effects Arsenic trioxide (TrisenoxTM, Cell Thera- proved hemoglobin level, quality of life, (any grade) included nausea (65%), fatigue peutics, Inc., Seattle, WA) has been identi- performance status, and levels of non-MM pro- (51%), diarrhea (50%), peripheral neuropa- fied and characterized as an effective agent tein immunoglobulins (Richardson, 2002). In thy (36%), and thrombocytopenia (36%). in treating acute promyelocytic leukemia this multicenter trial, patients received Grade three thrombocytopenia occurred (APL), also known as M3 acute leukemia bortezomib at 1.3 mg/m2 by IV push on days mostly in patients with baseline thrombocy- (Mayorga, Richardson-Hardin, & Dicke, 1, 4, 8, and 11 of a 21-day cycle for up to eight topenia, but no serious bleeding was re- 2002; Niu et al., 1999; Shen et al., 1997; cycles. Addition of dexamethasone was per- ported. Overall, 80% of patients had baseline Soignet et al., 1998). Research into the mitted in patients with progressive disease af- neuropathy at study entry, and only four pa- mechanisms by which arsenic targets malig- ter two cycles or stable disease after four cycles. tients without baseline neuropathy developed nant cell types led to the discovery that ar- Two cohorts consisted of 202 patients (78 in treatment-emergent neuropathy, with one senic affects myriad pathways that contrib- one group and 124 in the second group). Sev- case of grade three neuropathy (Richardson). ute to the cellular transformation process enty-eight patients in cohort one had a mean Patients should be monitored closely for any (Novick & Warrell, 2000). This increase in of five prior lines of therapy and a median sur- of these adverse effects. Failure to assess and understanding of the mechanisms by which vival of four years from diagnosis. Of the 202 lack of appropriate early interventions may arsenic affects cellular pathways and arsenic patients enrolled, 74% previously had received jeopardize patients’ health conditions. On- trioxide’s efficacy in treating APL provided thalidomide and 54% had received HDC. The cology nurses play a vital role in assessing a rationale for investigating the compound’s overall response rate to bortezomib alone was and monitoring these adverse effects and ini- use in treating other hematologic malignan- 32% (CR, partial response [PR], and minimal tiating immediate interventions before seri- cies, such as MM (Anderson, Boise, Louie, response) in cohort one. Twenty-seven percent ous health conditions or irreversible damage & Waxman, 2002; Munshi, 2001). The had major responses (4% CR, 23% PR), with occur. achievement of clinical responses marked by 9% of the PR patients meeting all of the crite- molecular conversion of the malignant phe- ria for CR, with the exception of negative im- Ongoing Clinical Trials notype and remissions in patients who had munofixation; therefore, the CR and near CR failed to respond to multiple courses of con- rate was 13%. Sixty-eight percent of all of the and Approval by the U.S. ventional chemotherapy provided the impe- patients enrolled in the study had either de- Food and Drug Administration tus to explore its use in MM (Anderson, creased or stable myeloma protein levels 2002). (Richardson, Barlogie, et al., 2002). The me- After promising results from phase I and In preclinical and clinical studies, arsenic dian duration of response in CR and PR pa- phase II studies, a phase III clinical trial com- trioxide has shown promise as an effective tients had not been reached at 10.2 months paring bortezomib with high-dose dexam- therapeutic option for the treatment of MM (median) follow-up. In this clinical trial, re- ethasone in patients with relapsed or refrac- as a single agent or in combination with other sponse rate was associated with clinical ben- tory MM was initiated and currently is drugs (Grad et al., 2001; Hussein, 2001, efit for patients with relapsed or refractory MM accruing patients in more than 50 trial sites 2002; Munshi, 2001; Munshi, Barlogie, progressing on last therapy (Richardson, across the United States and abroad. The pri- Desikan, & Wilson, 1999; Munshi, Desikan, Barlogie, et al.). mary purpose of this study is to compare the et al., 1999; Munshi et al., 2002; Murgo,

524 SEPTEMBER/OCTOBER 2003 • VOLUME 7, NUMBER 5 • CLINICAL JOURNAL OF ONCOLOGY NURSING 2001). Multiple events involved in the patho- with relapsed or resistant MM who received two hyperglycemia. No patients had alopecia genesis of MM coincide with pathways tar- at least one prior cycle of HDC with autolo- or severe nausea (Hussein et al.). geted by arsenic trioxide, and early results gous stem cell rescue were eligible for en- Preliminary findings of a single-center have suggested that clinical responses and rollment. Patients received arsenic trioxide phase I/II trial of arsenic trioxide in patients safety are promising in patients with ad- 0.15 mg/kg per day via IV over two hours with relapsed MM recently were reported vanced disease (Anderson, 2002). for as long as 60 days. Patients then were (Berenson, Yang, Vescio, Swift, & Sadler, evaluated for response, defined as a reduc- 2002). Patients received arsenic trioxide 0.25 tion in myeloma protein, at least on days 30 mg/kg twice a week for eight weeks, then no Preclinical Experience and 60. Treatment was continued for an ad- therapy for three weeks in repeated 11-week Preliminary data have suggested that the ditional 30 days in patients who responded. cycles. Patients who progressed were treated apoptotic effects of arsenic trioxide are not In this high-risk patient population with ex- with combination arsenic trioxide and high- specific for APL cells but also can be observed tensive prior therapy, 3 of the 14 patients ex- dose corticosteroids. The results showed that in other cell lines, including those of lymphoid perienced objective response, with myeloma two of seven evaluable patients had objective and myeloid origin (Calleja, Konig, Warrell, protein reductions of 75% (n = 1), 50%– response after one cycle of arsenic trioxide, as & Gabrilove, 1997), and in blast cells from 75% (n = 1), or 25%–50% (n = 1). Objective measured by a less than 25% decrease in se- patients with non-M3 acute myeloid leukemia response occurred in 8 patients, and 3 had rum myeloma protein, and one patient had (Lehman, Bengtzen, Paul, & Paul, 1997). The progressive disease. Although treatment was stable disease. Four patients had progressive in vitro effects of arsenic trioxide on human reasonably well tolerated in this high-risk disease during or after cycle one. Three pa- myeloma cells recently were reported population, 11 developed neutropenia, 5 with tients dropped out before the first scheduled (Rousselot et al., 1999). In clinically appro- infectious complications, and 3 developed evaluation visit, and one did not meet entry priate concentrations, arsenic trioxide caused deep vein thrombosis. criteria for the study. One drug-related serious a time- and dose-dependent inhibition of sur- Final results from a phase II study evaluat- adverse effect of epistaxis and anemia oc- vival and growth of myeloma cell lines via ing the use of a higher, less-frequent dose of curred. These preliminary results showed that apoptosis. Researchers have proposed that arsenic trioxide recently were published arsenic trioxide is well tolerated at this dose ascorbic acid decreases glutathione levels, (Hussein, Mason, Saleh, Rifkin, & Ravandi, and schedule, both as a single agent and in which, in turn, potentiates arsenic trioxide- 2002). The primary efficacy endpoint was re- combination with steroids. The study contin- mediated apoptosis (Grad et al., 2001). The sponse rate, based on Southwest Oncology ues to enroll patients, and the investigator has ability of arsenic trioxide to induce apoptosis Group response criteria, in patients who had increased the dose of arsenic trioxide to 0.35 in chemosensitive and chemoresistant my- relapsed or were refractory to conventional mg/kg using the same schedule. In addition, eloma cell lines was demonstrated further in treatment for MM. Arsenic trioxide was ad- based on the tolerability of arsenic trioxide and another study (Bahlis, Grad, Pandite, & Boise, ministered at a dose of 0.25 mg/kg via IV over studies that show chemosensitization effects 2000). Failure to undergo apoptosis may, in two to four hours five days per week during of this drug on myeloma cell lines, further itself, be an underlying pathophysiologic de- the first two weeks, followed by no therapy clinical trials are planned using arsenic triox- fect in MM, and arsenic trioxide appears to for the next two weeks of each four-week ide in combination with low-dose, oral cause apoptosis in myeloma cells via alteration cycle. Patients could receive as many as six melphalan (Berenson et al.). in the balance between pro- and antiapoptotic treatment cycles. Twenty relapsed, and four Arsenic trioxide also has been combined signals (Pearse et al., 1999). refractory patients were treated. Three patients with ascorbic acid. In a phase I study of six Another investigation reported on the ef- were not evaluable for response because of patients, two had partial response (greater than fects of arsenic trioxide on proliferation and progressive disease or withdrawal of consent or equal to a 25% decrease in myeloma pro- apoptosis in MM cell lines (Hussein, 2001). during cycle one. Nine of 21 (43%) evaluable tein), and four had stable disease (0%–25% The combination of arsenic trioxide and patients had objective response as measured decrease in myeloma protein). No patients ex- noncytotoxic concentrations of melphalan re- by a less than 25% decrease in serum myeloma perienced dose-limiting toxicities (median two sulted in increased sensitivity of MM cells to protein, and eight patients had stable disease. cycles per patient) at 0.15–0.25 mg/kg per day cell killing. In addition, arsenic trioxide de- One refractory patient had a 50% decrease in dosing with 500–1,000 mg of ascorbic acid creased the secretion of VEGF, consistent with plasmacytoma size. Five patients had arsenic administered via IV within 30 minutes after previous reports of arsenic trioxide’s trioxide-related serious adverse effects, which arsenic trioxide infusion. Grade one or two fa- antiangiogenic properties (Roboz et al., 2000). include leukopenia/anemia, anemia/thromb- tigue was the major side effect reported. Other Such findings are relevant because MM tumor ocytopenia, febrile neutropenia, fatigue, and side effects were sensory neuropathy, nausea, cells are known to secrete VEGF. These re- pulmonary edema. Transient increases in tran- rash, dry skin, leukopenia, and edema. No car- sults demonstrate the cytotoxic effects of ar- saminase levels occurred in 15 patients during diac arrhythmias were reported. The research- senic trioxide on MM cell lines and suggest cycle one: (National Cancer Institute Clinical ers concluded that arsenic trioxide and ascor- potential synergistic effects in combination Trials Center) grade one in seven patients, bic acid have acceptable toxicity when with melphalan and other chemotherapeutic grade two in seven patients, and grade three in combined and that promising evidence of ac- agents. Other investigations have found pre- one patient) and in four patients during the sec- tivity in refractory or relapsed MM exists clinical synergy with additional agents, includ- ond and third cycles (grade one and two). No (Bahlis et al., 2002). The phase II component ing dexamethasone, against MM cell lines patients were withdrawn, and no doses were of this study is ongoing. (Hayashi et al., 2001). decreased because of increased transaminase The adverse effects associated with arsenic levels. Fifteen patients had recurrent transient trioxide administration in patients with MM weight gain in most cycles (nine patients had during clinical trials usually were manage- Clinical Studies grade one weight gain, five had grade two, and able and well tolerated by patients. In patients Arsenic trioxide was evaluated in a phase one had grade four). Six of these patients re- with APL, careful monitoring of complete II trial of patients with advanced refractory ceived diuretics. Five patients, including four blood count two times per week and chemis- MM (Munshi et al., 2002). Fourteen patients with preexisting diabetes mellitus, had grade tries, including potassium and magnesium

CLINICAL JOURNAL OF ONCOLOGY NURSING • VOLUME 7, NUMBER 5 • UNDERSTANDING NOVEL THERAPEUTIC AGENTS FOR MULTIPLE MYELOMA 525 levels at least once per week, are essential lapsed or refractory MM. Several other trials clinical trials of these novel agents. Health- throughout therapy. These tests are needed are investigator-sponsored through various care providers, particularly nurses, must have to assess for severe myelosuppression and academic institutions or oncology collabora- adequate knowledge of these new therapeu- electrolyte imbalances during treatment. Pa- tive groups (Cell Therapeutics, Inc., Profes- tic agents to ensure safe administration. Po- tients also should have a weekly electrocar- sional Services, 2002) (see Table 1). tential adverse effects or toxicities are associ- diogram and be monitored for possible pro- ated with these novel drugs. Careful longation of the QTC interval and possible assessment and monitoring of patients’ atrioventricular block (Cell Therapeutics, Conclusion health status are critical throughout the Inc., 2002). Close monitoring of patients CC-5013, bortezomib, and arsenic triox- therapy period. Oncology nurses must keep with MM during therapy with arsenic trioxide have shown clinical activity in patients themselves abreast of the latest information ide also is highly recommended. with MM refractory to conventional therapy. on these novel drugs and develop compre- The adverse events or side effects reported in hensive nursing measures that address patients’ symptoms. Ongoing Clinical Trials phase II clinical trials usually were reversible and manageable. Healthcare providers The author would like to acknowledge Mary Numerous clinical trials are being spon- should support further investigations of these Beth Riley, RN, MSN, AOCN®, clinical nurse spe- sored by Cell Therapeutics, Inc., to evaluate agents and encourage patients with relapsed cialist at the Robert H. Lurie Comprehensive Can- the use of arsenic trioxidein patients with re- or refractory MM to participate in additional cer Center at Northwestern University, Chicago,

TABLE 1. SUMMARY OF ARSENIC TRIOXIDE CLINICAL TRIALS IN MULTIPLE MYELOMA

PROTOCOL TITLE INVESTIGATOR (INSTITUTION)TRIAL DESIGN

Combination of arsenic trioxide and M. Zangari (Arkansas Cancer Patients will receive arsenic trioxide for five consecutive days, then two days ascorbic acid for relapsed or refractory Research Center, Little Rock) per week for 11 weeks. Ascorbic acid will be given via IV with each dose of multiple myeloma: A dose- and schedule- arsenic trioxide. Patients with stable disease or response will continue. Cycle finding study based on pharmacokineticsa = 12 weeks Phase II study of arsenic trioxide in Multicenter. Primary investi- Arsenic trioxide is given on days 1–5 and 8–12 (two weeks on and two weeks patients with multiple myeloma gator: M. Hussein (Cleveland off). Cycle = four weeks. Evaluation after every second cycle (cycles two, four, and (CTI-1057) b (closed to accrual) Clinic, OH) six). Patients may continue on treatment indefinitely without disease progression. Phase II study of arsenic trioxide in pa- N. Vey (Institut Paoli- Patients will receive arsenic trioxide five days per week for one week followed tients with multiple myeloma (CTI-1062) c Calmettes, Marseille, France) by twice weekly dosing. Phase II study of arsenic trioxide twice J. Berenson (Cedars-Sinai Patients will receive arsenic trioxide twice weekly for eight weeks, then three weekly dosing in patients with multiple Medical Center, Los Angeles, weeks of no arsenic trioxide. Evaluation every cycle. If patients have progres- myeloma (CTI-1063) b CA) sive disease, they may receive as many as three more cycles at the same dose plus dexamethasone on the day of dosing. Phase II clinical trial of arsenic trioxide Multicenter. Primary investi- Patients will receive arsenic trioxide daily for five consecutive days, then two and dexamethasone as therapy for gator: R. Comenzo (Memo- days per week. Dexamethasone will be given on days one through five every relapsed or refractory multiple myeloma rial Sloan-Kettering Cancer four weeks. Assessment for myeloma protein is performed every four weeks (CTI-1060) b Center, New York, NY) and bone marrow aspiration every eight weeks. Phase II study of combination of arsenic C. Henderson (Access On- Patients will receive arsenic trioxide on days one through five, then two times trioxide, ascorbic acid, and dexametha- cology; Online Collaborative per week for weeks 2–10. Ascorbic acid will be given after every arsenic triox- sone as therapy for relapsed or refractory Oncology Group, Memphis, ide infusion. Dexamethasone will be given on days 1–4, 29–32, and 57–60. multiple myelomaa (closed to accrual) TN) Cycle = 12 weeks. Evaluation after every second cycle (cycles two, four, and six). Patients may continue on treatment until disease progression or unac- ceptable toxicity. Phase I/II trial of arsenic trioxide with Primary investigator: K. Lee Phase I: dose escalation of arsenic trioxide. Patients will receive ascorbic acid ascorbic acid in the treatment of re- (University of Miami, FL) with arsenic trioxide. Phase II: Patients will receive arsenic trioxide Monday lapsed and refractory multiple through Friday for five weeks; ascorbic acid will be given after every arsenic myeloma c trioxide infusion. Cycle = seven weeks. Evaluation after every second cycle. Patients may continue on treatment for as many as six cycles without disease progression. Phase II trial of arsenic trioxide with J. Hainsworth (Sarah Can- Patients will receive arsenic trioxide daily for five consecutive days, then two thalidomide in the treatment of patients non Cancer Center, Nash- days per week for three weeks. Patients will receive thalidomide loading dose with refractory multiple myeloma a ville, TN) for the first two weeks, followed by weekly dose escalation of thalidomide. a Investigator-sponsored trial b CTI trial c National Cancer Institute Cooperative Research and Development trial CTI—Cell Therapeutics, Inc. Note. Based on information from CTI Professional Services, 2002; data on file, CTI Professional Services.

526 SEPTEMBER/OCTOBER 2003 • VOLUME 7, NUMBER 5 • CLINICAL JOURNAL OF ONCOLOGY NURSING IL, for doing the initial review and critique of this (2002). Trisenox clinical trials in multiple my- multiple myeloma patients: No improvement article. eloma [Information package]. Seattle, WA: during two decades. Nordic Myeloma Study Author. Group (NMSG). European Journal of Author Contact: Joseph D. Tariman, RN, Corral, L.G., Haslett, P.A., Muller, G.W., Chen, R., Haematology, 62, 271–277. Wong, L.M., Ocampo, C.J., et al. (1999). Differ- Hussein, M.A. (2001). Arsenic trioxide: A new APN, MN, APRN, BC, OCN®, can be ential cytokine modulation and T cell activation immunomodulatory agent in the management reached at [email protected]. by two distinct classes of thalidomide analogues of multiple myeloma. Medical Oncology, 18, that are potent inhibitors of TNF-alpha. Journal 239–242. of Immunology, 163, 380–386. Hussein, M.A. (2002). 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Rapid Recap Understanding Novel Therapeutic Agents for Multiple Myeloma • Multiple myeloma is the second most common hematologic malignancy and most often affects the elderly (the mean age at diagnosis is 65 years). • Despite advances in high-dose chemotherapy and stem cell transplantation, a third of patients do not respond to induction chemotherapy, and the majority of those who do respond relapse and require additional treatment. • CC-5013 (an Immunomodulatory DrugTM that is a thalidomide derivative), bortezomib (a proteasome inhibitor), and arsenic trioxide (an arsenic compound) are novel therapeutic agents that have shown clinical therapeutic efficacy against relapsed or refractory multiple myeloma. • Adverse effects associated with these novel drugs are minor and well tolerated by patients. Careful assessment and monitoring of patients’ health status throughout therapy are critical to ensure patients’ safety. • All healthcare providers, especially oncology nurses, should continue to support clinical trials of these novel agents to expedite availability of newer therapeutic options for patients with relapsed or refractory multiple myeloma.

528 SEPTEMBER/OCTOBER 2003 • VOLUME 7, NUMBER 5 • CLINICAL JOURNAL OF ONCOLOGY NURSING