Multiple Myeloma by IMER

MULTIPLE MYELOMA TREATMENT OVERVIEW

Sponsored by:

This activity is supported by independent educational grants from Genentech BioOncology, Merck & Co., Inc., Millennium Pharmaceuticals, Inc., and Novartis Pharmaceuticals Corporation.

MULTIPLE MYELOMA TREATMENT OVERVIEW Beth Faiman, MSN, RN, AOCN® — Cleveland Clinic Taussig Cancer Institute

Multiple myeloma (MM) is a plasma cell disorder characterized by an uncontrolled proliferation of bone marrow plasma cells, resulting in the destruction of bone and bone marrow failure. According to the American Cancer Society, an estimated 20,580 new cases of MM are diagnosed annually, and 10,580 people die from the disease (Jemal et al, 2009). It is the second most common malignancy in the United States, and accounts for approximately 1% of all malignancies (Collins, 2005). Driven by improved understanding of MM biology, especially the genetic aberrations that underlie the disease, the use of new and more effective treatment options has increased the 5-year survival rate from 26% in 1975 to 35% in 2004 (Fonseca et al, 2004; Brenner et al, 2008; Kumar et al, 2008). The introduction of thalidomide, lenalidomide, and bortezomib, as well as the increased use of high-dose chemotherapy and autologous stem cell transplant (ASCT), has transformed MM from an incurable disease to a chronic illness. Ongoing investigations focus on finding the most effective treatment options while minimizing toxicities and maintaining quality of life.

DIagnosIs Patients with symptomatic MM present with hypercalcemia, renal dysfunction, anemia, and bone disease, which are known as CRAB symptoms (Durie et al, 2003; The International Myeloma Working Group, 2003). Initial work-up should include a comprehensive history, physical examination, skeletal survey, bone marrow aspirate and biopsy, and laboratory tests (Table 1). Clonal bone marrow plasma cells greater than 10% and serum or urinary monoclonal protein are important diagnostic criteria. Quantitative immunoglobulin levels and serum immunofixation studies can be used to identify the type of monoclonal protein present.

upper limits of normal. Higher stage is correlated with poorer prognosis, with a median overall survival (OS) of 29 months for stage III disease versus 62 months for stage I disease (Greipp et al, 2005).

InItIal treatment Patient eligibility for ASCT typically determines the course of initial treatment. Karnofsky performance status, age, and patient comorbidities are important factors to consider (Kyle & Rajkumar, 2009; Bensinger, 2008; Attal et al, 2006). In patients eligible for ASCT, initial treatment with alkylating agents such as melphalan is not recommended because stem cell harvest may be compromised (National Comprehensive Cancer Network [NCCN], 2010; Reece, 2007).

transplant-elIgIble patIents Patients who are eligible for transplant are treated with induction chemotherapy followed by high-dose chemotherapy and ASCT. NCCN recommendations for initial treatment include bortezomib-, lenalidomide-, and thalidomidebased regimens (2010). Choice of therapy is defined by

TABLE 1

Multiple Myeloma Diagnostic Panel

Test

Finding(s) With Myeloma

CBC with differential counts

↓ Hgb ↓ WBC ↓ platelets

Blood chemistry profile, LDH ↑ Creatinine ↑ Ca+2 ↓ albumin ↑ LDH Serum electrophoresis with ↑ Monoclonal protein in quantitative immunoglobulins serum; may have ↓ levels of normal immunoglobulins Immunofixation

Identifies light/heavy chain types of monoclonal protein

B2m

↑ Levels (measure of tumor burden)

C-reactive protein

↑ Levels (marker for myeloma growth factor)

24-Hour urine protein electrophoresis

↑ Monoclonal protein

Bone marrow biopsy + aspirate

≥ 10% Plasma cells

Skeletal survey

Osteolytic lesions, osteoporosis

Serum free light chain

↑ Free light chains

rIsk Factors anD stagIng MM risk factors include elevated serum beta 2-microglobulin and plasma cell labeling index, deletion 13 or hypodiploidy, deletion 17p-, and t(4;14) or t(14;16) translocations. Translocations can be detected through fluorescent in situ hybridization studies (Kyle & Rajkumar, 2009; Dispenzieri et al, 2007). Patients with more than one risk factor are considered to have high-risk disease, which is associated with a median survival of 2 to 3 years. Patients with standard-risk MM have a median survival of 5 years or longer (Kyle & Rajkumar, 2009). The International Staging System uses two predictors of survival (ie, beta 2-microglubin and albumin) to determine stage and prognosis. Stage I is characterized by low beta 2-microglobulin and normal serum albumin; stage III is characterized by beta 2-microglobulin higher than the

MRI

Vertebral compression

Cytogenetics/FISH

Del 13, del 17, t(4;14), t(11;14), t(14;16)

(Barlogie et al, 2006; Durie et al, 2006; Durie et al, 2003; Rajkumar et al, 2005) A series of laboratory tests may be performed to confirm a multiple myeloma diagnosis. This includes complete blood counts to evaluate hemoglobin, white blood cell, and platelet levels, serum electrophoresis to determine the presence of monoclonal protein, and bone marrow biopsy to confirm clonal-positive cell disorder. CBC = complete blood count; Hgb = hemoglobin; WBC = white blood cell; LDH = lactate dehydrogenase; Ca+2 = calcium; B2m = B2-microglobulin; MRI = magnetic resonance imaging; Del = chromosomal deletion; t = translocation; FISH = fluorescent in situ hybridization.

factors such as renal function, risk for thrombosis, preexisting neuropathy, past adherence to oral medications, and distance to travel to the treatment site. Bortezomib is a first-in-class proteasome inhibitor that acts directly on myeloma cells as well as on the interaction between the tumor cell and the bone marrow microenvironment (NCCN, 2010). In a phase III study, 482 patients with previously untreated MM were randomly assigned to receive induction therapy with either bortezomib/dexamethasone or vincristine/doxorubicin/dexamethasone (VAD). Patients in the bortezomib arm showed a significantly higher response rates that translated into better very good partial remission rates post-induction (Harousseau et al, 2008). Serious adverse events were similar between the two arms (38.2% in bortezomib arm and 40.6% in VAD). Neuropathic symptoms were more common in the bortezomib arm (35.3% vs. 22.6%). Based on these results, the bortezomib/dexamethasone regimen is considered an NCCN category 1 induction regimen in transplant-eligible patients (Harousseau et al, 2008; NCCN, 2010). The GIMEMA Italian Multiple Myeloma Network conducted a randomized phase III trial evaluating induction therapy with bortezomib in combination with thalidomide and dexamethasone versus thalidomide and dexamethasone alone (Cavo et al, 2008). Although patients in the tripletherapy arm demonstrated superior PFS (90% vs. 80%; p = .009), OS was not significantly different between the two arms (96% vs. 91%; Figure 1). Grade 3 peripheral neuropathy and rash were higher in the triple-therapy arm (8% and 6.5%, respectively) than in the thalidomide/dexamethasone arm (2% and 1%, respectively; whereas patients in the thalidomide/dexamethasone arm experienced more deep vein thrombosis (6.5%; Cavo et al, 2008). In a phase II study, 34 patients received induction therapy with lenalidomide 25 mg/d on Days 1–21 during a 28-day cycle and dexamethasone 40 mg/d on Days 1–4, 9–12,

FIGURE 1

and 17–20 during each cycle. Patients could discontinue treatment or undergo ASCT following four cycles of therapy (Lacy et al, 2007). Fifty-five percent of patients experienced grade 3 or higher toxicity, with the most common being fatigue (21%) and neutropenia (21%). Patients who proceeded to ASCT had a 2-year OS rate of 92% versus 90% for those who remained on the regimen. A study comparing lenalidomide plus high-dose versus low-dose dexamethasone in newly diagnosed patients showed that OS was superior in the low-dose group despite a lower response rate (Rajkumar, Jacobus, et al, 2008). Within the first four cycles, grade > 3 toxicities were reported in 50% of patients in the high-dose arm vs. 30% in the low-dose arm (p = .001). The thalidomide/dexamethasone regimen was studied in phase III trials and demonstrated a higher response rate (RR) and longer time to progression (TTP) when compared to dexamethasone alone (63% vs. 46% and 22.6 vs. 6. 5 months, respectively; Cavo et al, 2005; Rajkumar, Rosinol, et al, 2008). Thalidomide was associated with increased toxicity, especially thrombotic events (22%; Thalomid® prescribing information, 2007). Another study compared thalidomide/dexamethasone to the VAD regimen (Cavo et al, 2005). The thalidomide/dexamethasone combination demonstrated higher RR pre-ASCT (76% vs. 52%; Cavo et al, 2005). Post-ASCT rate was not improved when compared with dexamethasone or with VAD as initial treatment prior to ASCT (Kumar et al, 2006). Non-fatal deep vein thrombosis occurred more frequently in the thalidomide/dexamethasone regimen (15%), while patients in the VAD regimen experienced higher rates of granulocytopenia (12%; Cavo et al, 2005). In a phase II trial, the combination of lenalidomide, bortezomib, and dexamethasone resulted in a 100% RR with very good partial response of 74% (Table 2; Richardson et al, 2008). Toxicities were manageable and included no cases of grade 4 peripheral neuropathy, two deep vein

VTD Improves Patient Response to Therapy TABLE 2

Len/Cyc/ Dex N = 53

Len/Bort/ aDex N = 65

Bort/Dex/ Bort/Cyc/ Cyc/Len Dex → Bort/ Thal/Dex N = 25 N = 44

Best response 45 (85%) ORR

65 (100%)b

25 (100%)

41 (90%)

29 (44%)

9 (36%)

15 (33%)

17 (32%)

49 (74%)b

17 (68%)

24 (60%)

Efficacy

≥ nCR ≥ VGPR

(Cavo et al, 2007) The addition of bortezomib to TD treatment regimens was shown to significantly improve the response to therapy in patients with multiple myeloma. TD = thalidomide/dexamethasone; VTD = bortezomib/thalidomide/dexamethasone; CR = complete response; nCR = near complete response; VGPR = very good partial remission; PR = partial response; ASCT = autologous stem cell transplant.

RR for Multidrug Combinations in the Treatment of Transplant-Eligible Patients With MM

(Kumar, Hayman, et al, 2008; Richardson, et al, 2008; Kumar, Flinn, et al, 2008; Bensinger et al, 2008) The impact of multidrug combinations on long-term outcome for patients with multiple myeloma remains unclear. RR = response rate; MM = multiple myeloma; Len = lenalidomide; Cyc = cyclophosphamide; Dex = dexamethasone; Bort = bortezomib; ORR = overall response rate; nCR = near complete response; VGPR = very good partial response; NR = not reported; thal = thalidomide. aDexamethasone, 20 mg Days 1–2, 4–5, 8–9, and 11–12. bIndependent of International Staging System and high-risk cytogenetics. c≥ CR.

thromboses, and no treatment-related mortalities. This combination is an NCCN category 2B recommendation for transplant candidates (2010).

transplant-InelIgIble patIents Although the melphalan/prednisone (MP) regimen has demonstrated efficacy in transplant-ineligible patients, with an overall response rate (ORR) of 50%, the long-term complete response (CR) rate is less than 5% (Blade & Rosinol, 2009). Various combination therapies have been investigated in efforts to improve duration and rate of response. In patients aged 65 to 75 years with newly diagnosed disease, melphalan/dexamethasone produced higher RR and PFS when compared to MP (Facon et al, 2006). However, there was no difference in OS and dexamethasone-based therapy was associated with greater morbidity. No significant differences in severe hematologic toxicity were noted between the two arms (Facon et al, 2006). The thalidomide/dexamethasone regimen has also been compared to MP, which resulted in increased ORR in the thalidomide/dexamethasone arm, but PFS and OS were superior in the MP arm (Ludwig et al, 2007). Patients receiving the MP regimen experienced a higher incidence of grade 3/4 leukopenia (14% vs. 3%, respectively; p < .0001). Patients in the thalidomide/dexamethasone arm experienced more grade 2/3 neuropathy (28% vs. 10%; p < .001), constipation (30% vs. 10%; p < .001), psychological toxicity (18% vs. 6%; p < .001), skin toxicities (9% vs. 5%; p = .069), and infections (23% vs. 16%; p < .12). The melphalan/prednisone/thalidomide (MPT) regimen is considered a standard of care for most transplant-ineligible patients. Patients who received MPT showed a higher recovery rate and longer PFS than patients who received the MP regimen (Table 3; Palumbo et al, 2008). At a median follow-up of 38.1 months, median PFS was 21.8 months for MPT and 14.5 months for MP (p = .004). Median OS was 45.0 months for MPT and 47.6 months for MP (p = .79). Grade 3 or 4 adverse events were higher in the MPT arm (55% vs. 22%). The most frequently occurring grade 3 or 4 adverse eventsâ&#x20AC;&#x201D;hematologic events (23%), thromboembolism (11%), infections (10%), and

TABLE 3

gastrointestinal events (5%)â&#x20AC;&#x201D;were identical between the two arms. Transplant-ineligible patients with previously untreated MM were randomly assigned to receive MP or MP with bortezomib in the Velcade as Initial Standard Therapy (VISTA) trial (San Miguel et al, 2008). At 2 years follow-up, patients in the melphalan/prednisone/bortezomib arm had improved median TTP (24 months vs. 16.6 months) and OS (82.6% vs. 69.5%). Another trial evaluated the combination of MP with weekly bortezomib, comparing it to the same combination plus thalidomide followed by bortezomib and thalidomide combination. Administration of the weekly bortezomib resulted in significantly lower neuropathy rates. Maintenance therapy with bortezomib and thalidomide resulted in improved PFS (Palumbo et al, 2008).

relapseD/reFractory DIsease Bortezomib is an NCCN category 1 recommendation for the treatment of patients with relapsed MM (2010). The recommendation is based on the results of Assessment of Proteasome Inhibition for Extending Remissions (APEX), a phase III trial that compared bortezomib and high-dose dexamethasone in the relapsed setting (Richardson et al, 2007). RR and OS were superior with bortezomib therapy. ORR increased from 18% to 43% and median OS increased from 23.7 months to 29.8 months. One-year survival rate was also superior in the bortezomib arm (80% vs. 66%; p = .003), which translates to a 14% decrease in the risk of death during the first year. These results include data from 147 patients (44%) in the dexamethasone arm who crossed over to the bortezomib arm. A trial (N = 646) comparing pegylated liposomal doxorubicin (PLD)/bortezomib versus bortezomib alone showed that combination therapy was superior (Harrousseau, et al, 2007). Median TTP was 9.3 months in the combination arm and 6.5 months in the monotherapy arm (p = .000004; HR = 1.82). ORR was also superior in the PLD/bortezomib arm (44% vs. 41%, respectively), as was the 15-month survival rate (76% vs. 65%). The addition of PLD to bortezomib resulted in a significant improvement in OS (Figure

MP vs. MPT in Transplant-Ineligible Patients: PFS and OS GIMEMA

IFM 99-06

IFM 01-01

Nordic

HOVON

15 22

18 28

19 24

14 16

10a 13

.0004

< .0001

.001

TTPb

< .001

Median OS, months MP MPT

48 45

33 52

29 44

39 29

30 37

p Value

.0006

.028

Median PFS, months MP MPT p Value

(Palumbo et al, 2006, 2008; Facon et al, 2007; Hulin et al, 2009; Wijermans et al, 2008) The MPT regimen was superior to MP in PFS, TTP, or both. Results for OS were mixed. MPT = melphalan, prednisone, thalidomide; MP = melphalan and prednisone; PFS = progression-free survival; TTP = time to progression; OS = overall survival; NS = not significant. aEvent-free survival. bSignificant.

2). The safety profile of the combination arm was consistent with known toxicities for each agent. The most commonly occurring adverse events were neutropenia (35%), thrombocytopenia (30%), fatigue (31%), and anemia (23%; Orlowski et al, 2007). Bortezomib has also been evaluated in combination with lenalidomide and dexamethasone, thalidomide/dexamethasone, cyclophosphamide, prednisone, and liposomal doxorubicin. Out of all of the combinations, bortezomib plus thalidomide/dexamethasone and liposomal doxorubicin yielded superior CR/near complete response rates (52%). The highest CR rate (17%) was produced by the bortezomib, MP, and thalidomide combination (Richardson et al, 2006; Zangari et al, 2005; Reece et al, 2008; Ciolli et al, 2008; Palumbo et al, 2007). One study compared lenalidomide plus dexamethasone with dexamethasone and placebo in patients with relapsed MM (Weber et al, 2007). Superior ORR (CR + near complete response + partial response) was achieved in the lenalidomide group than in the placebo arm (61.0% vs. 19.9%; p < .001). Because this improvement also translated to an OS benefit, lenalidomide in combination with dexamethasone was approved for relapsed myeloma.

conclusIon Increased understanding of tumor cell biology and genetic aberrations that underlie MM has advanced treatment. Novel agents such as bortezomib, thalidomide, and lenalidomide, along with the increased used of high-dose chemotherapy and ASCT have increased survival rates in patients with MM. As patients are living longer, potential toxicities play an important role in therapeutic decisionmaking. Ongoing trials are investigating optimal combinations, dosing, and duration of therapy in efforts to further prolong survival while minimizing toxicities and maintaining quality of life. l

FIGURE 2

Bortezomib ± Pegylated Liposomal Doxorubicin: Overall Survival PLD + bortezomib Bortezomib Censored

Patients Alive (%)

100 80 60 40 20

Censored Died

B+PLD

80% 9%

64% 12%

HR (95% Cl) 1.48 (0.91 to 2.41) p < .113

50 100 150 200 250 300 350 400 450 500 550 600 650 700 Time (days)

(Harousseau, et al, 2007) Overall survival was significantly improved in patients treated with bortezomib and pegylated liposomal doxorubicin. HR = hazard ratio; CI = confidence interval; PLD = pegylated liposomal doxorubicin; B = bortezomib.

References Attal M, Harousseau JL, Leyvraz S, et al (2006). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood, 108(10), 3289–3294. Barlogie B, Kyle RA, Anderson KC, et al (2006). Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: Final results of phase III US Intergroup Trial S9321. J Clin Oncol 24(6), 929–936. Bensinger W (2008). Stem cell transplantation for multiple myeloma in the era of novel drugs. J Clin Oncol, 26(3), 480–492. Blade J, & Rosinol L (2009). Changing paradigms in the treatment of multiple myeloma. Haematologica 94(2), 163–166. Brenner H, Gondos A, & Pulte D (2008). Recent major improvement in longterm survival of younger patients with multiple myeloma. Blood, 111(5), 2521–2526. Cavo M, Attal M, Gertz MA, et al (2008). Newly diagnosed multiple myeloma: Making the right treatment choices. Leuk Research, 32(S1), S1–S2. Cavo M, Tacchetti P, Patriarca F, et al (2007). Bortezomib-thalidomide-dexamethasone vs thalidomide-dexamethasone in preparation for autologous stem-cell transplantation in newly diagnosed multiple myeloma [Abstract]. Blood (ASH Annual Meeting) 110, Abstract 73. Cavo M, Zamagni E, Tosi P, et al (2005). Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood, 106(1), 35–39. Ciolli S, Leoni F, Casini C, et al (2008). The addition of liposomal doxorubicin to bortezomib, thalidomide, and dexamethasone significantly improves clinical outcome of advanced multiple myeloma. Br J Haematol, 141(6), 814–819. Collins, CD (2005). Problems monitoring response in multiple myeloma. Cancer Imaging, 5(A), S119–126. Dispenzieri A, Rajkumar SV, Gertz MA, et al (2007). Treatment of newly diagnosed multiple myeloma based on Mayo stratification of myeloma and risk-adapted therapy (mSMART): Consensus statement. Mayo Clin Proc, 82(3), 323–341. Durie BGM, Kyle RA, Belch A, et al (2003). Myeloma management guidelines: A consensus report from the scientific advisors of the International Myeloma Foundation. Hematol J, 4(3), 379–398. Durie BG, Harousseau JL, Miguel JS, et al (2006). International uniform criteria for multiple myeloma. Leukemia, 20(9), 1467–1473. Facon T, Mary JY, Pegourie B, et al (2006). Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood, 107(4), 1292–1298. Facon T, Mary JY, Hulin C, et al (2007). 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): A randomised trial. Lancet, 370, 1209–1218. Fonseca R, Barlogie B, Bataille R, et al (2004). Genetics and cytogenetics of multiple myeloma: A workshop report. Cancer Res, 64(4), 1546–1558. Greipp PR, San Miguel J, Durie BG, et al (2005). International staging system for multiple myeloma. J Clin Oncol, 23(15), 3412–3420. Harousseau JL, Nagler A, Sonneveld P, et al (2007). Effect of the combination of pegylated liposomal doxorubicin and bortezomib on time to progression and overall survival of patients with relapsed/refractory multiple myeloma compared with bortezomib alone [Abstract]. J Clin Oncol, Proc Am Soc Clin Oncol, 25(June 20 suppl), Abstract 8002. Harousseau JL, Mathiot C, Attal M, et al (2008). Bortezomib/dexamethasone versus VAD as induction prior to autologous stem cell transplantation in previously untreated multiple myeloma: Updated data from IFM 2005/01 trial [Abstract]. J Clin Oncol, Proc Am Soc Clin Oncol, 26(May 20 suppl), Abstract 8505. Hulin C, Facon T, Rodon P, et al (2009). Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol, 27(22), 3664–3670. International Myeloma Working Group (2003). Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: A report of the International Myeloma Working Group. Br J Haematol, 121(5), 749–757. Jemal A, Siegel R, Ward E, et al (2009). Cancer statistics. CA Cancer J Clin, 59, 225–249. Kumar S, Flinn IW, Noga SJ, et al (2008). Safety and efficacy of novel combination therapy with bortezomib, dexamethasone, cyclophosphamide and lenalidomide in newly diagnosed multiple myeloma: Initial results from the phase I/II multi-center EVOLUTION study [Abstract]. Blood (ASH Annual Meeting), 112, Abstract 93.

Kumar S, Hayman S, Buadi F, et al (2008). Phase II trial of lenalidomide with cyclophosphamide and dexamethasone for newly diagnosed myeloma [Abstract]. Blood (ASH Annual Meeting), 112, Abstract 91. Kumar L, Vikram P, & Kochupillai V (2006). Recent advances in the management of multiple myeloma. The Nat J of India, 19(2), 80–89. Kumar SK, Rajkumar SV, Dispenzieri A, et al (2008). Improved survival in multiple myeloma and the impact of novel therapies. Blood, 111(5), 2516–2520. Kyle RA, & Rajkumar SV (2009). Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia, 23(1), 3–9. Lacy MQ, Gertz MA, Dispenzieri A, et al (2007). Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin Proc, 82(10), 1179–1184. Ludwig H, Tothova E, Hajek R, et al (2007). Thalidomide-dexamethasone versus melphalan-prednisone as first-line treatment and thalidomide-interferon versus interferon maintenance therapy in elderly patients with multiple myeloma [Abstract]. ASH Ann Mtg, Abstract 529. National Comprehensive Cancer Network (2010). Clinical practice guidelines in oncology. Multiple myeloma.v.3.2010. Retrieved February 12, 2010, from http://www.nccn.org/. Orlowski RZ, Nagler A, Sonneveld P, et al (2007). Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: Combination therapy improves time to progression. J Clin Oncol, 25(25), 3892–3901. Palumbo A, Avonto I, Bruno B, et al (2006). Intermediate-dose melphalan (100 mg/m2)/bortezomib/thalidomide/dexamethasone and stem cell support in patients with refractory or relapsed myeloma. Clin Lymphoma Myeloma, 6(6), 475–477. Palumbo A, Falco P, Corradini P, et al (2007). Melphalan, prednisone and lenalidomide treatment for newly diagnosed myeloma: A report from the GIMEMA—Italian Multiple Myeloma Network. J Clin Oncol, 25(28), 4459– 4465. Palumbo S, Bringhen S, Liberati AM, et al (2008). Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: Updated results of a randomized controlled trial. Blood, 112(8), 3107–3114. Rajkumar SV, Rosinol L, Hussein M, et al (2008). Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol, 26(13), 2171–2177. Rajkumar SV, Jacobus S, Callander N, et al (2008). Randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus lowdose dexamethasone in newly diagnosed myeloma, a trial coordinated by the Eastern Cooperative Oncology Group: Analysis of response, survival, and outcome [Abstract]. J Clin Oncol, Proc Am Soc Clin Oncol, 26(May 20 suppl), Abstract 8504. Rajkumar SV, Hymann SR, Lacy MQ, et al (2005). Combination therapy with lenalidomide plus dexamethasone for newly diagnosed myeloma. Blood, 106(13), 4050–4053. Reece DE (2007). Management of multiple myeloma: The changing landscape. Blood Rev, 21(6), 301–314. Reece DE, Rodriguez GP, Chen C, et al (2008). Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J Clin Oncol, 26(29), 4777–4783. Revlimid® (prescribing information). Summit, NJ: Celgene Corporation; 2009. Richardson P, Jagannath S, & Colson K (2006). Optimizing the efficacy and safety of bortezomib in relapsed refractory multiple myeloma. Clin Adv Hematol Oncol, 4(5), 1. Richardson PG, Lonial S, Jakubowiak A, et al (2008). Safety and efficacy of lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed multiple myeloma: A phase I/II study [Abstract]. J Clin Oncol, Proc Am Soc Clin Oncol, 26(May 20 suppl), Abstract 8520. Richardson PG, Sonneveld P, Schuster M, et al (2007). Extended follow-up of a phase 3 trial in relapsed multiple myeloma: Final time-to-event results of the APEX trial. Blood, 110(10), 3557–3560. San Miguel JF, Schlag R, Khuageva NK, et al (2008). Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med, 359(9), 906–917. Thalomid® (prescribing information). Summit, NJ: Celgene Corporation; 2009. Weber DM, Chen C, Niesvizky R, et al (2007). Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med, 357(21), 2133–2142. Wijermans P, Suciu S, Baila L, et al (2008). Myelodysplastic syndromes: Clinical studies: Genetic and epigenetic targets [Abstract]. Blood, 112(ASH Annual Meeting), Abstract 226.

Zangari M, Esseltine D, Lee CK, et al (2005). Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma. Br J Haematol, 131(1), 71–73.

pharmaceutical glossary

Pharmaceutical Glossary Generic

Brand Name

Generic

Brand Name

bortezomib

Velcade®

lenalidomide

Revlimid®

cyclophosphamide

Cytoxan®

melphalan

Alkeran®

Neosar®

prednisone

Sterapred®

Decadron®

thalidomide

Thalidomid®

Dexone®

vincristine

Oncovin®

dexamethasone

Hexadrol® doxorubicin

Vincasar PFS

Adriamycin® Rubex®

IMER supports

ÂŠ 2010 Institute for Medical Education & Research, Inc. www.IMERonline.com

Printed on recycled paper