Recent advances in the management of multiple myeloma

Recent Advances in the Management of Multiple Myeloma Nikhil C. Munshi Multiple myeloma (MM) is a B-cell malignancy that comprises 10% of all hematopoietic cancers. Even with aggressive chemotherapeutic regimens, the emergence of chemotherapy-resistant disease remains a notable therapeutic challenge, and there is no cure. The recent advances in understanding the mechanisms critical for MM cell growth and survival in its microenvironment have provided novel therapeutic targets to improve patient outcomes. Based on preclinical studies, the novel targeted agents thalidomide and its analogs, bortezomib and arsenic trioxide, have been evaluated in phase I and II clinical studies in refractory or relapsed MM and have demonstrated significant antimyeloma activity. Ongoing studies will further define their usefulness as primary therapies at earlier stages of disease. These innovative therapies for MM represent a new treatment paradigm, targeting tumor cells and their microenvironments to achieve greater tumor cytoreduction and potentially a cure. Semin Hematol 41(suppl 4):21-26. © 2004 Elsevier Inc. All rights reserved.

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OR THE PAST three decades, the standard induction chemotherapy for multiple myeloma (MM) consisted of a regimen of melphalan and prednisone (MP). This regimen achieves complete responses in only 5% of patients and improves median survival to 36 months.1 Other chemotherapeutic regimens subsequently have failed to show superiority over MP. In 1998, the Myeloma Trialists’ Collaborative published an overview of randomized trials of MP versus combination chemotherapy (CCT) with three or more agents.2 This worldwide joint overview encompassing data from 6,633 patients from 27 randomized trials found higher response rates with CCT than with MP (60% v 53.2%, respectively; P ⬍ .00001), but no significant differences in response duration or overall survival (OS) between MP and CCT was noted. Most patients with MM ultimately experience disease progression with the emergence of chemotherapy-resistant disease. A growing body of evidence suggests a role for dose intensification in treating MM. High-dose therapy achieves additional cytoreduction and improves response rates and survival. In prospective, randomized studies, superior response rates, event-free survival (EPS), and OS were observed with high-dose therapy plus transplantation compared with standard-dose chemotherapy.3-5 Complete response rates were improved from 5% to 25% with high-dose therapy and transplantation rather than standard-dose chemotherapy in two large trials.4,5 The Intergroupe Franc¸ais du Myelome 90 (IFM 90) study by Attal and associates6 and the Medical Research Council Myeloma VII Trial by Child and colleagues5 both reported statistically significant improvement in EFS and OS. However, the recent report of the US Intergroup study by Barlogie et al showed improvement in EFS (31 v 35 months), but failed to show improve-

ment in complete responses (15% v 17%) and OS (53 v 58 months).7 Based on the success of single high-dose therapy, the role of tandem high-dose therapy has been evaluated. The IFM 94 study evaluated double compared with single autologous transplantation in 399 previously untreated patients with MM and demonstrated improved EFS and OS.6 In this study, the 7-year probability of EFS with double transplantation compared with single transplantation was 20% versus 10%, respectively, and for OS it was 42% and 21%, respectively. However, other studies comparing single versus double high-dose therapy and transplantation (with follow-up for up to 36 months) have not reported any significant differences between the two cohorts of patients.8 Questions regarding the ideal time for high-dose therapy have been evaluated by Fermand and associates9 in patients younger than 55 years of age by randomizing them to immediate high-dose therapy following induction therapy (early) versus high-dose therapy as salvage treatment (late). The median EFS was longer in the early compared with the late highdose chemotherapy–treated group (39 v 13 months, respectively); however, there were no differences between the groups in OS.9 As hematopoietic stem cell From the Dana-Farber Cancer Institute and Boston VA Medical Center, Harvard Medical School, Boston, MA. Supported in part by NIH Grants No. P50CA100700 and PO178378, a Merit Review Award from the Research and Epidemiology Service, and a Leukemia Society Scholar in Translational Award. Address correspondence to Nikhil C. Munshi, MD, Dana-Farber Cancer Institute, Harvard Medical School, Room M557, 44 Binney St, Boston, MA 02115. © 2004 Elsevier Inc. All rights reserved. 0037-1963/04/4102-4004$30.00/0 doi:10.1053/j.seminhematol.2004.03.002

Seminars in Hematology, Vol 41, No 2, Suppl 4 (April), 2004: pp 21-26

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Nikhil C. Munshi

Table 1. Select Studies of Thalidomide in Multiple Myeloma Study

Patient Population

No. Patients

Dosing Regimen (mg/d)

Response Rate* (%)

Single-agent studies with thalidomide (Thal) Barlogie et al16 Relapse and refractory disease Yakoub-Agha et al17 Refractory Weber et al18 Previously untreated

169 83 28

200-800 Thal 50-800 Thal 100-600 Thal

30 66 (total response rate) 36†

In combination with dexamethasone (Dex) Palumbo et al19 Relapsed

120

100 Thal 40 Dex 200-400 Thal 20/m2 Dex 100-400 Thal 20/m2 Dex 200 Thal 40 Dex

41

Dimopoulos et al20

Relapsed

44

Weber et al18

Newly diagnosed

40

Rajkumar et al21

Newly diagnosed

50

55 72† 64

*50% or greater reduction in myeloma protein. †75% or greater reduction in myeloma protein.

damage due to prolonged conventional dose treatment can affect our ability to collect stem cells, if a late high-dose therapy is planned, then prior collection of stem cells before prolonged standard dose therapy is recommended.

Recent Advances in the Treatment of Multiple Myeloma Overcoming resistance to standard- and high-dose chemotherapy is essential for improving outcomes among MM patients who do not achieve adequate responses to these therapies. Current research approaches specifically target the mechanisms that enable MM cells to grow and survive in the bone marrow microenvironment. Evidence demonstrates that these mechanisms are mediated through the release of various cytokines, including interleukin (IL)-6, IL-21, insulin-like growth factor I (IGF-I), tumor necrosis factor-␣ (TNF-␣), vascular endothelial growth factor (VEGF), and transforming growth factor-␤1.10-12 IL-6 –mediated autocrine and paracrine mechanisms appear to mediate the growth and survival of MM.10 Molecular signals that mediate these effects include the Ras/Raf/mitogen-activated protein kinase (MAPK) cascade for proliferation and the phosphoinositol 3-kinase (PI3-K)/Akt pathway and activation of the regulatory protein NF-␬B, which provides growth, survival, and drug-resistance signals. In the past 4 years, novel and re-emerging therapeutic agents that target MM cells and the bone marrow microenvironment have been studied in the clinic after their validation by in vitro and in vivo animal models. These agents include thalidomide and its analog immunomodulatory drugs (IMiDs), the proteasome inhibitor bortezomib and arsenic tri-

oxide, all of which have demonstrated clinical antiMM activity even in patients with refractory or relapsed MM. Thalidomide The rationale for using thalidomide in MM was based on its known antiangiogenic activity, coupled with the reports of increased angiogenesis in MM bone marrow.13 However, more recent studies have confirmed that thalidomide and its analogs IMiD act not only to interrupt angiogenesis mediated by basic fibroblastic growth factor and VEGF, but they also act directly on MM cells.13 In addition, these agents abrogate the adhesion of MM cells to bone marrow stromal cells and block the secretion of MM growth and survival factors such as TNF-␣ and IL-6 (through reductions in TNF-␣–stimulated secretion).14 These agents also induce immune responses by expanding the number and/or function of natural killer (NK) cells and T cells.13 In an initial phase 2 trial investigating thalidomide at 200 mg to 800 mg daily as a single agent in 84 patients (42% of whom had highrisk cytogenetic abnormalities) with refractory or relapsed MM following high-dose chemotherapy, the response rate (defined as at least a 50% reduction in the myeloma protein in serum or Bence Jones protein in urine) was 25%.15 Two patients had complete remission. The efficacy of thalidomide as salvage therapy prompted its investigation as initial treatment of MM. In general, response rates are in the range of 30% when thalidomide is used as a single agent (Table 1).16-21 Questions remain regarding the optimal dose of thalidomide because no trials have formally investigated maximal tolerated or effective doses of thalidomide in MM. Dose-limiting adverse effects include somnolence, neurologic symptoms, and constipation.18

Recent Advances in Multiple Myeloma

Since thalidomide reverses dexamethasone resistance and dexamethasone also has significant antitumor activity in myeloma, the combination achieves higher responses. In relapsed or refractory MM, lower-dose thalidomide (100 mg to 400 mg daily) plus dexamethasone induced response rates ranging from 41% to 72% (Table 1). In a series of consecutive, previously untreated patients with MM, the response rate with thalidomide was 36% among asymptomatic patients at high risk for progression, whereas the response rate for thalidomide plus dexamethasone was 72% among symptomatic patients with low or intermediate tumor mass. Median time to remission was shorter with the combination (median, 0.7 months) than with single-agent thalidomide (median, 4.2 months).18 Safety profiles are comparable except that the combination regimen is associated with a higher incidence of thromboembolic events (15%) than single-agent thalidomide (4%).14 Immunomodulatory Drugs Thalidomide analogs are substantially more potent than the parent compound. CC-5013, the IMiDs, have direct antitumor effects through caspase 8 –mediated apoptosis and indirect effects on tumor cell growth by manipulating the tumor microenvironment. These multifactorial mechanisms are beneficial in overcoming drug resistance in MM. Compared with thalidomide, CC-5013 is 50 to 2,000 times more potent at stimulating T-cell proliferation and 50 to 100 times more potent at augmenting IL-2 and interferon-␥ production.22 CC-5013 has demonstrated activity in reducing MM cell binding to bone marrow stromal cells, downregulating the secretion of cytokines mediating MM cell growth and survival in the bone marrow, blocking angiogenesis, and stimulating anti-MM NK cell immunity, as well as T-cell costimulatory activity.23-25 In vivo, CC-5013 also inhibits the proliferation of MM cells to a greater degree than does thalidomide.23 A phase 1 trial established a maximal tolerated oral dose for CC-5013 of 25 mg daily in refractory and relapsed MM. After 28 days of treatment with CC-5013 over the dose range of 5 to 50 mg daily, 79% of patients had stable disease or a response, including patients previously treated with thalidomide.22 There were no reports of significant somnolence, constipation, or neuropathy as with thalidomide therapy. In a phase 2 trial by Richardson and colleagues, 79% of patients achieved responses (including complete responses) or had stable disease. A phase 3 trial is ongoing to assess the efficacy of the combination of CC-5013 plus dexamethasone compared with dexamethasone alone in relapsed MM. Future studies are planned to evaluate the efficacy of CC-5013 in earlystage MM, as post-transplant maintenance therapy, and in combination with conventional and novel

23

agents to elucidate its place in the therapeutic armamentarium for MM. Bortezomib The ubiquitin-proteasome pathway is involved in the regulation of a multitude of critical cellular processes, including cell proliferation, transcription, selective elimination of abnormal proteins, and antigen processing.26,27 The multienzyme proteasome complex is present in all cells and controls proteins that regulate cell cycle progression. Additionally, the proteasomes play a critical role in NF-␬B activation, which in turn upregulates the transcription of proteins promoting cell survival.26 It has recently been reported that ubiquitin-proteasome pathway–related genes were significantly upregulated in cells from a patient with MM compared with normal plasma cells from the patient’s identical twin.28 Thus, inhibition of the ubiquitin-proteasome pathway is of interest as a potential target for therapeutic intervention for various human diseases, including cancer. Bortezomib is the first proteasome inhibitor to be successfully developed for therapeutic application. The drug exhibits direct actions on MM cells and indirectly alters cellular interactions in the bone marrow milieu to inhibit tumor cell growth. In vitro, bortezomib inhibited the growth of MM-derived cell lines and patient MM cells, including those resistant to dexamethasone, doxorubicin, mitoxantrone, and melphalan, at pharmacologically achievable doses, and inhibited IL-6 –mediated increases in MM cell

Figure 1. Response rates with single-agent bortezomib in multiple myeloma in a phase 2 trial. Of 202 patients, 193 were evaluable for response and duration of response by an independent review committee. All response data were based on criteria by Blade ´ et al.31 †Immunofixation positive and 100% M-protein reduction by electrophoresis. From Richardson et al.30 CR, complete response; PR, partial response; MR, minimal response; SD, stable disease.

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Figure 2. Interactive effect of arsenic trioxide and dexamethasone on dexamethasone-sensitive MM.1s cells. Reprinted with permission from Hayashi T et al. Mol Cancer Ther 2002;1: 851-860.32

large, multicenter, phase 2 clinical trial.30 Two hundred two patients, the majority of whom were refractory to their last therapy for MM, received bortezomib 1.3 mg/m2 twice weekly for 2 weeks followed by 1 week off. Dexamethasone 20 mg was administered to patients with progressive disease after four cycles of bortezomib. Among the 193 evaluable patients, 92% had received three or more major classes of agents. Bortezomib was administered for a mean of 3.8 months. Response rates are depicted in Fig 1.31,30 In total, 59% of treated patients achieved stable disease or better response. Importantly, 89% of those who achieved responses had been refractory to their last MM therapy. Median duration of response was 12 months. The clinical development of bortezomib stands out as an example of successful bench-to-bedside research for the treatment of MM. The drug received an accelerated review and approval by the Food and Drug Administration in 2003. Preclinical and genomic studies are now providing the basis for clinical trials combining bortezomib with conventional and novel agents, including dexamethasone, DNAdamaging agents, and other IMiDs.

growth. These growth inhibitory effects are additive when bortezomib is combined with dexamethasone.29 In the bone marrow microenvironment, bortezomib inhibits the paracrine growth and survival of MM cells by reducing their adhesion to bone marrow stromal cells and blocking the associated NF-␬B activation and production of IL-6.29 The effectiveness and safety of bortezomib in relapsed and refractory MM has been confirmed in a

Arsenic Trioxide Similar to thalidomide and bortezomib, arsenic trioxide targets the MM cell and its microenvironment. At clinically achievable levels, arsenic trioxide dose and time dependently inhibits MM cell proliferation even in cell lines resistant to doxorubicin, melphalan, and dexamethasone.32 Additionally, arsenic trioxide induces the apoptosis of drug-resistant human MM cell lines and patient cells through the activation of caspase-9, loss of bcl-2 expression, and induction of

29

Table 2. Select Studies of Arsenic Trioxide in Relapsed/Refractory Multiple Myeloma Study

No. of Evaluable Patients

Dosing Regimen

Overall Objective Response, n (%)*

Stable Disease

Single-agent studies Munshi et al34 Hussein et al35

14 21

0.15 mg/kg ATO daily for 30 d 0.25 mg/kg ATO, 5 days per wk for 2 wk then no therapy for 2 wk in repeated 4-wk cycles

Borad et al36

10

Hussein et al37

17

0.25 mg/kg ATO for the first 4 d followed by twice weekly infusions 1,000 mg AA for the 4 d followed by twice weekly infusions 0.05-0.1 mg/kg Mel for 4 d every 6 wk 0.25 mg/kg ATO, d 1-5 for loading then biweekly for 11 additional wk 1,000 mg AA, within 15 min of each ATO infusion 40 mg Dex, d 1-4 and d 11-14 of each mo of the first cycle

3 (21%) 9 (43%)

1 (7%) 8 (38%)

Combination studies

*25% or greater reduction in serum M-protein. †25% or greater reduction in serum M-protein or 50% or greater reduction in urine M-protein, or both. Abbreviations: ATO, arsenic trioxide; AA, ascorbic acid; Dex, dexamethasone; Mel, melphalan.

10 (100%)†

7 (41%)

7 (41%)

25

Recent Advances in Multiple Myeloma

Figure 3. Novel therapies targeting the myeloma cell in its bone marrow microenvironment.

reactive oxygen species.33,32 In the bone marrow microenvironment, arsenic trioxide decreases TNF-␣– induced adhesion of MM cells to bone marrow stromal cells and inhibits cytokine production.32 Ascorbic acid potentiates arsenic trioxide–induced cell death in patient MM cells by depleting glutathione.33 Dexamethasone also has been shown to enhance the antiproliferative effects of arsenic trioxide on the dexamethasone-sensitive MM cells in vitro (Fig 2).33,32 The efficacy of arsenic trioxide in MM has been evaluated in several studies (Table 2).34-37 In an initial phase 2 trial conducted at the University of Arkansas, 14 patients with advanced relapsed or refractory MM received arsenic trioxide at 0.15 mg/kg for 30 to 60 days.34 Of the three (21%) responding patients, one each had at least a 25%, 50%, or 75% reduction in serum M-protein levels. A subsequent multicenter phase 2 trial evaluated higher doses of arsenic trioxide in 24 heavily pretreated patients.35 As the data in Table 2 show, 21 (43%) of the evaluable patients achieved at least a minimal response and 38% achieved stable disease. Seven of 15 patients with refractory disease had an objective response or achieved stable disease. The most frequent toxicity was cytopenia, which was managed with cytokine therapy without the necessity to interrupt arsenic trioxide. Based on the efficacy of single-agent arsenic trioxide and potentiation of its activity with ascorbic acid, the combination of melphalan, arsenic trioxide, and ascorbic acid (MAC) has been evaluated in 10 patients with refractory MM, who received this combination for 14 to 58 weeks.36 All patients responded, and reductions in serum and 24-hour urine M-protein levels ranged from 37% to 85% and 34% to 58%, respectively. In five patients with pre-existing renal failure, renal function improved on therapy. Four

patients eventually exhibited disease progression after 14 to 40 weeks of therapy. The adverse effects with this combination were grade 1 fatigue, grade 1 to 3 neutropenia, and anemia (70% for each effect). Preliminary results of an evaluation of the combination of arsenic trioxide, ascorbic acid, and dexamethasone has shown encouraging results with 82% of patients achieving a response of stable disease or better.37

Conclusion Despite improvements in therapy, the emergence of chemotherapy-resistant disease remains an important therapeutic challenge. The novel therapeutic agents under development target the mechanisms critical for MM cell growth and survival in its microenvironment and achieve responses in refractory and relapsed myeloma and improve patient outcomes. As shown in Fig 3, agents in development target myeloma cells, its microenvironment or both for greater cell kill. Cellular and signaling studies with cytotoxic agents, thalidomide and its analogs, bortezomib, and arsenic trioxide have provided the preclinical rationale for combining these novel agents with each other or with conventional therapies to enhance efficacy. Ongoing studies will further define their usefulness as primary therapies at earlier stages of disease. These novel therapies for MM represent a new treatment paradigm, targeting tumor cells and their microenvironments to achieve greater tumor cytoreduction by overcoming resistance and potentially providing a cure.

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2. Myeloma Trialists’ Collaborative Group: Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: An overview of 6,633 patients from 27 randomized trials. J Clin Oncol 16:3832-3842, 1998 3. Lenhoff S, Hjorth M, Holmberg E, et al: Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: A population-based study. Nordic Myeloma Study Group. Blood 95:7-11, 2000 4. Attal M, Harousseau JL, Stoppa AM, et al: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 335:91-97, 1996 5. Child JA, Morgan GJ, Davies FE, et al: High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348:1875-1883, 2003 6. Attal M, Harousseau JL, Facon T, et al: Double autologous transplantation improves survival of multiple myeloma patients: Final analysis of a prospective randomized study of the “Intergroupe Francophone du Myelome” (IFM 94). Blood 100:5a-6a, 2002 (abstr) 7. Barlogie B, Kyle R, Anderson K, et al: Comparable survival in multiple myeloma (mm) with high dose therapy (hdt) employing mel 140 mg/m2 ⫹ tbi 12 gy autotransplants versus standard dose therapy with vbmcp and no benefit from interferon (ifn) maintenance: Results of intergroup trial s9321. Blood 102:42a, 2003 (abstr) 8. Blade J, Vesole DH, Gertz M: High-dose therapy in multiple myeloma. Blood 102:3469-3470, 2003 9. Fermand JP, Ravaud P, Chevret S, et al: High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: Up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood 92: 3131-3136, 1998 10. Urashima M, Chauhan D, Uchiyama H, et al: CD40 ligand triggered interleukin-6 secretion in multiple myeloma. Blood 85:1903-1912, 1995 11. Urashima M, Ogata A, Chauhan D, et al: Transforming growth factor-beta1: Differential effects on multiple myeloma versus normal B cells. Blood 87:1928-1938, 1996 12. Chauhan D, Uchiyama H, Akbarali Y, et al: Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood 87:1104-1112, 1996 13. Raje N, Anderson K: Thalidomide—A revival story. N Engl J Med 341:1606-1609, 1999 14. Weber D: Thalidomide and its derivatives: New promise for multiple myeloma. Cancer Control 10:375-383, 2003 15. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999 16. Barlogie B, Desikan R, Eddlemon P, et al: Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: Identification of prognostic factors in a phase 2 study of 169 patients. Blood 98:492-494, 2001 17. Yakoub-Agha I, Attal M, Dumontet C, et al: Thalidomide in patients with advanced multiple myeloma: A study of 83 patients—Report of the Intergroupe Francophone du Myelome (IFM). Hematol J 3:185-192, 2002 18. Weber D, Rankin K, Gavino M, et al: Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 21:16-19, 2003 19. Palumbo A, Giaccone L, Bertola A, et al: Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma. Haematologica 86:399-403, 2001 20. Dimopoulos MA, Zervas K, Kouvatseas G, et al: Thalidomide

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