MULTIPLE MYELOMA A new era for an old disease

Emerging trends and recommendations MULTIPLE MYELOMA A new era for an old disease Nizar J. Bahlis, MD and Douglas A. Stewart, MD, FRCPC Top-line summary Multiple myeloma (MM) is the second most common hematologic malignancy, after non-hodgkin s lymphoma. It affects nearly 2000 Canadians per year with higher prevalence among men in their fifth to eighth decade. A clonal disorder of terminally differentiated B lymphocytes or plasma cells, it is characterized by a myriad of symptoms including bone pain and fractures, fatigue, neuropathy and recurrent infections. These symptoms result from the expansion (from a single progenitor cell) of plasma cells in the bone marrow leading to cytopenias, renal failure and loss of bone density due to osteoclast activation. The primary approach to treatment of multiple myeloma is systemic antineoplastic therapy. Conventional chemotherapy offers patients a median survival of approximately 3 years. Seminal advances over the last decade have led to better understanding of the biology and genetics of this disease, establishment of new prognostic indicators and, most importantly, introduction of new therapies that positively alter its natural history. Here, Oncology Exchange summarizes some of these developments, reviews recent therapeutic advances, including high-dose chemotherapy with stem cell rescue, and reports results with use of 2 novel classes of drugs, proteasome inhibitors and immunomodulatory drugs. Nizar J. Bahlis, MD is Assistant Professor at the University of Calgary, Division of Hematology and Bone Marrow Transplantation. Douglas A. Stewart, MD, FRCPC is Associate Professor in the Departments of Oncology and Medicine, University of Calgary and Tom Baker Cancer Centre, Calgary, AB. Address for correspondence: Dr. Nizar Bahlis, 1403 29th Street, Room 681, Calgary, AB T2N 2T9; Tel: (403) 944 1564; Fax: (403) 944 2102; Email: nizarbah@cancerboard.ab.ca MM cells are generated exclusively in the postgerminal centers, from B cells that have already undergone somatic hypermutation, antigen selection and immunoglobulin heavy chain (IgH) switch recombination (a type of DNA rearrangement). Errors mutations or double-strand DNA breaks in these specific DNA modifications result in the interposition of an oncogene near the immunoglobulin enhancer. NEW GENETIC INSIGHTS AND CLASSIFICATION Five recurrent translocations between oncogenes and the IgH gene have recently been identified. Present in 40% of MM patients, they are found in all clinical stages of the disease from monoclonal gammopathy of undetermined significance (MGUS) to smoldering multiple myeloma, multiple myeloma and plasma cell leukemia. These translocations are considered to be early events or primary translocations since they occur at the time of IgH switch recombination. IgH translocation partners include chromosomes 4p16 (MMSET and FGFR3); 6p21 (CCN D3); 11q13 (CCN D1), 16q23 (c-maf) and 20q11 (MAFB). 1-6 A second group of complex or imbalanced translocations or insertions, considered as secondary translocations, include p18 deletion, p53 mutation and MYC dysregulation. They rarely involve the IgH and are seen only in the late stages of MM. 7-9 Among these, MYC translocation is the most common, occurring in 50% of advanced tumours and nearly all human myeloma cell lines, but rarely seen in patients with MGUS. 10-11 Another recurrent deletion involves chromosome 13, which appears to be an early event since it is seen equally in MGUS and MM cases. 12 Finally, activating mutations of KRAS, t(4;14) and deletion of p53 appear to be more prevalent in intramedullary and/or advanced myeloma and thus related more to disease progression than to initiation. 7-9 A unifying event among all cases of MGUS and MM is increased mrna levels of cyclin D1, cyclin D2 or cyclin D3, despite a low proliferation index of plasma cells. In 40% of MM cases dysregulation of cyclin D is the direct consequence of one of the above-described recurrent primary translocations involving the IgH. Cyclin D dysregulation ΠVOL. 5, NO. 2, APRIL 2006 7

appears to occur nearly exclusively in nonhyperdiploid tumours which include hypodiploid ( 44 chromosomes), pseudodiploid (45 47 chromosomes) and near tetraploid (> 75 chromosomes) disease. In the remaining cases, which are mostly hyperdiploid (48 75 chromosomes), upregulation of cyclin D results from as yet unknown mechanisms (Figure 1). 8,13 Based on descriptions of these recurrent genetic abnormalities, Bergsagel and colleagues have proposed a new molecular classification for MM in which 8 groups can be distinguished based on the 5 recurrent IgH translocations (T) and cyclin D expression (C). 7 Expression level of cyclin D1, 2 and 3 and of the oncogenes dysregulated by the IgH translocations 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (MMSET and usually FGFR3), 16q23 (c-maf) and 20q11 (MAFB) is determined by gene expression profiling. 8,13 The definition of these TC groups integrates the genetic event into the classification and prognostication of MM, allowing identification of subgroups of patients with different prognoses and different predicted responses to various treatment modalities. Pending wide availability of gene array profiling, the current classification 8 Œ VOL. 5, NO. 2, APRIL 2006 of MM relies mostly on tumour mass and secondary features of host reaction to the disease, chiefly renal function and immune response. Using univariate and multivariate analyses, the International Staging System (ISS) for multiple myeloma has identified serum β2-microglobulin and serum albumin as powerful predictors of prognosis, and defined 3 disease stages: Stage I (serum β2-microglobulin < 3.5 mg/l and serum albumin 35 g/l), Stage II (neither Stage I or III) and Stage III (serum β2-microglobulin 5.5 mg/l), with median survivals of 62, 44 and 29 months respectively. 14 While useful and practical, the ISS does not take into account cytogenetic characteristics that include variables with profound prognostic significance like hypodiploidy, monosomy of chromosome 13/13q, translocation of chromosomes 4 and 14, monosomy of chromosome 17 with deletion of p53, chromosome 1q21 amplification, cyclin D1 expression and activating mutations of KRAS. These variables could be completely missed with the current ISS staging. For example, a Stage I myeloma patient with a (4;14) translocation has substantially shortened expected survival either with standard or high-dose therapy median OS of 26 months and 33 months respectively. Similarly, patients FIGURE 1. Cyclin D dysregulation in myeloma patients nonhyperdiploid 11q13 16q23 20q11 4p16 6p21 cyclin D1 cyclin D2 cyclin D3 hyperdiploid Increased mrna levels of cyclin D1, D2 or D3 are seen in most cases of MM. Usually the cyclin D dysregulation occurs in nonhyperdiploid tumours. In about 40% of MM cases it results from one of the IrgH translocations 11q13, 16q23, 20q11, 4p16 or 6p21. In the few hyperdiploid cases the mechanism of upregulation of cyclin D1 is unknown. 8,13 D1 with a (14;16) translocation have an equally poor if not worse prognosis, with median overall survival (OS) of 16 months, regardless of ISS staging. 13 INDUCTION TREATMENT The goal of MM therapy has changed significantly over the last decade. In the late 1960s Alexanian et al reported response rates to melphalan with and without prednisone in the 50% to 60% range, with median OS not exceeding 3 years. 15 Since that first evidence of chemotherapy improving prognosis, other combination chemotherapies have been explored in an attempt to achieve better outcomes. Despite the higher and more rapid responses achieved with combination chemotherapies, meta-analyses have failed to show any statistically significant survival advantage compared to that achieved with melphalan and prednisone alone. 16 Combination regimens nevertheless gained popularity, in particular with the introduction of stem cell transplantation to front-line treatment. An optimal induction (pretransplant) treatment regimen should be void of stem cell-damaging drugs like alkylating agents (e.g. melphalan), highly active, easy to administer and without significant toxicities. It is important to keep in mind that aggressive induction regimens including those with novel drugs have not yet shown a survival advantage over pulse dexamethasone or vincristine + doxorubicin + dexamethasone (VAD) alone. Greater and more rapid responses achieved prior to stem cell transplantation have not translated, at least yet, into superior OS. Further, while the achievement of complete remission post-stem cell transplantation appears to predict better disease-free survival (DFS) and OS, the currently available data which is scarce does not show any difference in outcome based on response to induction treatments. 17 The role of newer agents in induction treatment The introduction of highly active biological agents to the treatment of relapsed and refractory myeloma has led to exploration of their potential role in first-line treatment of MM. Immumodulatory drugs like thalidomide, lenalidomide and proteasome

inhibitors with bortezomib as the prototype are currently under investigation. Promising studies using single-agent thalidomide and bortezomib, or combinations (with dexamethasone), have reported higher overall and complete remission rates. Rajkumar et al compared thalidomide with dexamethasone to dexamethasone alone in newly diagnosed MM patients in the E1A00 Phase III randomized trial. 18 The response rate was higher with thalidomide + dexamethasone (69%) vs dexamethasone alone (51%), but Grade 3 nonhematologic toxicities were higher with the combination (68% vs 43%). No survival advantage has yet been demonstrated. Similarly, Cavo et al compared thalidomide + dexamethasone to VAD in a retrospective matched case-control analysis. The authors reported a higher rate of partial responders with thalidomide + dexamethasone (52% vs 76%, p < 0.001), but similar rates of complete response or remission (CR), near-complete remission and very good partial response (PR). 18,19 First-line treatment with bortezomib also showed high partial and complete response rates in several Phase II studies (response rate 73% to 95% and CR rate 17% to 29%). 20 A first-line study with lenalidomide + dexamethasone vs dexamethasone alone is ongoing. These new agents, although promising, have yet to demonstrate a survival advantage in first-line treatment of myeloma patients when compared to stem cell transplantation, except for the subgroup of elderly patients over 65 years old. In 2 recently completed randomized trials, thalidomide in combination with melphalan + prednisone provided a survival advantage compared to melphalan + prednisone alone in elderly patients (> 65 years old). 21,22 More importantly, in this group of patients thalidomide appeared to be superior to tandem transplant with reduced melphalan conditioning (100 mg/m 2 ). 21 It is unknown whether the use of these novel agents in the first-line treatment of myeloma patients prior to stem cell transplantation will eventually show an impact on survival outcomes, and whether these novel approaches will supplement or replace high-dose therapy TABLE 1. Randomized trials of autologous stem cell transplantation for multiple myeloma Study n age SDT* vs HDT (p-value) CR (%) median EFS (months) median OS (months) IFM90 24 200 65 5% vs 22% 18 vs 28 44 vs 57 (p < 0.001) (p = 0.01) (p = 0.03) MRC VII 25 401 65 8% vs 44% 19 vs 31 42 vs 54 (p < 0.001) (p = 0.001) (p < 0.001) US Intergroup 26 510 70 15% vs 17% 21 vs 25 53 vs 58 (p = NS) (p = 0.05) (p = NS) MAG 27 190 55 65 20% vs 36% 18.7 vs 25.3 47.6 vs 47.8 (p =NR) (p = 0.07) (p = 0.91) PETHEMA 28 164 65 11% vs 30% 33 vs 42 61 vs 66 (p = 0.002) (p = NS) (p = NS) * SDT = standard dose therapy HDT = high-dose therapy NR = not reported, NS = not significant. (except for elderly patients). Answers to these key questions are currently being sought in several ongoing trials. HIGH-DOSE THERAPY AND STEM CELL TRANSPLANTATION The first evidence of a role for high-dose chemotherapy and autologous stem cell rescue in the treatment of MM dates back to the mid 1980s. 23 Since then, 5 randomized trials have compared the outcome of patients treated with highdose therapy (HDT) and standard dose therapy (SDT) (Table 1). Two studies, the Intergroup Français du Myelome (IFM90) 24 and the Medical Research Council (MRC) VII, 25 have shown a statistically significant improvement in complete remission rate, event-free survival (EFS) and OS in favour of HDT. Conducted in younger patients (< 65 years old), the IFM90 and MRC VII studies were criticized for the suboptimal outcome of the patients randomized to SDT, with median OS of 44 and 42 months respectively. Nevertheless, higher CR rates achieved with HDT strongly correlated with the longer EFS and OS seen in that arm. Three other randomized trials failed to reproduce these positive results, although with some caveats in their study design. The US Intergroup trial showed no improvement in CR or OS for HDT compared to SDT, 26 but 52% of the patients in the SDT arm received salvage transplant and the CR rate of the HDT arm was only 17% compared to 15% in the SDT arm. These results are in frank contrast with the much higher CR rates achieved for HDT vs SDT in the IFM90 (22% vs 5%) and MRC VII trials (44% vs 8%). In IFM90 the 5-year probability of survival was 72% for the patients who achieved CR compared to 39% for partial responders. A similar trend was also observed in the MRC trial with improved survival in those HDT patients achieving PR (median OS 39.8 months) compared to CR (median OS 88.6 months). Thus it seems logical to conclude that the high CR rate achieved with HDT in the IFM90 and MRC studies is responsible for the superior EFS and OS. It would also seem reasonable to suggest that a non-hdt approach achieving higher remission rates would result in similar EFS and OS rates. Two recently published randomized trials have added new insights into this question. The Group Myelome-Autogreffe (MAG) reported a trend toward better EFS with HDT vs SDT that did not translate into superior OS. 27 CR rates were 36% for the HDT arm and 20% for the SDT arm. Responses to HDT Continued on page 12 Œ VOL. 5, NO. 2, APRIL 2006 9

Bahlis, continued from page 9 were similar to those reported in IFM90 and MRC VII, but SDT results were quite different. Post-SDT, 20% of the patients in the MAG study achieved CR or minimal residual disease (MRD) compared to 5% in IFM90 and 8% in MRC VII. Median OS post-sdt was 42 months in IFM90 and 44 months in MRC VII, compared with 48 months in the MAG study. In a fifth study comparing HDT and SDT, the Spanish cooperative group PETHEMA found no difference in OS between the HDT and SDT arms despite higher CR rates with HDT (30% vs 11%). 28 The authors suggested that the lack of improvement in OS for HDT was likely the result of a more dose-intense SDT arm, the use of maintenance therapy with interferon + dexamethasone and compared to IFM90 the higher CR rate achieved post-sdt. Importantly, only patients responding to induction treatments were enrolled in the PETHEMA study, which could be a confounding factor explaining the lack of survival benefit with HDT. While awaiting results of an ongoing meta-analysis of these 5 randomized trials, the authors agree that achievement of CR should be the goal of any treatment modality. Several groups have taken the approach of tandem transplantation to help reach that goal. Results of the IFM94 study and a recent update from the Bologna group have demonstrated superior EFS and OS in favour of tandem transplant, in particular for the subsets of patients who failed to achieve CR or a very 12 ΠVOL. 5, NO. 2, APRIL 2006 good PR (> 90% improvement in M protein) after a single transplant. 29,30 Another approach to achieving higher CR rates is based on the introduction of novel biological agents thalidomide, lenalidomide and bortezomib to firstline treatment of MM. Early results from ongoing or completed Phase II trials are very encouraging and are likely to, once again, change the treatment paradigm of this disease. Results of the IFM99-06 trial in elderly patients have already shown statistically better OS with the introduction of thalidomide in first-line treatment over both SDT and HDT. 20 Median OS was 30.5 months for melphalan + prednisone, not reached for melphalan + prednisone + thalidomide at 56 months, and 38.6 months for tandem transplant with melphalan 100 mg/m 2. Importantly, however, only 63% of the patients randomized to HDT received their second transplant. With better understanding of the biology and genetics of this disease, subsets of patients who benefit or not from stem cell transplantation are currently being identified. Retrospective analyses from the Mayo Clinic and the Princess Margaret Hospital demonstrate that patients with t(4;14) or 17p deletion reap little to no benefit from single stem cell transplantation (median PFS of 8 months) and thus should be considered candidates for clinical trials with newer agents. 31,32 NOVEL THERAPIES Since the original report by Singhal et al describing the activity of thalidomide TABLE 2. Results of randomized trials with bortezomib and lenalidomide in relapsed and refractory multiple myeloma patients Study novel agent n novel agent vs dexamethasone (p-value) CR + PR (%) median TTP* median OS (months) (months) APEX 35 bortezomib 669 38% vs 18% 6.2 vs 3.9 29.8 vs 23.7 (p < 0.001) (p < 0.05) (p = 0.0272) MM009 38 lenalidomide 341 61% vs 22% 15 vs 5.1 (p < 0.001) (p < 0.0001) MM010 39 lenalidomide 351 58% vs 22% 13.3 vs 5.1 not reached vs 104 weeks (p < 0.001) (p < 0.001) (p = 0.013) *TTP= time to progression in patients with relapsed and refractory myeloma, 33 3 large randomized trials have introduced two 2 classes of drugs: the proteasome inhibitors with bortezomib as prototype (APEX trial) and the immunomodulatory (ImiDs) drugs represented by lenalidomide (MM009 and MM010 trials). Proteasome inhibitors The discovery of the proteasome in eukaryotic cells and its importance in the regulation and degradation of intracellular proteins merited the 2002 Nobel Prize in physiology and medicine. Later work by Julian Adams led to the discovery of bortezomib (previously known as PS-341), pyrazylcarbonyl-phe-leuboronate, a dipeptidyl boronic acid that is a specific and selective inhibitor of the 26S proteasome. 34 A boron atom in this compound interacts reversibly with the catalytic threonine residue of the proteasome, inhibiting its chymotrypsin-like activity. Inhibition of the ubiquitin proteasome pathway with PS-341 was shown to arrest the growth and decrease survival of several malignant cell lines in vitro. These effects were mediated through multiple mechanisms, mainly by regulating the expression of proteins involved in cell cycle progression (p21cip1, p27kip1), oncogenesis (p53, IkB), apoptosis (BCL-2, ciap, XIAP, BAX) and DNA repair (DNA-PKcs, ATM). Bortezomib is the first in this class of agents to enter clinical trials. Several Phase I and II trials have demonstrated its safety and activity in MM and mantle cell lymphomas. Richardson et al recently published the results of the APEX trial, a large Phase III randomized trial of bortezomib + dexamethasone vs dexamethasone alone in relapsed and refractory myeloma. 35 As shown in Table 2, patients receiving bortezomib had significantly higher overall response rates, EFS and OS compared to those receiving dexamethasone alone. More importantly, responses to bortezomib appeared to be independent of cytogenetic abnormalities, with significant activity and durable responses reported in the subset of patients with 13q deletion or monosomy 13. 36 As mentioned previously, bortezomib is also under investigation in first-line treatment of MM as monotherapy or

in combination with chemotherapy (doxorubicin, liposomal doxorubicin, cyclophosphamide, melphalan) or other novel agents (thalidomide, 17AAG, lenalidomide). Preliminary reports of these studies indicate a high activity with response rates reaching 95%, and, more importantly, high CR rates reaching 24%. 21 IMMUNOMODULATORY AGENTS Since the introduction of thalidomide, a glutamic acid derivative and antiangiogenic agent, several clinical trials have explored its activity in various malignancies. The Arkansas group first reported overall response of 37%, 2-year EFS of 20% and OS of 48% for thalidomide in relapsed and refractory myeloma. 37 Thalidomide combinations with dexamethasone, cyclophosphamide and liposomal doxorubicin have yielded even higher response rates ranging from 40% to 75%. A second generation of thalidomide analogs known as the immunomodulatory drugs or ImiDs the first example being lenalidomide have also shown high efficacy with little toxicity. MM009 and MM010 are 2 recently completed large randomized clinical trials comparing lenalidomide + dexamethasone to dexamethasone + placebo. The response rates were 57.9% and 61.2% for the combination arm vs 21.7% and 22.8% in the dexamethasone arm. Importantly, CR rates of patients receiving lenalidomide were very high (Table 2) with median time to disease progression of 15 months in MM009 and 13.3 months in MM010. 38,39 Newer agents in first-line and maintenance therapy The question of whether these new agents used as first-line therapy will result in better outcome and OS has yet to be answered. Several ongoing clinical trials exploring bortezomib, thalidomide and lenalidomide in treatment-naive myeloma patients are currently ongoing, with very encouraging preliminary results. Palumbo et al recently showed thalidomide with melphalan + prednisone (MPT) to be superior to melphalan + prednisone alone (MP) in previously untreated elderly myeloma patients (> 65 years old, median age 72). Median PFS was 14 and 33 months for MP and MPT respectively. Similarly, 2-years OS rates were significantly higher: 82% for MPT vs 65% for MP alone. 22 The IFM 99-06 study (mentioned above) compared the treatment outcome of MP to MPT and an intermediate tandem dose of melphalan 100 mg/m 2 with stem cell rescue (melphalan 100 mg/m 2 x 2) in elderly myeloma patients. 20 Once again, the superiority of thalidomide + melphalan + prednisone was demonstrated, with significantly higher overall response and CR rates compared to MP or melphalan 100 mg/m 2 x 2. Perhaps more importantly, the higher response rates seen with thalidomide translated into higher PFS and OS compared to melphalan 100 mg/m 2 and stem cell rescue. Whether these results will extend to all age cohorts (i.e. younger than 65) and whether these novel agents will eventually replace high-dose therapy remains to be seen. Thalidomide was recently reported to improve EFS and OS of myeloma patients when administered as maintenance therapy post-tandem transplantation: updated results of the IFM99-02 study concluded that in low-risk patients without deletion of chromosome 13, those with high serum β2-microglobulin and failure to achieve CR or very good PR after tandem transplant benefitted the most from maintenance thalidomide. 40 Four-year EFS and OS were 50% and 87% in the thalidomide + pamidronate maintenance arm compared to 37% and 74% in the pamidronate-alone arm (p < 0.02 for EFS and p < 0.01 for OS). No difference in survival endpoints was seen between the no-maintenance arm and the pamidronate-alone arm. A NEW ERA Clearly, the introduction of novel biological agents along with better understanding of this disease at the molecular level has opened a new door in the fight against MM and is likely to revolutionize for a second time the treatment approach of this disease. With the promise of highly active targeted therapies for defined molecular subgroups, we may be at the beginning of the end of our fight against multiple myeloma. Œ References 1. Chesi M, Bergsagel PL, Brents LA. Dysregulation of cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines. Blood 1996;88:674-81. 2. Chesi M, Bergsagel PL, Shonukan OO et al. Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma. Blood 1998;91:4457-63. 3. Chesi M, Nardini E, Brents LA et al. 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