Multiple Myeloma: Biology, Standard Therapy, and Transplant Therapy

Abstract

The understanding of the pathogenesis of multiple myeloma has undergone a major transformation over the past eight years. New insights into the microenvironment of the plasma cell as well as elucidation of signaling pathways that prevent plasma cell apoptosis are leading to rapid new drug development. The introduction of novel agents has led to a significant increase in survival. Combinations of novel agents are expected to provide higher complete response rate with anticipated prolongation of relapse free and overall survival. Autologous and allogeneic stem cell transplantation remains an integral part of therapy further improving the outcomes following induction with novel agents.

BIOLOGY OF MULTIPLE MYELOMA

Multiple myeloma (MM) is the second most prevalent hematologic malignancy, with an incidence of 4.3 per 100,000 in the general population, and a median survival of 3 to 5 years [1]. Significant advances in understanding the underlying genetic and epigenetic alterations that lead to tumor initiation and progression have been elucidated recently [2]. These have lead to the constitutive activation of many signaling pathways that induce proliferation and resistance to therapy. In addition, the bone marrow (BM) microenvironment plays a crucial role in the development of resistance and progression of this disease [3]. These molecular events are triggered either directly, through cell adhesion molecule–mediated interactions of MM cells with BM stromal cells (BMSCs) and endothelial cells, osteoclasts, and osteoblasts, or indirectly, by growth factors released by these cells. These bidirectional MM cell–BM interactions have important clinical sequelae, including enhanced osteoclastogenesis, resulting in osteolytic lesions, as well as MM cell resistance to conventional chemotherapeutic agents, even in the absence of genetic lesions that confer constitutive resistance. Recently developed agents target the malignant cells and their microenvironment and are leading to improved survival in these patients [4].

MM cells are characterized by genetic instability with several chromosomal abnormalities. Translocations involving the immunoglobulin heavy-chain (IgH) locus are important factors in pathogenesis in 50% of patients. In the 50% patients without IgH translocations, hyperdiploidy is the hallmark of the disease. Several important genetic markers are associated with decreased survival, including chromosome 13 monosomy, hypodiploidy, and others [5,6]. Integrated analysis of high-density oligonucleotide array (aCGH) and gene expression profiling data have led to the discovery of many new abnormalities in these patients, including mutations in the nuclear factor kappa-beta (NF-κB) pathway in approximately 20% of patients [2]. These genetic alterations lead to constitutive activation of signaling proteins; for example, MM cells with t(14;16) translocations overexpress the transcription factor c-maf, which transactivates the cyclin D2 promoter, thereby enhancing MM cell proliferation as well as enhancing β7-integrin expression and tumor cell adhesion to BMSCs [7]. Hyperdiploidy renders MM cells uniquely dependent on the BM microenvironment, which induces cyclin D1 overexpression despite the absence of Ig translocations [8].

These genetic alterations, as well as external stimulation from the microenvironment, lead to activation of several proliferative/antiapoptotic signaling cascades, including phosphatidylinositol–3 kinase (PI3K)/Akt, NF-kκB, Ras/Raf/mitogen-activated protein kinase (MAPK) kinase (MEK)/extracellular signal–related kinase (ERK), and Janus kinase (JAK) 2/signal transducers and activators of transcription (STAT) 3 [3]. Downstream sequelae of activation of these pathways lead to cytoplasmic sequestration of many transcription factors (eg, FKFR), up-regulation of cell cycle–regulating proteins (eg, cyclin D) and antiapoptotic proteins (eg, Bcl-2, Bcl-xL, Mcl-1), and increased activity of telomerase. Interactions between these pathways lead to proliferation, survival, resistance to therapy as well as dynamic migration, and adhesion of MM cells to the BM milieu [6].

The BM microenvironment consists of a landscape of cells, including hematopoietic stem cells, BMSCs, BM endothelial cells, fibroblasts, osteoclasts, and osteoblasts, as well as the extracellular matrix proteins, such as laminin, collagen, fibronectin, and osteopontin [9]. It is well established that the BM microenvironment plays a pivotal pathophysiologic role in MM. The interactions of MM cells with the microenvironment are due to direct cell–cell interactions or through soluble factors secreted by the MM cells or the BM milieu cells. Direct adhesion of MM cells to endothelial cells, BMSCs, and extracellular matrix proteins, such as fibronectin, lead to enhanced survival and proliferation and confer resistance to drug-induced apoptosis. Conversely, the presence of MM cells and their proliferation in the BM milieu lead to enhanced angiogenesis, increased activity of osteoclasts, and inhibition of osteoblasts, resulting in the development of lytic lesions and enhanced morbidity in these patients [9]. Similarly, growth factors secreted by the interaction of MM cells with BM microenvironment cells induce pleiotropic effects, such as stimulating osteoclastogenesis (eg, interleukin [IL]-6, IL-1, vascular endothelial growth factor, stromal-derived cell factor 1α, macrophage inflammatory protein 1α) or modulating adhesion molecule profiles on MM cells and BMSCs (eg, tumor necrosis factor α). Importantly, this growth factor circuit between MM cells and BMSCs in the BM milieu promotes MM cell growth, survival, and migration, contributing to both MM progression and resistance to conventional therapies. The dynamic trafficking of MM cells (homing to the BM and egress from the BM to new sites) leads to rapid dissemination of MM into multiple focal lesions in the BM. This process is highly regulated by chemokines, adhesion molecules, and selectins, which are secreted and regulated by the MM cells and the BM microenvironmental cells [10].

Advances in understanding the underlying molecular alterations in MM and the BM microenvironment have led to a rapid development of clinical trials using novel targeted therapeutic agents. The treatment of MM has evolved from the era of melphalan and prednisone in the 1960s through high-dose chemotherapy and stem cell transplantation in the 1990s and to the introduction of novel targeted therapeutic agents in the last decade [1,4]. Within the last 4 years, 3 novel agents—bortezomib, thalidomide, and lenalidomide— have received Food and Drug Administration (FDA) approval for use in treating MM, leading to a paradigm shift in the treatment algorithm of MM [4]. These agents have become integral in the therapy for MM in both induction therapy for newly diagnosed patients and in the salvage setting for patients with relapsed and refractory disease. The success of targeted therapy in MM has led to the development and testing of more than 30 new therapeutic agents in the preclinical or in early phase I and II clinical setting [4]. Some of these agents target specific signaling pathways, including heat shock protein inhibitors (17- AAG, KOS-953, IPI-504), protein kinase C inhibitors (eg, enzastaurin), PI3K/Akt inhibitors (BEZ235, perifosine, CCI-779, RAD001, AP23573), MEK/ERK inhibitors (AZD-6244, tipifarnib), p38MAPK inhibitors (SCIO-469), and SAPK/JNK inhibitors (aplidin). Other inhibitors target specific mechanisms of cell survival and proliferation, including proteasome activity inhibitors (NPI-0052, PR-171), histone deacetylase inhibitors (SAHA, LBH-589), and DNA synthesis inhibitors (AVN944). Finally, other novel agents target cell surface receptors, including anti-CD40 antibodies (SGN40), IGF-1R inhibitors (NVP-ADW742, CP- 51871), and FGFR3 inhibitors (TKI-258) [4]. These agents target specific signaling pathways in MM cells as well as in the BM microenvironment, leading to increased responses and prolonged survival and making MM a model disease for the development of targeted therapeutic agents [4].

STANDARD THERAPY

In the United States, 19,900 cases of MM are diagnosed annually, leading to more than 10,790 deaths. The median survival is 4 to 5 years. MM is the second most common hematologic malignancy and is incurable with current approaches. The median age at presentation is 66 years [11]. Treatment of MM should be driven by the patient’s biological risk and suitability for high-dose therapy. The most common classification of risk is cytogenetically based, in which patients who show FISH del(17p), t(4;14), t(14;16), metaphase cytogenetic deletion 13, or hypodiploidy are considered high-risk patients; this accounts for approximately 25% of newly diagnosed cases of MM. All other patients, including those with metaphase hyperdiploid cytogenetics, t(11;14), or t(6;14), are considered to be at standard risk [12]. In most European nations, all patients up to age 65 are considered eligible for stem cell transplantation. In the United States, any patient who is deemed able to withstand the rigors of high-dose therapy with a mortality risk of<2% is considered a viable candidate. Patients who are not considered candidates for stem cell transplantation receive a melphalan-containing regimen, which is not be suitable for patients in whom high-dose therapy is being considered.

A prospective randomized phase III study of bortezomib- thalidomide-dexamethasone versus thalidomide- dexamethasone in newly diagnosed MM cases has been reported [13]. Patients received thalidomide 200 mg daily; bortezomib on a standard schedule of 1.3 mg/m² on days 1, 4, 8, and 11; and dexamethasone 40 mg on the day of and the day after bortezomib therapy. All patients were under age 65. A total of 351 patients enrolled, of whom 256 were evaluable. At the completion of induction therapy, a complete response or near-complete response was seen in 36% of the bortezomib thalidomide dexamethasone (VTD) patients versus 9% in the thalidomide dexamethasone (TD) patients. Very good partial remission (VGPR) or better was seen in 60% of the VTD patients, compared with 27% of the TD patients (P=.001). Peripheral neuropathy was significantly higher (7%) in the bortezomib-containing group. Skin rashes were seen in 6.5%. The incidence of deep venous thrombosis (DVT) was only half in the bortezomib-containing group; DVT prophylaxis included aspirin, warfarin, or enoxaparin in a randomized scheme. After stem cell transplantation, the rate of complete remission (CR) or near CR was 57% in the VTD group and 28% in the TD group, and VGPR or better was seen in 77% of the VTD group and in 54% of the TD group.

A phase III trial of lenalidomide and high-dose dexamethasone at a standard dose of 40 mg on days 1 to 4, 9 to 12, and 17 to 21 was compared with dexamethasone at a dosing schedule of 40 mg 1 day per week [14]. At 2 years, overall survival (OS) was significantly higher in the low-dose dexamethasone group (87%vs 75%; P=.006). The difference in OS between the 2 groups was attributed to the higher early mortality in patients over age 65 in the high-dose dexamethasone group. Stem cell transplantation was performed in 29% of the patients in the high-dose dexamethasone group and in 31% of the patients in the low-dose dexamethasone group. In the patients who continued on primary therapy beyond 4 induction cycles, 1-year OS was 96% in the high-dose group and 99% in the low-dose group, and 2-year OS was 80% in the high-dose group and 91% in the low-dose group. These findings indicate that reduced dexamethasone intensity resulted in superior OS. The early death rate was 5% in the high-dose group versus 0.5% in the low-dose group. The median progression-free survival (PFS) was 19.3 months in the high-dose group versus 22 months in the low-dose group.

Higher response rates should not be equated with a superior OS. In a long-term follow-up of patients receiving melphalan-prednisone-thalidomide (MPT) and those receiving melphalan-prednisone (MP), the median PFS was 21.8 months for the former and 14.5 months for the latter, but the OS did not differ significantly between the 2 groups (45 months vs 47.6 months). The use of thalidomide or bortezomib as salvage therapy significantly improved survival after first progression in the MP group but not in the MPT group. The availability of novel agents for salvage therapy can compensate for the lower response rate and response duration when they are omitted from the initial therapy [15].

The Southwest Oncology Group randomized 200 patients to both lenalidomide and high-dose dexamethasone and to dexamethasone alone. The rate of CR was 22% in the lenalidomide-dexamethasone arm and 4% in the dexamethasone arm, with corresponding 12-month PFS of 77% and 55%. The additive benefit of lenalidomide in relapsed disease was reported by pooling the data from 2 studies covering 700 patients, demonstrating CR rates of 24% for lenalidomide-dexamethasone versus 3.4% for dexamethasone and a superior OS in those patients who had received more than 1 regimen before study entry [16]. At a median of 35 months from the start of salvage therapy, 58% of the patients were alive. The median survival in the dexamethasone arm was 31 months (P=.02). This benefit of lenalidomide was seen whether or not the patient underwent previous stem cell transplantation. Lenalidomide may affect stem cell mobilization, and thus earlier collection may need to be considered [17].

For patients not eligible for transplantation, a melphalan- based regimen combined with a novel agent (bortezomib, thalidomide, or lenalidomide) is the current treatment of choice. The VISTA trial used 4 cycles of bortezomib on days 1, 4, 8, 11, 22, 25, 29, and 32 every 42 days, followed by 5 cycles of bortezomib on days 1, 8, 22, and 29 every 42 days, combined with melphalan 9 mg/m² for 4 days and prednisone 60 mg/m² for 4 days every 42 days (MPV arm) compared to melphalan and prednisone alone (MP arm) [18]. The median age of the group was 71 years. Unfavorable cytogenetics had no adverse impact on outcome. The overall response rate was 82% in the MPV arm and 50% in the MP arm. Complete or near-complete response was 35% in the MPV arm, but only 5% in the MP arm. The 2-year OS was 83% in the MPV arm versus 70% in the MP arm, with respective median time to progression of 24 months versus 17 months. These findings led to the FDA’s 2008 approval of bortezomib for initial combination therapy for newly diagnosed MM. Although grade 3–4 peripheral neuropathy was reported in 13% of the patients in the MPV arm, it resolved in 75% of cases. The MPV regimen was superior to the MP regimen in terms of time to progression, time to next therapy, PFS, OS, and complete response rate [18].

Another study compared melphalan-prednisone-thalidomide (MPT) and melphalan-prednisone (MP) in patients with MM over age 75 years (median age, 78.5 years) [19]. The thalidomide dose was 100 mg/day. The MPT arm demonstrated significantly better OS and PFS. Despite the fact that 77% of the MP group received thalidomide as salvage therapy, this did not eliminate the survival advantage conferred by the use of thalidomide as initial therapy in the MPT arm [19]. The median OS was 45 months in the MPT arm versus 28 months in the MP arm. The rate of peripheral neuropathy grade 2–4 was 20% in the MPT arm and 5% in the MP arm.

A phase I–II trial of melphalan-prednisone-lenalidomide was reported in elderly patients with MM (median age, 70 years). At the completion of the phase I study, the optimal dosage schedule was determined to be lenalidomide 10 mg/day and melphalan 0.18 mg/kg/day for 4 days every 4 to 6 weeks for a maximum of 9 cycles [20]. At a median of 7 cycles, CR was 24%, VGPR was 29%, and partial remission was 33%. In a historical comparison, lenalidomide-melphalan-prednisone produced an overall response rate of 85%, compared with 76% for melphalan-prednisone-thalidomide and only 48% for melphalan-prednisone. Moreover, like bortezomib, lenalidomide appears to be capable of overcoming the poor prognosis conferred by del(13q) and t(4;14) in MM [21].

Lenalidomide is excreted renally and requires dosage modification in patients with renal failure. Current recommendations suggest a maximum lenalidomide dose of 10 mg/day in patients with a creatinine clearance of 30 to 50 mg/min,; 15 mg every 48 hours in patients with a creatinine clearance of<30 mg/min, and 15 mg 3 times a week after each dialysis treatment in those with end-stage renal disease [22]. Bortezomib requires no dose modification for renal failure and has been successfully administered in full dosages with no significantly increased toxicity [23].

In conclusion, the addition of novel agents to standard therapies, either melphalan- or high-dose dexamethasone–based, has been found to improve response rates, PFS, and OS. The addition of high-dose therapy results in higher complete response and very good partial response rates after induction with novel agents. These novel agents appear to overcome the adverse prognosis associated with unfavorable cytogenetics. For newly diagnosed patients, lower-intensity dexamethasone therapy produces higher 12- and 24-month OS. Combining immunomodulatory drugs (IMIDs) and proteasome inhibitors is feasible and can result in higher complete and near-complete response rates.

AUTOLOGOUS AND ALLOGENEIC STEM CELLTRANSPLANTATION IN MULTIPLE MYELOMA

Autologous Stem Cell Transplantation

The introduction of high-dose melphalan therapy supported by autologous transplantation of peripheral hematopoietic stem cells (ASCTs) was the first improvement in MM treatment after 3 decades of stagnation. ASCT is currently considered the standard of care in patients with MM under age 65 years and without renal failure, and MM is the leading indication for ASCT worldwide. This situation is the consequence of 2 randomized trials performed in the 1990s demonstrating the superiority of ASCT over conventional chemotherapy in terms of response rate, PFS, and OS [24]. The benefit from ASCT was related to more effective tumor burden reduction, and a significant relationship with CR or at least VGPR was demonstrated. The findings of subsequent randomized studies were not as positive, however; although CR rate and PFS were almost always increased with ASCT, OS was not [24]. This was attributed in part to the use of ASCT at relapse in the conventional chemotherapy arms; therefore, ASCT did improve OS, but its optimal timing remained a matter of debate.

Further dosage intensification was then explored with the objective of increasing the CR rate. Three randomized studies found that double ASCT was superior to single ASCT in terms of PFS, but only 1 study found an advantage in terms of OS [24]. The only factor predicting the impact of the second ASCT was the result of the first ASCT; only patients achieving less than VGPR after the first ASCT had a better outcome after undergoing a second ASCT. Drawing definite conclusions from this study is complicated by the fact that this subanalysis had not been planned initially and may have been underpowered [24].

Moreover, patients with poor-risk MM, defined by a high β2-microglobulin level plus poor-risk cytogenetic abnormalities like t(4;14) or del(17p), still had a poor outcome despite undergoing 2 ASCTs. Clearly, new approach were needed, at least for these patients. Moreover, the role of double ASCT should be reevaluated in the context of new available therapies.

The introduction of novel agents (thalidomide, bortezomib, and lenalidomide) was the next step. The first advance was the use of thalidomide in maintenance treatment after ASCT. Three randomized studies showed that thalidomide after ASCT improves the CR/VGPR rate, PFS, and OS [24]; however, 2 questions remain:

• Do all patients need a maintenance treatment?

• What are the optimal dose and duration of thalidomide maintenance?

Prolonged treatment increases the risk of neurologic toxicity and possibly of resistance. Lenalidomide, which is better tolerated in long-term use, appears to be a logical maintenance treatment and is currently under evaluation in randomized trials. Novel agents have been studied as induction therapy before ASCT, with the objective of further increasing the CR/VGPR rate. The thalidomide-dexamethasone combination was found to induce better response than dexamethasone alone or in combination with vincristine and doxorubicin (in the vincristine doxorubicin dexamethasone [VAD] regimen); however, 4 cycles of this combination did not appear to increase the CR/VGPR rate either before or after high-dose melphalan therapy [24]. Three-drug combinations (plus doxorubicin or cyclophosphamide) appear to be more effective (VGPR of 49% and 67%, respectively) [25,26]. A large Intergroupe Francophone du Myélome (IFM) randomized study found that bortezomib plus dexamethasone increased the CR/VGPR rate compared with VAD both before ASCT (44% vs 19%) and after ASCT (63% vs 44%) [27] and could become a new standard or the backbone of more complex combinations (with the addition of doxorubicin, cyclophosphamide, or thalidomide).

These 3-drug bortezomib-based combinations are currently undergoing testing in randomized trials. Preliminary results of an Italian trial have shown a WGPR rate of up to 77% after ASCT with 3 cycles of VTD as induction treatment [28]. Thus, with the use of novel agents before ASCT, high CR/VGPR rates can be achieved both before and after ASCT, and although the follow-up remains short, this improved tumor burden reduction hopefully will translate into longer PFS.

Finally, these novel agents can be used both before and after ASCT. A number of randomized trials are currently evaluating this approach. Some results from an Arkansas group have been made available; in the Total Therapy 2 program, all patients received a complex program including tandem ASCT and were randomly allocated to receive or not receive thalidomide throughout treatment. The thalidomide arm has demonstrated significantly superior 5-year PFS (56% vs 45%) [29]. The same group recently reported preliminary results from the Total Therapy 3 program, in which bortezomib was added in induction and consolidation/maintenance to the thalidomide arm of the previous protocol. The findings to date are impressive, with 2-year PFS of 84% and OS of 87% [30].

Some other trials including novel agents without ASCT have yielded outstanding results as well [31–33]. A series of randomized trials have compared the classical MP combination with MP plus a novel agent— thalidomide (MPT), bortezomib (MPV), and, more recently, lenalidomide (MPR)—in elderly patients. The findings demonstrate not only that the novel agent–containing regimens are clearly superior to MP in terms of response rate, including CR and PFS, but also that CR/VGPR rates and median PFS are quite comparable to those achieved with single ASCT (40% to 45% and 24 to 28 months, respectively), even with an older study population.

Trials with lenalidomide-dexamethasone are more recent and the follow-up is too short to allow definite conclusions; nonetheless, the preliminary results are impressive, particularly with lower doses of dexamethasone, which are better tolerated. Long-term treatment with lenalidomide-dexamethasone or with a 3-drug combination including bortezomib have yielded very high CR/VGPR rates (approximately 70%) [34,35]. Short-term OS rates also are unprecedentedly high [36]. Although these studies of lenalidomide- dexamethasone are still premature and often mix older patients and younger patients undergoing ASCT, this approach without upfront ASCT appears to be very attractive. Further randomized studies comparing novel agents with or without ASCT are planned.

Allogeneic Stem Cell Transplantation

Although myeloablative allogeneic (allo) SCT may be the only curative treatment for MM (because it induces molecular remissions and plateau of the PFS curves), it has been almost completely abandoned because of its high transplantation-related mortality rate, up to 50% in even front-line therapy [37]. The current approach is to reduce the tumor burden with high-dose melphalan plus ASCT and to use the graft-versus-myeloma effect of lymphoid donor cells with reduced-intensity conditioning (RIC) allo SCT. Three prospective studies have been published [38– 40]. Their results differ, which can be attributed to differences in selection criteria and conditioning regimens. Whereas the Italian study showed the superiority of tandem ASCT–RIC allo SCT over double ASCT, the results of the IFM study in poor-risk patients failed to show a benefit of RIC allo SCT [41]. Although RIC allo SCT is much better tolerated than myeloablative allo SCT, it still carries a 10% to 15% rate of 1-year transplantation-related mortality and a 30% to 40% rate of chronic graft-versus-host disease [42]. Considering the good results achieved with novel agents with or without ASCT, RIC allo SCT probably should not be offered to good-risk MM patients and should be proposed to other patients only in prospective clinical trials.