多发性骨髓瘤

Annals of Oncology 21 (Supplement 7): vii313–vii319, 2010 doi:10.1093/annonc/mdq363symposium article Multiple myeloma J. Blade´*, M. Teresa Cibeira, C. Ferna´ndez de Larrea & L. Rosin˜ol Hematology and Oncology Institute, Hematology Department, IDIBAPS, Hospital Clı´nic, Barcelona, Spain Multiple myeloma (MM) constitutes 1% of malignant diseases and 15% of haematological malignancies. In virtually all patients MM is preceded by monoclonal gammopathy of undetermined significance (MGUS). The cause of monoclonal gammopathies and the mechanisms of progression are unknown. The diagnosis of MM requires the presence of an M-protein in serum and/or urine, increased bone marrow plasma cells and related organ or tissue impairment. Cytogenetic status, serum b2-microglobulin and response to therapy are the key prognostic factors. The treatment of younger patients with MM should include a triple-agent induction regimen (i.e. bortezomib/thalidomide/ dexamethasone), autologous stem cell transplantation (ASCT) and consolidation and maintenance incorporating novel agents along with sequential minimal residual disease studies to determine for how long treatment is still of benefit. Allogeneic transplantation with reduced-intensity conditioning is promising but remains experimental. For patients not eligible for ASCT the best initial regimens are melphalan/prednisone/thalidomide (MPT), melphalan/prednisone/ bortezomib (MPV) and lenalidomide/dexamethasone. In relapsing patients, the choice of salvage therapy should depend on: (i) the components of initial therapy, (ii) the degree and duration of response, (iii) type of relapse: aggressive versus indolent, (iv) previous toxicities and (v) age and performance status. A sequential approach is preferred over combination of multiple agents. Supportive measures include the use of bisphosphonates and erythropoietin according to the updated guidelines. Key words: allogeneic stem cell transplantation, b2-microglobulin, monoclonal gammopathy, multiple myeloma introduction Multiple myeloma (MM) is characterized by the neoplastic proliferation of a plasma cell clone that produces a monoclonal immunoglobulin. The plasma cell proliferation usually results in extensive skeletal involvement with lytic bone lesions and/or severe osteoporosis with or without compression fractures, hypercalcaemia, anaemia or extramedullary plasmacytomas. The excessive production of M-protein can result in renal failure due to the so-called myeloma kidney (precipitation of light chains within the distal and collecting tubules—cast formation) and recurrent bacterial infections due to a decrease in polyclonal immunoglobulins or associated systemic amyloidosis. The annual incidence of MM is �4 per 100 000 inhabitants. It constitutes 1% of malignant diseases and almost 15% of all haematological malignancies. The incidence in blacks is twice that in whites. The peak of higher incidence is between 60 and 70 years of age. Only 15% and 2% of patients are younger than 50 and 40 years, respectively [1]. It is evident that MM is an age-related disease but the ultimate cause is unknown. It has been recently recognized that virtually all cases of MM are preceded by monoclonal gammopathy of undetermined significance (MGUS) [(an asymptomatic condition with an M-protein concentration of <3 g/dl and <10% bone marrow plasma cells (BMPCs)] [2–4]. However, the cause of MGUS, the precise mechanisms that maintain the MGUS state and the mechanisms that trigger progression from MGUS to MM are still unknown [5]. diagnostic criteria The differential diagnosis of monoclonal gammopathies has been established by the International Myeloma Working Group [6]. MGUS is characterized by the presence of a serum M-protein concentration of <3 g/dl and <10% BMPCs with no symptoms or organ or tissue impairment attributable to the monoclonal gammopathy (Table 1). When both the M-protein size and the proportion of BMPCs are consistent with MGUS but the patient has a nephrotic syndrome, congestive heart failure, peripheral neuropathy, orthostatic hypotension or massive hepatomegaly, the most likely diagnosis is primary systemic amyloidosis resulting from the deposition of amyloidogenic light chains [6]. Smouldering (asymptomatic) multiple myeloma (SMM) is defined by the presence of M-protein at ‡3 g/dl and/or ‡10% BMPCs in the absence of symptoms or tissue or organ impairment due to the monoclonal gammopathy [7] (Table 2). The diagnosis of symptomatic MM requires the presence of M-protein in serum and/or urine, increased number of BMPCs or plasmacytoma, and related organ or tissue impairment, including bone lesions [6] (Table 3). It must be remarked that neither serum nor urine M-protein levels were included, since s y m p o s iu m a rt ic le *Correspondence to: Dr J. Blade´, Villarroel 170, 08036 Barcelona, Spain. E-mail: jblade@clinic.ub.es ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org �40% of patients with symptomatic MM have a serum M-protein <3 g/dl and 5% have non-secretory or oligosecretory MM. Also, no minimal proportion of BMPCs was required, since 5% of patients with symptomatic MM have <10% plasma cells in the bone marrow [6]. The most critical factor for disease requiring therapy is the evidence of tissue or organ impairment manifested by the clinical features shown in Table 4 [6]. prognostic factors With the use of conventional chemotherapy the median survival of patients with MM has ranged from 2 to 3 years for patients >65 years and from 5 to 6 years for younger patients. However, there is wide variability in survival due to differences related to both the host and the tumour. It is well established that good performance status and younger age are favourable prognostic features. For many years, the most important prognostic feature for MM has been the serum b-2-microglobulin level (b2-m), as a measure of both tumour mass and renal function. Other consistently reported prognostic factors in MM have been: haemoglobin (Hb) levels, hypercalcaemia, renal function impairment, low serum albumin, presence of circulating plasma cells, proliferative status measured by plasma cell labelling index or by flow cytometry, and plasmablastic morphology. A number of prognostic staging systems have been developed for MM throughout the past 35 years. These prognostic systems have been derived from multivariate regression models. However, none of the proposed systems has been entirely satisfactory. Recently, the International Myeloma Working Group has developed the so-called International Staging System (ISS), based on two easily available parameters: serum b2-m and albumin levels (Table 5). This prognostic classification was reproducible in all age groups and in patients treated with conventional chemotherapy as well in those who had received high-dose therapy/autologous stem cell transplantation (ASCT). The cytogenetic status is the most important prognostic factor in patients with MM (Table 6). Patients with hyperdiploidy or with immunoglobulin heavy chain (IgH) translocation t(11;14) have good/average survival. Poor cytogenetics features are: retinoblastoma (Rb) and 17p deletion, chromosome 1q gains as well as the IgH translocations t(4;14) and t(14;16) [9–11]. The 13q deletion as a single abnormality assessed by FISH is no longer an adverse prognostic feature [10, 11]. Gene expression profiling (GEP) provides information on a large number of genes associated with crucial features of the Table 1. Monoclonal gammopathy of undetermined significance (MGUS) Serum M-protein <3 g/dl Bone marrow clonal plasma cells <10% No evidence of other B-cell proliferative disorders No related organ or tissue impairment Table 2. Asymptomatic myeloma (smouldering myeloma) Serum M-protein ‡3 g/dl or urine light chain ‡1 g/24 h or Bone marrow clonal plasma cells ‡10% No related organ or tissue impairment (including bone lesions) or symptoms Table 3. Symptomatic multiple myelomaa M-protein in serum and/or urine Bone marrow (clonal) plasma cells or plasmacytomab Related organ or tissue impairment (end organ damage, including bone lesions) aSome patients may have no symptoms but have related organ or tissue impairment. bIf flow cytometry is performed, most plasma cells (>90%) will show ‘neoplastic’ phenotype. Table 4. Myeloma-related organ or tissue impairment (end organ damage) (ROTI) due to the plasma cell proliferative process Increased serum calcium Renal insufficiency Anaemia: haemoglobin 2 g/dl below the lowest normal limit Bone lesions: lytic lesions or osteoporosis with compression fractures (possibly confirmed by MRI or CT) Other: symptomatic hyperviscosity (rare), amyloidosis, recurrent bacterial infections (>2 episodes in 12 months), extramedullary plasmacytomas CRAB (Calcium, Renal insufficiency, Anaemia or Bone lesions); CT, computed tomography; MRI, magnetic resonance imaging. Table 5. New international staging system for multiple myeloma Stage Criteria Median survival (months) I Serum b2-microglobulin <3.5 mg/l plus serum albumin ‡3.5 g/dl 62 II Neither stage I nor III 44 III Serum b2-microglobulin ‡5.5 mg/l 29 Table 6. Cytogenetic prognostic subgroups in multiple myeloma Good/average prognosis Hyperdiploidy t(11;14)(q13;q32): cyclin D1 upregulation Bad prognosis Hypodiploidy t(4;14)(p16.3;q32): FGFR3 and MMSET upregulation t(14;16)(q32;q23): c-MAF upregulation Chromosome 1 abnormalities: 1q gains or 1p deletion 17p deletions FGFR3, fibroblastic growth factor receptor 3; MMSET, multiple myeloma SET domain. symposium article Annals of Oncology vii314 | Blade´ et al. Volume 21 | Supplement 7 | October 2010 disease such as proliferative capacity, apoptosis, DNA repair and drug resistance. GEP has been used to define molecular subgroups with clinical correlations based on gene expression signatures. More recently, high-resolution array comparative genomic hybridization, mRNA microarray, FISH analysis and novel microinformatics have defined clinico-pathological subgroups of MM based on recurrent DNA copy number changes [12]. The findings from molecular genomic studies will allow a better understanding of the pathogenesis of MM, facilitating the discovery of drugs targeting the molecular pathways of specific genomic subgroups of MM [13]. It is of note that new agents, particularly bortezomib, can overcome the negative prognostic impact, at least in the short to mid- term, of poor cytogenetics [14]. The response to therapy is a crucial prognostic factor in patients with MM. Thus, it has been shown that patients who achieve immunofixation electrophoresis-negative complete response (CR) after ASCT had an event-free survival (EFS) and overall survival (OS) significantly longer than those who remained in partial response (PR) [15–17]. Lahuerta et al. [18] have shown that the improvement in the depth of response was associated with a significantly longer EFS and OS. In addition, in a recent meta-analysis, the achievement of CR highly correlated with progression-free surivival (PFS) and with long- term survival [19]. The achievement of negative minimal residual disease by multiparameter flow cytometry [20] or by molecular studies [21] is crucial for remission duration and long-term survival. With the incorporation of novel drugs in the up-front setting, a significant number of patients achieve CR with primary therapy. A longer follow-up is needed to establish the impact of these CRs on EFS and OS in the non- transplant populations. criteria of response to therapy Response criteria for MM were first established by the Chronic Leukemia Myeloma Task Force (CLMTF) in 1968 [22]. The main response parameter was a 50% reduction in M-protein. In 1972, the Southwest Oncology Group (SWOG) defined partial response as a decrease of at least 75% of the serum M-protein synthetic rate and/or a decrease of at least 90% in urinary light chain protein excretion [23]. Since CR was rarely observed with old conventional therapy, neither the CLMTF nor the SWOG response criteria included a definition of CR. In addition, there were no definitions for disease progression and relapse. The European Group for Blood and Marrow Transplantation (EMBT) developed new criteria defining CR (negative immunofixation in serum and urine in the absence of increased BMPCs), PR, minimal response (MR), as well as the criteria for relapse (reappearance of the M-protein in patients who had achieved CR), and progression from PR or MR [24]. Any type of response should be maintained for a minimum of 6 weeks. The International Myeloma Working Group expanded the EBMT criteria by adding the categories of stringent CR (sCR) and very good partial response (VGPR) (Table 7) [25]. In addition, other important concepts such as the time to event, duration of response, clinical relapse and time to next therapy were emphasized as critical end points [25]. treatment of MM patients eligible for high-dose therapy/ haematopoietic stem cell transplantation ASCT is an essential part of up-front therapy in patients with MM younger than 65–70 years [26–28]. The question of whether ASCT is beneficial for the majority of patients or whether the overall benefit comes from certain subsets of patients remains to be determined. The achievement of CR is the most important step for a long-lasting response and prolonged survival in patients with MM. On the other hand, sensitivity to the initial chemotherapy measured by the M-protein level at the time of transplantation is the most important predictor of CR post-transplant and an association between response to induction and survival has been reported [26–28]. With induction with conventional chemotherapy regimens the pre- and post-transplant CR rates are 5%–10% and 35%, respectively and the median survival �6 years [26]. The association of thalidomide and dexamethasone (TD) has replaced vincristin, adriamycin and dexamethasone and been approved by the US Food and Drug Administration for its use as pre-transplant induction regimen. However, the pre- transplant CR rate is <10% and these regimens seem suboptimal in patients with high-risk cytogenetics and in those with extramedullary plasmacytomas [29]. Induction with bortezomib/dexamethasobe (VD) results in pre- and post- transplant CR rates of 12% and 33%, respectively [30, 31]. Although VD can overcome, at least in the short and medium term, the poor prognosis of high-risk cytogenetics, the post- transplant CR rate is not higher than with conventional chemotherapy and long-term results are not yet available. More promising are the so-called ‘triple’ regimens such as bortezomib/adriamycyn/dexamethasone (PAD) or bortezomib/ thalidomide/dexamethasone (VTD) with pre- and post- transplant CR rates ranging from 19% to 31% and from 43% to Table 7. Uniform response criteria for multiple myeloma Stringent complete response (sCR) CR as defined below plus Normal FLC ratio and Absence of clonal cells in bone marrow Complete response Negative immunofixation on serum and urine and Disappearance of any soft tissue plasmacytomas and £5% plasma cells in bone marrow Very good partial reaponse Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ‡90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 h Partial response ‡50% reduction of serum M-protein ‡90% urine M-protein reduction or <200 mg/24 h ‡50% decrease in soft-tissue plasmacytomas Stable disease Not meeting criteria for CR, VGPR, PR or progressive disease FLC, free light chain. Annals of Oncology symposium article Volume 21 | Supplement 7 | October 2010 doi:10.1093/annonc/mdq363 | vii315 52%, respectively [32–34]. The Spanish PETHEMA Group has finished the accrual of a trial comparing TD versus VTD versus four cycles of alternating chemotherapy with vincristine, BCNU, melphalan, cyclophosphamide and prednisone (VBMCP) and vincristine, BCNU, adriamycin and dexamethasone (VBAD) plus two cycles of bortezomib as pre- transplant induction regimens. The preliminary results show that the best regimen is VTD with pre- and post-transplant CR rates of 31% and 52%, respectively [34]. Post-transplant consolidation/maintenance with novel agents can become an important step forward. Thus, it has recently been reported that post-transplant consolidation with all thalidomide, lenalidomide or bortezomib increases the CR rate. In this regard, it has been shown that post-ASCT consolidation with VTD can induce long-lasting molecular remission [21]. Thalidomide maintenance prolonged the OS in two transplant series [35, 36]. The role of lenalidomide and bortezomib as post-transplant maintenance is being investigated in large prospective trials. On the other hand, minimal residual disease assessment either by multiparameter flow cytometry [20] or molecular studies [21] can be useful to determine for how long post-transplant treatment can be of benefit, particularly in patients already in serological CR. With the availability of novel drugs, the role of tandem ASCT is being questioned [28]. Although there is no doubt of the short- and mid-term benefit with the incorporation of novel drugs in the treatment of younger patients with MM, long-term results are needed to have an objective measurement of improvement in comparison with the previous era. The best curative approach for younger patients with MM is allogeneic transplantation. However, allogeneic transplantation with myeloablative conditioning results in a transplant-related mortality (TRM) of between 30% and 50% and the proportion of cured patients does not exceed 15% [28]. In order to decrease the TRM, so-called allogeneic transplantation with reduced-intensity conditioning has been introduced. With this approach, the TRM has decreased to 10%–20% while the CR rate is �50%. The incidence of acute and chronic graft-versus-host disease (GvHD) is 30% and 60%, respectively. The most important predictors of outcome are the development of chronic GvHD and a low tumour burden at the time of transplant. In this regard, the use of ASCT to reduce tumour burden followed by allogeneic transplantation with dose-reduced intensity conditioning (Allo-RIC) in order to obtain a benefit from the graft-versus-myeloma (GvM) effect has been recently investigated showing a PFS plateau of 25%–30% beyond 6 years from Allo-RIC [37–39]. There is a need to continue the investigation of conditioning intensity regimens as well as peri- and post-transplant strategies aimed at enhancing the GvM effect while minimizing GvHD [28]. patients not eligible for high-dose therapy/ haematopoietic stem cell transplantation In patients older than 65 years, or younger patients with comorbidities, the standard of care has been for many years the association of melphalan and prednisone (MP), dexamethasone-based therapies—VAD or VAD-like regimens, or even dexamethasone alone. In recent years, the novel drugs thalidomide, lenalidomide and bortezomib have been incorporated in the above-mentioned ‘old’ regimens. Thus, MP–thalidomide (MPT) resulted in a significantly higher response rate as well as in a significantly longer EFS and OS when compared with MP [40]. In patients older than 75 years, the MPT with a daily dose of thalidomide of 100 mg instead of 200 mg was also superior to MP in response rate, EFS and OS [41]. The Italian Group has reported a higher response rate and longer EFS in favour of MPT versus MP, with no significant impact on OS [42]. Two other studies showed a significantly longer EFS with no differences in OS [43, 44]. A large international trial compared MP and MPR (MP plus lenalidomide) with no maintenance versus MPR-R (MPR followed by lenalidomide maintenance). The preliminary resu