	Multiple myeloma (MM) is a clonal plasma cell malignancy with a highly heterogeneous genetic background, characterized by bone marrow (BM) plasmacytosis, production of monoclonal proteins, osteolytic bone lesions, hypercalcemia, renal disease, anemia, and immunodeficiency. Several advances in diagnosis and treatment have been achieved during the past years. More sensitive imaging techniques, cytogenetic evaluations, and novel assays to measure paraprotein levels help to discern monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) from MM, and thereby enable the selection of patients who need treatment. Progress in our understanding of MM pathogenesis has led to the identification of new therapeutic targets. The introduction of derived agents, including thalidomide, bortezomib, and lenalidomide, into conventional chemotherapeutic regimens has fundamentally changed treatment strategies in MM during the last decade and steadily improved patient outcome.

	Multiple myeloma (MM) is the second most common hematologic malignancy in the United States. Age-adjusted incidence and mortality rates of MM in the United States are 5.6 and 3.6 cases per 100,000 persons per year, respectively.

 MM is a disorder of terminally differentiated B lymphocytes, called plasma cells, that are preferentially located within the bone marrow and secrete monoclonal immunoglobulin (IgG in about 60%, and IgA in about 20%) or light chains (κ or λ). Deregulated tumor cell growth and paraprotein production induce myelosuppression, bone destruction and hypercalcemia, immunodeficiency, hyperviscosity, and renal failure. Other plasma cell disorders include monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and solitary plasmacytoma. MGUS and SMM, also referred to as indolent or asymptomatic MM, are characterized by the absence of symptoms and require regular follow-up but no treatment. The rare solitary plasmacytoma occurs as a single lesion and benefits from local therapies. Recent advances in the diagnostic workup helped to distinguish these forms of disease from symptomatic MM, and thereby helped to select patients who needed treatment. Improvements have been achieved also by the identification of tumor microenvironment-directed agents, including thalidomide, bortezomib, and lenalidomide. Their inclusion in current MM treatment regimens has extended median overall survival (OS) from 3 to at least 7 years, especially in the younger patient population.

 In addition, novel effective supportive therapies have improved patients’ quality of life.

	Despite therapeutic advances, MM ultimately relapses and remains an incurable disease. Current research goals aim to further increase our knowledge, to identify additional targeted therapies, and to define patient-specific sequence and combination regimens in order to reduce adverse effects and improve response rates. Here, we summarize recent advances in both diagnosis and treatment strategies.

		Table 1. Staging Systems in Multiple Myeloma

		- Serum calcium value normal or ≤12 mg/dL

		- Bone x-ray, normal bone structure, or solitary bone plasmacytoma only

		- Low M-component production rate (IgG value <5 g/dL; IgA value <3 g/dL Bence Jones protein <4 g/24 h)

		Stage II: Neither stage I nor stage III

		Stage III: one or more of the following:

		- High M-component production rate (IgG value >7 g/dL; IgA value >5 g/dL, Bence Jones protein >12 g/24 h).

		Patients are further subclassified in either A or B:

		A: Relatively normal renal function (serum creatinine value <2.0 mg/dL)

		B: Abnormal renal function (serum creatinine value ≥2.0 mg/dL)

		Stage I: β-2 microglobulin <3.5 mg/L and albumin ≥3.5 g/dL

		Stage III: β-2 microglobulin ≥5.5 mg/L

	Plasma cell disorders are characterized by bone marrow infiltrate of monoclonal tumor cells and paraprotein production. MGUS is defined by the absence of symptoms and a lower grade of bone marrow infiltration compared to SMM and MM (MGUS: <30g/L paraprotein, BM clonal plasma cells <10%). MM in contrast to SMM presents with symptoms related to calcium levels above 10.5 mg/dL, renal impairment with creatinine levels >2 mg/dL, anemia with Hb <10 g/dL, and/or bone disease (CRAB-criteria). MM requires prompt antitumor and supportive treatment. MGUS and SMM are managed by regular clinical follow-up and serum and/or urine paraprotein determination. In order to predict survival and choose the most appropriate treatment, patients are categorized according to the Durie-Salmon Staging System and the International Staging System (ISS) (

 Advances in cytogenetic analysis pro-vides additional prognostic features. The recommended current diagnostic workup of MM patients is summarized in 

		Table 2. Recommended Diagnostic Workup in Multiple Myeloma

		• Serum and urine protein electrophoresis and immunofixation

		Evaluation of plasma cell infiltrates and cytogenetic abnormalities

		Bone marrow aspiration and biopsy with flow cytometry, immunohistochemistry, and cytogenetics

		Assessment of organ function and tumor burden

		Complete blood cell count, serum creatinine, calcium level, lactate dehydrogenase, albumin, and β2-microglobulin

 Recently, diagnostic advances have been made in the detection of bone lesions. Up to 80% of MM patients at diagnosis present with osteolytic lesions, often complicated by pain, bone fractures, and hypercalcemia. Malignant plasma cells stimulate activity of bone-resorbing cells (osteoclasts) while inhibiting bone-producing cells (osteoblasts). The resulting unbalanced bone destruction leads to the development of lytic bone lesions. Due to the absence of osteoblastic activity, bone scintigraphy scans and serum alkaline phosphatase levels are normal in MM patients. The recommended test to assess bone involvement at diagnosis and in the relapsed setting is conventional radiography, although techniques with higher sensitivity are currently under evaluation.

 Specifically, MRI and the new whole-body MRI (wbMRI) are more sensitive than skeletal survey to detect focal lesions, as they assess bone marrow involvement rather than bone destruction. MRI identifies lesions in up to 30% of patients with negative skeletal survey, and is therefore recommended in symptomatic patients with normal radiography in order to determine either treatment or follow-up. It is also recommended in cases of solitary bone plasmacytoma to determine the need for aggressive systemic chemotherapy versus local therapy.

 MRI or CT without contrast is critical to confirm cord compressions in the emergency setting.

	In contrast to conventional skeletal survey, focal lesions identified by MRI at diagnosis worsen patients’ prognosis. However, their resolution after therapy is associated with longer survival.11 Moreover, wbMRI in patients with asymptomatic MM is a strong predictor for progression to symptomatic MM.

 Due to the prognostic value of focal lesions identified by MRI, a modification of the Salmon-Durie Staging System has been proposed that includes MRI instead of conventional x-ray results (Salmon-Durie Plus). By using this new system, diagnosis of MGUS and plasmacytoma and staging of MM patients are upgraded in most cases. Derived therapeutic decisions are still a matter of debate.

	PET-CT, which demonstrates high sensitivity to detect tumor active sites and bones at risk for fractures, is performed in the context of clinical trials. Suppression of PET activity after induction therapy or after autologous stem cell transplantation (ASCT) may confer longer survival, suggesting its potential use as an indicator of response.

 Genetic testing, including fluorescence in situ hybridization (FISH) on primary bone marrow samples of MM patients, has become increasingly important for its prognostic relevance and therapeutic implications. Nearly 45% of MM patients present with hyperdiploid genetic anomalies, which are associated with older age at presentation, IgGκ paraprotein, and a more indolent form of MM. Standard risk is determined by the presence of translocation t(11;14).

 In contrast, hypodi-ploid subtypes are related to more aggressive disease, young-er age at presentation, and IgAλ paraprotein secretion.

 Genetic events associated with poor prognosis and shorter survival include translocation t(4;14), deletions of chromo- some 13 (del 13) and 17 (del 17), and amplification or deletion of chromosome 1.

 The presence of either of these genetic abnormalities characterizes the high-risk patient population whose OS after treat- ment with conventional chemotherapeutic regimens is shorter than in patients with standard-risk disease.

 Specifically, upfront treatment with bortezomib overcomes the negative prognostic impact of t(4;14) in MM patients compared to conventional chemotherapy, but provides no benefits to patients bearing the del 17.

 In the relapsed/refractory setting, lenalidomide with or without bortezomib improves the outcome of patients with del 13 or t(4;14). In contrast, outcome remains poor in patients with del 17 or chromosome 1 abnormalities.

 Therefore, patients with high-risk cytogenetic features, especially del 17 and chromosome 1 abnormalities, should be enrolled in clinical trials assessing novel agents.

 In 90% of MM patients, a paraprotein can be detected in serum or urine using electrophoresis and immunofixation techniques. The remaining 10% without a detectable paraprotein have been classified as oligosecretory or nonsecretory MM patients. In these cases, tumor response can be assessed only by bone marrow plasma cell infiltration. Most recently, the availability of the serum immunoglobulin-free light chain (FLC) assay, now a routine assay for screening of plasma cell disorders, has greatly improved diagnostic procedures. Along with serum electrophoresis and immunofixation, FLC increases the sensitivity to diagnose plasma cell disorders.

 Moreover, baseline light chain measurements and κ/λ ratio may be used as independent prognostic factors together with ISS index to improve prognostic evaluation.

 Importantly, an abnormal FLC ratio is associated with a higher risk of MGUS and SMM progression to MM, therefore requiring closer follow-up.

	Not all patients with a new diagnosis of plasma cell disorder require treatment. Patients with SMM or MGUS should be closely monitored to initiate a therapy in case of progression. If treatment is needed, regimens now include new nonchemotherapeutic agents. Indeed, thalidomide, bortezomib, and lenalidomide have dramatically changed the course of disease by improving remission rates, duration of response, and survival, and overcoming, at least in part, adverse genetic features.

 Therapies are tailored to patients’ age, comorbidities, and preferences. Current standard of care for patients with good performance status and without severe comorbidities is high-dose therapy and autologous stem cell transplant (HDT/ASCT). In contrast, therapies achieving the longest remission without excessive toxicity should be offered to patients aged <65 years, or older if in good performance status (eg, Eastern Cooperative Oncology Group [ECOG] >3, New York Heart Association [NYHA] >3). The role of long-term treatment to maintain a remission status after induction therapy or ASCT is currently under evaluation. In case of relapse or progression, regimens that include new drug combinations and novel anti-MM agents should be given within clinical trials.

		Table 3. Clinical Trials on Recommended Induction Strategies in Transplant-Eligible Patients

		ASCT indicates autologous stem cell transplant; CR, complete remission; IFE, immunofixation electrophoresis; NA, not available; nCR, near CR; OS, overall survival; PAD, bortezomib plus doxorubicin plus dexamethasone; PR, partial remission; Rd, lenalidomide plus low-dose dexamethasone; RD, lenalidomide plus high-dose dexamethasone; TD, thalidomide plus dexamethasone; VAD, vincristine plus adriamycin plus dexamethasone; VBMCP/VBAD, vincristine plus carmustine plus cyclophosphamide plus melphalan plus prednisone/vincristine plus carmustine plus doxorubicin plus dexamethasone; VD, bortezomib plus dexamethasone; VTD, bortezomib plus thalidomide plus dexamethasone.

 Treatment of the young patient population, aged <65 years or older if in good performance status, should be based on HDT/ASCT. After initial induction therapy, stem cells are collected to perform HDT/ASCT. Subsequent consolidation and maintenance strategies are still not recommended outside of clinical trials.

 The aim of induction therapy is maximal disease control to collect tumor-free peripheral blood stem cells (PBSCs). Recommended induction regimens include bortezomib- and lenalidomide-based combinations (

). Alkylating agents should be avoided for their negative impact on stem cell collection. Specifically, bortezomib plus dexamethasone (VD) versus standard chemotherapeutic induction strategies (VAD; vincristine, adriamycin, and dexamethasone) achieves higher response rate before and after ASCT, and shows a trend towards improvement of progression-free survival (PFS).

 In contrast, the combination of thalidomide plus dexamethasone (TD) failed to maintain the response rate advantage after ASCT when compared to VAD.

 Other strategies achieving high remission rates before transplant include bortezomib plus dexamethasone plus doxorubicin (PAD), and bortezomib plus thalidomide plus dexamethasone (VTD). PAD is superior to VAD in terms of response rate after ASCT.

 VTD is significantly superior to TD in terms of response rates before and after ASCT, although with higher toxicity.

 To overcome this problem, a regimen with low-dose bortezomib plus thalidomide plus dexamethasone (vTD) has been proposed. Compared to VD, vTD achieves a significantly higher response rate before ASCT, with comparable toxicity.

 Lenalidomide plus dexamethasone is considered to be another standard induction regimen for transplant candidates.

 Due to the positive results obtained with bortezomib- and lenalidomide-based regimens, their combination (VRD) is currently being evaluated. Preliminary data suggest an overall response rate of 96% before ASCT and 13% complete remission (CR).

 After 3 to 4 months of induction therapy, peripheral blood stem cell collection using granulocyte-colony stimulating factor (G-CSF), with or without cyclophosphamide follows. Importantly, with the exception of lenalidomide, novel agents do not influence stem cell yield.

 In order to overcome the negative influence of lenalidomide on stem cell collection, early harvesting and priming with cyclophosphamide is recommended.

 More recently, a new chemokine receptor inhibitor has been studied for its effects on stem cell mobilization: plerixafor in combination with G-CSF facilitated optimal stem cell collection at earlier time points than G-CSF alone, without major toxicity. Plerixafor in combination with G-CSF has been successfully used in patients failing previous mobilization attempts. Importantly, it overcomes negative effects of lenalidomide on stem cell mobilization.

 These positive results led to the FDA and European Medicines Agency (EMA) approval of plerixafor in combination with G-CSF in 2008 and 2009, respectively, in patients with non-Hodgkin lymphoma and MM.

	The backbone of conditioning therapy is melphalan, administered at doses ranging from 100 to 200 mg/m

, dependent on age and preexisting comorbidities.

 A second ASCT is recommended by the NCCN Guidelines within 6 months of the initial ASCT for those patients who did not achieve at least a very good partial remission (VGPR) after the first ASCT.

 Although allogeneic stem cell transplantation remains the only potential curative treatment for MM patients, high toxicity rates and transplant-related mortality limit this approach to young patients with high-risk features or a relapse within 12 months of ASCT. The graft versus myeloma effect obtained with allogeneic transplantation after reduced-intensity conditioning has been evaluated as consolidation strategy after ASCT, but due to controversial data this treatment strategy remains restricted to clinical trials.

 With the purpose of increasing depth of response after ASCT, consolidation strategies have been explored. Thalidomide plus prednisone for 12 months after first ASCT prolongs both PFS and OS compared to prednisone alone; 3-year OS is 86% versus 75%, respectively.

 Two cycles of VTD after the second transplant induce high rates of durable molecular response associated with a better outcome.

 Four cycles of lenalidomide together with prednisone as consolidation therapy and thereafter alone as maintenance strategy increase the CR rate from 38% after ASCT to 66%.

 These promising data need further confirmation in randomized trials to assess the effective benefits on response and survival in light of increased toxicity.

 Older patients with reduced performance status, defined as ECOG performance status or NYHA class >3, have higher morbidity and mortality if they undergo HDT/ASCT because of increased therapy-related toxicity.

 Therefore, this patient group should be offered alternative strategies that achieve disease control while limiting therapy-induced adverse events. According to the most recent guidelines, any upfront therapies in this setting should include thalidomide, lenalidomide, or bortezomib in doublet or triplet combination with conventional therapies, such as melphalan and/or prednisone (

 The choice is based on comorbidities and preference. Ongoing clinical trials explore quadruplet regimens and novel agents to further improve patient outcome.

		Table 4. Clinical Trials on Recommended Induction Strategies in Transplant-Ineligible Patients

		CR indicates complete remission; Mel100, melphalan 100 mg/m

; MP, melphalan plus prednisone; MPT, melphalan plus prednisone plus thalidomide; MPV, melphalan plus prednisone plus bortezomib; NA, not available; nCR, near CR; OS, overall survival; PR, partial remission; Rd, lenalidomide plus low-dose dexamethasone; RD, lenalidomide plus high-dose dexamethasone; Tm, thalidomide maintenance; VGPR: very good partial remission.

	Since 2006, thalidomide in combination with melphalan and prednisone (MPT) belongs to the standard treatment in newly diagnosed transplant-ineligible MM patients.

 Several consecutive studies supported the superiority of this regimen to melphalan plus prednisone (MP) in terms of response rate.

 Two meta-analyses of 6 randomized controlled trials comparing MPT versus MP as initial therapy for transplant-ineligible patients showed a superior response rate and PFS with minimal additional toxicity in patients treated with MPT. A 6.6-month increase in OS has also been reported.

 Common side effects associated with thalidomide treatment are constipation, fatigue, dose-dependent neuropathy, and thrombosis. Notably, the combination with dexamethasone (TD) is poorly tolerated by patients aged >75 years, with increased toxicity-related deaths compared to MP and reduced OS (19.8 mo in TD arm vs 41.3 mo in MP arm).

 This study raises important questions on the safety profile of the novel nonchemotherapeutic agents, suggesting cautious use in the older population.

	Similar to thalidomide, bortezomib in combination with melphalan plus prednisone (MPV) achieved significantly higher survival rates than MP and complete remission rates comparable to those obtained with HDT/ASCT. The VISTA trial demonstrated that at a median follow-up of 36.7 months, OS was not estimable in the MPV group versus 43.1 months in the MP group.

 Due to the observed significant benefit on OS, MPV is also considered a standard upfront regimen for older patients. Common bortezomib-associated dose-limiting adverse side effects include peripheral neuropathy, gastrointestinal toxicity, and thrombocytopenia. Bortezomib-containing therapies are especially recommended for patients with renal disease, since elimination of bortezomib is independent of renal clearance and bortezomib may even help to normalize MM-associated renal dysfunction in selected patients.

 Due to the high response rates achieved with thalidomide and bortezomib, the combination of both agents with prednisone (VTP) has been investigated. Compared to MPV, VTP induced similar CR rates but showed a different toxicity profile that was predominantly hematological for MPV and cardiac for VTP.

 Further studies are needed to confirm the safety and efficacy of this new regimen.

	Positive results have also been demonstrated using lenalidomide in combination with low-dose dexamethasone (Rd) versus high-dose dexamethasone (RD). The higher toxicity rate observed with RD translates to a shorter OS, with a 2-year OS of 75% for the RD arm versus 87% of the Rd arm.

 Adverse side effects of the combination include neutropenia and thromboembolic events (deep vein thrombosis and pulmonary emboli) requiring antithrombotic prophylaxis in all lenalidomide-treated patients.

 The combination of lenalidomide plus melphalan plus prednisone (MPR) in the upfront setting of elderly transplant-ineligible patients has also been explored. In a dose-determining study, after 9 cycles of MPR, 24% of the patients obtained a complete immunofixation-negative response. Grade 4 adverse events were mainly hematologic.

 Several trials have explored the benefits of maintenance strategies after ASCT or after induction therapy in transplant-ineligible patients in terms of response rate and survival. Maintenance therapy aims to prolong remission in long-term tumor control and to reduce the risk of relapse.

 However, data are still preliminary and maintenance strategies do not yet belong to the standard of care. In the post-ASCT setting, long-term treatment with thalidomide and prednisone is superior to placebo in terms of response and disease-free survival (DFS); however, no effects on OS have been demonstrated. In addition, thalidomide-related toxicity, neuropathy in particular, reduces patients’ quality of life.

 It therefore represents a limitation to long-term use. In contrast, lenalidomide may overcome this problem due to better tolerability.

 Compared to placebo, lenalidomide maintenance significantly delays the time to progression (TTP). Specifically, McCarthy and colleagues

 showed an estimated median TTP of 42.3 months for the lenalidomide arm versus a TTP of 21.8 months for the placebo arm at 17.5 months from ASCT. Similarly, Attal and associates

 observed a median PFS from diagnosis of 52 versus 34 months in lenalidomide versus placebo-maintained patients. Advantages in terms of PFS by lenalidomide maintenance have also been demonstrated by Palumbo and colleagues

 in the nontransplant setting.At a median follow-up of 9.4 months, PFS for MPRm (MPR plus lenalidomide maintenance) was not reached; for MP, PFS was 13 months; and for MPR, PFS was 13.2 months. In contrast to thalidomide, bortezomib is better tolerated as maintenance therapy. Sonneveld and associates

 noted a rate of discontinuation of 9% in bortezomib-treated patients versus 31% in thalidomide-treated patients. In addition, a survival advantage in patients with negative prognostic features, such as gain 1q21 and t(4;14), was observed.

 Improved response rates have also been demonstrated in patients not eligible for transplant, although a longer follow-up is needed to assess any survival advantage.

 Finally, long-term treatment with bortezomib in combination with thalidomide has also been explored. Preliminary data confirm the advantage at PFS and suggest a favorable safety profile.

 Salvage treatment regimens are proposed for patients with progressive disease or relapse after induction therapy, ASCT, or allo-SCT.

 If possible, patients with relapsed/refractory disease should be enrolled in clinical trials. Treatment choices depend on previous therapies, duration of response and toxicities, and presence of high-risk cytogenetic features.

 Patients relapsing more than 6 months after completion of induction therapy may be rechallenged with the same initial treatment regimen or a combination of previous therapies. If relapse occurs after a shorter period of time from induction, treatment options include HDT/ASCT or the switch to a new regimen.

 Allo-SCT may be offered to a selected population of young patients with preferably HLA-matched donors.

 Strategies approved in the relapsed setting include bortezomib alone or in combination with pegylated liposomal doxorubicin, and lenalidomide in combination with dexamethasone.

 The combination of bortezomib and doxorubicin versus bortezomib alone significantly prolonged TTP (9.3 mo vs 6.5 mo, respectively), however, with more grade 3/4 toxicities. Similarly, TTP was improved by adding lenalidomide to dexamethasone in relapsed/refractory patients, from 4 to 11 months.

	Ongoing studies are evaluating double, triple, and quadruple combinations, as well as additional targeted novel agents. Thalidomide has been combined with a variety of agents, such as dexamethasone, cisplatin, cyclophosphamide, and etoposide (DT-PACE).

 Safety and efficacy of lenalidomide plus pegylated liposomal doxorubicin or cyclophosphamide and dexamethasone have been additionally evaluated.

	Among the novel agents currently tested in myeloma, pomalidomide, carfilzomib, and bendamustine are the most promising. In the relapsed/refractory setting, an overall response of 30% was achieved by the new immunomodulatory drug pomalidomide, alone or in combination with dexamethasone. The dose-limiting adverse effect was myelosuppression.

 Notably, activity of pomalidomide was also observed in patients refractory to thalidomide, lenalidomide, or bortezomib.

 Ongoing phase II clinical trials are assessing the combination of pomalidomide plus bortezomib.

	Carfilzomib is a highly active new proteasome inhibitor targeting both the chymotrypsin-like and immuno- proteasome activities. In contrast to bortezomib, carfilzomib has an irreversible mechanism of action.

 Higher doses twice weekly seem to be better tolerated than lower doses administered for 5 days.

 Although high response rates were demonstrated in patients previously treated with lenalidomide, bortezomib, and HDT/ASCT, even higher response rates were observed in bortezomib-naïve patients.

 Reported toxicity was mainly hematologic; in contrast to bortezomib, neuropathy was not a major problem. A larger randomized phase III trial is planned to assess the combination of carfilzomib plus lenalidomide plus dexamethasone in the setting of relapsed disease.

	Bendamustine hydrochloride is a DNA alkylating anticancer agent, approved for the treatment of chronic lymphocytic leukemia.

 In heavily pretreated patients, bendamustine in combination with thalidomide and prednisone conferred median PFS and OS of 11 and 19 months, respectively.

 Similar results have been observed with the combination of bendamustine with bortezomib and dexamethasone.

 Supportive therapies in MM aim to prevent and treat bone disease and its complications, thromboembolic events, renal impairment, hyperviscosity, infections, and anemia (

). Patients with symptomatic bone disease or asymptomatic patients whose bone imaging suggests decreased bone density benefit from therapy with bisphosphonates.

 Indeed, monthly infusions with zoledronate or pamidronate reduce skeletal complications (hypercalcemia, fractures, and pain).

 Discontinuation after 2 years of treatment is recommended in patients with responsive or stable disease.

 Bisphosphonates have also been used in patients with MGUS and SMM and concomitant bone loss. However, although improved bone mineral density was observed, no data suggest prevention of skeletal complications or antitumor effects in this patient population; therefore, the use of bisphosphonates is questionable.

 Patients undergoing thalidomide- and lenalidomide-based therapies are at high risk for thromboembolic events and benefit from the regular use of anticoagulants. Based on risk-stratification analysis, aspirin, low-molecular-weight heparin, or warfarin may be administered.

		Table 5. Supportive Therapies in Multiple Myeloma

		• Surgery (kyphoplasty and vertebroplasty)

		Hydration and bisphosphonates, eventually calcitonin

		Herpes zoster prophylaxis in case of bortezomib-based regimens

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