Multiple myeloma (MM) is a plasma cell neoplasm involving the bone marrow environment and causing multiple osteolytic lesions. Plasma cells produce immunoglobulins that form the characteristic monoclonal spike (M component) in the standard serum protein electrophoresis. Typical symptoms are bone pain, renal impairment and infections. MM is an incurable disease, and, until the last decade, patient survival was no more than 3 years. In the last few years, new active compounds have considerably improved response, duration of remission, quality of life and survival.



MM represents approximately 1-2% of all neoplasms and approximately 10% of hematologic malignancies (Kristinsson SY et al, 2007PubMed; Palumbo A, Anderson K, 2011PubMed). It is typical in the elderly, with the highest incidence in subjects around 70 years of age: about 30% of MM patients are over 75 at diagnosis, and less than 10% from 20 to 40 years of age. The risk factors associated with the development of this disease are still unknown. In most patients, MM disease is preceded by the “monoclonal gammopathy of undetermined significance” (MGUS) condition.



MM derives from a neoplastic transformation of the B lymphocyte line. Genetic modifications and interactions with the marrow microenvironment are responsible for neoplastic growth (Palumbo A, Anderson K, 2011PubMedHideshima T et al, 2007PubMed). Transformation takes place at the level of post-germinal B cells. The level of transformation is principally supported by the identification of mutations in the variable region of immunoglobulin genes signaling the passage through germinal centers and reflecting the selective pression of the antigen.

In MM, complex gene alterations may occur, and they can be primary or secondary chromosome translocations. In 40-50% of patients, primary translocations occur in the 14q32 (IgH) of the immunoglobulin, and they are typical of MM and MGUS (Hideshima T et al, 2007)PubMed. These lesions are essential for the process through which normal cells acquire tumor characteristics and finally, after a second ‘hit,’ they actually turn into tumor cells. Secondary lesions occur with disease progression and include loss of chromosome 13, mutations activating NRAS and KRAS oncogenes, inactivating mutations or deletion of p53, and inactivation of PTEN. MM patients can be classified into hyperdiploid and non hyperdiploid. Based on the hyper- or hypo-diploidy of chromosome translocations involving the 14q32 region, different patient subgroups can be identified. However, this distinction has not allowed the identification of specific therapeutic approaches. The gene/chromosome characteristics of the patients play an important prognostic role: translocation t(4;14) or deletion of chromosome 17 are associated with shorter survival.

The bone marrow microenvironment is fundamental for the development of genetically modified plasma cells. Adhesion of plasma cells to hematopoietic cells induces the secretion of cytokines and growth factors (interleukin-6, vascular endothelial growth factor, insulin growth factor-1) and thus the creation of autocrine and paracrine loops. Moreover, the adhesion of plasma cells to the extracellular matrix proteins induces the production of proteins that regulate the cellular cycle and anti-apoptotic proteins.

Osteolytic lesions are the result of an imbalance between bone production by the osteoblasts and bone resorption by the osteoclasts. The increased activity of the osteoclasts is due to an imbalance between the “receptor activator of nuclear factor kB” (RANK) and the osteoprotegerin (OPG), which, in turn, is caused by an increase in RANK ligand (RANKL) production and a reduced production of osteoprotegerin. Stromal damage is so significant that bone re-construction is rarely observed, even in patients in complete remission (Roodman GD, 2009)PubMed.



The diagnosis of MM is based on the presence of three core elements: serum and/ or urine monoclonal component, an increase in bone marrow plasma cells, and osteolytic lesions (Table I) (IMWG, 2003)PubMed.



Table I: Multiple Myeloma: diagnostic parameters


Treatment should be started only in case of symptomatic MM. Before the development of the symptomatic or active disease, close observation is recommended to verify whether MGUS turns into symptomatic MM. MM becomes symptomatic when it causes organ damage. Organ damage includes osteolytic lesions, anemia, renal impairment, recurrent infections, or hypercalcemia (Table II).



Table II: Criteria for the diagnosis of symptomatic multiple myeloma


Laboratory tests

To better characterize the disease, the quantification of the monoclonal component is crucial. This can be done through serum protein electrophoresis, immunoglobulin and 24-hr Bence-Jones proteinuria assessment. The identification of light-chains and heavy-chains involved by immunofixation is also necessary (Table III) (Dimopoulos M et al, 2011PubMed; Kyle RA, Rajkumar SV, 2009PubMed). Free light-chain assay is suggested in patients with plasma cell disorder at diagnosis and particularly in patients with: a) non secretory myeloma (absence of monoclonal component): b) small amounts of monoclonal component (oligo-secretory myeloma); c) light-chain only myeloma (Dispenzieri A et al, 2009)PubMed. However, free light-chain assays should not replace the 24-hr urine Bence-Jones protein evaluation.



Table III: Laboratory tests


The presence of plasma cells in the bone marrow is confirmed by bone marrow aspirate or bone biopsy. The percentage of plasma cells can be precisely evaluated through the anti-CD138 antibodies, whereas clonality may be assessed through the identification of the cytoplasm immunoglobulin light-chains. In addition, fluorescent in situ hybridization” (FISH) analysis should be performed to detect chromosome abnormalities such as deletion of chromosome 17p13, translocations t(4;14) and t(14;16) (Avet-Loiseau H, 2007)PubMed.
Osteolytic lesions can be detected through skeletal X-ray survey. In case of negative X-ray, magnetic resonance imaging (MRI) may be necessary, and it may also be useful to identify any bone compressions (Terpos E et al, 2011)PubMed. Bone scintigraphy is not usually required because it generally has negative results in many patients (presence of pure osteolytic lesions). The role of PET-CT in MM still has to be better defined, and may be useful to identify extra-bone metastases. Negative 18-F FDG PET-CT after transplantation had shown itself to be an independent prognostic factor (Zamagni E et al, 2011)PubMed.


Prognostic factors

The prognosis of MM disease depends on patient-related factors such as patient age, presence of comorbidities (renal impairment and thus increase in the Beta-2 microglobulin level) and disease-related factors such as the entity of the tumor mass (once again, Beta-2 microglobulin level), its proliferation, and the presence of chromosomal abnormalities.

Durie and Salmon stages identify 3 different prognostic groups based on simple clinical data. More than 70% of patients fall into stage III category (the worst) and the predictive value of Durie and Salmon stage in the individual patient is not high, but this staging continues to be used because it is easy to perform (Durie BGM, Salmon SE, 1975)PubMed. The International Staging System (ISS) is a new classification that takes into account 2 parameters only: Beta-2 microglobulin level, which is closely related to renal function and the tumor mass, and albumin level. This is also a simple classification and is now widely used (Greipp PR et al, 2005)PubMed. Recently, new cytogenetic parameters have emerged, such as deletion of chromosome 13, translocation 4;14 and deletion of chromosome 17p. In particular, t(4;14) and d17p are predictors of shorter survival (Avet-Loiseau H, 2007)PubMed.


Clinical aspects

The clinical approach to MM has changed over time: in the past, the diagnosis of MM was often made with advanced disease, while today at least 1/4 of MM cases are casually diagnosed during routine tests. The most common signs of MM are:
• bone pain: this is a common symptom (occurring in more than 50% of patients) caused by osteolytic lesions. Bone plasma cells produce cytokines that stimulate osteoclasts (osteoclast activating factors) and in turn the osteoclasts produce factors stimulating the proliferation of plasma cells (IL-6) (Roodman GD, 2009)PubMed. The bone lesions are evident, the resolution process is slow or absent, and these lesions generally do not improve even in patients achieving a complete remission after therapy. Bone lesions are more frequent in the regions with hematopoietic marrow (vertebrae, flat bones, skull). The pain is usually localized in the spine and ribs; when the pain is particularly intense, it may indicate the presence of a pathologic fracture.
• hypercalcemia: this is directly related to the bone metabolism. Hypercalcemia can be symptomatic (anorexia, polyuria and polydipsia, nausea, vomiting, dehydration and signs of hypercalcemic encephalopathy in the most severe cases), in some cases it may be worsened by concomitant renal insufficiency.
• asthenia: plasma cell proliferation in the bone marrow affects the normal hematopoietic activity, leading to a reduced red blood cell production and progressive anemia. Asthenia is the more significant expression of the anemic state of patients.
• recurrent infections: the increase in clone neoplastic cells is accompanied by a reduction in normal immunoglobulins, and thus patients present with a significant immunosuppression. Pulmonary and urinary infections are common, as are viruses such as Herpes Zoster, Hepstein-Barr and Cytomegalovirus.
• renal impairment: its pathogenesis is multi-factorial, and excessive monoclonal light-chains in the plasma, which undergoes both glomerular filtration and tubular catabolization, play a crucial role. During these processes, light-chains may deposit along the tubular or glomerular basal membrane, or may damage tubular cells, directly or through the mediation of lysosomal enzymes. MM most frequently affects the morpho-functional condition of the kidneys, and chronic renal impairment is common (acute renal insufficiency is rare and usually occurs when other concomitant factors, such as hyperuricemia and dehydration, are present). Light-chain disease and AL amyloidosis, although more rare, should also be considered as responsible for renal impairment especially in the presence of a non-selective proteinuria (nephrotic syndrome).
• neurologic dysfunction: bone damage and consequent possible vertebral collapse, or, to a lesser degree, the presence of plasmacytoma in the rib or vertebra regions, may cause medullary or radicular compression with subsequent neurologic signs and symptoms. Motor and sensory neuropathy may be due to the production of antibodies against the different nervous structures (the most common are the anti myelin-associated glycoprotein antibodies, MAG) or to amyloid deposition along the nervous structures.
• hyper-viscosity syndrome: it is more frequent in IgA MM (because of the tendency towards polymerization of the immunoglobulins). It is associated with problems of vision, neurologic dysfunctions, peripheral vascular insufficiency, cardiac dysfunction and hemorrhagic diathesis.



In the last few years, many advances have been made in the treatment of MM leading to significant improvements in quality of life and survival. In the 1980-90s, response (at least 50% reduction of the monoclonal component) was reported in 50% of patients, with a median survival of approximately 2.5 years. Today, the response rate is approximately 80-90%, with a survival of about 5 years, and further improvements are expected, especially in good prognosis patients.

Progress is mainly due to the introduction of autologous transplantation in the 90s and the introduction of novel agents, such as thalidomide, bortezomib and lenalidomide, after 2000. These new drugs have different mechanisms of action and have been variously combined with each other and with standard chemotherapy. They were first used at relapse, and later have been gradually introduced into treatment at diagnosis.

Despite therapeutic advances and prolonged remission, most patients eventually relapse; therefore, planning both therapies at diagnosis and at relapse is necessary.

Age is the major criterion for choice of therapy. Patients under 65 years of age are considered young patients. However, biological age and presence of comorbidities may influence treatment selection.

Therapy at diagnosis

Young patients are considered eligible for autologous stem cell transplantation (Cavo M et al, 2011)PubMed. Therapy includes induction treatment for an initial cytoreduction of the neoplasm. The combination of vincristine-adriamycin-dexamethasone (VAD) was one of the most commonly used induction therapies (leading to a response rate of 60%). To date, new combinations including new drugs are available and treatment outcomes are improved. For instance, the combination of bortezomib or lenalidomide with steroids or chemotherapeutic agents showed to be superior to standard chemotherapy (response rate of 80%, with 10-15% of complete response) (Cavo M et al, 2010)PubMed. None of these drugs has been reported as negatively interfering with mobilization of autologous hematopoietic progenitor cells. The next phase consists in the mobilization of stem cells, for which cyclophosphamide and growth factors are used. Finally, patients receive high-dose chemotherapy: conditioning with melphalan (200 mg/m2) followed by stem cell transplantation, which reduces the hematologic toxicity induced by the conditioning regimen. A significant overall survival and event-free survival improvement with tandem transplantation was detected as compared with single transplantation, particularly in patients achieving at least very good partial response (90-100% reduction of monoclonal component) after first transplantation. Clinical studies are needed to confirm the role of single versus tandem transplantation in the era of new drugs.

Allogeneic transplantation is a feasible option for young patients with compatible donor. Reduced-dose chemotherapy and increased immunosuppressive therapy (mini allogeneic transplantation) have brought about a decrease in morbidity and mortality associated with treatment. Chronic graft-versus-host-disease (GVHD) remains the major cause of morbidity and significantly reduces the patient’s quality of life. In a randomized study, allogeneic transplantation showed to be superior to autologous transplantation (Bruno B et al, 2007PubMed; Giaccone L et al, 2011PubMed). After the introduction of novel agents (thalidomide, bortezomib and lenalidomide) allogeneic transplantation has become a less appealing option, and it should not be performed outside clinical trials. Randomized studies to evaluate the role of allogeneic transplantation in association with novel agents in high-risk patients (for instance with deletion of chromosome 17) are warranted.

In elderly patients, various combinations including novel agents (thalidomide, bortezomib and lenalidomide) in association with standard chemotherapy and corticosteroids are available. Until recently, the combination of melphalan and prednisone (MP) was considered the standard of care for elderly patients with MM. The addition of thalidomide to MP (Palumbo A et al, 2006)PubMed has been evaluated in 5 randomized studies, where increased response rate, remission duration, and, in some trials, also enhanced survival were detected. Complete response improved from 3-5% to more than 25%, remission duration from 18 to 25-28 months (Waage A et al, 2010). MP plus bortezomib (San Miguel JF et al, 2008PubMed; Mateos MV et al, 2010PubMed) was also found to be an effective treatment option, and MP plus lenalidomide led to positive results as well (Palumbo A et al, 2010). To date, there are no randomized studies to directly compare these combinations and it is therefore difficult to decide which option is the best (Table IV). However, there are some clinical indications based on the characteristics of novel agents that may help physicians choose the most appropriate treatment. Thalidomide is administered orally, it is not myelotoxic, and can be administered along with full-dose therapy; yet it is associated with neurotoxicity, which is common after prolonged exposure to thalidomide-containing treatment. Other common adverse events include cardiac dysfunction (bradycardia) and thrombosis, for which anti-thrombotic prophylaxis is needed. Bortezomib is administered intravenously and can be safely used in patients with renal impairment (also in patients on dialysis). It is associated with neurotoxicity, but, recently, dose-modifications significantly decreased the incidence of this complication (Bringhen S et al, 2010)PubMed. Lenalidomide is given orally, it is a derivative of thalidomide but it has a different mechanism of action: it is more active and is not associated with neurotoxicity.



Table IV: Phase III studies including thalidomide, bortezomib and lenalidomide in combination with melphalan and prednisone


Ongoing studies are evaluating various associations of novel agents: for instance the use of two new drugs (thalidomide-bortezomib, or lenalidomide-bortezomib) plus conventional chemotherapeutic agents (melphalan, cyclophosphamide, or adriamycin). The four-drug combination bortezomib-melphalan-prednisone-thalidomide showed a high response rate, prolonged remission duration and overall survival in comparison with the three-drug bortezomib-melphalan-prednisone (Palumbo A et al, 2010b)PubMed.

Survival outcome observed in very elderly patients (>75 years) is inferior compared with those reported in younger patients. Very elderly patients usually experience more treatment-related adverse events and receive lower drug doses (Palumbo A et al, 2011)PubMed. In addition, outcome is improved in patients who do not interrupt therapy and who receive treatment for a prolonged period. Future trials should consider the patient’s age and comorbidities, and should include a geriatric assessment to appropriately stratify patients according to the risk of mortality. This will provide elderly patients with an effective tailored therapy (Palumbo A et al, 2011)PubMed.
Maintenance therapy can prolong remission both after autologous transplantation and after conventional chemotherapy in the elderly patient. Lenalidomide is an ideal option for prolonged treatment because it is administered orally and is well tolerated. Data reported by the Intergroup Francais sur le Myelome (IFM) (Attal M et al, 2010) and the American group CALGB (McCarthy PL et al, 2010) showed a significant event-free survival difference between patients assigned to lenalidomide maintenance and those allocated to the placebo arm (p <10-7). Preliminary results of the American study also found a survival advantage with lenalidomide maintenance. In the MM015 study, patients received melphalan-prednisone-lenalidomide induction for nine months. Afterwards, lenalidomide maintenance or placebo was given. In this study, a significant prolonged event-free survival was seen in patients allocated to melphalan-prednisone-lenalidomide followed by lenalidomide (Palumbo A et al, 2010c).

Therapy at relapse

All the novel agents are active at relapse. Large randomized studies showed the efficacy of thalidomide, bortezomib (Singhal S et al, 1999)PubMed, and lenalidomide (San Miguel JF et al, 2008PubMed; Dimopoulos M et al, 2007PubMed; Weber DM et al, 2007PubMed) in this setting. The choice should therefore be based on the type of therapy previously received by the patient, the response achieved, and the presence of comorbidities.

Re-challenge with previous therapy is an option if the patient achieved a good response lasting at least one year. Conversely, in the case of a response lasting less than one year, a different regimen should be offered.

Patient characteristics, particularly the presence of comorbidities, should influence the choice of treatment. In patients with renal impairment, bortezomib is the most suitable drug, and it may also be used for patients on dialysis. Lenalidomide is appropriate in case of neurotoxicity. Thalidomide should not be used in patients with cardiac conditions.

MM responds to various therapy lines. However, after each subsequent line of therapy, response rate and duration decreases while toxicity increases. Therefore, it is necessary to assess carefully each patient to balance the benefits and toxicities associated with therapy.

In the near future, second generation novel agents will be available. Phase III studies with the new proteasome inhibitor, carfilzomib, and the new thalidomide derivative, pomalidomide, are underway.
Many promising compounds (histon-deacetylase, mTor inhibitors, monoclonal antibodies) are currently being tested in phase II studies. Therefore, it is likely that the treatment paradigm of MM will undergo further dramatic changes in the coming years.


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