Recent Advances in Diagnosis and Management of Multiple Myeloma: An Update

Chapter 80 Recent Advances in Diagnosis and Management of Multiple Myeloma: An Update PS Ghalaut, Soumik Chaudhuri, Ragini Singh INTRODUCTION Multiple myeloma (from Greek myelo bonemarrow) is one of the plasma cell dyscrasias and refers to an incurable clonal B-cell malignancy with an annual incidence of 1% of all malignancies and 10% of all hematological malignancies. 1 There are approximately 19,000 new cases/year in United States of America (USA) and an Indian incidence of 6,000 new cases/year. The male/female ratio is 1.4:1 and mean 5-year survival rate of 33%. 2 Plasma cell dyscrasias can be broadly subdivided into the following heads: Monoclonal gammopathy of unknown significance (MGUS) Plasmacytoma solitary mass of neoplastic monoclonal plasma cells in either bone or soft tissue (extramedullary) Asymptomatic myeloma Symptomatic myeloma. MONOCLONAL GAMMOPATHY OF UNKNOWN SIGNIFICANCE It is a premalignant condition with an annual incidence of 3.2% in patients above 50 years of age. Approximately 1 2% of these patients develop multiple myeloma every year and is characterized by the following features: A monoclonal paraprotein band (M-protein) less than 3 g/dl Plasma cells less than 10% on bone marrow examination No evidence of hypercalcemia, renal failure, anemia or bony lesions. A risk stratification model developed by the Mayo Clinic, USA utilizes three parameters to define the risk of progression of MGUS to multiple myeloma over a period of 5 20 years and utilizes the following parameters (Table 1): 3 Serum M-protein levels Heavy chain subtype [immunoglobulin G (IgG) or nonimmunoglobulin G (non-igg)] Free light chain (FLC) ratio. PLASMACYTOMA This refers to malignant plasma cell tumors present either in the skeletal system (solitary bone plasmacytoma) or in the soft tissues (extramedullary plasmacytoma) (Figure 1). The diagnostic criteria for both are as follows (Table 2): Figure 1: Plasmacytoma of the tibia ASYMPTOMATIC MYELOMA This is an intermediate phase in the spectrum of multiple myeloma and is also known as smoldering myeloma. It is characterized by the following features: 5 Serum paraprotein greater than 3 g/dl [and/or] Clonal plasma cells greater than 10% on bone marrow biopsy and TABLE 1 Risk stratification model for the progression of MGUS to multiple myeloma 4 Risk group Low-risk (serum M-protein less than 1.5 g/ dl, IgG subtype, normal FLC ratio 0.26 1.65) Low-intermediate risk (anyone factor abnormal) High-intermediate risk (any two factors abnormal) High-risk (all three factors abnormal) Patients (N) Relative risk 449 1 5% 420 5.4 21% 226 10.1 37% 53 20.8 58% Absolute risk of progression at 20 years

Section 10 Chapter 80 Recent Advances in Diagnosis and Management of Multiple Myeloma... TABLE 2 Diagnostic criteria for plasmacytoma 5 Solitary bone plasmacytoma Single area of bone destruction due to clonal plasma cells Bone marrow plasma cell infiltration not exceeding 5% of all nucleated cells Absence of osteolytic bone lesions or other tissue involvement (no evidence of myeloma) Absence of anemia, hypercalcemia or renal impairment attributable to myeloma Low, if present, concentrations of serum or urine monoclonal protein Preserved levels of uninvolved immunoglobulins Soft tissue (extramedullary) plasmacytoma Tissue biopsy showing monoclonal plasma cell histology Bone marrow plasma cell infiltration not exceeding 5% of all nucleated cells Absence of osteolytic bone lesions or other tissue involvement (no evidence of myeloma) Absence of hypercalcemia or renal failure Low serum M-protein concentration, if present No myeloma-related organ or tissue impairment viz. Hypercalcemia, Renal insufficiency, Anemia and Bone lesions (CRAB). The average duration of progression from smoldering myeloma to symptomatic disease is less than 2 years. Symptomatic Multiple Myeloma As defined by the International Myeloma Working Group (IMWG) in 2003 and subsequently revised in 2009, the criteria for symptomatic multiple myeloma includes: 5 Clonal plasma cells greater than 10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma) A monoclonal protein (paraprotein) in either serum or urine Evidence of end-organ damage related to the plasma cell disorder (commonly referred to as CRAB symptoms): Hypercalcemia (> 10.5 mg/dl or > 0.5 mg above normal limits) Renal insufficiency attributable to myeloma (creatinine > 2 mg/dl) Anemia (hemoglobin <10 g/dl or <2 g/dl below normal limits) Bone lesions (lytic lesions or osteoporosis with compression fractures). TYPES OF PARAPROTEINS IN MULTIPLE MYELOMA Serum heavy chain immunoglobulins (77%): Immunoglobulin G kappa or lambda multiple myeloma Immunoglobulin A kappa or lambda multiple myeloma Urinary light chain immunoglobulins or Bence-Jones proteins (20%): Kappa light chain multiple myeloma Lambda light chain multiple myeloma No serum or urinary M-protein (3%): Nonsecretory multiple myeloma. CLINICAL FEATURES As described earlier, multiple myeloma can present with myriad manifestations with the common features including: 6 Bone pain, lytic bone lesions, osteoporosis, pathological fractures and hypercalcemia (70%) Increased susceptibility to bacterial infections, especially pyelonephritis and pneumonias (> 25%). Common organisms include Streptococcus pneumonie, Staphylococcus aureus and Klebsiella pneumonie Renal failure (including amyloidosis and urate nephropathy) in ~25% patients Anemia-normocytic, normochromic type in ~80% patients. Clotting abnormalities including deep vein thrombosis and platelet dysfunction Neurological symptoms including neuropathies, cord compression, headache, visual disturbances and carpal tunnel syndrome. Note: Enlargement of spleen, lymph nodes and gut-associated lymphoid tissue is rare in multiple myeloma. STAGING OF MULTIPLE MYELOMA There are currently two staging systems in vogue for the staging of multiple myeloma. The older system is known as Durie-Salmon staging and is more popular (Table 3). 7 The newer International Staging System (ISS) was formulated in 2005 and is more of a prognostic index and ideally combined with the Durie-Salmon staging (Table 4). 8,9 The parameters used in both these systems are as follows: Note: Serum β 2 -microglobulin levels are an independent prognosticator of mean survival and can substitute staging systems in clinical practice. INVESTIGATIONS AND MONITORING All patients of multiple myeloma should undergo a battery of investigations which would aid in diagnosis as well as direct prognosis and monitoring. Ideal investigations would include: Complete and differential blood counts Serum albumin, serum calcium, serum creatinine Serum β 2 -microglobulin, C-reactive protein, lactate dehydrogenase (LDH) Quantitative immunoglobulins Free light chain assay Serum and urine electrophoresis Serum protein immunofixation Radiological skeletal bone survey Cytogenetics, fluorescent in situ hybridization (FISH) Gene expression profiling (GEP). Monoclonal gammopathy of unknown significance and smoldering myeloma are both premalignant condition with a definite proportion transforming into overt multiple myeloma every year. Hence, it is imperative that monitoring of such patients be undertaken at regular intervals so as to identify and arrest the disease at an early stage. 10 An ideal calendar would include follow-ups at these durations (Table 5): TREATMENT OF MULTIPLE MYELOMA Treatment of multiple myeloma should be focused on therapies to improve symptoms of the disease and decrease the clonal plasma cell population. Asymptomatic disease (e.g. smoldering myeloma) should be carefully monitored for progression and treatment ideally deferred. The initial treatment for a myeloma patient would depend upon whether or not the patient is a candidate for stem cell transplantation. In eligible patients, high-dose chemotherapy with 361

Hematology Section 10 TABLE 3 Durie-Salmon staging system for multiple myeloma 7 Stage Criteria Estimated tumor burden ( 10 12 /m 2 ) I All of the following: Hemoglobin >10 g/dl Serum calcium <12 mg/dl Normal bone X-ray or solitary lesion Low M-component production IgG level <50 g/l (<5 g/dl) IgA level <30 g/l (<3 g/dl) Urine light chain <4 g/24 hours <0.6 (low) II Fitting neither I nor III 0.6 1.20 (intermediate) III One or more of the following: Hemoglobin <8.5 g/dl Serum calcium >12 mg/dl Advanced lytic bone lesions High M-component production IgG level > 70 g/l (>7 g/dl) IgA level > 50 g/l (>5 g/dl) Urine light chains >12 g/24 hours autologous hematopoietic stem-cell transplantation (ASCT) has become the preferred treatment for patients under the age of 65. An initial induction chemotherapy is administered before stem cell transplantation. This includes both conventional and novel induction agents like: Conventional therapy: Glucocorticoids + anthracycline/alkylator Melphalan Melphalan + prednisone VAD (vincristine + doxorubicin + dexamethasone). This produces a remission in about 40% of cases. 11 >1.20 (high) TABLE 4 International staging system for multiple myeloma 8 Stage Criteria Median survival I Serum β 2 -microglobulin (β 2 M) <3.5 mg/l Serum albumin 3.5 g/dl II Serum β 2 -microglobulin <3.5 mg/l and albumin <3.5 g/dl; or β 2 M <3.5 5.5 mg/l, irrespective of the serum albumin TABLE 5 Follow-up calendar for plasma cell dyscrasias Diagnosis Monitoring Supportive therapy Monoclonal gammopathy of unknown significance Smoldering myeloma Every 2 3 months Indolent myeloma Every 1 2 months Stage I myeloma Every 1 2 months Diseasespecific therapy Annual None None Usually none 62 months 44 months III Serum β 2 -microglobulin >5.5 mg/l 29 months None +/ None +/ +/ Stage II, III myeloma Every month Yes Yes Novel therapy: Immunomodulators: Thalidomide, lenalidomide Proteasome inhibitors: Bortezomib. This produces remission in more than 70% of patients. Novel agents may also overcome poor prognostic factors [del(13q), t(4;14)] and prolong event-free and overall survival. 12 NOVEL AGENTS IN MULTIPLE MYELOMA Bortezomib 13 Class of drug: Proteasome inhibitor Mechanism of action: As a reversible inhibitor of the 26S proteasome complex, bortezomib prevents proteolysis, thus affecting a number of cellular signaling cascades and ultimately leading to cellular death or apoptosis. Its half-life ranges from 15 19 hours Recommended dosage: The recommended dose of bortezomib is 1.3 mg/m² as 3 5 second bolus intravenous (IV) injection twice weekly for 2 weeks (days 1, 4, 8 and 11) followed by a 10-day rest period (days 12 21) for 8 cycles Adverse events: Thrombocytopenia, neutropenia, asthenia, peripheral neuropathy, anemia Precautions and dose alterations: Renal failure dose alteration is not needed, even in those requiring dialysis. Hepatic insufficiency use it with caution. Regular monitoring is needed. Thalidomide Thalidomide is an immunomodulator and has a number of mechanisms of action including antiangiogenic activity, inhibition of tumor necrosis factor-α (TNF-α), secretion of interferon-α (IFN-α) and interleukin-2 (IL-2), induction of apoptosis and regulation of adhesion molecule expression. 14 The usual adult dose is 200 mg orally once a day with water, preferably at bedtime and at least 1 hour after the evening meal. Thalidomide is administered in combination with dexamethasone in 28-day treatment cycles. The dexamethasone dose is 40 mg orally daily, administered on days 1 through 4, 9 through 12 and 17 through 20, every 28 days. Adverse effects include venous thromboembolism (VTE), sensory neuropathy, constipation and rashes. It is absolutely contraindicated in pregnancy or young females. Lenalidomide Lenalidomide is an orally administered thalidomide analogue with a different side-effect profile. It has more potent in vitro activity, including the inhibition of angiogenesis, cytokine modulation and T-cell costimulation than thalidomide. It is better tolerated than thalidomide and does not cause significant somnolence, neuropathy or constipation. The most frequently seen toxicities occurring grade greater than 3 are myelosuppression (which can usually be managed with dose reduction and growth factor support if necessary) and thrombosis. 15 It is also prudent at this juncture to review the terms used in describing the response to treatment and assessment of remission status. The IMWG uniform response criteria defines the following terms as (Table 6): There has been a paradigm shift in the traditional way that this disease has been approached and managed in recent years. The previous emphasis was on treating the clinical phenotype but was limited by the observation that the overall survival in some subgroups had not improved, despite the availability of new treatment options. This led to the realization that molecular cytogenetic type is an important criterion which influences choice of, as well as response 362

Section 10 Chapter 80 Recent Advances in Diagnosis and Management of Multiple Myeloma... TABLE 6 International Myeloma Working Group uniform response criteria for multiple myeloma 16 Response subcategory Response criteria 1. Stringent complete response (scr) Complete response (CR) as defined below <plus> Normal serum free light chain (SFLC) ratio Absence of phenotypically aberrant plasma cells by multiparameter flow cytometry 2. Complete response Negative immunofixation on the serum and urine Disappearance of any soft tissue plasmacytomas Less than 5% bone marrow plasma cells 3. Very good partial response (VGPR) Serum and urine M-protein detectable by immunofixation but not on electrophoresis Or Greater than 90% reduction in serum M-protein plus reduction in 24 hours urinary M-protein by greater than 90% or to greater than 100 mg/24 hours 4. Partial response (PR) Greater than 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by greater than 90% or to less than 200 mg/24 hours 5. Stable disease (SD) Not meeting criteria for CR, VGPR, PR or progressive disease to, treatment. The correlation between cytogenetic subtypes and prognostic risk could be summed up in the following (Table 7): 17 High-risk cytogenetic factors: del(17p), del(13q), t(14;16) and hypodiploid. Some of the primary induction regimens that have been utilized to produce remission in multiple myeloma have included the following combination schedules as shown in Table 8. 18 A proposed treatment algorithm (as developed by the Mayo Clinic, USA) for transplant eligible and transplant ineligible patients has prolonged overall survival and complete remission (Flow charts 1 and 2): 34 TABLE 7 Risk stratification for multiple myeloma Category Risk factors Frequency Low-risk multiple myeloma Intermediate-risk multiple myeloma High-risk multiple myeloma Absence of intermediate and high-risk factors. t(4;14) plus absence of 17p deletion or high-risk gene expression profiling signature. Presence of 17p deletion or high-risk gene-expression profiling signature. ~75% ~10% ~15% TABLE 8 Primary induction regimens (combination) in multiple myeloma Regimen Usual dosing schedule Melphalan-prednisone (7-day schedule) 19 Melphalan: 8 10 mg oral days 1 7 Prednisone: 60 mg/day oral days 1 7 Repeated every 6 weeks Thalidomide-dexamethasone 20,21 Thalidomide: 200 mg oral days 1 28 Dexamethasone: 40 mg oral days 1, 8, 15 and 22 Lenalidomide-dexamethasone 22 Lenalidomide: 25 mg oral days 1 21 every 28 days Dexamethasone: 40 mg oral days 1, 8, 15 and 22 every 28 days Bortezomib-dexamethasone 23 Bortezomib: 1.3 mg/m 2 subcutaneous or IV days 1, 8, 15 and 22 Dexamethasone: 20 mg oral on day of and day after bortezomib (or 40 mg days 1, 8, 15 and 22) Melphalan-prednisone-thalidomide 24,25 Melphalan: 0.25 mg/kg oral days 1 4 (use 0.20 mg/kg/day oral; days 1 4 in patients more than 75 years) Prednisone: 2 mg/kg oral days 1 4 Thalidomide: 100 200 mg oral days 1 28 (use 100 mg dose in patients more than 75 years) Repeated every 6 weeks Bortezomib-melphalan-prednisone 26-28 Bortezomib: 1.3 mg/m 2 subcutaneous or IV days 1, 8, 15, and 22 Melphalan: 9 mg/m 2 oral days 1 4 Prednisone: 60 mg/m 2 oral days 1 4 Repeated every 35 days Bortezomib-thalidomide-dexamethasone 29 Bortezomib: 1.3 mg/m 2 subcutaneous or IV days 1, 8, 15 and 22 Thalidomide: 100 200 mg oral days 1 21 Dexamethasone: 20 mg oral on day of and day after bortezomib (or 40 mg days 1, 8, 15 and 22) 4 cycles as pretransplant induction therapy Bortezomib-cyclophosphamide-dexamethasone Cyclophosphamide: 300 mg/m 2 orally on days 1, 8, 15 and 22 (VCD) 30,31 Bortezomib: 1.3 mg/m 2 subcutaneous or intravenously on days 1, 8, 15 and 22 Dexamethasone: 40 mg orally on days on days 1, 8, 15 and 22 Bortezomib-lenalidomide-dexamethasone 32,33 Bortezomib: 1.3 mg/m 2 subcutaneous or IV days 1, 8 and 15 Lenalidomide: 25 mg oral days 1 14 Dexamethasone: 20 mg oral on day of and day after bortezomib (or 40 mg days 1, 8, 15 and 22) Repeated every 3 weeks 363

Hematology Section 10 Flow chart 1: For transplant eligible patients. Copyright 2009 Mayo Foundation for Medical Education and Research Pegylated liposomal doxorubicin (PLD) based regimens: Significant increase in thrombotic thrombocytopenic purpura (TTP) at the cost of higher adverse effects. 37 364 *If age > 65 years or 4 cycles of Rd, consider adding granulocyte colonystimulating factor to chemotherapy for stem cell mobilization. Rd maintenance is an option for patients responding well to induction therapy with low toxicities; dexamethasone is typically discontinued after the first year. Flow chart 2: For transplant ineligible patients. Copyright 2009 Mayo Foundation for Medical Education and Research *Clinical trials strongly recommended as the first option. Rd maintenance is an option for patients responding well to induction therapy with low toxicities; dexamethasone is typically discontinued after the first year. Bortezomib containing regimens preferred in renal failure or if rapid response needed. TREATMENT OF RELAPSED DISEASE The treatment of relapsed disease remains an area of concern as the response in such patients is generally poor. Since no therapy is curative, all options need to be tried sequentially and there is no good data on optimum sequence or regimen. All patients should be encouraged to participate in ongoing clinical trials and cumulative toxicities from prior therapies may influence decision. The salvage therapies available include: Thalidomide-dexamethasone: Induces PR in 30% of patients (47% if combined with dexamethasone) but increased risk of neuropathies and VTE Lenalidomide-dexamethasone: More potent immuno modulator than thalidomide but causes greater myelo suppression 35 Bortezomib-dexamethasone: Then, apex trial (2011) found a significant increase in mean survival (6.22 vs 3.49 months; p < 0.001) and 1 year survival rates (80 vs 66%; p = 0.003) with bortezomib as opposed to high-dose dexamethasone alone 36 SUPPORIVE THERAPY IN MULTIPLE MYELOMA Treatment of bone disease: Bisphosphonates, surgical procedures like vertebroplasty and balloon kyphoplasty and radiotherapy [American Society of Clinical Oncology (ASCO) guidelines] 38 Treatment of anemia: Improve iron and vitamin B 12 /folate levels, erythropoietin therapy, packed cell blood transfusions (ASCO guidelines) 39 Treatment of renal failure: Avoid dehydration and toxic drugs, consider dialysis Treatment of infections: Prophylactic antibiotics, aseptic precautions Venous thromboembolism prevention: Low-molecular weight heparin and full dose warfarin are recommended. Consider aspirin in low-risk patients. NEWER THERAPIES A number of newer agents have been tried in multiple myeloma with variable results (Table 9). EXPERIENCE WITH MULTIPLE MYELOMA AT POST- GRADUATE INSTITUTE OF MEDICAL SCIENCES, ROHTAK, HARYANA A total of 100 new patients of multiple myeloma have been evaluated at our hematology clinic over the past two decades (1992 2012), with 88 being male and 12 being female patients. It constituted 2.5% of total hematological malignancies. 67% of our patients were over 50 years of age and only 11% were younger than 30 years at presentation. Most males presented at a later mean age (56 ± 5.6 years) as compared to females (51 ± 6.2 years). The most common presenting features were bony pain (58%), generalized weakness/anemia (54%), renal failure (35%), fever (26%), pathological fractures (20%) and paraplegia (6%). This correlated well with the data published by Kyle at al. from Mayo Clinic, who found bony lesions (79%), anemia (73%) and renal failure (32%) as the most common presenting signs and symptoms. 19 The treatment options in multiple myeloma have undergone a paradigm shift in the past two decades and this is reflected in our data as well. Melphalan-prednisolone (MP) was used in 48 patients, whereas 18 patients were treated with the Vincristine-Doxorubucin- Dexamethasone (VAD) regimen. Fourteen received MP + thalidomide and 10 were treated with thalidomide-dexamethasone. Five patients received bortezomib alone. Seventy-eight percent of patients have expired over a 20-year review period whereas 12% are still under monitoring. Ten patients were lost in follow-up. The overall prognosis was poor due to poor socioeconomic conditions precluding use of novel therapeutic options. TABLE 9 New therapeutic agents for multiple myeloma 17 Therapeutic target or class of agent Immunomodulatory agents Proteasome inhibitors Histone deacetylase inhibitors Phosphatidylinositol-3 kinase pathway inhibitors Anti-CS1 Heat shock protein 90 inhibitors Agent Pomalidomide Carfilzomib, MLN9708 Vorinostat, panobinostat Perifosine Elotuzumab Tanespimycin

Section 10 Chapter 80 Recent Advances in Diagnosis and Management of Multiple Myeloma... SUMMARY AND CONCLUSION Multiple myeloma is not uncommon in our country and constituted 2.5% of all hematological malignancies. The disease presentation is similar to that seen in the west. The introduction of novel agents like thalidomide, lenalidomide and bortezomib have altered the present day management of myeloma and made it possible to convert it into a chronic disease with which one can live for a decade or more. The outcome in our patients was poor probably because of late presentation, treatment failure and nonavailability of latest modes of treatment due to socioeconomic factor. REFERENCES 1. Raab MS, Podar K, Breitkreutz I, et al. Multiple myeloma. Lancet. 2009;374(9686):324-39. 2. Ries LAG, Melbert D, Krapcho M, et al. (2007). SEER Cancer Statistics Review, 1975 2004. Bethesda, MD: National Cancer Institute. [online]. Available from http://seer.cancer.gov/csr/1975_2004/ [Accessed November, 2012]. 3. Rajkumar SV, Kyle RA, Buadi FK. Advances in the diagnosis, classification, risk stratification and management of monoclonal gammopathy of undetermined significance: implications for recategorizing disease entities in the presence of evolving scientific evidence. Mayo Clin Proc. 2010;85(10):945-8. 4. Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005;106(3):812-7. 5. The International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121(5):749-57. 6. Munshi NC, Longo DL, Anderson KC. Plasma cell disorders. In: Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Longo DL, Jameson JL (Eds). Harrison s Principles of Internal Medicine, 17th edn. New York, NY: McGraw-Hill; 2008. p. 702. 7. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment and survival. Cancer. 1975;36(3):842-54. 8. Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23(15):3412-20. 9. Hari PN, Zhang MJ, Roy V, et al. Is the international staging system superior to the Durie-Salmon staging system? A comparison in multiple myeloma patients undergoing autologous transplant. Leukemia. 2009;23(8):1528-34. 10. Landgren O, Kyle RA, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009;113(22):5412-7. 11. Attal M, Harousseau JL. Standard therapy versus autologous transplantation in multiple myeloma. Hematol Oncol Clin North Am. 1997;11(1):133-46. 12. Mitsiades N, Mitsiades CS, Poulaki V, et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood. 2002;99(12):4525-30. 13. Reece D, Imrie K, Stevens A, et al. Bortezomib in multiple myeloma and lymphoma: a systematic review and clinical practice guideline. Curr Oncol. 2006;13(5):160-72. 14. Hideshima T, Anderson KC. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer. 2002;2(12):927-37. 15. Richardson P, Mitsiades C, Lauback J, et al. Lenalidomide in multiple myeloma: an evidence-based review of its role in therapy. Core Evid. 2009;4:215-45. 16. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467-73. 17. Rajkumar SV. Treatment of multiple myeloma. Nat Rev Clin Oncol. 2011;8(8):479-91. 18. Rajkumar SV. Multiple myeloma: 2012 update on diagnosis, riskstratification and management. Am J Hematology. 2012;87(1):78-88. 19. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004; 351(18):1860-73. 20. Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the eastern cooperative oncology group. J Clin Oncol. 2006;24(3):431-6. 21. Rajkumar SV, Rosin ol L, Hussein M, et al. A multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone versus dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol. 2008;26:2171 7. 22. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: An open-label randomised controlled trial. Lancet Oncol. 2010;11:29 37. 23. Harousseau J, Attal M, Leleu X, et al. Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: Results of an IFM phase II study.haematologica. 2006;91:1498 1505. 24. Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reducedintensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99 06): A randomised trial. Lancet. 2007;370:1209 18. 25. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 Trial. J Clin Oncol. 2009;27:3664 70. 26. Mateos MV, Oriol A, Martinez-Lopez J. Bortezomib/melphalan/ prednisone (VMP) versus bortezomib/thalidomide/prednisone (VTP) as induction therapy followed by maintenance treatment with bortezomib/thalidomide (VT) versus bortezomib/prednisone (VP): A randomised trial in elderly untreated patients with multiple myeloma older than 65 years. Lancet Oncol. 2010;11:934 41. 27. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalanprednisonethalidomide followed by maintenance with bortezomibthalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: A randomized controlled trial. J Clin Oncol. 2010;28:5101 09. 28. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906 17. 29. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stemcell transplantation in newly diagnosed multiple myeloma: A randomised phase 3 study. Lancet. 2010;376:2075 85. 30. Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: High response rates in a phase II clinical trial. Leukemia. 2009;23:1337 41. 31. Kumar S, Flinn IW, Hari PN, et al. Novel three- and four-drug combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide, for newly diagnosed multiple myeloma: Encouraging results from the multi-center, randomized, phase 2 EVOLUTION Study. ASH Annu Meet Abstr. 2009;114:127. 32. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple yeloma. Blood. 2010;116:679 86. 33. Kumar S, Flinn IW, Richardson PG, et al. Novel three- and fourdrug combination regimens of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide, for previously untreated multiple myeloma: Results From the Multi-Center, Randomized, Phase 2 Evolution Study. ASH Annu Meet Abstr. 2010;116:621. 34. Kumar SK, Mikhael JR, Buadi FK, et al. Management of newly diagnosed symptomatic multiple myeloma: Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (msmart) Consensus Guidelines. Mayo Clinic Proc. 2009;84:1095 1110. 35. Weber D. ASCO 2005; Dimopoulos Blood 2005;106:abstract 6. 36. Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007;110:3557-60. 37. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized Phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: Combination therapy improves time to progression. J Clin Oncol. 2007;25:3892 3901. 38. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007;25:2464-72. 39. Durie BGM, Kyle R, Belch A, et al: Myeloma management guidelines: A consensus report from the Scientific Advisors of the International Myeloma Foundation. Hematol J. 2003;4:379-98. 365