Multiple myeloma accounts for approximately 10% of hematologic malignancies. The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events: CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging. Patients with del(17p), t(14;16), and t(14;20) have high‐risk multiple myeloma. Patients with t(4;14) translocation and gain(1q) have intermediate‐risk. All others are considered standard‐risk. Initial treatment consists of bortezomib, lenalidomide, dexamethasone (VRd). In high‐risk patients, carfilzomib, lenalidomide, dexamethasone (KRd) is an alternative to VRd. In eligible patients, initial therapy is given for approximately 3‐4 cycles followed by autologous stem cell transplantation (ASCT). Standard risk patients can opt for delayed ASCT at first relapse. Patients not candidates for transplant are treated with VRd for approximately 8‐12 cycles followed by lenalidomide or lenalidomide plus dexamethasone. After ASCT, lenalidomide maintenance is recommended for standard risk patients, while maintenance with a bortezomib‐based regimen is needed for patients with intermediate or high‐risk disease. Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse. Aggressive relapse with extramedullary plasmacytomas or plasma cell leukemia may require anthracycline containing combination chemotherapy regimens.

1 DISEASE OVERVIEW Multiple myeloma accounts for 1% of all cancers and approximately 10% of all hematologic malignancies.1 Each year over 30 000 new cases are diagnosed in the United States, and over 12 000 patients die of the disease.2 The annual age‐adjusted incidence in the United States has remained stable for decades at approximately 4 per 100 000.3 Multiple myeloma is slightly more common in men than in women, and is twice as common in African‐Americans compared with Caucasians.4 The median age of patients at the time of diagnosis is about 65 years.5 Unlike other malignancies that metastasize to bone, the osteolytic bone lesions in multiple myeloma exhibit no new bone formation.6 Bone disease is the main cause of morbidity and can be detected on routine skeletal radiographs, low‐dose whole body computed tomography (WB‐CT), magnetic resonance imaging (MRI), or fluoro‐deoxyglucose positron emission tomography/computed tomographic scans (PET/CT).7, 8 Other major clinical manifestations are anemia, hypercalcemia, renal failure, and an increased risk of infections. Approximately, 1% to 2% of patients have extramedullary disease (EMD) at the time of initial diagnosis, while 8% develop EMD later on in the disease course.9 Almost all patients with multiple myeloma evolve from an asymptomatic premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS).10, 11 MGUS is present in over 3% of the population above the age of 50,12, 13 and the prevalence is approximately 2‐fold higher in blacks compared with whites.14, 15 MGUS progresses to multiple myeloma or related malignancy a rate of 1% per year.16, 17 Since MGUS is asymptomatic, over 50% of individuals who are diagnosed with MGUS have had the condition for over 10 years prior to the clinical diagnosis.18 In some patients, an intermediate asymptomatic but more advanced premalignant stage referred to as smoldering multiple myeloma (SMM) can be recognized clinically.19 SMM progresses to multiple myeloma at a rate of approximately 10% per year over the first 5 years following diagnosis, 3% per year over the next 5 years, and 1.5% per year thereafter. This rate of progression is influenced by the underlying cytogenetic type of disease; patients with t(4;14) translocation, del(17p), and gain(1q) are at a higher risk of progression from MGUS or SMM to multiple myeloma.20-22

2 DIAGNOSIS The revised International Myeloma Working Group criteria for the diagnosis of multiple myeloma and related disorders are shown on Table 1.1 The diagnosis of multiple myeloma requires the presence of one or more myeloma defining events (MDE) in addition to evidence of either 10% or more clonal plasma cells on bone marrow examination or a biopsy‐proven plasmacytoma. MDE consists of established CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features as well as 3 specific biomarkers: clonal bone marrow plasma cells ≥60%, serum free light chain (FLC) ratio ≥100 (provided involved FLC level is ≥100 mg/L), and more than one focal lesion on MRI. Each of the new biomarkers is associated with an approximately 80% risk of progression to symptomatic end‐organ damage in two or more independent studies. The updated criteria represent a paradigm shift since they allow early diagnosis and initiation of therapy before end‐organ damage. Table 1. International myeloma working group diagnostic criteria for multiple myeloma and related plasma cell disorders Disorder Disease definition Non‐IgM monoclonal gammopathy of undetermined significance (MGUS) All 3 criteria must be met: Serum monoclonal protein (non‐IgM type) <3 gm/dL

Clonal bone marrow plasma cells <10%a

Absence of end‐organ damage such as hyper c alcemia, r enal insufficiency, anemia, and bone lesions (CRAB) that can be attributed to the plasma cell proliferative disorder Smoldering multiple myeloma Both criteria must be met: Serum monoclonal protein (IgG or IgA) ≥3 g/dL, or urinary monoclonal protein ≥500 mg per 24 hours and/or clonal bone marrow plasma cells 10%‐60%

Absence of myeloma defining events or amyloidosis Multiple myeloma Both criteria must be met: Clonal bone marrow plasma cells ≥10% or biopsy‐proven bony or extramedullary plasmacytoma

Any one or more of the following myeloma defining events: Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: Hypercalcemia: serum calcium >0·25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2·75 mmol/L (>11 mg/dL) Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177 μmol/L (>2 mg/dL) Anemia: hemoglobin value of >2 g/dL below the lower limit of normal, or a hemoglobin value <10 g/dL Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography‐CT (PET‐CT) Clonal bone marrow plasma cell percentage ≥60% Involved: uninvolved serum free light chain (FLC) ratio ≥100 (involved free light chain level must be ≥100 mg/L) >1 focal lesions on magnetic resonance imaging (MRI) studies (at least 5 mm in size)

IgM Monoclonal gammopathy of undetermined significance (IgM MGUS) All 3 criteria must be met: Serum IgM monoclonal protein <3 g/dL

Bone marrow lymphoplasmacytic infiltration <10%

No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder. Light Chain MGUS All criteria must be met: Abnormal FLC ratio (<0.26 or >1.65)

Increased level of the appropriate involved light chain (increased kappa FLC in patients with ratio > 1.65 and increased lambda FLC in patients with ratio < 0.26)

No immunoglobulin heavy chain expression on immunofixation

Absence of end‐organ damage that can be attributed to the plasma cell proliferative disorder

Clonal bone marrow plasma cells <10%

Urinary monoclonal protein <500 mg/24 hours Solitary Plasmacytoma All 4 criteria must be met Biopsy proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells

Normal bone marrow with no evidence of clonal plasma cells

Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)

Absence of end‐organ damage such as hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB) that can be attributed to a lympho‐plasma cell proliferative disorder Solitary Plasmacytoma with minimal marrow involvementb All 4 criteria must be met Biopsy proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells

Clonal bone marrow plasma cells <10%

Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)

Absence of end‐organ damage such as hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB) that can be attributed to a lympho‐plasma cell proliferative disorder When multiple myeloma is suspected clinically, patients should be tested for the presence of M proteins using a combination of tests that should include a serum protein electrophoresis (SPEP), serum immunofixation, and the serum FLC assay.23 Approximately, 2% of patients with multiple myeloma have true nonsecretory disease and have no evidence of an M protein on any of the above studies.5, 24 Bone marrow studies at the time of initial diagnosis should include fluorescent in situ hybridization (FISH) probes designed to detect t(11;14), t(4;14), t(14;16), t(6;14), t(14;20), trisomies, and del(17p) (see Risk‐Stratification below).25 Conventional karyotyping to detect hypodiploidy and deletion 13 has value, but if FISH studies are done, additional value in initial risk‐stratification is limited. Gene expression profiling if available can provide additional prognostic value.26 Serum CrossLaps to measure carboxy‐terminal collagen crosslinks (CTX) may be useful in assessing bone turnover and to determine adequacy of bisphosphonate therapy.27, 28 The extent of bone disease is best assessed by low‐dose WB‐CT or PET/CT imaging.8 MRI scans are useful in patients with suspected SMM to rule out focal bone marrow lesions that can be seen before true osteolytic disease occurs. MRI imaging is also useful in assessing EMD, suspected cord compression, or when detailed imaging of a specific symptomatic area is needed. Conventional skeletal survey is less sensitive than low‐dose WB‐CT and PET/CT and recommended only if resources for more advanced imaging are not available. The M protein is considered to be measurable if it is ≥1 g/dL in the serum and or ≥200 mg/day in the urine. The M protein level is monitored by SPEP and serum FLC assay to assess treatment response every month while on therapy, and every 3–4 months when off‐therapy. The serum FLC assay is particularly useful in patients who lack a measurable M protein, provided the FLC ratio is abnormal and the involved FLC level is ≥100 mg/L.29 Urine protein electrophoresis is recommended at least once every 3–6 months, to follow the urine M protein level as well as to detect other renal complications that may result in albuminuria. Response to therapy assessment and minimal residual disease (MRD) evaluation is based on the revised International Myeloma Working Group uniform response criteria.30

3 MOLECULAR CLASSIFICATION Although multiple myeloma is still considered a single disease, it is in reality a collection of several different cytogenetically distinct plasma cell malignancies (Table 2).31, 32 On FISH studies of the bone marrow, approximately 40% of multiple myeloma is characterized by the presence of trisomies in the neoplastic plasma cells (trisomic multiple myeloma), while most of the rest have a translocation involving the immunoglobulin heavy chain (IgH) locus on chromosome 14q32 (IgH translocated multiple myeloma).33-36 A small proportion of patients have both trisomies and IgH translocations. Trisomies and IgH translocations are considered primary cytogenetic abnormalities and occur at the time of establishment of MGUS. In addition, other cytogenetic changes termed secondary cytogenetic abnormalities arise along the disease course of multiple myeloma, including gain(1q), del(1p), del(17p), del(13), RAS mutations, and secondary translocations involving MYC. Both primary and secondary cytogenetic abnormalities can influence disease course, response to therapy, and prognosis. Importantly, the interpretation and impact of cytogenetic abnormalities in multiple myeloma vary depending on the disease phase in which they are detected (Table 3).37 Table 2. Primary molecular cytogenetic classification of multiple myeloma Subtype Gene(s)/chromosomes affecteda Percentage ofmyeloma patients Trisomic multiple myeloma Recurrent trisomies involving odd‐numbered chromosomes with the exception of chromosomes 1, 13, and 21 42 IgH translocated multiple myeloma 30 t(11;14) (q13;q32) CCND1 (cyclin D1) 15 t(4;14) (p16;q32) FGFR‐3 and MMSET 6 t(14;16) (q32;q23) C‐MAF 4 t(14;20) (q32;q11) MAFB <1 Other IgH translocationsa CCND3 (cyclin D3) in t(6;14) multiple myeloma 5 Combined IgH translocated/trisomic multiple myeloma Presence of trisomies and any one of the recurrent IgH translocations in the same patient 15 Isolated Monosomy 14 Few cases may represent 14q32 translocations involving unknown partner chromosomes 4.5 Other cytogenetic abnormalities in absence of IgH translocations or trisomy or monosomy 14 5.5 Normal 3 Table 3. Cytogenetic abnormalities on clinical course and prognosis in multiple myeloma Cytogenetic abnormality Clinical setting in which abnormality is detected Smoldering multiple myeloma Multiple myeloma Trisomies Intermediate‐risk of progression, median TTP of 3 years Good prognosis, standard‐risk MM, median OS 7–10 years Most have myeloma bone disease at diagnosis Excellent response to lenalidomide‐based therapy t(11;14) (q13;q32) Standard‐risk of progression, median TTP of 5 years Good prognosis, standard‐risk MM, median OS 7–10 years t(6;14) (p21;q32) Standard‐risk of progression, median TTP of 5 years Good prognosis, standard‐risk MM, median OS 7–10 years t(4;14) (p16;q32) High‐risk of progression, median TTP of 2 years Intermediate‐risk MM, median OS 5 years Needs bortezomib‐based initial therapy, early ASCT (if eligible), followed by bortezomib‐based consolidation/maintenance t(14;16) (q32;q23) Standard‐risk of progression, median TTP of 5 years High‐risk MM, median OS 3 years Associated with high levels of FLC and 25% present with acute renal failure as initial MDE t(14;20) (q32;q11) Standard‐risk of progression, median TTP of 5 years High‐risk MM, median OS 3 years Gain(1q21) High‐risk of progression, median TTP of 2 years Intermediate‐risk MM, median OS 5 years Del(17p) High‐risk of progression, median TTP of 2 years High‐risk MM, median OS 3 years Trisomies plus any one of the IgH translocations Standard‐risk of progression, median TTP of 5 years May ameliorate adverse prognosis conferred by high risk IgH translocations, and del 17p Isolated Monosomy 13, or Isolated Monosomy 14 Standard‐risk of progression, median TTP of 5 years Effect on prognosis is not clear Normal Low‐risk of progression, median TTP of 7–10 years Good prognosis, probably reflecting low tumor burden, median OS >7–10 years

4 PROGNOSIS AND RISK STRATIFICATION Survival estimates in multiple myeloma vary based on the source of the data. Data from randomized controlled trials using modern therapy show that the median survival in multiple myeloma is approximately 6 years.38 In the subset of patients eligible for ASCT, 4‐year survival rates are more than 80%39; the median overall survival (OS) among these patients is approximately 8 years.40 Among elderly patients (age >75 years), median OS is lower, and is approximately 5 years.38 These numbers likely underestimate current survival probabilities since they predate the arrival of monoclonal antibodies and several other new agents that have been introduced in the last 3 to 5 years. Conversely, they may be overestimates of the true population‐based survival since they are derived from randomized controlled trials where patients with poor performance status and comorbidities are typically excluded. Nevertheless, these estimates are valuable benchmarks, and appear generalizable to newly diagnosed myeloma patients in good performance status.41 More precise estimation of prognosis requires an assessment of multiple factors. As in other cancers, OS in multiple myeloma is affected by host characteristics, tumor burden (stage), biology (cytogenetic abnormalities), and response to therapy.42, 43 Tumor burden in multiple myeloma has traditionally been assessed using the Durie‐Salmon Staging44 and the International staging system (ISS).45, 46 Disease biology best reflected based on the molecular subtype of multiple myeloma (Table 2), the presence or absence of secondary cytogenetic abnormalities such as del(17p), gain(1q), or del(1p).25, 32 In addition to cytogenetic risk factors, two other markers that are associated with aggressive disease biology are elevated serum lactate dehydrogenase and evidence of circulating plasma cells on routine peripheral smear examination (plasma cell leukemia). The Revised International Staging System (RISS) combines elements of tumor burden (ISS) and disease biology (presence of high risk cytogenetic abnormalities or elevated lactate dehydrogenase level) to create a unified prognostic index that and helps in clinical care as well as in comparison of clinical trial data (Table 4).47 To ensure uniform availability, only 3 widely available cytogenetic markers are used in the RISS; the Mayo Clinic mSMART risk stratification (www.msmart.org) (Table 5) has additional detail that is valuable in formulating a therapeutic strategy.48 Table 4. Revised international staging system for myeloma Stage Stage 1 All of the following: Serum albumin ≥3.5 gm/dL

Serum beta‐2‐microglobulin <3.5 mg/L

No high risk cytogenetics

Normal serum lactate dehydrogenase level Stage II Not fitting Stage I or III Stage III Both of the following: Serum beta‐2‐microglobulin >5.5 mg/L

High risk cytogenetics [t(4;14), t(14;16), or del(17p)] or Elevated serum lactate dehydrogenase level Table 5. Mayo clinic risk stratification for multiple myeloma (mSMART) Risk group Percentage of newly diagnosedpatients with the abnormality Standard Risk 75% Trisomies t(11;14) t(6;14) Intermediate Risk 10% t(4;14) Gain(1q) High Risk 15% t(14:16) t(14;20) del(17p) Treated appropriately, the survival of patients with certain high risk categories can approach that of patients with standard risk disease. In a large trial using bortezomib‐based induction, early tandem ASCT, and bortezomib maintenance, the median OS of patients with del(17p) was approximately 8 years (8‐year survival rate of 52%), and was identical to patients with standard risk multiple myeloma. In contrast, survival was lower for patients with t(4;14) translocation (8‐year survival rate, 33%) and for patients with gain(1q) abnormality (8‐year survival rate, 36%). These findings underscore the limitations of current risk stratification models in the context of modern therapy and highlight the need to stratify multiple myeloma based on individual cytogenetic groups rather than arbitrary heterogeneous risk categories.31

5 INDICATIONS FOR THERAPY To initiate therapy, patients must meet criteria for multiple myeloma as outlined in Table 1. In earlier trials, treatment of asymptomatic patients with SMM was associated with a benefit in progression free survival (PFS) but not OS.49 However, a recent randomized trial found that early therapy with lenalidomide and dexamethasone in patients with high risk SMM can prolong PFS and OS.50 Although these results need further confirmation, they indicate the potential benefit of early intervention in selected asymptomatic patients.

6 TREATMENT OF NEWLY DIAGNOSED MYELOMA Survival in multiple myeloma has improved significantly in the last 15 years.51 The initial impact came from the introduction of thalidomide,52 bortezomib,53 and lenalidomide.54, 55 In the last 5 years, carfilzomib, pomalidomide, panobinostat, ixazomib, elotuzumab, and daratumumab have been approved by the Food and Drug Administration (FDA) for the treatment of relapsed multiple myeloma, and promise to improve outcomes further. Numerous combinations have been developed using drugs that have shown activity in multiple myeloma, and the most commonly used regimens are listed in Table 6.56-75 These drugs work through a variety of mechanisms, some of which are not fully understood. Thalidomide, lenalidomide, and pomalidomide are termed immunomodulatory agents (IMiDs). IMiDs bind to cereblon and activate cereblon E3 ligase activity, resulting in the rapid ubiquitination and degradation of two specific B cell transcription factors, Ikaros family zinc finger proteins Ikaros (IKZF 1) and Aiolos (IKZF3).76-78 They may cause direct cytotoxicity by inducing free radical mediated DNA damage.79 They also have anti‐angiogenic, immunomodulatory, and tumor necrosis factor alpha inhibitory properties. Bortezomib, carfilzomib, and ixazomib are proteasome inhibitors.80-82 Elotuzumab and daratumumab are monoclonal antibodies targeting SLAMF7 and CD38 respectively.73, 83, 84 Panobinostat is a deacetylase inhibitor.75, 85 Table 6. Major treatment regimens in multiple myeloma Regimen Usual Dosing Schedulea Thalidomide‐dexamethasone (Td)b 56, 57 Thalidomide 200 mg oral days 1–28 Dexamethasone 40 mg oral days 1, 8, 15, 22 Repeated every 4 weeks Lenalidomide‐dexamethasone (Rd) 58 Lenalidomide 25 mg oral days 1–21 every 28 days Dexamethasone 40 mg oral days 1, 8, 15, 22 every 28 days Repeated every 4 weeks Pomalidomide‐dexamethasone (Pom/Dex) 59 Pomalidomide 4 mg days 1–21 Dexamethasone 40 mg oral on days on days 1, 8, 15, 22 Repeated every 4 weeks Bortezomib‐melphalan‐prednisone (VMP)b 60-62 Bortezomib 1.3 mg/m2 subcutaneous days 1, 8, 15, 22 Melphalan 9 mg/m2 oral days 1–4 Prednisone 60 mg/m2 oral days 1 to 4 Repeated every 35 days Bortezomib‐thalidomide‐dexamethasone (VTd)b 63 Bortezomib 1.3 mg/m2 subcutaneous days 1, 8, 15, 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, 22) Repeated every 4 weeks × 4 cycles as pretransplant induction therapy Bortezomib‐ Cyclophosphamide‐Dexamethasoneb (VCd or CyBord) 64, 65 Cyclophosphamide 300 mg/m2 orally on days 1, 8, 15, and 22 Bortezomib 1.3 mg/m2 subcutaneous on days 1, 8, 15, 22 Dexamethasone 40 mg oral on days on days 1, 8, 15, 22 Repeated every 4 weeksc Bortezomib‐Lenalidomide‐Dexamethasone (VRd)b 65, 66 Bortezomib 1.3 mg/m2 subcutaneous days 1, 8, 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, 22) Repeated every 3 weeksd Carfilzomib‐ Cyclophosphamide‐Dexamethasone (KCd)e 67 Carfilzomib 20 mg/m2 (days 1 and 2 of Cycle 1) and 27 mg/ m2 (subsequent doses) intravenously on days 1, 2, 8, 9, 15, 16 Cyclophosphamide 300 mg/m2 orally on days 1, 8, 15 Dexamethasone 40 mg oral on days on days 1, 8, 15, 22 Repeated every 4 weeks Carfilzomib‐Lenalidomide‐Dexamethasone (KRd)e 68 Carfilzomib 20 mg/m2 (days 1 and 2 of Cycle 1) and 27 mg/ m2 (subsequent doses) intravenously on days 1, 2, 8, 9, 15, 16 Lenalidomide 25 mg oral days 1–21 Dexamethasone 40 mg oral days 1, 8, 15, 22 Repeated every 4 weeks Carfilzomib‐Pomalidomide‐Dexamethasone (KPd)e 69 Carfilzomib 20 mg/m2 (days 1 and 2 of Cycle 1) and 27 mg/ m2 (subsequent cycles) intravenously on days 1, 2, 8, 9, 15, 16 Pomalidomide 4 mg oral on days 1–21 Dexamethasone 40 mg oral on days on days 1, 8, 15, 22 Repeated every 4 weeks Daratumumab‐Lenalidomide‐Dexamethasone (DRd) 70 Daratumumab 16 mg/ kg intravenously weekly x 8 weeks, and then every 2 weeks for 4 months, and then once monthly Lenalidomide 25 mg oral days 1–21 Dexamethasone 40 mg intravenous days 1, 8, 15, 22 (given oral on days when no daratumumab is being administered) Lenalidomide‐Dexamethasone repeated in usual schedule every 4 weeks Daratumumab‐Bortezomib‐Dexamethasone (DVd)b 71 Daratumumab 16 mg/ kg intravenously weekly x 8 weeks, and then every 2 weeks for 4 months, and then once monthly Bortezomib 1.3 mg/m2 subcutaneous on days 1, 8, 15, 22 Dexamethasone 40 mg intravenous days 1, 8, 15, 22 (given oral on days when no daratumumab is being administered) Bortezomib‐Dexamethasone repeated in usual schedule every 4 weeks Daratumumab‐Pomalidomide‐Dexamethasone (DPd) 72 Daratumumab 16 mg/kg intravenously weekly × 8 weeks, and then every 2 weeks for 4 months, and then once monthly Pomalidomide 4 mg oral on days 1–21 Dexamethasone 40 mg intravenous days 1, 8, 15, 22 (given oral on days when no daratumumab is being administered) Repeated every 4 weeks Elotuzumab‐Lenalidomide‐Dexamethasone (ERd) 73 10 mg/ kg intravenously weekly x 8 weeks, and then every 2 weeks Lenalidomide 25 mg oral days 1–21 Dexamethasone per prescribing information Lenalidomide‐Dexamethasone repeated in usual schedule every 4 weeks Ixazomib‐Lenalidomide‐Dexamethasone (IRd) 74 Ixazomib 4 mg oral days 1, 8, 15 Lenalidomide 25 mg oral days 1–21 Dexamethasone 40 mg oral days 1, 8, 15, 22 Repeated every 4 weeks Panobinostat‐Bortezomibb 75 Panobinostat 20 mg oral three times a week × 2 weeks Bortezomib 1.3 mg/m2 subcutaneous days 1, 8, 15 Repeated every 3 weeks The approach to treatment of symptomatic newly diagnosed multiple myeloma is outlined in Figure 1 and is dictated by eligibility for ASCT and risk‐stratification. The data to support their use from recent randomized trials using new active agents for multiple myeloma are provided in Table 7.38, 39, 60, 86-88 There is an ongoing “cure versus control” debate on whether we should treat multiple myeloma with an aggressive multi‐drug strategy targeting complete response (CR) or a sequential disease control approach that emphasizes quality of life as well as OS.89, 90 Figure 1 Open in figure viewer PowerPoint Approach to the treatment of newly diagnosed multiple myeloma in transplant eligible (A) and transplant ineligible (B) patients. ASCT, autologous stem cell transplantation; CR, complete response; KRD, carfilzomib, lenalidomide, dexamethasone; Rd, lenalidomide plus dexamethasone; VGPR, very good partial response; VRD, bortezomib, lenalidomide, dexamethasone Table 7. Results of recent randomized studies in newly diagnosed myeloma Trial Regimen No. ofpatients Overallresponserate (%) CR plusVGPR (%) Progression‐freesurvival (Medianin months) P value forprogressionfree survival Overall survival(Median inmonths)a P value foroverallsurvival San Miguel et al;Mateos et alb 60, 86 MP 331 35 8 17 43 VMP 337 71 41 24 <0.001 NR <.001 Benboubker et al 87 MPT 547 62 28 21 <0.001 48 .016c Rd x 18 months 541 73 43 21 53 Rd till progression 535 75 44 26 56 Durie et al 38 Rd 229 72 32 31 0.002 64 .025 VRd 242 82 43 43 75 Moreau et al 88 VCd 169 83 56 N/A N/A N/A VTd 169 92 66 N/A N/A N/A Attal et al 39 VRd 350 97 77 36 NR; 82%at 4 years .87 VRd‐ASCT 350 98 88 50 <0.001 NR; 81%at 4 years Recent data show that MRD negative status (as estimated by next generation molecular methods or flow cytometry) has favorable prognostic value.30 However, additional trials are needed to determine if changes in treatment need to be made based on MRD status. At present, MRD results are recommended mainly as a prognostic metric and not for used in making treatment decisions. We also need additional data to determine if MRD negativity can be used as a surrogate endpoint for regulatory approval, and if sustained MRD negativity may be a marker of cure in at least a subset of patients.91 6.1 Initial treatment in patients eligible for ASCT Typically, patients are treated with approximately 3–4 cycles of induction therapy prior to stem cell harvest. After harvest, patients can either undergo frontline ASCT or resume induction therapy delaying ASCT until first relapse. There are many options for initial therapy, and the most common treatment regimens are discussed below. These regimens can also be used at the time of relapse. In general, the low‐dose dexamethasone regimen (40 mg once a week) is preferred in all regimens to minimize toxicity. In a randomized trial conducted by the EasternCooperative Oncology Group (ECOG), the low‐dose dexamethasone approach was associated with superior OS and significantly lower toxicity.58 6.1.1 Bortezomib‐containing regimens Bortezomib, lenalidomide, dexamethasone (VRd) is the current standard of care for newly diagnosed multiple myeloma. In a recent randomized trial conducted by the Southwest Oncology Group (SWOG), response rates, PFS, and OS were significantly superior with VRd compared with Rd (Table 7).38 If lenalidomide is not available for use as initial therapy or in the presence of acute renal failure, other bortezomib‐containing regimens such as bortezomib‐thalidomide‐dexamethasone (VTd) or bortezomib‐cyclophosphamide‐dexamethasone (VCd) can be used instead of VRd. A recent randomized trial found that VTd results in superior response rates compared with VCd, but impact on long‐term outcomes is not known.88 Therefore both are reasonable alternatives to VRd. In initial studies, peripheral neuropathy was a major concern with bortezomib therapy. Neuropathy with bortezomib can occur abruptly, and can be significantly painful and debilitating. However, the neurotoxicity of bortezomib can be greatly diminished by administering bortezomib once a week instead of twice‐weekly,61, 62 and by administering the drug subcutaneously instead of the intravenous route.92 The once‐weekly subcutaneous bortezomib schedule (Table 6) has made serious neuropathy an uncommon problem, and has made regimens such as VRd, VCd, and VTd much more tolerable. Bortezomib does not appear to have any adverse effect on stem cell mobilization.93 6.1.2 Lenalidomide‐low dose dexamethasone (Rd) Rd which combines lenalidomide with a lower dose of dexamethasone (40 mg once weekly) is an active regimen in newly diagnosed multiple myeloma, and has less toxicity and better OS than lenalidomide plus high dose dexamethasone or MPT.58, 87 Currently Rd is recommended mainly for patients who are unable to tolerate a triplet regimen due to advanced age, poor performance status, or comorbidities. Stem cell collection with granulocyte stimulating factor (G‐CSF) alone may be impaired when Rd is used as induction therapy.94 Thus, patients over the age of 65 and those who have received more than 4 cycles of Rd stem cells must be mobilized with either cyclophosphamide plus G‐CSF or with plerixafor.95, 96 All patients treated with Rd require anti‐thrombosis prophylaxis. Aspirin is adequate for most patients, but in patients who are at higher risk of thrombosis, either low‐molecular weight heparin or warfarin is needed.97-99 6.1.3 Carfilzomib‐lenalidomide‐dexamethasone (KRd) Two phase II trials have reported excellent results with the newly approved proteasome inhibitor carfilzomib when used in combination with lenalidomide and dexamethasone for newly diagnosed multiple myeloma.100, 101 However, more data on safety and efficacy of KRd are needed before this regimen can be recommended in newly diagnosed multiple myeloma, except in young patients with high risk cytogenetics. A randomized trial in the United States (referred to as the Endurance trial) is currently ongoing comparing VRd versus KRd as initial therapy. 6.1.4 Multi‐drug combinations Besides the regimens discussed above, other options include anthracycline‐containing regimens such as bortezomib, doxorubicin, dexamethasone (PAD)40 or multi‐agent combination chemotherapy regimens such as VDT‐PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide).102, 103 These regimens are particularly useful in patients with aggressive disease such as plasma cell leukemia or multiple extramedullary plasmacytomas. Several other regimens have been tested in newly diagnosed multiple myeloma, but there are no clear data from randomized controlled trials that they have an effect on long‐term endpoints compared with the regimens discussed earlier. Recommendations In standard‐risk and intermediate‐risk patients eligible for ASCT, I favor VRd as initial therapy for 3–4 cycles, followed by ASCT and lenalidomide maintenance therapy. In patients who are tolerating therapy and responding well, an alternative is VRd for 8 to 12 cycles followed by lenalidomide maintenance therapy; in such patients stem cells must be collected for cryopreservation after the first 3–4 cycles of VRd, and ASCT must be considered at first relapse.

In high‐risk patients, I favor KRd as initial therapy for 3–4 cycles followed by ASCT and then maintenance with a proteasome inhibitor‐based regimen.

In patients presenting with acute renal failure suspected to be secondary to light‐chain cast nephropathy, I prefer VCd or VTd as initial therapy in conjunction with plasma exchange (or dialysis with high‐cut‐off filter). Plasma exchange is continued daily until the serum FLC levels are less than 50 mg/dL and then repeated as needed till chemotherapy is fully effective.

In patients presenting with plasma cell leukemia or multiple extramedullary plasmacytomas, I prefer VDT‐PACE as initial therapy followed by ASCT and then maintenance with a bortezomib‐based regimen.

Once weekly subcutaneous bortezomib is preferred in most patients for initial therapy, unless there is felt to be an urgent need for rapid disease control.

Dexamethasone 40 mg once a week (low‐dose dexamethasone) is preferred in most patients for initial therapy, unless there is felt to be an urgent need for rapid disease control. 6.2 Initial treatment in patients not eligible for ASCT In patients with newly diagnosed multiple myeloma who are not candidates for ASCT due to age or other comorbidities, the major options for initial therapy are the same as those discussed earlier for patients eligible for ASCT. Typically treatment is given with a bortezomib‐based regimen for approximately 8–12 cycles followed by maintenance. Although melphalan‐based regimens have been extensively tested in these patients, they are not recommended due to concerns about stem cell damage and secondary myelodysplastic syndrome and leukemia. In the United States transplant eligibility is not determined by a strict age cut‐off, and many patients enrolled in the melphalan‐based clinical trials would be considered candidates for ASCT. 6.2.1 Bortezomib‐based regimens VRd has shown a survival benefit compared with Rd, and is the preferred choice for initial therapy in patients who are not candidates for ASCT (Table 7).38 VRd is administered for approximately 8–12 cycles, followed by maintenance therapy. Alternatives to VRd include VCd and VTd as discussed earlier. In patients in whom initial therapy with VRd is not possible mainly for logistical reasons (such as problems with compliance due to need for parenteral administration), ixazomib can be considered in place of bortezomib. 6.2.2 Lenalidomide plus dexamethasone (Rd) Rd is an option for the treatment of elderly patients with newly diagnosed multiple myeloma who are unable to tolerate triplet therapy due to advanced age, poor performance status, or co‐morbidities. An international phase III trial compared MPT versus Rd for 18 cycles versus Rd until progression in 1623 patients.87 PFS was superior with Rd until progression compared with the other two arms; OS was superior with Rd until progression compared with MPT. This trial provided the first evidence that OS can be improved in patients who are not eligible for transplant using a regimen that does not contain melphalan. 6.2.3 Melphalan‐based regimens VMP is a bortezomib‐based regimen that has shown better OS compared with MP.60, 86 Substituting melphalan with thalidomide in the VMP regimen has not shown a benefit.61 Melphalan‐based regimens are considered only if there is problems with access to lenalidomide. Even in these situations, the risks of melphalan can be reduced by using cyclophosphamide instead, and studies show this substitution does not alter efficacy.104 Thus, the VCd regimen can be considered as a minor modification of the VMP regimen, in which cyclophosphamide is used as the alkylating agent in place of melphalan. This variation has the advantage of not affecting stem cell mobilization, and dosing is more predictable. A randomized trial found superior PFS and OS with 4‐drug regimens such as Daratumumab‐VMP and VMPT compared with VMP in a randomized phase III trial, but the contribution of the fourth drug to the induction component cannot be ascertained from these trials and more data on overall survival are needed.62 Recommendations In standard‐risk patients, I prefer VRd as initial therapy administered for approximately 8–12 cycles, followed by lenalidomide maintenance

In frail elderly patients, I prefer Rd as initial therapy, administered until progression. Dexamethasone may be started at 20 mg once a week, then reduced as much as possible after the first 4–6 cycles, and possibly discontinued after the first year.

In intermediate‐ and high‐risk patients, I favor VRd as initial therapy for approximately 8–12 cycles followed if possible by a lower intensity (one dose every two weeks) maintenance schedule of bortezomib. 6.3 Hematopoietic stem cell transplantation 6.3.1 Autologous stem cell transplantation (ASCT) ASCT improves median OS in multiple myeloma by approximately 12 months.105-108 However, randomized trials found similar OS with early ASCT (immediately following 4 cycles of induction therapy) versus delayed ASCT (at the time of relapse as salvage therapy).109-111 A recent trial by the Intergroupe Francophone du Myelome (IFM) compared early versus delayed ASCT in patients treated with VRd followed by lenalidomide maintenance.39 Patients were randomized to receive either VRd (3 cycles) followed by ASCT and then VRd consolidation (2 cycles) versus VRd × 8 cycles with ASCT reserved for relapse. Both arms received lenalidomide maintenance for one year. A significant improvement in PFS was seen as expected with early ASCT, but this has so far not translated into a difference in OS (Table 7). Based on these results, it is reasonable to consider a delayed ASCT in patients with standard‐risk multiple myeloma who prefer such an approach for personal and logistic reasons. The role of tandem (double) ASCT is unclear. In earlier randomized trials, an improvement in OS was seen in two studies,112, 113 but other studies failed to show such an improvement.114, 115 More recent data are available from two other randomized trials are also inconclusive. In a trial conducted in Europe, an improvement in PFS and OS was seen with tandem ASCT in both standard and high risk patients.116 However, no survival benefit was seen in a randomized trial conducted in the United States by the Bone Marrow Transplantation Clinical Trials Network (BMT‐CTN) in standard or high risk multiple myeloma (BMT‐CTN 0702 trial).117 The US trial more likely reflects the impact of tandem ASCT in the context of modern therapy when most new options for salvage are available. Thus routine tandem ASCT is not recommended outside of a clinical trial setting except in selected young patients with high risk multiple myeloma. 6.3.2 Post‐transplant consolidation Consolidation therapy is a term used for the administration of a short course of therapy, usually with 2 or more drugs, prior to the start of long‐term maintenance. The BMT‐CTN 0702 trial had an arm that investigated the benefit of post‐transplant consolidation therapy followed by lenalidomide maintenance versus lenalidomide maintenance alone. In this trial, additional cycles of VRd chemotherapy administered as consolidation after ASCT did not result in significant benefit. Unlike earlier trials, the BMT‐CTN 0702 trial specifically isolated the effect of consolidation and is therefore more compelling than trials where one could not ascertain the precise added value of consolidation therapy on PFS and OS. Consolidation therapy after ASCT is not recommended and patients should proceed to standard low‐intensity maintenance therapy. 6.3.3 Allogeneic transplantation The role of allogeneic and nonmyeloablative‐allogeneic transplantation in multiple myeloma is controversial with studies showing conflicting results.118, 119 The treatment related mortality (TRM) rate (10%‐20%) and GVHD rates are fairly high.120 Although allogenic transplantation should still be considered as investigational, it may be a consideration for young patients with high‐risk disease who are willing to accept a high TRM and the unproven nature of this therapy for a chance at better long‐term survival. Recommendations ASCT should be considered in all eligible patients. But in standard‐risk patients responding well to therapy, ASCT can be delayed until first relapse provided stem cells are harvested early in the disease course.

Tandem ASCT is not recommended outside of clinical trials except in selected young patients with high risk multiple myeloma.

At present, allogeneic transplantation as frontline therapy should largely be considered investigational. 6.4 Maintenance therapy Maintenance therapy is indicated following ASCT. Maintenance therapy should also be considered in following completion of 8–12 cycles of initial therapy in patients treated without ASCT. Lenalidomide is the standard of care for maintenance therapy for most patients.87, 121-125 In a meta‐analysis of randomized trials, a significant improvement in PFS and OS was seen with lenalidomide maintenance compared with placebo or no therapy.126 Lenalidomide maintenance is associated with a 2–3‐fold increase in the risk of second cancers and patients must be counseled in this regard and monitored. The impact of lenalidomide maintenance in patients with intermediate‐ and high risk multiple myeloma is unclear. In the meta‐analysis, no significant OS benefit was seen in these subsets of high risk patients.126 In contrast, bortezomib administered every other week has been shown to improve OS, particularly in patients with del(17p).124 Bortezomib‐based maintenance may thus be preferable for intermediate‐ and high‐risk patients. The benefit of maintenance therapy in patients who did not undergo upfront ASCT is less clear. Based on the results of the SWOG trial, maintenance therapy with lenalidomide or Rd should be considered in patients who are in good performance status after completion of initial 8–12 cycles of triplet therapy. Patients who are treated with double therapy with Rd due to frailty or performance status are usually treated with this regimen until disease progression. After the first 18 cycles, the dose of dexamethasone can be lowered to minimize side effects. In some patients dexamethasone may need to be discontinued. Although the benefit of maintenance is now established, data on optimal duration are lacking. We also need to consider the cost, toxicity, and inconvenience of long‐term indefinite maintenance therapy. Many patients seek a drug‐free interval. An ECOG trial is comparing lenalidomide maintenance given until progression versus a limited duration of 2 years. Trials are also examining if the duration of maintenance can be modified based on MRD results. Recommendations I recommend lenalidomide maintenance for standard‐risk patients following ASCT. I also recommend lenalidomide or Rd maintenance following 8–12 cycles of initial therapy among patients who did not receive ASCT as part of initial therapy.

I recommend maintenance with bortezomib (or an alternative proteasome inhibitor) for patients with intermediate‐ and high‐risk multiple myeloma

7 TREATMENT OF RELAPSED MULTIPLE MYELOMA Almost all patients with multiple myeloma eventually relapse. The remission duration in relapsed multiple myeloma decreases with each regimen.127 The median PFS and OS in patients with relapsed multiple myeloma refractory to lenalidomide and bortezomib is poor, with median times of 5 months and 9 months, respectively.128 The choice of a treatment regimen at relapse is complicated and is affected by many factors including the timing of the relapse, response to prior therapy, aggressiveness of the relapse, and performance status (TRAP). Patients are eligible for an ASCT should be considered for the procedure if they have never had one before, or if they have had an excellent remission duration with the first ASCT defined as a remission of at least 36 months or longer with maintenance. In terms of drug therapy, a triplet regimen containing at least two new drugs that the patient is not refractory to should be considered. An approach to the treatment of relapsed multiple myeloma is given in Figure 2. Major regimens used in the treatment of multiple myeloma, including relapsed disease are listed in Table 6. Recent advances in the treatment of relapsed multiple myeloma, including new active agents and results of major randomized trials are discussed below (Table 8).68, 70, 71, 73-75, 130-134 One important consideration is that the lenalidomide‐containing regimens listed in Table 8 were tested mainly in patient populations who were not previously exposed to lenalidomide. In contrast, current clinical practice typically consists of patients who have been treated with lenalidomide and are often relapsing while on a lenalidomide‐containing regimen. In patients who are considered refractory to lenalidomide, one option is to consider pomalidomide‐based regimens. Figure 2 Open in figure viewer PowerPoint Suggested options for the treatment of relapsed multiple myeloma in first relapse (A) and second or higher relapse (B). ASCT, autologous stem cell transplantation; DRd, daratumumab, lenalidomide, dexamethasone; DPd, daratumumab, pomalidomide, dexamethasone; DVd, daratumumab, bortezomib, dexamethasone; Elo‐Rd, Elotuzumab, lenalidomide, dexamethasone; IRd, ixazomib, lenalidomide, dexamethasone; KPd, carfilzomib, pomalidomide, dexamethasone; KRd, carfilzomib, lenalidomide, dexamethasone; Pd, pomalidomide, dexamethasone; VCD, bortezomib, cyclophosphamide, dexamethasone Table 8. Results of recent randomized studies in relapsed myeloma Trial Regimen No. ofpatients Overallresponserate (%) CR plusVGPR (%) Progression‐freesurvival (Medianin months) P value forprogressionfree survival Overallsurvivala (Median inmonths) P value foroverall survival Lonial et al 73, 129 Rd 325 66 28 15 40 N/A Elo‐Rd 321 79 33 19 <.001 44 0.03 Stewart et al 68, 130 Rd 396 67 14 18 40 0.04 KRd 396 87 32 26 .0001 48 Moreau et al 74 Rd 362 72 7 15 N/A N/A IRd 360 78 12 21 .012 N/A Dimopoulos et al 70 Rd 283 76 44 18.4 <.001 N/A; 87%at 1 year NS DRd 286 93 76 NR N/A; 92%at 1 year Palumbo et al 71 Vd 247 63 29 7.2 <.001 N/A; 70%at 1 year 0.30 DVd 251 83 59 NR N/A; 80%at 1 year San Miguel et al 75, 131 Vd 381 55 6 8.1 36 0.54 Pano‐Vd 387 61 11 12 <.0001 40 San Miguel et al 132 Dex 153 10 0 1.9 8 NS Pd 302 31 1 4.0 <.0001 13 Dimopoulos et al 133, 134 Vd 465 63 6 9 40 0.01 Kd 464 77 13 19 <.0001 48 7.1 Bortezomib‐based regimens These regimens are appropriate for patients who received a bortezomib‐based triplet for a period of time, and then stopped therapy. In these patients if relapse occurs after a reasonable period of remission off all therapy, then restarting the same (or similar) bortezomib‐based triplet is reasonable and also carries lower cost and risk. As in newly diagnosed multiple myeloma, VRd, VCd, and VTd are active regimens in relapsed disease.136, 137 7.2 Daratumumab Daratumumab targeting CD38 has shown promise in relapsed, refractory multiple myeloma.83 In a phase II trial, daratumumab as a single‐agent was produced a response rate of approximately 30% in heavily pretreated patients.84 Based on these findings, daratumumab was first granted accelerated approval by the FDA in 2015 for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent, or who are double‐refractory to a proteasome inhibitor and an immunomodulatory agent. Subsequently 3 other daratumumab‐based combinations have shown efficacy and have been approved by the FDA. These include daratumumab, lenalidomide, dexamethasone (DRd), daratumumab, bortezomib, dexamethasone (DVd), and daratumumab, pomalidomide, dexamethasone (DPd) (Table 8). The various triplets available for use in relapsed disease have not been compared head‐to‐head, but daratumumab‐based regimens appear to have the greatest reduction in risk of progression, and may be preferred for first relapse subject to availability and cost considerations.138 7.3 Carfilzomib Carfilzomib is a novel keto‐epoxide tetrapeptide proteasome inhibitor initially approved in 2013 for the treatment of relapsed refractory multiple myeloma in patients who have been previously treated with lenalidomide and bortezomib. In a phase 2 study (PX‐171‐003‐A1), of 266 patients (80% of patients whom were refractory or intolerant to both bortezomib and lenalidomide), single‐agent carfilzomib resulted in a response rate of 24% for a median duration of approximately 8 months.139 KRd has been subsequently shown to be effective in a randomized trial, and is a major option for the treatment of relapsed disease (Table 8).68 In another randomized trial carfilzomib plus dexamethasone was associated with an improvement in PFS and OS compared with bortezomib plus dexamethasone in relapsed multiple myeloma.133, 134 However, the dose of carfilzomib used in this trial (56 mg/m2) is twice the standard dose, and carries a much higher cost compared with bortezomib. Carfilzomib is typically administered twice‐weekly at a dose of 27 mg/m2 (refer to Table 6), but a once‐weekly schedule of 70 mg/m2 may be equally effective and safe, and more convenient. Carfilzomib carries a lower risk of neurotoxicity than bortezomib, but a small proportion (5%) of patients can experience serious cardiac side effects. Carfilzomib‐based regimens are important options at relapse, and can work well even in patients who are refractory to a bortezomib‐containing regimen. 7.4 Pomalidomide Pomalidomide is an analog of lenalidomide and thalidomide initially approved in 2013 for the treatment of relapsed refractory multiple myeloma. It has significant activity in relapsed refractory multiple myeloma, even in patients failing lenalidomide.140, 141 Response rate with pomalidomide plus dexamethasone (Pd) in patients refractory to lenalidomide and bortezomib is approximately 30%.59, 142 In a randomized trial, Pd was found superior to high‐dose dexamethasone in patients refractory to other forms of therapy for multiple myeloma (Table 8).132 Pomalidomide‐containing triplet regimens such as daratumumab, pomalidomide, dexamethasone (DPd) and carfilzomib, pomalidomide, dexamethasone (KPd) are active and are important options at relapse for patients who are considered lenalidomide‐refractory. In frail patients and in those with indolent relapse, the doublet regimen of Pd is a reasonable option for patients with indolent relapse. 7.5 Elotuzumab Elotuzumab, a monoclonal antibody targeting the signaling lymphocytic activation molecule F7 (SLAMF7).73 Unlike daratumumab, elotuzumab does not have single‐agent activity but shows synergistic activity when combined with Rd. In a phase III trial of 646 patients, elotuzumab, lenalidomide, dexamethasone (ERd) was superior to Rd (Table 8).73 Elotuzumab is well tolerated, and was initially approved in 2015 by the FDA to be given in combination with Rd for the treatment of patients with multiple myeloma who have received one to three prior therapies. 7.6 Ixazomib Ixazomib is an oral proteasome inhibitor that is active in both the relapsed refractory setting and in newly diagnosed multiple myeloma.74, 143 It has the advantage of once‐weekly oral administration. Compared with bortezomib it has more gastrointestinal adverse events, but lower risk of neurotoxicity. In a randomized controlled trial in relapsed multiple myeloma, ixazomib, lenalidomide, dexamethasone (IRd) was found to improve PFS compared with Rd (Table 8).74 Based on these results ixazomib was initially approved by the FDA in 2015 to be given in combination with Rd for the treatment of patients with multiple myeloma who have received at least one prior therapy. 7.7 Doxorubicin and liposomal doxorubicin Anthracyclines have marginal single‐agent activity in multiple myeloma. A phase III randomized trial found that median time to progression (TTP) was superior with bortezomib plus pegylated liposomal doxorubicin compared with bortezomib alone, 9.3 months versus 6.5 months, respectively, P < 0.001.144 OS at 15 months was also superior, 76% compared with 65%, respectively, P = 0.03. Despite this study, liposomal doxorubicin is infrequently used in the treatment of relapsed multiple myeloma given availability of other active agents. Doxorubicin‐containing regimens such as PAD or VDT‐PACE may be useful in the treatment of patients with aggressive multiple myeloma refractory to other standard myeloma agents. 7.8 Panobinostat Panobinostat is a pan‐deacetylase inhibitor initially approved by the FDA in 2015 for the treatment of patients with multiple myeloma who have received at least two prior standard therapies, including bortezomib and an immunomodulatory agent.75 Its putative mechanism of action is blockade of the aggresome pathway, an alternative route for cells to bypass the lethal effects of proteasome inhibition. By combining bortezomib and panobinostat, there is simultaneous blockade of both proteasome and aggresome pathways.145, 146 In a randomized trial of 768 patients, bortezomib/dexamethasone plus panobinostat was associated with superior PFS compared with bortezomib/dexamethasone plus placebo.75 However, panobinostat therapy is associated with grade 3 diarrhea in approximately 25% of patients, and care should be exercised when using this drug. I recommend a lower initial dose of panobinostat than the approved starting dose, and that bortezomib be used in the once‐weekly subcutaneous schedule rather than the twice weekly regimen used in the pivotal trial (Table 6) 7.9 Other options Despite the multiple option available, more patients eventually become refractory to all drug classes. Some additional options to consider for relapsed disease in refractory multiple myeloma include bendamustine‐containing regimens such as bendamustine, lenalidomide, dexamethasone or bendamustine, bortezomib, dexamethasone.147, 148 Other options include the addition of panobinostat to a proteasome‐inhibitor containing regimen, or the use of quadruplet regimen in which daratumumab is added to a standard triplet regimen. Venetoclax is not approved for use in multiple myeloma, but is commercially available, and appears to have single‐agent activity in patients with t(11;14) subtype of multiple myeloma.149 For young high‐risk patients with a suitable donor, allogeneic transplantation is an option as well. 7.10 Emerging options There are several investigational approaches that are promising and patients should be considered for clinical trials investigating these approaches. Two of the most exciting options include antigen receptor T cells (CAR‐T) targeting B cell maturation antigen (BCMA) such as bb2121,150 and GSK2857916 (a humanized anti‐BCMA antibody that is conjugated to monomethyl auristatin‐F, a microtubule disrupting agent).151 Other agents with single‐agent activity that are promising include isatuximab (a CD38 monoclonal antibody), marizomib (a new proteasome inhibitor), oprozomib, (an oral proteasome inhibitor related to carfilzomib), filanesib (a kinesin spindle protein inhibitor), dinaciclib (a cyclin dependent kinase inhibitor), and LGH‐447 (a pan PIM kinase inhibitor). Recommendations Patients who are eligible for ASCT should consider ASCT as salvage therapy at first relapse if they have never had a transplant before, or if they have had a prolonged remission with the first ASCT.

If relapse occurs more than 6 months after stopping therapy, the initial treatment regimen that successfully controlled the multiple myeloma initially can be re‐instituted when possible.

At first relapse, for patients who are not refractory to lenalidomide, my preferred option is DRd. Alternatives include KRd, IRd, and ERd.

At first relapse, for patients who are refractory to lenalidomide, my preferred option is DPd. Alternatives include DVd, KPd, and VCd

Patients who have an indolent relapse or who are frail can be treated with oral regimens such as IRd or Pd.

At second or higher relapse, I switch to a triplet regimen that contains at least 2 new drugs that the patient is not refractory to.

Additional options to consider in patients with multiple relapses and disease that is refractory to conventional regimens include bendamustine‐based regimens, the addition of panobinostat to a proteasome‐inhibitor containing regimen, quadruplet daratumumab‐containing regimens, multi‐drug chemotherapy regimens, allogenic transplantation in young high risk patients with a suitable donor, and venetoclax in patients with t(11;14) multiple myeloma.

Patients with more aggressive relapse with plasma cell leukemia or extramedullary plasmacytomas often require therapy with a multi‐drug anthracycline containing regimen such as VDT‐PACE.

The duration of therapy has not been well addressed in relapsed multiple myeloma, and in some regimens such as those employing parenteral proteasome inhibitors it may be reasonable to stop therapy once a stable plateau has been reached to limit minimize risks of serious toxicity.

8 SMOLDERING MULTIPLE MYELOMA SMM is a stage that is clinically positioned between MGUS and multiple myeloma.135 It comprises of a heterogeneous group of patients, some of whom have multiple myeloma which has not yet manifested with MDEs, and some who have premalignant MGUS. Patients with SMM have a risk of progression of approximately 10% per year for the first 5 years, 3% per year for the next 5 years, and 1% per year thereafter.19 Patients with the highest risk of progression (ultra‐high risk) have now been reclassified as having multiple myeloma by the new IMWG criteria.1 Within the current definition of SMM (Table 1), there are two groups of patients: high risk (25% per year risk of progression in the first 2 years) and low risk (∼ 5% per year risk of progression).135 Criteria for high risk SMM are given on Table 9. Presence of one or more of these factors is associated with a median TTP to multiple myeloma of approximately 2 years. Early studies in SMM failed to show an advantage to early intervention, but were limited by lack of power, safe and effective drugs, and a risk‐adapted strategy.152, 153 A recent randomized trial conducted in Spain found that patients with high risk SMM had significant prolongation of PFS and OS with Rd compared with observation.50, 154 These are very promising results, and further confirmatory studies are ongoing. Observation is still the standard of care for SMM; however, selected high risk SMM patients with multiple risk factors can be considered for therapy. They are also candidates for clinical trials testing early intervention, some of which are testing intensive therapy with curative intent.155 Table 9. Criteria for high risk smoldering multiple myeloma Bone marrow clonal plasma cells ≥10% and any one or more of the following: Serum M protein ≥30 g/L IgA SMM Immunoparesis with reduction of two uninvolved immunoglobulin isotypes Serum involved/uninvolved free light chain ratio ≥8 (but less than 100) Progressive increase in M protein level (Evolving type of SMM)b Bone marrow clonal plasma cells 50%‐60% Abnormal plasma cell immunophenotype (≥95% of bone marrow plasma cells are clonal) and reduction of one or more uninvolved immunoglobulin isotypes t (4;14) or del 17p or 1q gain Increased circulating plasma cells MRI with diffuse abnormalities or 1 focal lesion PET‐CT with focal lesion with increased uptake without underlying osteolytic bone destruction Recommendations I recommend observation for most patients with SMM.

Consideration of multiple myeloma therapy can be given to the small subset of patients with SMM who have multiple high risk factors especially if there is progressive rise in monoclonal protein levels.

ACKNOWLEDGMENTS Supported in part by grants CA 107476, CA 168762, and CA186781 from the National Cancer Institute, Rockville, MD, USA.

AUTHORS' CONTRIBUTION SVR conceived of the article, researched the literature, and wrote the manuscript.

CONFLICT OF INTERESTS SVR declares no conflict of interest.