The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE) namely 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 (MRI).

Risk stratification

The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation is considered high-risk multiple myeloma. Presence of any two high risk factors is considered double-hit myeloma; three or more high risk factors is triple-hit myeloma.

Risk-adapted initial therapy

In transplant eligible patients, induction therapy consists of bortezomib, lenalidomide, dexamethasone (VRd) given for approximately 3-4 cycles followed by autologous stem cell transplantation (ASCT). In high-risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) is an alternative to VRd. Selected standard risk patients can get additional cycles of induction, and delay transplant until first relapse. Patients not candidates for transplant are typically treated with VRd for approximately 8-12 cycles followed by lenalidomide; alternatively these patients can be treated with daratumumab, lenalidomide, dexamethasone (DRd).

Maintenance therapy

After ASCT, standard risk patients need lenalidomide maintenance, while bortezomib-based maintenance is needed for patients with high-risk myeloma.

Management of refractory disease

Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse.

1 DISEASE OVERVIEW

Multiple myeloma accounts for 1% of all cancers and approximately 10% of all hematologic malignancies.¹ Each year over 32 000 new cases are diagnosed in the United States, and almost 13 000 patients die of the disease.² The annual age-adjusted incidence in the United States has remained stable for decades at approximately four 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 best detected using low-dose whole body computed tomography (WB-CT), fluoro-deoxyglucose (FDG) positron emission tomography/computed tomographic scans (PET/CT), or magnetic resonance imaging (MRI).⁷ 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.⁸

Almost all patients with multiple myeloma evolve from an asymptomatic pre-malignant stage termed monoclonal gammopathy of undetermined significance (MGUS).^{9, 10} It is present in over 3% of the population above the age of 50,^{11, 12} and the prevalence is approximately 2-fold higher in blacks compared with whites.^{13, 14} And, MGUS progresses to multiple myeloma or related malignancy at a rate of 1% per year.^{15, 16} Note, MGUS is asymptomatic, and over 50% of individuals who are diagnosed with MGUS have had the condition for over 10 years prior to the clinical diagnosis.¹⁷ In some patients, an intermediate asymptomatic, but more advanced pre-malignant stage referred to as smoldering multiple myeloma, (SMM) can be recognized clinically.¹⁸ Smoldering multiple myeloma 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.^19-21

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 consist of established CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features as well as three 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 three criteria must be met: Serum monoclonal protein (non-IgM type) <3 g/dL Clonal bone marrow plasma cells <10% ^a Absence of end-organ damage such as hypercalcemia, renal 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 h and/or clonal bone marrow plasma cells 10-60% Absence of myeloma defining events (MDE) 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 MDE: 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 FLC 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 three 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 h
Solitary plasmacytoma	All four 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 involvement ^b	All four 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

a A bone marrow can be deferred in patients with low risk MGUS (IgG type, M protein <15 g/L, normal free light chain [FLC] ratio) in whom there are no clinical features concerning for myeloma.
b Solitary plasmacytoma with 10% or more clonal plasma cells is considered as multiple myeloma.
Source: Reproduced from Rajkumar et al.¹

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 (SIFE), and the serum FLC assay.²² Approximately 2% of patients with multiple myeloma have true non-secretory disease and have no evidence of an M protein on any of the above studies.^{5, 23} 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).²⁴ 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 (GEP) if available can provide additional prognostic value.²⁵ Serum CrossLaps to measure carboxy-terminal collagen crosslinks (CTX) may be useful in assessing bone turnover and to determine adequacy of bisphosphonate therapy.^{26, 27} The extent of bone disease is best assessed by low-dose WB-CT or PET/CT imaging.^{7, 28} 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. Also, MRI imaging is useful in assessing extramedullary disease, 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 affected ^a	Percentage of myeloma 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 translocations ^a	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

a Includes the t(6;14)(p21;q32) translocation, and rarely, other IgH translocations involving uncommon partner chromosomes.
Source: Modified from Kumar et al.⁴⁷

Table 3. Cytogenetic abnormalities on clinical course and prognosis in multiple myeloma

Cytogenetic abnormality	Clinical setting in which abnormality is detected
Cytogenetic abnormality	Smoldering multiple myeloma	Multiple myeloma
Trisomies	Intermediate-risk of progression, median TTP of 3 y	Good prognosis, standard-risk MM, median OS 7-10 y 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 y	Good prognosis, standard-risk MM, median OS 7-10 y
t(6;14) (p21;q32)	Standard-risk of progression, median TTP of 5 y	Good prognosis, standard-risk MM, median OS 7-10 y
t(4;14) (p16;q32)	High-risk of progression, median TTP of 2 y	High-risk MM, median OS 5 y Needs early ASCT (if eligible), followed by bortezomib-based consolidation/maintenance
t(14;16) (q32;q23)	Standard-risk of progression, median TTP of 5 y	High-risk MM, median OS 5 y 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 y	High-risk MM, median OS 5 y; Needs early ASCT (if eligible), followed by bortezomib-based consolidation/maintenance
Gain(1q21)	High-risk of progression, median TTP of 2 y	High-risk MM, median OS 5 y; Needs early ASCT (if eligible), followed by bortezomib-based consolidation/maintenance
Del(17p)	High-risk of progression, median TTP of 2 y	High-risk MM, median OS 5 y; Needs early ASCT (if eligible), followed by bortezomib-based consolidation/maintenance
Trisomies plus any one of the IgH translocations	Standard-risk of progression, median TTP of 5 y	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 y	Effect on prognosis is not clear
Normal	Low-risk of progression, median TTP of 7–10 y	Good prognosis, probably reflecting low tumor burden, median OS >7-10 y

Abbreviations: ASCT, autologous stem cell transplantation; FISH, fluorescent in situ hybridization, MM, multiple myeloma; OS, overall survival; SMM, Smoldering multiple myeloma; TTP, time to progression.
Source: Modified from Rajan and Rajkumar.³⁷

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. On the other hand, 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 Staging (DSS)⁴⁴ 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).^{24, 47} 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).⁴⁸ In order to ensure uniform availability, only three 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.

Table 4. Revised international staging system for myeloma⁴⁸

Stage

Stage 1

All of the following:

Serum albumin ≥3.5 g/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

Source: Derived from: Palumbo et al.⁴⁸

Table 5. Mayo clinic risk stratification for multiple myeloma (mSMART)

Risk group	Percentage of newly diagnosed patients with the abnormality
Standard risk	75%
Trisomies
t(11;14)
t(6;14)
High risk	25%
t(4;14)
t(14:16)
t(14;20)
del(17p)
gain(1q)
Double-hit: any two high-risk factors
Triple-hit: any three or more high-risk factors

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 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%).⁴⁰ 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 TREATMENT OF NEWLY DIAGNOSED MYELOMA

Survival in multiple myeloma has improved significantly in the last 15 years.⁴⁹ The initial impact came from the introduction of thalidomide,⁵⁰ bortezomib,⁵¹ and lenalidomide.^{52, 53} In the last decade, carfilzomib, pomalidomide, panobinostat, ixazomib, elotuzumab, daratumumab, isatuximab, and selinexor 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.^54-76 These drugs work through a variety of mechanisms, some of which are not fully understood. Thalidomide, lenalidomide, and pomalidomide are termed immunomodulatory agents (IMiDs);they bind to cereblon and activate cereblon E3 ligase activity. This results in the rapid ubiquitination and degradation of two specific B cell transcription factors, Ikaros family zinc finger proteins Ikaros (IKZF 1) and Aiolos (IKZF3).^77-79 They may cause direct cytotoxicity by inducing free radical mediated DNA damage.⁸⁰ They also have anti-angiogenic, immunomodulatory, and tumor necrosis factor alpha inhibitory properties. Bortezomib, carfilzomib, and ixazomib are proteasome inhibitors.^81-83 Elotuzumab targets SLAMF7; daratumumab and isatuximab target CD38 respectively.^{71, 84-86} Panobinostat is a deacetylase inhibitor.^{73, 87}

Table 6. Major treatment regimens in multiple myeloma

Regimen	Usual Dosing Schedule ^a
Thalidomide-dexamethasone (Td) ^b ^{54, 55}	Thalidomide 200 mg oral days 1-28 Dexamethasone 40 mg oral days 1, 8, 15, 22 Repeated every 4 wk
Lenalidomide-dexamethasone (Rd)⁵⁶	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 wk
Pomalidomide-dexamethasone (Pom/Dex)⁵⁷	Pomalidomide 4 mg days 1-21 Dexamethasone 40 mg oral on days on days 1, 8, 15, 22 Repeated every 4 wk
Bortezomib-melphalan-prednisone (VMP) ^b ^58-60	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 ⁶¹	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 wk × 4 cycles as pre-transplant induction therapy
Bortezomib- cyclophosphamide-dexamethasone ^b(VCd or CyBord)^{62, 63}	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 wk ^c
Bortezomib-lenalidomide-dexamethasone (VRd) ^b ^{63, 64}	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 wk ^d
Carfilzomib-cyclophosphamide-dexamethasone (KCd) ^e ⁶⁵	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 wk
Carfilzomib-lenalidomide-dexamethasone (KRd) ^e ⁶⁶	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 wk
Carfilzomib-pomalidomide-dexamethasone (KPd) ^e ⁶⁷	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 wk
Daratumumab-lenalidomide-dexamethasone (DRd)⁶⁸	Daratumumab 16 mg/kg intravenously weekly × 8 wk, and then every 2 wk 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 wk
Daratumumab-bortezomib-dexamethasone (DVd) ^b ⁶⁹	Daratumumab 16 mg/kg intravenously weekly × 8 wk, and then every 2 wk 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 wk
Daratumumab-pomalidomide-dexamethasone (DPd)⁷⁰	Daratumumab 16 mg/kg intravenously weekly × 8 wk, and then every 2 wk 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 wk
Elotuzumab-lenalidomide-dexamethasone (ERd)⁷¹	10 mg/kg intravenously weekly × 8 wk, and then every 2 wk Lenalidomide 25 mg oral days 1-21 Dexamethasone per prescribing information Lenalidomide-Dexamethasone repeated in usual schedule every 4 wk
Ixazomib-lenalidomide-dexamethasone (IRd)⁷²	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 wk
Panobinostat-bortezomib ^b ⁷³	Panobinostat 20 mg oral three times a week × 2 wk Bortezomib 1.3 mg/m² subcutaneous days 1, 8, 15 Repeated every 3 wk
Elotuzumab-pomalidomide-dexamethasone (EPd)⁷⁴	10 mg/kg intravenously weekly × 8 wk, and then 20 mg/kg every 4 wk Pomalidomide 4 mg oral days 1-21 Dexamethasone per prescribing information Lenalidomide-Dexamethasone repeated in usual schedule every 4 wk
Isatuximab-pomalidomide-dexamethasone (Isa-Pd)⁷⁵	10 mg/kg intravenously weekly × 4 wk, and then every 2 wk Pomalidomide 4 mg oral days 1-21 Dexamethasone per prescribing information Pomalidomide-Dexamethasone repeated in usual schedule every 4 wk
Selinexor-dexamethasone ^b ⁷⁶	Selinexor 100 mg/kg oral once weekly Dexamethasone 20 mg oral twice weekly

a All doses need to be adjusted for performance status, renal function, blood counts, and other toxicities.
b Doses of dexamethasone and/or bortezomib reduced based on other data showing lower toxicity and similar efficacy with reduced doses; dose of selinexor reduced based on better tolerability with once weekly dosing in subsequent randomized trial; subcutaneous route of administration of bortezomib preferred based on data showing lower toxicity and similar efficacy compared to intravenous administration.
c The day 22 dose of all three drugs is omitted if counts are low, or after initial response to improve tolerability, or when the regimen is used as maintenance therapy. When used as maintenance therapy for high risk patients, further delays can be instituted between cycles.
d Omit day 15 dose if counts are low or when the regimen is used as maintenance therapy. When used as maintenance therapy for high risk patients, lenalidomide dose may be decreased to 10-15 mg per day, and delays can be instituted between cycles as done in total therapy protocols.
e Carfilzomib can also considered in a once a week schedule of 56 mg/m² on days 1, 8 and 15 every 28 days (cycle 1, day 1 should be 20 mg/ m²); day 8, 9 doses of carfilzomib can be omitted in maintenance phase of therapy after a good response to improve tolerability; KCd dosing lowered from that used in the initial trial which was conducted in newly diagnosed patients.

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, 88, 89} In order to initiate therapy, patients must meet criteria for multiple myeloma as outlined in Table 1. Early therapy with lenalidomide and dexamethasone or single-agent lenalidomide is beneficial in patients with high risk smoldering multiple myeloma, and is discussed separately.^{90, 91} 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.^{92, 93}

Details are in the caption following the image — **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. Abbreviations: ASCT, autologous stem cell transplantation; Dara-VRd, daratumumab, bortezomib, lenalidomide, dexamethasone; DRd, daratumumab, lenalidomide, dexamethasone; VRd, bortezomib, lenalidomide, dexamethasone

Table 7. Results of recent randomized studies in newly diagnosed myeloma

Trial	Regimen	Number of patients	Overall response rate (%)	CR plus VGPR (%)	Progression-free survival (median in months)	P value for progression free survival	Overall survival (median in months) ^a	P value for overall survival
Durie et al³⁸	Rd	229	72	32	31	.002	64	.025
Durie et al³⁸	VRd	242	82	43	43		75
Attal et al³⁹	VRd	350	97	77	36		NR; 82% at 4 y	.87
Attal et al³⁹	VRd-ASCT	350	98	88	50	<.001	NR; 81% at 4 y
Facon et al⁸⁸	Rd	369	81	53	32		NR	N/A
Facon et al⁸⁸	DRd	368	93	79	NR; 71% at 30 mo	<.001	NR
Moreau et al⁸⁹	VTd	542	90	78	NR; 85% at 18 mo	<.001	NR; 90% at 30 mo	<.05
Moreau et al⁸⁹	Dara-VTd	543	90	83	NR; 93% at 18 mo		NR; 96% at 30 mo

Abbreviations: ASCT, autologous stem cell transplantation; CR, complete response; Dara-VTd, daratumumab, bortezomib, thalidomide, dexamethasone; DRd, daratumumab, lenalidomide, dexamethasone; N/A, not available; Rd, lenalidomide plus dexamethasone; VGPR, very good partial response; VRd, bortezomib, lenalidomide plus dexamethasone;VTd, bortezomib, thalidomide, dexamethasone.
a Estimated from survival curves when not reported.

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.³²

5.1 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 Eastern Cooperative Oncology Group (ECOG), the low-dose dexamethasone approach was associated with superior OS and significantly lower toxicity.⁵⁶

5.1.1 Triplet regimens

Bortezomib, lenalidomide, dexamethasone (VRd) is the current standard of care for newly diagnosed multiple myeloma. In a 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 Stem cell collection with granulocyte stimulating factor (G-CSF) alone may be impaired when lenalidomide is used as induction therapy.⁹⁴ Patients who have received more than 4-6 cycles of lenalidomide may need plerixafor for stem cell mobilization. All patients treated with lenalidomide 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.^95-97 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.⁹⁸ Therefore both are reasonable alternatives to VRd. Daratumumab, lenalidomide, dexamethasone (DRd) has shown significant activity in patients who are not candidates for transplantation, and is an additional alternative to VRd.⁸⁸

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,^{59, 60} and by administering the drug subcutaneously instead of the intravenous route.⁹⁹ 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.¹⁰⁰

Two phase II trials reported results with carfilzomib when used in combination with lenalidomide and dexamethasone for newly diagnosed multiple myeloma.^{101, 102} However, there is concern for greater risk of serious toxicity with carfilzomib, and more data are needed. A randomized trial in the United States (referred to as the ENDURANCE trial) is currently ongoing comparing VRd vs KRd as initial therapy.

5.1.2 Quadruplet regimens

Quadruplet regimens containing daratumumab, a monoclonal antibody targeting CD38 are showing promise. In one randomized trial, daratumumab, bortezomib, thalidomide, dexamethasone (Dara-VTd) showed superior response rates, progression-free survival (PFS), and a trend to better OS compared with VTd.⁸⁹ A randomized phase II trial found that the addition of daratumumab to VRd increases the rate and depth of response to therapy.¹⁰³ In these trials, as expected, the benefit of daratumumab in terms of surrogate endpoints was more pronounced in the standard risk patients, a positive effect was nevertheless seen in both standard and high risk disease. Phase III data on the incremental PFS and OS benefit with quadruplet regimens over the current standard of VRd is awaited. Therefore, it is prudent to restrict the use of quadruplet regimens to transplant eligible patients with high risk double or triple hit myeloma, until we have clear OS data to justify adding potential long-term costs and risks to standard risk patients who currently have excellent outcomes with the VRd triplet. Trials with other quadruplet regimens are ongoing. A randomized trial to determine the patient subset that can benefit most from quadruplets is also expected to open soon in the United States.

5.1.3 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).^{104, 105} 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.

5.1.4 Recommendations

In standard-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, especially those with double-hit or triple-hit myeloma, I favor Dara-VRd as initial therapy for 3-4 cycles followed by ASCT and then bortezomib-based maintenance (eg, bortezomib every 2 weeks, or a low intensity VRd 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.

5.2 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 VRd and DRd. 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.

5.2.1 Bortezomib-based regimens

Therapy with 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 So, VRd is administered for approximately 8-12 cycles, followed by maintenance therapy. 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. In frail elderly patients, a lower dose of lenalidomide should be used; dexamethasone may be started at 20 mg once a week, then reduced as much as possible after the first 4-6 cycles, and discontinued after the first year.

5.2.2 DRd

Note, DRd has been recently approved for patients with newly diagnosed myeloma, based on the results of an international multicenter randomized trial.⁸⁸ PFS at 30 months was higher with DRd compared to Rd, 70.6% vs 55.6%, P < .001. MRD negative rates were also superior, 24.2% vs 7.3%, P < .001. DRd is an alternative to VRd in this setting. However, unlike VRd where the triplet regimen is only used for a limited duration, therapy with DRd requires treatment with all three drugs until progression which makes this a much more expensive regimen in the long-term.¹⁰⁶

5.2.3 Alkylator-based regimens

Melphalan-based regimens are considered only if there are 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.¹⁰⁷ 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 a four-drug regimen of Dara plus VMP compared with VMP in a randomized phase III trial, but the contribution of the fourth drug to the induction component cannot be ascertained from this trial.¹⁰⁸

5.2.4 Recommendations

In standard-risk patients, I prefer VRd as initial therapy administered for approximately 8-12 cycles, followed by lenalidomide maintenance. DRd is an alternative to VRd but adds cost and toxicity of long-term triplet therapy.
In high-risk patients, I favor VRd as initial therapy for approximately 8-12 cycles followed by bortezomib-based maintenance (eg, bortezomib every 2 weeks, or a low intensity VRd regimen).

5.3 Hematopoietic stem cell transplantation

5.3.1 Autologous stem cell transplantation (ASCT)

ASCT improves median OS in multiple myeloma by approximately 12 months.^109-112 However, randomized trials found similar OS with early ASCT (immediately following four cycles of induction therapy) vs delayed ASCT (at the time of relapse as salvage therapy).^113-115 A trial by the Intergroupe Francophone du Myelome (IFM) compared early vs delayed ASCT in patients treated with VRd followed by lenalidomide maintenance.³⁹ Patients were randomized to receive either VRd (three cycles) followed by ASCT and then VRd consolidation (two cycles) vs VRd × eight cycles with ASCT reserved for relapse. Both arms received lenalidomide maintenance for 1 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,^{116, 117} but other studies failed to show such an improvement.^{118, 119} 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.¹²⁰ However, no survival benefit has been seen so far 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).¹²¹ 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.

5.3.2 Post-transplant consolidation

Consolidation therapy is a term used for the administration of a short course of therapy, usually with two 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 vs lenalidomide maintenance alone.¹²¹ 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.

5.3.3 Allogeneic transplantation

The role of allogeneic and non-myeloablative-allogeneic transplantation in multiple myeloma is controversial with studies showing conflicting results.^{122, 123} The treatment related mortality (TRM) rate (10%-20%) and GVHD rates are fairly high.¹²⁴ 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.

5.3.4 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
Allogeneic transplantation as frontline therapy should be considered investigational.

5.4 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.^125-130 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.¹³¹ 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 high risk multiple myeloma is unclear. In a meta-analysis, no significant OS benefit was seen in these subsets of high risk patients.¹³¹ However, in a more recent trial that was not part of the meta-analysis, benefit was seen in high risk patients.¹³² Bortezomib administered every other week has been shown to improve OS, particularly in patients with del(17p).¹²⁸ Bortezomib-based maintenance is preferable for high-risk patients. This can either consist of bortezomib alone given every other week, or low intensity VRd, to capture the effect of bortezomib and lenalidomide.¹³³ In patients unable to access or tolerate bortezomib, ixazomib is a reasonable alternative that has shown benefit in a placebo controlled randomized trial.¹³⁴

Among patients who did not undergo upfront ASCT, based on the results of the SWOG trial, maintenance therapy with lenalidomide should be considered in patients who are in good performance status after completion of initial 8-12 cycles of triplet therapy.

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 vs a limited duration of 2 years. Trials are also examining if the duration of maintenance can be modified based on MRD results.

5.4.1 Recommendations

I recommend lenalidomide maintenance for standard-risk patients following ASCT. I also recommend lenalidomide maintenance following 8-12 cycles of VRd among patients who did not receive ASCT as part of initial therapy.
I recommend maintenance with bortezomib alone or low intensity VRd for patients with high-risk multiple myeloma.

6 TREATMENT OF RELAPSED MULTIPLE MYELOMA

Almost all patients with multiple myeloma eventually relapse. The remission duration in relapsed multiple myeloma decreases with each regimen.¹³⁵ The median PFS and OS in patients with relapsed multiple myeloma refractory to lenalidomide and bortezomib was low prior to the introduction of daratumumab respectively.¹³⁶ 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).^{66, 68, 69, 71-73, 75, 137-140} 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.

Table 8. Results of recent randomized studies in relapsed myeloma

Trial	Regimen	Number of patients	Overall response rate (%)	CR plus VGPR (%)	Progression-free survival (median in months)	P value for progression free survival	Overall survival ^a (median in months)	P value for overall survival
Stewart et al.^{66, 137}	Rd	396	67	14	18		40	.04
Stewart et al.^{66, 137}	KRd	396	87	32	26	<.0001	48
Dimopoulos et al.⁶⁸	Rd	283	76	44	18.4	<.001	N/A; 87% at 1 y	NS
Dimopoulos et al.⁶⁸	DRd	286	93	76	NR		N/A; 92% at 1 y
Palumbo et al.⁶⁹	Vd	247	63	29	7.2	<.001	N/A; 70% at 1 y	.30
Palumbo et al.⁶⁹	DVd	251	83	59	NR		N/A; 80% at 1 y
Lonial et al.^{71, 141}	Rd	325	66	28	15		40	N/A
Lonial et al.^{71, 141}	Elo-Rd	321	79	33	19	<.001	44	.03
Moreau et al.⁷²	Rd	362	72	7	15		N/A	N/A
Moreau et al.⁷²	IRd	360	78	12	21	.012	N/A
San Miguel et al.^{73, 142}	Vd	381	55	6	8.1		36	.54
San Miguel et al.^{73, 142}	Pano-Vd	387	61	11	12	<.0001	40
Attal et al.⁷⁵	Pd	153	35	9	6.5		NR; 63% at 1 y	.06
Attal et al.⁷⁵	Isa-Pd	154	60	32	11.5	<.001	NR; 72% at 1 y
Dimopoulos et al.^{139, 140}	Vd	465	63	6	9		40	.01
Dimopoulos et al.^{139, 140}	Kd	464	77	13	19	<.0001	48

Abbreviations: CR, complete response; Dex, high dose dexamethasone; DRd, daratumumab, lenalidomide, dexamethasone; DVd, daratumumab, bortezomib, dexamethasone; Elo-Rd, Elotuzumab, lenalidomide, dexamethasone; IRd, ixazomib, lenalidomide, dexamethasone; Isa-Pd, isatuximab, pomalidomide, dexamethasone; Kd, carfilzomib, dexamethasone; KRd, carfilzomib, lenalidomide, dexamethasone; N/A, not available; NS, not significant; Pano-Vd, panobinostat, bortezomib, dexamethasone; Pd, pomalidomide, dexamethasone; Rd, lenalidomide plus dexamethasone; Vd, bortezomib, dexamethasone; VGPR, very good partial response.
a Estimated from updated publications when available; estimated from survival curves when not reported.

6.1 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.^{143, 144}

6.2 Daratumumab

Daratumumab targeting CD38 has shown promise in relapsed, refractory multiple myeloma.⁸⁴ In a phase II trial, daratumumab as a single-agent was produced a response rate of approximately 30% in heavily pre-treated patients.⁸⁵ 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 three other daratumumab-based combinations have shown efficacy and have been approved by the FDA for relapsed disease. These include 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, 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.¹⁴⁵

6.3 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. The KRd regimen has been shown to be effective in a randomized trial, and is a major option for the treatment of relapsed disease (Table 8).⁶⁶ In another randomized trial carfilzomib plus dexamethasone (Pd) was associated with an improvement in PFS and OS compared with bortezomib Pd in relapsed multiple myeloma.^{139, 140} 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 56 mg/m² may be equally effective and safe, and more convenient when used in triplet combinations.¹⁴⁶ 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.

6.4 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.^{147, 148} Response rate with pomalidomide Pd in patients refractory to lenalidomide and bortezomib is approximately 30%.^{57, 149} 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).¹³⁸ Pomalidomide-containing triplet regimens such as DPd and carfilzomib, pomalidomide, dexamethasone (KPd) are active and are important options at relapse for patients who are considered lenalidomide-refractory.^{70, 150} In frail patients and in those with indolent relapse, the doublet regimen of Pd is a reasonable option.

6.5 Elotuzumab

Elotuzumab, a monoclonal antibody targeting the signaling lymphocytic activation molecule F7 (SLAMF7).⁷¹ Unlike daratumumab, elotuzumab does not have single-agent activity but shows synergistic activity when combined with Rd (Table 8).⁷¹ 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. However, elotuzumab may be more active in combination with pomalidomide than with lenalidomide. In a randomized trial conducted in patients refractory to lenalidomide and a proteasome inhibitor elotuzumab, pomalidomide, dexamethasone (EPd) was superior to Pd; median PFS 10.3 vs 4.7 months, P = .008. Based on this trial, EPd has been approved by the FDA for patients with myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

6.6 Ixazomib

Ixazomib is an oral proteasome inhibitor that is active in both the relapsed refractory setting and in newly diagnosed multiple myeloma.^{72, 151} 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).⁷² 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.

6.7 Selinexor

Selinexor blocks exportin 1 (XPO1), and leads to the accumulation and activation of various tumor suppressor proteins and the inhibition of nuclear factor kappaB. In one phase II trial, oral selinexor Pd was found to have a response rate of 26% in patients refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab.⁷⁶ Major side effects include thrombocytopenia, fatigue, nausea, and anorexia. In a recent randomized trial, Selinexor has been granted accelerated approval by the FDA for patients with relapsed refractory myeloma who have received at least four prior therapies, and whose disease is resistant to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

6.8 Isatuximab

Istatuximab is a monoclonal antibody targeting CD38 that has shown promise in relapsed, refractory multiple myeloma. In a randomized trial, isatuximab, pomalidomide, dexamethasone (Isa-Pd) was associated with better PFS compared to Pd in patients with relapsed and refractory multiple myeloma; median PFS 11.5 months vs 6.5 months, P = .001.⁷⁵ Based on these data, isatuximab has been approved by the FDA for the treatment of relapsed refractory myeloma in patients who have received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Isatuximab provides an alternative to daratumumab in myeloma, and further studies will define its place in myeloma treatment.

6.9 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 vs 6.5 months, respectively, P < .001.¹⁵² The OS at 15 months was also superior, 76% compared with 65%, respectively, P = .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.

6.10 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.⁷³ 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.^{153, 154} In a randomized trial of 768 patients, bortezomib/dexamethasone plus panobinostat was associated with superior PFS compared with bortezomib/dexamethasone plus placebo.⁷³ 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).

6.11 Other options

Despite the multiple options available, most patients eventually become refractory to all drug classes. Some additional options to consider for relapsed disease in refractory multiple myeloma include the use of an alkylator containing regimen such as VCd, or a quadruplet regimen in which a monoclonal antibody is added to a standard triplet regimen such as VRd or KRd. Other options include selinexor-containing regimens, bendamustine-containing regimens such as bendamustine, lenalidomide, dexamethasone or bendamustine, bortezomib, dexamethasone,^{155, 156} or the addition of panobinostat to a proteasome-inhibitor containing regimen. For young high-risk patients with a suitable donor, allogeneic transplantation is an option as well.

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.¹⁵⁷ However, the results of a recent randomized trial found significantly higher mortality with venetoclax in relapsed myeloma, despite producing deeper responses and better PFS.¹⁵⁸ Therefore, venetoclax is best considered investigational, and its use should be restricted to patients with t(11;14) who have relapsed disease and limited options.

6.12 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 bb2121,¹⁵⁹ and belantamab mafodotin (a humanized anti-BCMA antibody that is conjugated to monomethyl auristatin-F, a microtubule disrupting agent).¹⁶⁰ Another option that is promising is the use of a bispecific T cell engager, such as AMG 701.

6.13 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 DVd. Alternatives include pomalidomide-based combinations such as DPd, Isa-Pd, KPd, or EPd.
Patients who are frail with an indolent relapse can be treated with oral IRd.
At second or higher relapse, I switch to a triplet regimen that contains at least two 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 VCd, 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, in order to limit minimize risks of serious toxicity.

7 SMOLDERING MULTIPLE MYELOMA

Smoldering multiple myeloma is a stage that is clinically positioned between MGUS and multiple myeloma.¹⁶¹ It comprises 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.¹⁸ 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).¹⁶¹ Risk factors for high risk SMM are given on Table 9.¹⁶² Presence of two or three of these factors is associated with a median TTP to multiple myeloma of approximately 2 years, and is considered high risk SMM (Mayo 2018 criteria).

Table 9. Criteria for high risk smoldering multiple myeloma*

Mayo 2018 criteria

Any 2-3 of the following:

Serum M protein >2 g/dL

Serum FLC ratio (involved/uninvolved) >20

Serum M protein ≥30 g/L

Bone marrow plasma cells >20%

Other high risk factors

Progressive increase in M protein level (evolving type of SMM) ^b

Bone marrow clonal plasma cells 50%-60%

t (4;14) or del 17p or 1q gain

Increased circulating plasma cells

MRI with diffuse abnormalities or with one focal lesion

PET-CT with focal lesion with increased uptake but without underlying osteolytic bone destruction

Abbreviations: M, monoclonal; MRI, magnetic resonance imaging; PET-CT, positron emission tomography-computed tomography; SMM, smoldering multiple myeloma.
a Note that the term smoldering multiple myeloma excludes patients without end-organ damage who meet the revised definition of multiple myeloma, namely clonal bone marrow plasma cells ≥60% or serum free light chain (FLC) ratio ≥100 (plus measurable involved FLC level ≥100 mg/L), or more than one focal lesion on MRI. The risk factors listed in this table variables associated with a higher risk of progression of SMM, and identify patients who need close follow up and consideration for clinical trials. Patients who are high risk by Mayo 2018 criteria are candidates for prophylactic therapy with lenalidomide or lenalidomide plus dexamethasone in the absence of clinical trials.
b Increase in serum monoclonal protein by ≥25% on two successive evaluations within a 6 months period.

Early studies in SMM failed to show an advantage to preventive intervention, but were limited by lack of power, safe and effective drugs, and a risk-adapted strategy.^{163, 164} A randomized trial conducted in Spain found that patients with high risk SMM had significant prolongation of PFS and OS with Rd compared with observation.^{90, 165} A recent ECOG randomized trial provided additional confirmation, and found that early therapy with lenalidomide prolonged time to end-organ damage in patients with high risk SMM.⁹¹ Based on these two trials, patients with newly diagnosed high risk SMM patients should be considered for early intervention with lenalidomide or lenalidomide Pd. An ongoing ECOG randomized trial is testing whether a standard myeloma therapeutic triplet (DRd) will be superior to prophylactic doublet therapy with lenalidomide Pd. They are also candidates for clinical trials testing early intervention, some of which are testing intensive therapy with curative intent.¹⁶⁶

7.1 Recommendations

I recommend lenalidomide or lenalidomide plus dexamethasone for patients with newly diagnosed high risk SMM. All other patients should be observed without therapy.

ACKNOWLEDGMENTS

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

CONFLICT OF INTEREST

SVR declares no conflict of interest.

AUTHOR CONTRIBUTIONS

S.V.R. conceived of the paper, researched the literature, and wrote the manuscript.

REFERENCES

1Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group Updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014; 15: e538-e548.
10.1016/S1470-2045(14)70442-5
PubMed Web of Science® Google Scholar
2Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020; 70: 7-30.
10.3322/caac.21590
PubMed Web of Science® Google Scholar
3Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Melton LJ 3rd. Incidence of multiple myeloma in Olmsted County, Minnesota: trend over 6 decades. Cancer. 2004; 101: 2667-2674.
10.1002/cncr.20652
PubMed Web of Science® Google Scholar
4Landgren O, Weiss BM. Patterns of monoclonal gammopathy of undetermined significance and multiple myeloma in various ethnic/racial groups: support for genetic factors in pathogenesis. Leukemia. 2009; 23: 1691-1697.
10.1038/leu.2009.134
CAS PubMed Web of Science® Google Scholar
5Kyle RA, Gertz MA, Witzig TE, et al. Review of 1,027 patients with newly diagnosed multiple myeloma. Mayo Clinic Proc. 2003; 78: 21-33.
10.4065/78.1.21
PubMed Web of Science® Google Scholar
6Roodman GD. Pathogenesis of myeloma bone disease. Leukemia. 2009; 23: 435-441.
10.1038/leu.2008.336
CAS PubMed Web of Science® Google Scholar
7Hillengass J, Usmani S, Rajkumar SV, et al. International myeloma working group consensus recommendations on imaging in monoclonal plasma cell disorders. Lancet Oncol. 2019; 20: e302-e312.
10.1016/S1470-2045(19)30309-2
PubMed Web of Science® Google Scholar
8Short KD, Rajkumar SV, Larson D, et al. Incidence of extramedullary disease in patients with multiple myeloma in the era of novel therapy, and the activity of pomalidomide on extramedullary myeloma. Leukemia. 2011; 25: 906-908.
10.1038/leu.2011.29
CAS PubMed Web of Science® Google Scholar
9Landgren O, Kyle RA, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009; 113: 5412-5417.
10.1182/blood-2008-12-194241
CAS PubMed Web of Science® Google Scholar
10Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM. A monoclonal gammopathy precedes multiple myeloma in most patients. Blood. 2009; 113: 5418-5422.
10.1182/blood-2008-12-195008
CAS PubMed Web of Science® Google Scholar
11Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006; 354: 1362-1369.
10.1056/NEJMoa054494
CAS PubMed Web of Science® Google Scholar
12Dispenzieri A, Katzmann JA, Kyle RA, et al. Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study. Lancet. 2010; 375: 1721-1728.
10.1016/S0140-6736(10)60482-5
PubMed Web of Science® Google Scholar
13Landgren O, Graubard BI, Katzmann JA, et al. Racial disparities in the prevalence of monoclonal gammopathies: a population-based study of 12 482 persons from the national health and nutritional examination survey. Leukemia. 2014; 28: 1537-1542.
10.1038/leu.2014.34
CAS PubMed Web of Science® Google Scholar
14Landgren O, Graubard BI, Kumar S, et al. Prevalence of myeloma precursor state monoclonal gammopathy of undetermined significance (MGUS) in 12,309 individuals 10 to 49 years old: a population-based study from the National Health and Nutritional Examination Survey. Blood Cancer J. 2017; 7(10):e618.
10.1038/bcj.2017.97
CAS PubMed Web of Science® Google Scholar
15Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis of monoclonal gammopathy of undetermined significance. N Engl J Med. 2002; 346: 564-569.
10.1056/NEJMoa01133202
PubMed Web of Science® Google Scholar
16Kyle RA, Larson DR, Therneau TM, et al. Long-term follow-up of monoclonal gammopathy of undetermined significance. N Engl J Med. 2018; 378: 241-249.
10.1056/NEJMoa1709974
CAS PubMed Web of Science® Google Scholar
17Therneau TM, Kyle RA, Melton LJ III, et al. Incidence of monoclonal gammopathy of undetermined significance and estimation of duration before first clinical recognition. Mayo Clin Proc. 2012; 87: 1071-1079.
10.1016/j.mayocp.2012.06.014
PubMed Web of Science® Google Scholar
18Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007; 356: 2582-2590.
10.1056/NEJMoa070389
CAS PubMed Web of Science® Google Scholar
19Rajkumar SV, Gupta V, Fonseca R, et al. Impact of primary molecular cytogenetic abnormalities and risk of progression in smoldering multiple myeloma. Leukemia. 2013; 27: 1738-1744.
10.1038/leu.2013.86
CAS PubMed Web of Science® Google Scholar
20Neben K, Jauch A, Hielscher T, et al. Progression in smoldering myeloma is independently determined by the chromosomal abnormalities del(17p), t(4;14), gain 1q, hyperdiploidy, and tumor load. J Clin Oncol. 2013; 31: 4325-4332.
10.1200/JCO.2012.48.4923
PubMed Web of Science® Google Scholar
21Lakshman A, Paul S, Rajkumar SV, et al. Prognostic significance of interphase FISH in monoclonal gammopathy of undetermined significance. Leukemia. 2018; 32: 1811-1815.
10.1038/s41375-018-0030-3
PubMed Web of Science® Google Scholar
22Katzmann JA, Dispenzieri A, Kyle R, et al. Elimination of the need for urine studies in the screening algorithm for monoclonal gammopathies by using serum immunofixation and free light chain assays. Mayo Clin Proc. 2006; 81: 1575-1578.
10.4065/81.12.1575
CAS PubMed Web of Science® Google Scholar
23Chawla SS, Kumar SK, Dispenzieri A, et al. Clinical course and prognosis of non-secretory multiple myeloma. Eur J Haematol. 2015; 95: 57-64.
10.1111/ejh.12478
CAS PubMed Web of Science® Google Scholar
24Kumar 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 Clin Proc. 2009; 84: 1095-1110.
10.4065/mcp.2009.0603
CAS PubMed Web of Science® Google Scholar
25Zhou Y, Barlogie B, Shaughnessy JD Jr. The molecular characterization and clinical management of multiple myeloma in the post-genome era. Leukemia. 2009; 23: 1941-1956.
10.1038/leu.2009.160
CAS PubMed Web of Science® Google Scholar
26Dizdar O, Barista I, Kalyoncu U, et al. Biochemical markers of bone turnover in diagnosis of myeloma bone disease. Am J Hematol. 2007; 82: 185-191.
10.1002/ajh.20794
CAS PubMed Web of Science® Google Scholar
27Silvestris F, Lombardi L, De Matteo M, Bruno A, Dammacco F. Myeloma bone disease: pathogenetic mechanisms and clinical assessment. Leuk Res. 2007; 31: 129-138.
10.1016/j.leukres.2006.04.014
CAS PubMed Web of Science® Google Scholar
28Hillengass J, Moulopoulos LA, Delorme S, et al. Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: a study of the International Myeloma Working Group. Blood Cancer J. 2017; 7:e599.
10.1038/bcj.2017.78
CAS PubMed Web of Science® Google Scholar
29Dispenzieri A, Kyle R, Merlini G, et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia. 2009; 23: 215-224.
10.1038/leu.2008.307
CAS PubMed Web of Science® Google Scholar
30Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016; 17: e328-e346.
10.1016/S1470-2045(16)30206-6
PubMed Web of Science® Google Scholar
31Kumar S, Rajkumar SV. The multiple myelomas — current concepts in cytogenetic classification and therapy. Nat Rev Clin Oncol. 2018; 15: 409-421.
10.1038/s41571-018-0018-y
CAS PubMed Web of Science® Google Scholar
32Moreau P, Rajkumar SV. Multiple myeloma–translation of trial results into reality. Lancet. 2016; 388: 111-113.
10.1016/S0140-6736(16)30954-0
PubMed Web of Science® Google Scholar
33Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer. 2002; 2: 175-187.
10.1038/nrc746
CAS PubMed Web of Science® Google Scholar
34Bergsagel PL, Kuehl WM. Chromosome translocations in multiple myeloma. Oncogene. 2001; 20: 5611-5622.
10.1038/sj.onc.1204641
CAS PubMed Web of Science® Google Scholar
35Fonseca R, Bailey RJ, Ahmann GJ, et al. Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood. 2002; 100: 1417-1424.
10.1182/blood.V100.4.1417.h81602001417_1417_1424
CAS PubMed Web of Science® Google Scholar
36Seidl S, Kaufmann H, Drach J. New insights into the pathophysiology of multiple myeloma. Lancet Oncol. 2003; 4: 557-564.
10.1016/S1470-2045(03)01195-1
CAS PubMed Web of Science® Google Scholar
37Rajan AM, Rajkumar SV. Interpretation of cytogenetic results in multiple myeloma for clinical practice. Blood Cancer J. 2015; 5:e365.
10.1038/bcj.2015.92
CAS PubMed Web of Science® Google Scholar
38Durie BGM, Hoering A, Abidi MH, et al. Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone induction followed by lenalidomide and dexamethasone maintenance in patients with newly diagnosed myeloma without intent for immediate autologous stem cell transplant: results of the randomised phase III SWOG trial S0777. Lancet. 2017; 389: 519-527.
10.1016/S0140-6736(16)31594-X
CAS PubMed Web of Science® Google Scholar
39Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017; 376: 1311-1320.
10.1056/NEJMoa1611750
CAS PubMed Web of Science® Google Scholar
40Goldschmidt H, Lokhorst HM, Mai EK, et al. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018; 32: 383-390.
10.1038/leu.2017.211
CAS PubMed Web of Science® Google Scholar
41Paquin A, Kumar SK, Buadi FK, et al. Overall survival of transplant eligible patients with newly diagnosed multiple myeloma: comparative effectiveness analysis of modern induction regimens on outcome. Blood. 2017; 130: 3138.
Web of Science® Google Scholar
42Russell SJ, Rajkumar SV. Multiple myeloma and the road to personalised medicine. Lancet Oncol. 2011; 12: 617-619.
10.1016/S1470-2045(11)70143-7
PubMed Web of Science® Google Scholar
43Vu T, Gonsalves W, Kumar S, et al. Characteristics of exceptional responders to lenalidomide-based therapy in multiple myeloma. Blood Cancer J. 2015; 5: e363.
10.1038/bcj.2015.91
CAS PubMed Web of Science® Google Scholar
44Durie 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: 842-854.
10.1002/1097-0142(197509)36:3<842::AID-CNCR2820360303>3.0.CO;2-U
CAS PubMed Web of Science® Google Scholar
45Greipp PR, San Miguel JF, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005; 23: 3412-3420.
10.1200/JCO.2005.04.242
PubMed Web of Science® Google Scholar
46Hari 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: 1528-1534.
10.1038/leu.2009.61
CAS PubMed Web of Science® Google Scholar
47Kumar S, Fonseca R, Ketterling RP, et al. Trisomies in multiple myeloma: impact on survival in patients with high-risk cytogenetics. Blood. 2012; 119: 2100-2105.
10.1182/blood-2011-11-390658
CAS PubMed Web of Science® Google Scholar
48Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015; 33: 2863-2869.
10.1200/JCO.2015.61.2267
CAS PubMed Web of Science® Google Scholar
49Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014; 28: 1122-1128.
10.1038/leu.2013.313
CAS PubMed Web of Science® Google Scholar
50Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999; 341: 1565-1571.
10.1056/NEJM199911183412102
CAS PubMed Web of Science® Google Scholar
51Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005; 352: 2487-2498.
10.1056/NEJMoa043445
CAS PubMed Web of Science® Google Scholar
52Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005; 106: 4050-4053.
10.1182/blood-2005-07-2817
CAS PubMed Web of Science® Google Scholar
53Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006; 108: 3458-3464.
10.1182/blood-2006-04-015909
CAS PubMed Web of Science® Google Scholar
54Rajkumar SV, Blood E, Vesole DH, Fonseca R, Greipp PR. 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: 431-436.
10.1200/JCO.2005.03.0221
CAS PubMed Web of Science® Google Scholar
55Rajkumar SV, Rosiñol 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: 2171-2177.
10.1200/JCO.2007.14.1853
CAS PubMed Web of Science® Google Scholar
56Rajkumar 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.
10.1016/S1470-2045(09)70284-0
CAS PubMed Web of Science® Google Scholar
57Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014; 123: 1826-1832.
10.1182/blood-2013-11-538835
CAS PubMed Web of Science® Google Scholar
58San 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: 906-917.
10.1056/NEJMoa0801479
CAS PubMed Web of Science® Google Scholar
59Mateos MV, Oriol A, Martinez-Lopez J. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010; 11: 934-941.
10.1016/S1470-2045(10)70187-X
CAS PubMed Web of Science® Google Scholar
60Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010; 28: 5101-5109.
10.1200/JCO.2010.29.8216
CAS PubMed Web of Science® Google Scholar
61Cavo 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 stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010; 376: 2075-2085.
10.1016/S0140-6736(10)61424-9
CAS PubMed Web of Science® Google Scholar
62Reeder 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: 1337-1341.
10.1038/leu.2009.26
CAS PubMed Web of Science® Google Scholar
63Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012; 119: 4375-4382.
10.1182/blood-2011-11-395749
CAS PubMed Web of Science® Google Scholar
64Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010; 116: 679-686.
10.1182/blood-2010-02-268862
CAS PubMed Web of Science® Google Scholar
65Bringhen S, Petrucci MT, Larocca A, et al. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014; 124: 63-69.
10.1182/blood-2014-03-563759
CAS PubMed Web of Science® Google Scholar
66Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015; 372: 142-152.
10.1056/NEJMoa1411321
CAS PubMed Web of Science® Google Scholar
67Shah JJ, Stadtmauer EA, Abonour R, et al. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015; 126: 2284-2290.
10.1182/blood-2015-05-643320
CAS PubMed Web of Science® Google Scholar
68Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016; 375: 1319-1331.
10.1056/NEJMoa1607751
CAS PubMed Web of Science® Google Scholar
69Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016; 375: 754-766.
10.1056/NEJMoa1606038
CAS PubMed Web of Science® Google Scholar
70Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017; 130: 974-981.
10.1182/blood-2017-05-785246
CAS PubMed Web of Science® Google Scholar
71Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015; 373: 621-631.
10.1056/NEJMoa1505654
CAS PubMed Web of Science® Google Scholar
72Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016; 374: 1621-1634.
10.1056/NEJMoa1516282
CAS PubMed Web of Science® Google Scholar
73San-Miguel MD, Hungria VT, Yoon MD. Randomized phase 3 trial of the deacetylase inhibitor panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in relapsed or relapsed and refractory multiple myeloma. Lancet Oncol. 2014; 15: 1195-1206.
10.1016/S1470-2045(14)70440-1
CAS PubMed Web of Science® Google Scholar
74Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018; 379: 1811-1822.
10.1056/NEJMoa1805762
CAS PubMed Web of Science® Google Scholar
75Attal M, Richardson PG, Rajkumar SV, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019; 394: 2096-2107.
10.1016/S0140-6736(19)32556-5
CAS PubMed Web of Science® Google Scholar
76Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019; 381: 727-738.
10.1056/NEJMoa1903455
CAS PubMed Web of Science® Google Scholar
77Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010; 327: 1345-1350.
10.1126/science.1177319
CAS PubMed Web of Science® Google Scholar
78Krönke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014; 343: 301-305.
10.1126/science.1244851
CAS PubMed Web of Science® Google Scholar
79Lu G, Middleton RE, Sun H, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of ikaros proteins. Science. 2014; 343: 305-309.
10.1126/science.1244917
CAS PubMed Web of Science® Google Scholar
80Parman T, Wiley MJ, Wells PG. Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity. Nat Med. 1999; 5: 582-585.
10.1038/8466
CAS PubMed Web of Science® Google Scholar
81Rajkumar SV, Richardson PG, Hideshima T, Anderson KC. Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol. 2004; 23: 630-639.
10.1200/JCO.2005.11.030
CAS Web of Science® Google Scholar
82Kumar S, Rajkumar SV. Many facets of bortezomib resistance/susceptibility. Blood. 2008; 112: 2177-2178.
10.1182/blood-2008-07-167767
CAS PubMed Web of Science® Google Scholar
83Gutman D, Morales AA, Boise LH. Acquisition of a multidrug-resistant phenotype with a proteasome inhibitor in multiple myeloma. Leukemia. 2009; 23: 2181-2183.
10.1038/leu.2009.123
CAS PubMed Web of Science® Google Scholar
84Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015; 373: 1207-1219.
10.1056/NEJMoa1506348
CAS PubMed Web of Science® Google Scholar
85Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016; 387: 1551-1560. https://doi.org/10.1016/S0140-6736(15)01120-4.
10.1016/S0140-6736(15)01120-4
CAS PubMed Web of Science® Google Scholar
86Martin T, Baz R, Benson DM, et al. A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma. Blood. 2017; 129: 3294-3303.
10.1182/blood-2016-09-740787
CAS PubMed Web of Science® Google Scholar
87Rajkumar SV. Panobinostat for the treatment of multiple myeloma. Lancet Oncol. 2014; 15: 1178-1179.
10.1016/S1470-2045(14)70443-7
CAS PubMed Web of Science® Google Scholar
88Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019; 380: 2104-2115.
10.1056/NEJMoa1817249
CAS PubMed Web of Science® Google Scholar
89Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019; 394: 29-38.
10.1016/S0140-6736(19)31240-1
CAS PubMed Web of Science® Google Scholar
90Mateos M-V, Hernández M-T, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013; 369: 438-447.
10.1056/NEJMoa1300439
CAS PubMed Web of Science® Google Scholar
91Lonial S, Jacobus SJ, Weiss M, et al. E3A06: randomized phase III trial of lenalidomide versus observation alone in patients with asymptomatic high-risk smoldering multiple myeloma. J Clin Oncol. 2019; 37: 8001.
10.1200/JCO.2019.37.15_suppl.8001
Web of Science® Google Scholar
92Rajkumar SV. Treatment of myeloma: cure vs control. Mayo Clin Proc. 2008; 83: 1142-1145.
10.4065/83.10.1142
PubMed Web of Science® Google Scholar
93Rajkumar SV, Gahrton G, Bergsagel PL. Approach to the treatment of multiple myeloma: a clash of philosophies. Blood. 2011; 118: 3205-3211.
10.1182/blood-2011-06-297853
CAS PubMed Web of Science® Google Scholar
94Kumar S, Dispenzieri A, Lacy MQ, et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia. 2007; 21: 2035-2042.
10.1038/sj.leu.2404801
CAS PubMed Web of Science® Google Scholar
95Palumbo A, Cavo M, Bringhen S, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011; 29: 986-993.
10.1200/JCO.2010.31.6844
CAS PubMed Web of Science® Google Scholar
96Larocca A, Cavallo F, Bringhen S, et al. Aspirin or enoxaparin thromboprophylaxis for newly-diagnosed multiple myeloma patients treated with lenalidomide. Blood. 2011; 119: 933-939.
10.1182/blood-2011-03-344333
CAS PubMed Web of Science® Google Scholar
97Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008; 22: 414-423.
10.1038/sj.leu.2405062
CAS PubMed Web of Science® Google Scholar
98Moreau P, Hulin C, Macro M, et al. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016; 127: 2569-2574.
10.1182/blood-2016-01-693580
CAS PubMed Web of Science® Google Scholar
99Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011; 12: 431-440.
10.1016/S1470-2045(11)70081-X
PubMed Web of Science® Google Scholar
100Moreau P, Hulin C, Marit G, et al. Stem cell collection in patients with de novo multiple myeloma treated with the combination of bortezomib and dexamethasone before autologous stem cell transplantation according to IFM 2005-01 trial. Leukemia. 2010; 24: 1233-1235.
10.1038/leu.2010.82
CAS PubMed Web of Science® Google Scholar
101Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012; 120: 1801-1809.
10.1182/blood-2012-04-422683
CAS PubMed Web of Science® Google Scholar
102Zingone A, Kwok ML, Manasanch EE, et al. Phase II clinical and correlative study of carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide extended dosing (CRD-R) induces high rates of MRD negativity in newly diagnosed multiple myeloma (MM) patients. Blood. 2013; 122: 538.
10.1182/blood.V122.21.538.538
Web of Science® Google Scholar
103Voorhees PM, Kaufman JL, Laubach JP, et al. Depth of response to daratumumab (DARA), lenalidomide, bortezomib, and dexamethasone (RVd) improves over time in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): Griffin study update. Blood. 2019; 134: 691.
10.1182/blood-2019-123465
Web of Science® Google Scholar
104Barlogie B, Anaissie E, van Rhee F, et al. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol. 2007; 138: 176-185.
10.1111/j.1365-2141.2007.06639.x
CAS PubMed Web of Science® Google Scholar
105van Rhee F, Szymonifka J, Anaissie E, et al. Total therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide and dexamethasone, relevant to all phases of therapy. Blood. 2010; 116: 1220-1227.
10.1182/blood-2010-01-264333
CAS PubMed Web of Science® Google Scholar
106Kapoor P, Rajkumar SV. MAIA under the microscope - bringing trial design into focus. Nat Rev Clin Oncol. 2019; 16: 339-340.
10.1038/s41571-019-0198-0
PubMed Web of Science® Google Scholar
107Magarotto V, Bringhen S, Offidani M, et al. A randomized phase 3 trial of melphalan-lenalidomide-prednisone (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) vs lenalidomide plus dexamethsone (Rd) in elderly newly diagnosed multiple myeloma patients. Blood. 2013; 122: 536.
10.1182/blood.V122.21.536.536
Web of Science® Google Scholar
108Mateos MV, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020; 395: 132-141.
10.1016/S0140-6736(19)32956-3
CAS PubMed Web of Science® Google Scholar
109Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996; 335: 91-97.
10.1056/NEJM199607113350204
CAS PubMed Web of Science® Google Scholar
110Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003; 348: 1875-1883.
10.1056/NEJMoa022340
CAS PubMed Web of Science® Google Scholar
111Blade J, Vesole DH, Gertz M. Transplantation for multiple myeloma: who, when, how often? Blood. 2003; 102: 3469-3477.
10.1182/blood-2003-01-0073
CAS PubMed Web of Science® Google Scholar
112Kumar A, Loughran T, Alsina M, Durie BG, Djulbegovic B. Management of multiple myeloma: a systematic review and critical appraisal of published studies. Lancet Oncol. 2003; 4: 293-304.
10.1016/S1470-2045(03)01077-5
PubMed Web of Science® Google Scholar
113Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood. 1998; 92: 3131-3136.
10.1182/blood.V92.9.3131
CAS PubMed Web of Science® Google Scholar
114Facon T, Mary JY, Harousseau JL, et al. Front-line or rescue autologous bone marrow transplantation (ABMT) following a first course of high dose melphalan (HDM) in multiple myeloma (MM). Preliminary results of a prospective randomized trial (CIAM) protocol. Blood. 1996; 88(Suppl1): 685a.
Google Scholar
115Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol. 2006; 24: 929-936.
10.1200/JCO.2005.04.5807
CAS PubMed Web of Science® Google Scholar
116Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003; 349: 2495-2502.
10.1056/NEJMoa032290
CAS PubMed Web of Science® Google Scholar
117Cavo M, Tosi P, Zamagni E, et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007; 25: 2434-2441.
10.1200/JCO.2006.10.2509
PubMed Web of Science® Google Scholar
118Fermand JP, Alberti C, Marolleau JP. Single versus tandem high dose therapy (HDT) supported with autologous blood stem cell (ABSC) transplantation using unselected or CD34-enriched ABSC: results of a two by two designed randomized trial in 230 young patients with multiple myeloma (MM). Hematol J. 2003; 4(suppl 1): S59.
Google Scholar
119Goldschmidt H. Single vs. tandem autolgous transplantation in multiple myeloma: the GMMG experience. Hematol J. 2003; 4(suppl 1): S61.
Google Scholar
120Cavo M, Gay FM, Patriarca F, et al. Double autologous stem cell transplantation significantly prolongs progression-free survival and overall survival in comparison with single autotransplantation in newly diagnosed multiple myeloma: an analysis of phase 3 EMN02/HO95 study. Blood. 2017; 130: 401.
Web of Science® Google Scholar
121Stadtmauer EA, Pasquini MC, Blackwell B, et al. Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: results of the BMT CTN 0702 trial. J Clin Oncol. 2019; 37: 589-597.
10.1200/JCO.18.00685
CAS PubMed Web of Science® Google Scholar
122Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011; 12: 1195-1203.
10.1016/S1470-2045(11)70243-1
PubMed Web of Science® Google Scholar
123Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007; 356: 1110-1120. https://doi.org/10.1056/NEJMoa065464.
10.1056/NEJMoa065464
CAS PubMed Web of Science® Google Scholar
124Stewart AK. Reduced-intensity allogeneic transplantation for myeloma: reality bites. Blood. 2009; 113: 3135-3136.
10.1182/blood-2008-12-173526
CAS PubMed Web of Science® Google Scholar
125Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012; 366: 1782-1791.
10.1056/NEJMoa1114138
CAS PubMed Web of Science® Google Scholar
126McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012; 366: 1770-1781.
10.1056/NEJMoa1114083
CAS PubMed Web of Science® Google Scholar
127Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014; 371: 895-905.
10.1056/NEJMoa1402888
CAS PubMed Web of Science® Google Scholar
128Sonneveld P, Schmidt-Wolf IGH, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012; 30: 2946-2955.
10.1200/JCO.2011.39.6820
CAS PubMed Web of Science® Google Scholar
129Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012; 366: 1759-1769.
10.1056/NEJMoa1112704
CAS PubMed Web of Science® Google Scholar
130Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014; 371: 906-917.
10.1056/NEJMoa1402551
CAS PubMed Web of Science® Google Scholar
131Attal M, Palumbo A, Holstein SA, et al. Lenalidomide (LEN) maintenance (MNTC) after high-dose melphalan and autologous stem cell transplant (ASCT) in multiple myeloma (MM): a meta-analysis (MA) of overall survival (OS). J Clin Oncol. 2016; 34(suppl):A8001.
10.1200/JCO.2016.34.15_suppl.8001
Web of Science® Google Scholar
132Jackson GH, Davies FE, Pawlyn C, et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019; 20: 57-73.
10.1016/S1470-2045(18)30687-9
CAS PubMed Web of Science® Google Scholar
133Nooka AK, Kaufman JL, Muppidi S, et al. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014; 28: 690-693.
10.1038/leu.2013.335
CAS PubMed Web of Science® Google Scholar
134Dimopoulos MA, Gay F, Schjesvold F, et al. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2019; 393: 253-264.
10.1016/S0140-6736(18)33003-4
CAS PubMed Web of Science® Google Scholar
135Kumar SK, Therneau TM, Gertz MA, et al. Clinical course of patients with relapsed multiple myeloma. Mayo Clin Proc. 2004; 79: 867-874.
10.4065/79.7.867
CAS PubMed Web of Science® Google Scholar
136Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012; 26: 149-157.
10.1038/leu.2011.196
CAS PubMed Web of Science® Google Scholar
137Siegel DS, Dimopoulos MA, Ludwig H, et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018; 36: 728-734.
10.1200/JCO.2017.76.5032
CAS PubMed Web of Science® Google Scholar
138San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013; 14: 1055-1066.
10.1016/S1470-2045(13)70380-2
CAS PubMed Web of Science® Google Scholar
139Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016; 17: 27-38.
10.1016/S1470-2045(15)00464-7
CAS PubMed Web of Science® Google Scholar
140Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017; 18: 1327-1337.
10.1016/S1470-2045(17)30578-8
CAS PubMed Web of Science® Google Scholar
141Pineda-Roman M, Zangari M, van Rhee F, et al. VTD combination therapy with bortezomib-thalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma. Leukemia. 2008; 22: 1419-1427.
10.1038/leu.2008.99
CAS PubMed Web of Science® Google Scholar
142Richardson PG, Weller E, Jagannath S, et al. Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol. 2009; 27: 5713-5719.
10.1200/JCO.2009.22.2679
CAS PubMed Web of Science® Google Scholar
143Rajkumar SV, Kyle RA. Progress in myeloma - a monoclonal breakthrough. N Engl J Med. 2016; 375: 1390-1392.
10.1056/NEJMe1609835
PubMed Web of Science® Google Scholar
144Bringhen S, Mina R, Petrucci MT, et al. Once-weekly versus twice-weekly carfilzomib in patients with newly diagnosed multiple myeloma: a pooled analysis of two phase I/II studies. Haematologica. 2019; 104: 1640-1647.
10.3324/haematol.2018.208272
CAS PubMed Web of Science® Google Scholar
145Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009; 27: 5008-5014.
10.1200/JCO.2009.23.6802
CAS PubMed Web of Science® Google Scholar
146Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010; 24: 1934-1939.
10.1038/leu.2010.190
CAS PubMed Web of Science® Google Scholar
147Lacy MQ, Allred JB, Gertz MA, et al. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011; 118: 2970-2975.
10.1182/blood-2011-04-348896
CAS PubMed Web of Science® Google Scholar
148Bringhen S, Mina R, Cafro AM, et al. Once-weekly carfilzomib, pomalidomide, and low-dose dexamethasone for relapsed/refractory myeloma: a phase I/II study. Leukemia. 2018; 32: 1803-1807.
10.1038/s41375-018-0024-1
CAS PubMed Web of Science® Google Scholar
149Kumar SK, Berdeja JG, Niesvizky R, et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014; 15: 1503-1512.
10.1016/S1470-2045(14)71125-8
CAS PubMed Web of Science® Google Scholar
150Orlowski 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.
10.1200/JCO.2006.10.5460
CAS PubMed Web of Science® Google Scholar
151Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci U S A. 2005; 102: 8567-8672.
10.1073/pnas.0503221102
CAS PubMed Web of Science® Google Scholar
152San-Miguel JF, Richardson PG, Gunther A, et al. Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma. J Clin Oncol. 2013; 31: 3696-3703.
10.1200/JCO.2012.46.7068
CAS PubMed Web of Science® Google Scholar
153Mey UJ, Brugger W, Schwarb H, et al. Bendamustine, lenalidomide and dexamethasone (BRd) has high activity as 2^nd -line therapy for relapsed and refractory multiple myeloma - a phase II trial. Br J Haematol. 2017; 176: 770-782.
10.1111/bjh.14481
CAS PubMed Web of Science® Google Scholar
154Rodon P, Hulin C, Pegourie B, et al. Phase II study of bendamustine, bortezomib and dexamethasone as second-line treatment for elderly patients with multiple myeloma: the Intergroupe Francophone du Myelome 2009-01 trial. Haematologica. 2015; 100: e56-e59.
10.3324/haematol.2014.110890
CAS PubMed Web of Science® Google Scholar
155Kumar S, Kaufman JL, Gasparetto C, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017; 130: 2401-2409.
10.1182/blood-2017-06-788786
CAS PubMed Web of Science® Google Scholar
156Kumar S, Rajkumar SV. Surrogate endpoints in randomised controlled trials: a reality check. Lancet. 2019; 394: 281-283.
10.1016/S0140-6736(19)31711-8
PubMed Web of Science® Google Scholar
157Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019; 380: 1726-1737.
10.1056/NEJMoa1817226
CAS PubMed Web of Science® Google Scholar
158Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020; 21: 207-221.
10.1016/S1470-2045(19)30788-0
CAS PubMed Web of Science® Google Scholar
159Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma. Blood. 2015; 125: 3069-3075.
10.1182/blood-2014-09-568899
CAS PubMed Web of Science® Google Scholar
160Lakshman A, Rajkumar SV, Buadi FK, et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J. 2018; 8: 59.
10.1038/s41408-018-0077-4
PubMed Web of Science® Google Scholar
161Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rodjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I–a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993; 50: 95-102.
10.1111/j.1600-0609.1993.tb00148.x
CAS PubMed Web of Science® Google Scholar
162Grignani G, Gobbi PG, Formisano R, et al. A prognostic index for multiple myeloma. Br J Cancer. 1996; 73: 1101-1107.
10.1038/bjc.1996.212
CAS PubMed Web of Science® Google Scholar
163Mateos MV, Hernandez MT, Giraldo P, et al. Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol. 2016; 17: 1127-1136.
10.1016/S1470-2045(16)30124-3
CAS PubMed Web of Science® Google Scholar
164Mateos M-V, Martinez Lopez J, Rodriguez-Otero P, et al. Curative strategy for high-risk smoldering myeloma (GEM-CESAR): carfilzomib, Lenalidomide and dexamethasone (KRd) as induction followed by HDT-ASCT, consolidation with Krd and maintenance with Rd. Blood. 2017; 130: 402.
Web of Science® Google Scholar
165Dimopoulos MA, Lonial S, White D, et al. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol. 2017; 178: 896-905.
10.1111/bjh.14787
CAS PubMed Web of Science® Google Scholar
166San-Miguel JF, Hungria VT, Yoon SS, et al. Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. Lancet Haematol. 2016; 3: e506-e515.
10.1016/S2352-3026(16)30147-8
PubMed Web of Science® Google Scholar

Citing Literature

Volume95, Issue5

May 2020

Pages 548-567

Multiple myeloma: 2020 update on diagnosis, risk-stratification and management

Correction(s) for this article

Erratum

Abstract

Disease overview

Diagnosis