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Abstract

  1. Top of page
  2. Abstract
  3. Disease Overview
  4. Diagnosis
  5. Risk-Stratification
  6. Risk-Adapted Therapy
  7. References

Disease overview

Multiple myeloma accounts for approximately 10% of hematologic malignancies.

Diagnosis

The diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end-organ damage. In addition, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma regardless of the presence or absence of end-organ damage.

Risk stratification

In the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high-risk myeloma. Patients with t(4;14) translocation are considered intermediate-risk. All others are considered as standard-risk.

Risk-adapted initial therapy

Standard-risk patients can be treated with lenalidomide plus low-dose dexamethasone (Rd), or a bortezomib-containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate-risk and high-risk patients require a bortezomib-based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard-risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients are not candidates for transplant, initial therapy is given for approximately 12–18 months.

Maintenance therapy

After initial therapy, lenalidomide maintenance is considered for standard-risk patients who are not in very good partial response or better, while maintenance with a bortezomib-based regimen should be considered in pateints with intermediate or high-risk myeloma.

Management of refractory disease

Patients with indolent relapse can be treated first with two-drug or three-drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. Am. J. Hematol. 88:225–235, 2013. © 2013 Wiley Periodicals, Inc.


Disease Overview

  1. Top of page
  2. Abstract
  3. Disease Overview
  4. Diagnosis
  5. Risk-Stratification
  6. Risk-Adapted Therapy
  7. References

Multiple myeloma accounts for 1% of all cancers and approximately 10% of all hematologic malignancies [1, 2] Each year over 20,000 new cases are diagnosed in the United States [3]. The annual age-adjusted incidence in the United States has remained stable for decades at approximately four per 100,000 [4]. Multiple myeloma is slightly more common in men than in women, and is twice as common in African-Americans compared with Caucasians [5]. The median age of patients at the time of diagnosis is about 65 years [6].

Unlike other malignancies that metastasize to bone, the osteolytic bone lesions in myeloma exhibit no new bone formation. Bone disease is the main cause of morbidity and can be detected on routine skeletal radiographs, magnetic resonance imaging (MRI), or fluoro-deoxyglucose (FDG) positron emission tomography/computed tomographic scans (PET/CT) [7]. Other major clinical manifestations are anemia, hypercalcemia, renal failure, and an increased risk of infections. Approximately 1–2% 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 myeloma evolve from an asymptomatic pre-malignant stage termed monoclonal gammopathy of undetermined significance (MGUS) [9, 10]. MGUS is present in over 3% of the population above the age of 50, and progresses to myeloma or related malignancy a rate of 1% per year [11, 12]. Since MGUS is asymptomatic, over 50% of individuals who are diagnosed with MGUS have had the condition for over 10 years before the clinical diagnosis [13]. In some patients, an intermediate asymptomatic but more advanced pre-malignant stage referred to as smoldering multiple myeloma (SMM) can be recognized clinically [14]. SMM progresses to 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.

Diagnosis

  1. Top of page
  2. Abstract
  3. Disease Overview
  4. Diagnosis
  5. Risk-Stratification
  6. Risk-Adapted Therapy
  7. References

The diagnosis of myeloma requires: (1) 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma and (2) evidence of end-organ damage (hypercalcemia, renal insufficiency, anemia, or bone lesions) that is felt to be related to the underlying plasma cell disorder (Table 1) [15]. In addition, the presence of 60% or more clonal plasma cells in the marrow should also be considered as myeloma regardless of the presence or absence of end-organ damage [16]. Highly selected patients previously considered as SMM who are considered to have a greater than 80% risk of developing imminent damage within 2 years should also be considered candidates for therapy [17]. This includes patients with SMM who have an involved/uninvolved serum free light-chain (FLC) ratio in excess of 100 who are at a high risk for myeloma and light-chain cast nephropathy [18, 19]. 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 [20]. 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 [6]. Bone marrow studies at the time of initial diagnosis should include fluorescent in situ hybridization (FISH) designed to detect t(11;14), t(4;14), t(14;16), t(6;14), t(14;20), hyperdiploidy, and deletion 17p (see Risk-Stratification below) [21]. 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 [22] Serum CrossLaps to measure carboxy-terminal collagen crosslinks (CTX) may be useful in assessing bone turnover and to determine adequacy of bisphosphonate therapy [23, 24] Although plain radiographs of the skeleton are typically required to assess the extent of bone disease, PET/CT and MRI scans are more sensitive and are indicated when symptomatic areas show no abnormality on routine radiographs, when there is doubt about the true extent of bone disease on plain radiographs alone, and when solitary plasmacytoma or SMM are suspected [25].

Table 1. Diagnostic Criteria for Plasma Cell Disorders
DisorderDisease definitionReferences
  1. a

    The source data do not define an optimal cut off value for considering elevated VEGF level as a major criterion. We suggest that VEGF measured in the serum or plasma should be at least 3–4 fold higher than the normal reference range for the laboratory that is doing the testing to be considered a major criteria.

  2. b

    To consider endocrinopathy as a minor criterion, an endocrine disorder other than diabetes or hypothyroidism is required since these two disorders are common in the general population.

  3. From Kyle RA, Rajkumar SV. Leukemia 2009;23:3–9, reproduced by permission.

Monoclonal gammopathy of undetermined significance (MGUS)All three criteria must be met:[15, 117]
Serum monoclonal protein <3 g/dL
Clonal bone marrow plasma cells <10%, and
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; or in the case of IgM MGUS no evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.
Smoldering multiple myeloma (also referred to as asymptomatic multiple myeloma)Both criteria must be met:[15, 117]
Serum monoclonal protein (IgG or IgA) ≥3 g/dL and/or clonal bone marrow plasma cells 10%-60%, and
Absence of end-organ damage such as lytic bone lesions, anemia, hypercalcemia, or renal failure that can be attributed to a plasma cell proliferative disorder
Multiple myelomaAll criteria must be met except as noted:[15, 17, 117]
Clonal bone marrow plasma cells ≥10% or biopsy proven plasmacytoma, and
Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically
Hypercalcemia: Serum calcium > 11.5 mg/dL or
Renal insufficiency: Serum creatinine > 1.73 mmol/L (or >2 m/dL) or estimated creatinine clearance less than 40 mL/min
Anemia: Normochromic, normocytic with a hemoglobin value of >2 g/dL below the lower limit of normal or a hemoglobin value <10 g/dL
Bone lesions: Lytic lesions, severe osteopenia or pathologic fractures
In the absence of end-organ damage: Clonal bone marrow plasma cells ≥60%
IgM monoclonal gammopathy of undetermined significance (IgM MGUS)All three criteria must be met:[15, 117-122]
Serum IgM monoclonal protein <3 g/dL
Bone marrow lymphoplasmacytic infiltration <10%, and
No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.
Smoldering Waldenström's macroglobulinemia (also referred to as indolent or asymptomatic Waldenström's macroglobulinemia)Both criteria must be met:[15, 117-122]
Serum IgM monoclonal protein ≥3 g/dL and/or bone marrow lymphoplasmacytic infiltration ≥10%, and
No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.
Waldenström's macroglobulinemiaAll criteria must be met:[15, 117-122]
IgM monoclonal gammopathy (regardless of the size of the M protein), and
≥10% bone marrow lymphoplasmacytic infiltration (usually intertrabecular) by small lymphocytes that exhibit plasmacytoid or plasma cell differentiation and a typical immunophenotype (eg., surface IgM+, CD5+/-, CD10-, CD19+, CD20+, CD23-) that satisfactorily excludes other lymphoproliferative disorders including chronic lymphocytic leukemia and mantle cell lymphoma.
Evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.
Light-chain MGUSAll criteria must be met:[123]
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 such as lytic bone lesions, anemia, hypercalcemia, or renal failure that can be attributed to a plasma cell proliferative disorder
Solitary plasmacytomaAll four criteria must be met[124, 125]
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 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
Systemic AL amyloidosisAll four criteria must be met:[15, 126]
Presence of an amyloid-related systemic syndrome (such as renal, liver, heart, gastrointestinal tract, or peripheral nerve involvement)
Positive amyloid staining by Congo red in any tissue (e.g., fat aspirate, bone marrow, or organ biopsy)
Evidence that amyloid is light-chain related established by direct examination of the amyloid using Mass Spectrometry (MS)-based proteomic analysis, or immunoelectron microscopy, and
Evidence of a monoclonal plasma cell proliferative disorder (serum or urine M protein, abnormal free light chain ratio, or clonal plasma cells in the bone marrow).
Note: Approximately 2–3% of patients with AL amyloidosis will not meet the requirement for evidence of a monoclonal plasma cell disorder listed above; the diagnosis of AL amyloidosis must be made with caution in these patients.
POEMS syndromeAll four criteria must be met[127, 128]
Polyneuropathy
Monoclonal plasma cell proliferative disorder (almost always lambda)
Any one of the following three other major criteria:
1. Sclerotic bone lesions
2. Castleman's disease
3. Elevated levels of vascular endothelial growth factor (VEGF)a
Any one of the following six minor criteria
1. Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)
2. Extravascular volume overload (edema, pleural effusion, or ascites)
3. Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)b
4. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, white nails)
5. Papilledema
6. Thrombocytosis/polycythemia
Note: Not every patient meeting the above criteria will have POEMS syndrome; the features should have a temporal relationship to each other and no other attributable cause. Anemia and/or thrombocytopenia are distinctively unusual in this syndrome unless Castleman disease is present.

The M protein is considered to be measurable if it is ≥1gm/dL in the serum and or ≥200 mg/day in the urine. The M protein level is monitored by serum and urine protein electrophoresis to assess treatment response every month while on therapy, and every 3–4 months when off-therapy. The serum FLC assay is used to monitor patients with myeloma who lack a measurable M protein, provided the FLC ratio is abnormal and the involved FLC level is ≥100 mg/L [26]. Response to therapy is assessed using the International Myeloma Working Group uniform response criteria [27].

Risk-Stratification

  1. Top of page
  2. Abstract
  3. Disease Overview
  4. Diagnosis
  5. Risk-Stratification
  6. Risk-Adapted Therapy
  7. References

Prognosis in myeloma depends on host factors (age, performance status, comorbidities), stage, disease aggressiveness, and response to therapy [28]. Staging of myeloma using the Durie-Salmon Staging (DSS) [29] or the International Staging System (ISS) [30, 31] provides prognostic information but is not helpful in making therapeutic choices. A risk-stratification model that relies on a number of independent molecular cytogenetic markers to assess disease aggressiveness is useful for both counseling and therapeutic decision-making [32]. At the Mayo Clinic, newly diagnosed myeloma is stratified into standard-, intermediate-, and high-risk disease using the Mayo stratification for myeloma and risk-adapted therapy (mSMART) classification (Table 2) [21, 33]. Patients with standard-risk myeloma have a median overall survival (OS) of 6–7 years while those with high-risk disease have a median OS of less than 2–3 years despite tandem autologous stem cell transplantation (ASCT) [1].

Table 2. Risk-Stratification of Myeloma
  1. a

    In the presence of concurrent trisomies, patients with high risk cytogenetics should be considered standard-risk.

A. Standard-risk
1. Trisomies (hyperdiploidy)
2. t(11;14)
3. t(6;14)
B. Intermediate-risk
1. t(4;14)
C. High-riska
1. 17p deletion
2. t(14;16)
3. t(14;20)
4. High-risk gene expression profiling signature

Risk-Adapted Therapy

  1. Top of page
  2. Abstract
  3. Disease Overview
  4. Diagnosis
  5. Risk-Stratification
  6. Risk-Adapted Therapy
  7. References

OS in myeloma has improved significantly in the last decade [34] with the emergence of thalidomide [35], bortezomib [36], and lenalidomide [37, 38]. Bortezomib is a proteasome inhbitor [39-41]; the mechanism of action of thalidomide and lenalidomide is unclear, but they are considered immunomodulatory agents [42] and may require cereblon (the putative primary teratogenic target for thalidomide) [43] expression for their anti-myeloma activity [44].

The approach to treatment of symptomatic newly diagnosed multiple myeloma is outlined in Fig. 1 and is dictated by eligibility for ASCT and risk-stratification [1]. The major regimens used for therapy and the data to support their use are listed in Tables 3 and 4. There is an ongoing “cure versus control” debate on whether we should treat myeloma with an aggressive multidrug strategy targeting complete response (CR) or a sequential disease control approach that emphasizes quality of life as well as OS [2, 45]. Based on recent data, high-risk patients require a CR for long-term OS and hence clearly need an aggressive strategy [46]. On the other hand, standard-risk patients have similar OS regardless of whether CR is achieved or not and therefore have the option of pursuing either an aggressive or a sequential approach.

image

Figure 1. Approach to the treatment of newly diagnosed myeloma in patients elgible for transplantation (A) and not eligible for transplantation (B). Abbreviations: ASCT, autologous stem cell transplantation; CR, complete response; Dex, dexamethasone; Rd, lenalidomide plus low-dose dexamethasone; VCD, bortezomib, cyclophosphamide, dexamethasone; VGPR, very good partial response; VRD, bortezomib, lenalidomide, dexamethasone. (From Rajkumar SV, Nature Rev Clin Oncol, 2011, Vol. 8, 479–491,

© Nature Publishing Group reproduced by permission

.)

Download figure to PowerPoint

Table 3. Major Treatment Regimens in Multiple Myeloma
RegimenUsual dosing schedulea
  1. a

    All doses need to be adjusted for performance status, renal function, blood counts, and other toxicities.

  2. b

    Doses of dexamethasone and/or bortezomib reduced based on subsequent data showing lower toxicity and similar efficacy with reduced doses.

  3. c

    Omit Day 22 dose if counts are low or when the regimen is used as maintenance therapy; When used as maintenance therapy for high risk patients, delays can be instituted between cycles.

  4. 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 [62, 63].

Melphalan-Prednisone (7-day schedule) [129]Melphalan 8–10 mg oral days 1–7
Prednisone 60 mg/day oral days 1–7
Repeated every 6 weeks
Thalidomide-Dexamethasoneb [47, 48]Thalidomide 200 mg oral days 1–28
Dexamethasone 40 mg oral days 1, 8, 15, 22
Repeated every 4 weeks
Lenalidomide-Dexamethasone [49]Lenalidomide 25 mg oral days 1–21 every 28 days
Dexamethasone 40 mg oral days 1, 8, 15, 22 every 28 days
Repeated every 4 weeks
Bortezomib-Dexb [130]Bortezomib 1.3 mg/m2 intravenous days 1, 8, 15, 22
Dexamethasone 20 mg on day of and day after bortezomib (or 40 mg days 1, 8, 15, 22)
Repeated every 4 weeks
Melphalan-Prednisone-Thalidomide [70, 71]Melphalan 0.25 mg/kg oral days 1–4 (use 0.20 mg/kg/day oral days 1–4 in patients over the age of 75)
Prednisone 2 mg/kg oral days 1-4
Thalidomide 100–200 mg oral days 1–28 (use 100 mg dose in patients >75)
Repeated every 6 weeks
Bortezomib-Melphalan-Prednisone-b [65, 66, 78]Bortezomib 1.3 mg/m2 intravenous days 1, 8, 15, 22
Melphalan 9 mg/m2 oral days 1–4
Prednisone 60 mg/m2 oral days 1–4
Repeated every 35 days
Bortezomib-Thalidomide-Dexamethasoneb [58]Bortezomib 1.3 mg/m2 intravenous days 1, 8, 15, 22
Thalidomide 100-200 mg oral days 1–21
Dexamethasone 20 mg on day of and day after bortezomib (or 40 mg days 1, 8, 15, 22)
Repeated every 4 weeks × four cycles as pre-transplant induction therapy
Bortezomib-Cyclophosphamide-Dexamethasoneb (VCD) [60, 61]Cyclophosphamide 300 mg/m2 orally on days 1, 8, 15, and 22
Bortezomib 1.3 mg/m2 intravenously on days 1, 8, 15, 22
Dexamethasone 40 mg orally on days on days 1, 8, 15, 22
Repeated every 4 weeksc
Bortezomib-Lenalidomide-Dexamethasoneb [57, 61]Bortezomib 1.3 mg/m2 intravenous days 1, 8, 15
Lenalidomide 25 mg oral days 1–14
Dexamethasone 20 mg on day of and day after bortezomib (or 40 mg days 1, 8, 15, 22)
Repeated every 3 weeksd
Table 4. Results of Recent Randomized Studies in Newly Diagnosed Myeloma
TrialRegimenNo. of patientsOverall response rate (%)CR plus VGPR (%)Progression-free survival (Median in months)P value for progression free survivalThree-year overall survival rate (%)aOverall survival (Median in months)P value for overall survival
  1. a

    Estimated from survival curves when not reported.

  2. b

    Progression-free survival not reported, numbers indicate time to progression.

  3. Abbreviations: CR, complete response; MP, melphalan plus prednisone; MPT, melphalan plus prednisone plus thalidomide; N/A, not available; NS, not significant; Rd, lenalidomide plus dexamethasone; TD, thalidomide plus dexamethasone; VGPR, very good partial response; VMP, bortezomib plus melphalan plus prednisone; VTD, bortezomib, thalidomide, dexamethasone.

Rajkumar et al. [49]RD223815019.1 75NR 
Rd222704025.30.02674NR0.47
Harousseau et al. [56]VAD242631530 77NR 
VD2407938360.0681NR0.46
Cavo et al. [58]TD238792840 84NR 
VTD2369362NR0.00686NR0.3
Moreau et al. [59]VD998135N/A N/AN/A 
VTD1009051N/A N/AN/A 
Facon et al. [70]MP19635717.8 4833.2 
Mel 100126654319.4 5238.3 
MPT125764727.5<0.0016651.6<0.001
Hulin et al. [71]MP + Placebo11631718.5 4029.1 
MPT113622124.10.00155440.028
Wijermans et al. [74]MP16845109 4331 
MPT165662713<0.00155400.05
Palumbo et al. [131]MP164481114.5 6547.6 
MPT167692921.80.00465450.79
Waage et al. [73]MP+ Placebo17533714 4332 
MPT182342315NS43290.16
San Miguel et al.b [78, 79]MP33135816.6 5443 
VMP337714124<0.00169NR<0.001

Options for initial treatment in patients eligible for ASCT

Typically, patients are treated with approximately two to four cycles of induction therapy before stem cell harvest. After harvest, patients can either undergo frontline ASCT or resume induction therapy delaying ASCT until first relapse. Although thalidomide plus dexamethasone (TD) is approved for the treatment of newly diagnosed myeloma [47, 48], it is inferior in terms or activity and toxicity compared with lenalidomide-based regimens and is not recommended as the standard frontline therapy except in countries where lenalidomide is not available for initial therapy and in patients with acute renal failure where it can be used effectively in combination with bortezomib.

Lenalidomide-low dose dexamethasone (Rd)

Rd which combines lenalidomide with a lower dose of dexamethasone (40 mg once weekly) is an active regimen in newly diagnosed myeloma, and has less toxicity and better OS than lenalidomide plus high dose dexamethasone [49]. Stem cell collection with granulocyte colony-stimulating factor (G-CSF) alone may be impaired when Rd is used as induction therapy [50]. Thus patients over the age of 65 and those who have received more that four cycles of Rd) stem cells must be mobilized with either cyclophosphamide plus G-CSF or with plerixafor [51, 52]. All patients treated with Rd require antithrombosis prophylaxis. Aspirin is adequate for most patients, but in patients who are at higher risk of thrombosis, either low-molecular weight heparin or coumadin is needed [53-55].

Bortezomib-containing regimens

Harousseau et al. compared bortezomib plus dexamethasone (VD) versus vincristine, Adriamycin, dexamethasone (VAD) as pre-transplant induction therapy [56]. Post-induction very good partial response (VGPR) was superior with VD compared with VAD, 38% versus 15%, respectively. This translated into superior VGPR post-transplant, 54% versus 37%, respectively. However, progression-free survival (PFS) improvement was modest, 36 months versus 30 months, respectively, and did not reach statistical significance. No OS benefit is apparent so far.

Three-drug regimens containing bortezomib such as bortezomib-cyclophosphamide-dexamethasone (VCD), bortezomib-thalidomide-dexamethasone (VTD), and bortezomib-lenalidomide-dexamethasone (VRD) are highly active in newly diagnosed myeloma [57]. In randomized trials, VTD has shown better response rates and PFS compared with TD [58], as well as VD [59]. Results from randomized trials are not available for VRD and VCD, and the use of these two regimens in clinical practice is driven by promising results from Phase II studies. VCD has significant activity in newly diagnosed multiple myeloma [60], and is less expensive than either VTD or VRD. In the randomized Phase II evolution trial, VCD was well tolerated and had similar activity compared with VRD [61]. There are no data on whether these regimens are superior to Rd in terms of OS, and no data comparing the quality of life across the various combinations that can be used in initial therapy. However, bortezomib-containing regimens appear to overcome the poor prognosis associated with the t4;14 translocation, and certain other cytogenetic abnormalities [58, 62-64].

The major drawback of bortezomib-containing regimens is the risk of neurotoxicity early in the disease course. The neuropathy with bortezomib can occur abruptly, and can be significantly painful and debilitating in a subset of patients. Recent studies show that the neurotoxicity of bortezomib can be greatly diminished by administering bortezomib using a once-weekly schedule [65, 66], and by administering the drug subcutaneously [67]. Unlike lenalidomide, bortezomib does not appear to have any adverse effect on stem cell mobilization [68].

Multidrug combinations

Besides the regimens discussed above, another option is multi-agent combination chemotherapy, such as VDT–PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) [62, 63]. VDT–PACE is particularly useful in patients with aggressive disease such as plasma cell leukemia or multiple extramedullary plasmacytomas. Several other regimens have been tested in newly diagnosed multiple myeloma, but there are no clear data from randomized controlled trials that they have an effect on long-term endpoints compared with the regimens discussed earlier.

Recommendations

Unfortunately the various options for treatment discussed above have not been compared in adequately powered clinical trials with relevant end-points to determine the best treatment strategy.

  • In standard-risk patients, Rd or VCD can be used as initial therapy for 4 months, followed by stem cell harvest and ASCT. In patients who are tolerating therapy and responding well, it is equally reasonable to continue initial therapy after stem cell collection, reserving ASCT for first relapse. With such a strategy, therapy is usually stopped after 12–18 months. Unless there are contraindications, between the two regimens, I prefer Rd as initial therapy in standard-risk patients.
  • In intermediate-risk patients, I favor VCD as initial therapy for four cycles followed by ASCT and then maintenance with a bortezomib-based regimen for at least 2 years.
  • In high-risk patients, I favor VRd as initial therapy for four cycles followed by ASCT and then long-term maintenance with a bortezomib-based regimen.
  • In patients presenting with acute renal failure suspected to be secondary to light-chain cast nephropathy, I prefer VCD or VTD as initial therapy in conjunction with plasma exchange. 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 preferred in most patients for initial therapy, unless there is felt to be an urgent need for rapid disease control.

Options for initial treatment in patients not eligible for ASCT

In patients with newly diagnosed multiple myeloma who are not candidates for ASCT due to age or other comorbidities, the major options for initial therapy are the same as those discussed earlier for patients eligible for ASCT [1]. For example, Rd is an attractive option for the treatment of elderly patients with newly diagnosed myeloma because of its excellent tolerability, convenience, and efficacy. The 3-year OS rate with Rd in patients 70 and older who did not receive ASCT is 70% [69], and is comparable with results with melphalan, prednisone, thalidomide (MPT), and VMP. An ongoing Phase III trial is currently comparing MPT versus Rd for 18 months versus Rd until progression.

Although the melphalan-based regimens discussed below have been extensively tested in these patients, they are falling out of favor 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. In general, initial therapy in patients who are not candidates for transplant is for a fixed duration of time (9–18 months). However, with Rd, it is unclear whether treatment should continue until relapse or be stopped after a fixed duration of therapy. Maintenance therapy is considered for intermediate and high-risk patients.

Melphalan, prednisone, thalidomide

Six randomized studies have compared MPT with melphalan, prednisone (MP) [70-75]. An OS advantage has been observed in three trials [70, 71, 74]. Two metaanalyses show a clear superiority of MPT over MP [76, 77]. MPT is associated with a Grade 3–4 toxicity rate of over 50%, and a DVT risk of 20% [72].

Bortezomib, melphalan, prednisone (VMP)

In a large Phase III trial, VMP demonstrated better OS compared with MP [78, 79]. There is a suggestion that VMP can overcome some high-risk cytogenetic features [79]. Substituting melphalan with thalidomide in the VMP regimen has not shown an advantage; in a randomized trial, bortezomib, thalidomide, prednisone (VTP) was not superior to VMP [65]. Neuropathy is a significant risk with VMP therapy when bortezomib is administered in the usual twice weekly schedule; Grade 3 neuropathy occurred in 13% of patients versus 0% with MP [78]. This rate can be greatly decreased by administering bortezomib using a once-weekly schedule [65, 66]. VCD 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.

Bortezomib, melphalan, prednisone, thalidomide (VMPT)

Preliminary results suggest superior PFS and OS with VMPT compared with VMP in a randomized Phase III trial [80]. However, patients in the VMPT arm received maintenance therapy with bortezomib and thalidomide, while patients in the VMP arm did not receive any additional therapy beyond 9 months making it difficult to determine whether the OS difference is due to the addition of the fourth drug to the induction regimen or to the addition of maintenance. Additional data and longer follow up are needed.

Other regimens

MP may still have a role in elderly patients who do not have access to Rd in whom therapy with MPT or VMP is not considered safe or feasible [81, 82]. TD is inferior to MP, and is not recommended in elderly patients [83]. The addition of lenalidomide to MP (MPR) does not improve PFS or OS compared with MP alone [84]. An ECOG randomized trial (E1A06) is currently comparing MPR to MPT.

Recommendations

Unfortunately the various options for treatment discussed above have not been compared in adequately powered clinical trials with relevant end-points to determine the best treatment strategy.

  • In standard-risk patients, as in the transplant eligible population, Rd or VCD can be used as initial therapy. Dexamethasone dose is reduced as much as possible after the first 4–6 months, and possibly discontinued after the first year. For frail patients, dexamethasone may be started at 20 mg once a week. Unless there are contraindications, between the two regimens, I prefer Rd as initial therapy in standard-risk patients.
  • In intermediate-risk patients, I favor VCD as initial therapy for approximately one year followed if possible by a lower intensity (one dose every 2 weeks) maintenance schedule of bortezomib for 2 years.
  • In high-risk patients, I favor VRd as initial therapy for approximately 1 year followed by a lower intensity maintenance schedule of bortezomib.

Role of hematopoietic stem cell transplantation

Autologous stem cell transplantation

ASCT improves median OS in multiple myeloma by approximately 12 months [85-88]. However, three randomized trials show that OS is similar whether ASCT is done early (immediately following four cycles of induction therapy) or delayed (at the time of relapse as salvage therapy) [89-91]. Further, in a Spanish randomized trial, patients responding to induction therapy failed to benefit from ASCT trial, suggesting that the greatest benefit from early ASCT may be mainly among the small proportion of patients with disease refractory to induction therapy [92]. Two randomized trials have found benefit with tandem (double) versus single ASCT, with the benefit primarily seen in patients failing to achive CR or VGPR with the first ASCT [93, 94]. Two other randomized trials, however, have yet to show significant improvement in OS with double ASCT [95, 96].

Allogeneic transplantation

The role of allogeneic and nonmyeloablative-allogeneic transplantation in myeloma is controversial. The TRM (10–20%) and high GVHD rates even with non-myeloablative allogeneic transplantation are fairly high [97].Although allogenic transplantation should still be considered as investigational, it may be a consideration for young patients with high-risk disease who are willing to accept a high TRM and the unproven nature of this therapy for a chance at better long-term survival.

Recommendations
  • ASCT should be considered in all eligible patients. But in standard-risk patients responding well to therapy, ASCT can be delayed until first relapse provided stem cells are harvested early in the disease course.
  • Tandem ASCT is considered only if patients fail to achieve a VGPR with the first ASCT. With modern induction regimens such patients are a small minority, and even in this circumstance patients can be probably treated with maintenance therapy rather than tandem ASCT.
  • At present, allogeneic transplantation as frontline therapy should largely be considered investigational.

Post-transplant maintenance therapy

There is confusion about whether post-transplant strategies should be referred to as “consolidation” or “maintenance,” but these distinctions are semantic and do not distract from the main questions: Should we administer post-transplant therapy? Who should receive such therapy? Thalidomide has shown modest PFS and OS benefit as maintenance therapy in two randomized trials [98, 99]. More recently, two randomized studies have shown better PFS with lenalidomide as post ASCT maintenance therapy [100, 101]. However, patients in the control arm of these trials lacked uniform access to the active drug (thalidomide or lenalidomide) at relapse, and it is not clear whether the PFS improvement will be neutralized since patients in the control arm can always initiate the same therapy at the time of first relapse [2]. There was also a clear increased risk of second cancers with lenalidomide maintenance in both trials. Further, although one of the two trials is showing some OS benefit with lenalidomide maintenance, the data are preliminary and the magnitude of that benefit is unclear. We need to await mature OS results from both these studies before routine lenalidomide maintenance can be recommended [102].

In one study, bortezomib administered every other week post-transplant produced better OS than thalidomide maintenance [103]. Although more studies are needed, bortezomib-based maintenance may be important for intermediate- and high-risk patients.

Recommendations
  • At this point it is not clear whether all patients should receive maintenance therapy post ASCT with either thalidomide or lenalidomide, but results of the maintenance trials must be discussed with the patient, along with the pros and cons of maintenance versus therapy at first relapse.
  • I recommend observation alone for most patients post-transplant except standard-risk patients who fail to achieve VGPR after ASCT (candidates for lenalidomide maintenance) and those with intermediate or high-risk disease (candidates for bortezomib-based maintenance).

Treatment of relapsed multiple myeloma

Almost all patients with multiple myeloma eventually relapse. The remission duration in relapsed myeloma decreases with each regimen [104]. The median PFS and OS in patients with relapsed myeloma refractory to lenalidomide and bortezomib is poor, with median times of 5 months and 9 months, respectively [105]. Alkylators, corticosteroids, and thalidomide are all known options for therapy. Other options are discussed below.

Bortezomib and lenalidomide-based regimens

Approximately one-third of patients with relapsed refractory myeloma respond to bortezomib when used as a single agent [36]. Two large Phase III trials have shown superior TTP and OS with lenalidomide (25 mg oral days 1–21 every 28 days) plus dexamethasone compared with placebo plus dexamethasone in relapsed multiple myeloma [106, 107]. Bortezomib and the immunomodulatory drugs (thalidomide or lenalidomide) can be combined effectively with each other and with other chemotherapy drugs such as cyclophosphamide and melphalan to produce highly active combination regimens. For example, in a study of 85 patients with refractory myeloma treated with VTD, 63% achieved PR including 22% near CR [108]. Similarly, VRd has also shown significant activity in relapsed, refractory myeloma [109].

Liposomal doxorubicin

A Phase III randomized trial found that median TTP was superior with bortezomib plus pegylated liposomal doxorubicin (PLD) compared with bortezomib alone, 9.3 months versus 6.5 months, respectively, P < 0.001 [110]. OS at 15 months was also superior, 76% compared with 65%, respectively, P = 0.03. Based on this study, liposomal doxorubicin appears to have modest activity in relapsed myeloma, and can be considered as an option for the treatment of relapsed myeloma.

Carfilzomib

Carfilzomib is a novel keto-epoxide tetrapeptide proteasome inhbitor recently approved for the treatment of relapsed refractory myeloma in patients who have been previously treated with lenalidomide and bortezomib. In a Phase II study (PX-171-003-A1), 266 patients were treated with single-agent carfilzomib, including 80% of patients who were refractory or intolerant to both bortezomib and lenalidomide [111]. The overall response rate was 24%, and the median duration of response was 7.8 months. The most common side effects were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%) [111]. Neuropathy was minimal. In a separate Phase II trial (PX-171-004) that treated 129 patients who were bortezomib naiive, the response rate with single-agent carfilzomib was approximately 50% [112]. Carfilzomib is now being tested in newly diagnosed myeloma, with high activity reported in a Phase II trial of carfilzomib plus Rd (CRd) [113]. An upcoming ECOG Phase III trial will compared CRd and VRD in newly diagnosed myeloma.

Emerging options

Pomalidomide has significant activity in relapsed refractory myeloma, even in patients failing lenalidomide [114, 115]. Response rate in patients refractory to lenalidomide and bortezomib is approximately 30% [116]. MLN-9708 is an oral proteasome inhibitor that has shown promise in both the relapsed refractory setting and in newly diagnosed myeloma. Other promising agents under investigation include histone deacetylase inhibitors (vorinostat and panabinostat); anti-cyclin dependent kinase inhibitors; daratumumab, a human anti-CD38 monoclonal antibody; and elotuzumab, an anti CS-1 monoclonal antibody.

Recommendations
  • Patients who have cryopreserved stem cells early in the disease course should consider ASCT as salvage therapy at first relapse.
  • If relapse occurs more than 6 months after stopping therapy, the initial treatment regimen that successfully controlled the myeloma initially can be reinstituted when possible.
  • Patients who have an indolent relapse can often be treated first with lenalidomide, bortezomib, or alkylators plus low-dose corticosteroids. These patients present with asymptomatic increases in serum and urine monoclonal protein levels, progressive anemia, or a few small lytic bone lesions.
  • Patients refractory or intolerant to bortezomib and lenalidomide are candidates for carfilzomib.
  • Patients with more aggressive relapse often require therapy with a combination of active agents, e.g., VCD, VTD, VRd, or VDT-PACE.
  • The duration of therapy has not been well addressed in relapsed myeloma, and in some regimens such as those employing bortezomib or alkylators it may be reasonable to stop therapy once a stable plateau has been reached in order to minimize risks of serious toxicity.

References

  1. Top of page
  2. Abstract
  3. Disease Overview
  4. Diagnosis
  5. Risk-Stratification
  6. Risk-Adapted Therapy
  7. References
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