Multiple Myeloma

Kenneth C. Anderson; Melissa Alsina; William Bensinger; J. Sybil Biermann; Asher Chanan-Khan; Adam D. Cohen; Steven Devine; Benjamin Djulbegovic; Edward A. Faber; Cristina Gasparetto; Carol Ann Huff; Adetola Kassim; Bruno C. Medeiros; Ruby Meredith; Noopur Raje; Jeffrey Schriber; Seema Singhal; George Somlo; Keith Stockerl-Goldstein; Steven P. Treon; Guido Tricot; Donna M. Weber; Joachim Yahalom; Furhan Yunus

doi:10.6004/jnccn.2011.0095

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Multiple Myeloma

Authors:

Kenneth C. Anderson

Kenneth C. Anderson
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Melissa Alsina

Melissa Alsina
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William Bensinger

William Bensinger
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J. Sybil Biermann

J. Sybil Biermann
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Asher Chanan-Khan

Asher Chanan-Khan
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Adam D. Cohen

Adam D. Cohen
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Steven Devine

Steven Devine
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Benjamin Djulbegovic

Benjamin Djulbegovic
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MD, PhD

Edward A. Faber Jr.

Edward A. Faber Jr.
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DO, MS

Cristina Gasparetto

Cristina Gasparetto
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Carol Ann Huff

Carol Ann Huff
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Adetola Kassim

Adetola Kassim
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MD, MS

Bruno C. Medeiros

Bruno C. Medeiros
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Ruby Meredith

Ruby Meredith
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MD, PhD

Noopur Raje

Noopur Raje
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Jeffrey Schriber

Jeffrey Schriber
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Seema Singhal

Seema Singhal
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George Somlo

George Somlo
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Keith Stockerl-Goldstein

Keith Stockerl-Goldstein
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Steven P. Treon

Steven P. Treon
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MD, PhD

Guido Tricot

Guido Tricot
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MD, PhD

Donna M. Weber

Donna M. Weber
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Joachim Yahalom

Joachim Yahalom
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Furhan Yunus

Furhan Yunus
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Volume/Issue:: Volume 9: Issue 10

Online Publication Date:: Oct 2011

DOI:: https://doi.org/10.6004/jnccn.2011.0095

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NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. The American Cancer Society estimates 20,520 new cases of MM will be diagnosed in the United States in 2011, including 11,400 cases in men and 9,120 in women, with an estimated 10,610 deaths.¹ The mean age of affected individuals is 62 years for men (75% older than 70 years) and 61 years for women (79% older than 70 years). The treatment of MM has dramatically improved over the past decade. The 5-year survival rate reported in the Surveillance, Epidemiology and End Results database increased from 25% in 1975 to 34% in 2003 because of newer and more effective treatment options.^2,3

MM is typically sensitive to a variety of cytotoxic drugs, both as initial treatment and as treatment of relapsed disease. Unfortunately, responses are transient, and MM is not considered curable with current approaches. However, over the past few years, treatment has been evolving rapidly because of the introduction of new drugs, such as thalidomide, lenalidomide, and bortezomib. In addition, the microenvironment of the bone marrow is becoming better understood, creating the rationale for new combinations of therapies and new drug development.⁴ Studies of the associated cytogenetic abnormalities indicate that MM is a heterogeneous disease, suggesting that risk-adapted approaches and individualizing treatment will help further refine patient management.

These guidelines developed by the NCCN Multiple Myeloma Panel address diagnosis, treatment, and follow-up for patients with MM.

Multiple Myeloma

Initial Diagnostic Workup

The initial diagnostic workup in all patients should include a history and physical examination and the following baseline blood studies and biological assessments to differentiate symptomatic and asymptomatic MM: a CBC with differential and platelet counts; blood urea nitrogen (BUN); serum creatinine and serum electrolytes; serum calcium; albumin; lactate dehydrogenase (LDH); and β₂-microglobulin. Increased BUN and creatinine indicate decreased kidney function, whereas LDH levels help assess tumor cell burden. The level of β₂-microglobulin reflects the tumor mass and is now considered a standard measure of the tumor burden.

The monoclonal protein (M-protein) component in serum and urine is detected and evaluated by various urine and serum analyses. Urine analysis as part of the initial diagnostic workup includes evaluating 24-hour urine for total protein, urine protein electrophoresis (UPEP), and urine immunofixation electrophoresis (UIFE).

Serum analysis also includes quantitative immunoglobulin levels of different types of antibodies (IgG, IgA, and IgM); serum protein electrophoresis (SPEP); and serum immunofixation electrophoresis (SIFE) to obtain more specific information about the type of abnormal antibodies present. Assessing changes and proportions of various proteins, particularly the M-protein, helps track the progression of myeloma and the response to treatment. Use of the serum free light chain (FLC) assay along with SPEP and SIFE yields high sensitivity while screening for MM and related plasma cell disorders.⁵ Therefore, this assay is now included as a part of the initial diagnostic workup in these guidelines. The serum FLC assay also has prognostic value in plasma cell disorders, including monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, active myeloma, immunoglobulin light chain amyloidosis, and solitary plasmacytoma.^5,6 The serum FLC assay also allows for quantitative monitoring of patients with light chain amyloidosis and oligosecretory myeloma. In addition, the FLC ratio is required for documenting stringent complete response according to the International Myeloma Working Group Uniform Response Criteria.⁷ The FLC assay cannot replace the 24-hour urine protein electrophoresis for monitoring patients with measurable urinary M-proteins.

Most patients have serum proteins with or without associated urinary protein. In the Mayo Clinic review of 1027 patients with newly diagnosed MM, 20% of patients had secretory urinary proteins; however, 3% of patients had neither serum nor urine proteins and therefore had nonsecretory myeloma.⁸ Once the myeloma or M-protein is quantified, the same test must be used for serial studies to ensure accurate relative quantification.

To evaluate bone marrow plasma cell infiltration, bone marrow aspiration and biopsy are recommended to detect quantitative and/or qualitative abnormalities of bone marrow plasma cells. To evaluate lytic bone lesions, a full skeletal radiographic survey is recommended.

Although MM may be morphologically similar, several subtypes of the disease have been identified at the genetic and molecular level. Bone marrow studies performed at initial diagnosis should include chromosome analysis using conventional karyotyping (cytogenetics) and fluorescent in situ hybridization (FISH) performed with the plasma cells obtained from bone marrow aspiration. Specific chromosomal abnormalities involving translocations, deletions, or amplifications have been identified in patients with MM.

Deletion of chromosome 13 [del(13)] seems to have an amplifying effect on cell cycle gene expression and is reported to be associated with short event-free and overall survivals.⁹ Deletion of 17p13 (the locus for the tumor-suppressor gene, p53) leads to loss of heterozygosity of TP53 and is considered a high-risk feature in MM.^10-12 Other high-risk chromosomal aberrations in MM are characterized by structural changes that include specific rearrangements involving the IGH gene (encoding immunoglobulin heavy chain), located at 14q32. Several subgroups of patients are identified based on 14q32 translocations, the 3 main ones being t(11;14)(q13;q32), t(4;14) (p16;q32), and t(14;16)(q32;q23). From a clinical point of view, t(4;14) is the most important. Several studies have confirmed that patients with this translocation have a poor prognosis.^13,14

Conflicting data exist regarding t(14;16); although one study showed no impact on prognosis,¹⁵ others have shown a negative prognostic impact.^16,17 A translocation between 11 and 14 [t(11;14)] was reported to be associated with improved survival.^18,19 Abnormalities of chromosome 1 are also among the frequent chromosomal alterations in MM.²⁰ The short arm is most often associated with deletions and the long arm with amplifications.²¹ Gains/amplification of 1q21 increases the risk of MM progression, and incidence of the amplification is higher in relapsed than in newly diagnosed cases.^20,22

Some centers are stratifying patients into various risk groups based on the chromosomal markers for use in prognostic counseling, selection, and sequencing of therapy approaches.^23,24 According to the panel, the FISH panel for prognostic estimation should include t(4;14), t(14;16), t(11;14), 17p13 deletion, chromosome 13 deletion, and chromosome 1 amplification. This information helps determine biological subtype and prognostic recommendations.

In addition to cytogenetic markers of prognosis, biological factors or gene expression signatures are postulated to be capable of discerning prognosis and helping in therapeutic decision-making.^25,26 Further understanding of the molecular subtypes of MM is emerging from the application of high-throughput genomic tools, such as gene expression profiling (GEP).²⁷ With the currently available novel treatment approaches, most patients with MM can now anticipate long-term disease control. However, patients with cytogenetically and molecularly defined high-risk disease do not receive the same benefit from current approaches as those with low-risk disease. GEP is a powerful and fast tool with the potential to provide additional prognostic value to further refine risk stratification, help therapeutic decisions, and inform novel drug design and development. Currently, standardized testing for GEP is not available and data are inadequate to determine how this prognostic information should be used to direct patient management.

Bone marrow immunohistochemistry may be useful in some cases to confirm the presence of monoclonal plasma cells to more accurately measure plasma cell involvement, and bone marrow flow cytometry can help define the disease.

Additional Diagnostic Tests

The panel recommends additional tests that may be useful under some circumstances. These include MRI,²⁸ CT, or PET/CT scan. Active myeloma is positive on PET scan.^29,30 PET/CT and MRI scans are more sensitive than plain radiographs and are indicated when symptomatic areas show no abnormality on routine radiographs.

A tissue biopsy may also be necessary to confirm the presence of plasmacytomas. Plasma cell labeling index may be helpful to identify the fraction of the myeloma cell population that is proliferating.³¹ Bone marrow and fat pad staining should be performed to determine the presence of amyloid, and serum viscosity should be evaluated if hyperviscosity is suspected.

In selected patients with MM, physicians may use allogeneic (i.e., from someone else) transplantation. In this approach, physicians administer non-myeloablative therapy and infuse stem cells (i.e., peripheral blood or bone marrow) obtained from a donor, preferably a human leukocyte antigen (HLA)-identical sibling. In these cases, the patient will need to be HLA-typed.

Because bisphosphonate therapy is a consideration in patients with MM, a baseline bone densitometry test may be recommended.

Diagnostic Categories

Based on the results of the clinical and laboratory evaluation discussed in previous sections, patients are initially classified as either having smoldering (asymptomatic) or active (symptomatic) disease (see page 1153).

The criteria agreed on by the International Myeloma Working Group (IMWG) for smoldering (asymptomatic) MM includes low concentrations of M-protein (≥ 30 g/L) and/or bone marrow infiltration greater than or equal to 10% plasma cells, but with no anemia, renal failure, hypercalcemia, or bone lesions.³²

Patients with active disease are then further categorized according to stage, based on either the Durie-Salmon staging system or the International Staging System (ISS).³³ The ISS is based on easily obtained laboratory measures (serum β₂-microglobulin and serum albumin) and is easier to use than the Durie-Salmon staging system for patients with previously untreated MM.

Response Criteria

Assessing the response to treatment is a key determinant of myeloma treatment. The IMWG response criteria were developed using the European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry/American Bone Marrow Transplant Registry (EBMT/IBMTR/ABMTR) response criteria,³⁴ with revisions and improvements to help uniform reporting.

The updated IMWG response criteria definitions³⁵ for complete response (CR), stringent CR, very good partial response (VGPR), partial response (PR), stable disease (SD), and progressive disease are outlined in the guidelines on page 1154. The panel recommends that the IMWG uniform response criteria be used in future clinical trials.

Solitary Plasmacytoma

The diagnosis of solitary plasmacytoma requires a thorough evaluation to rule out the presence of systemic disease, because many patients presumed to have solitary plasmacytomas are found to have occult disease. Solitary plasmacytomas are further categorized as osseous or extraosseous. Osseous plasmacytoma is defined as a plasmacytoma emanating from bone without other evidence of disease. Solitary plasmacytomas derived from soft tissue are termed extraosseous.³⁶ However, the treatment and follow-up options for osseous and extraosseous plasmacytomas are similar.

Primary Therapy

For those patients with osseous plasmacytoma, primary radiation therapy (≥ 45 Gy) to the involved field is the initial treatment and is potentially curative.^37,38 Extraosseous plasmacytomas are treated initially with radiation therapy (≥ 45 Gy) to the involved field followed by surgery if necessary.

Surveillance/Follow-Up Tests

Follow-up and surveillance tests for both solitary plasmacytoma and extraosseous plasmacytoma consist of blood and urine tests performed every 4 weeks initially to monitor response to the primary radiation therapy. If complete disappearance of the paraprotein occurs, then the frequency could be reduced to every 3 to 6 months or as indicated clinically. If the protein persists, then the monitoring should continue every 4 weeks.

The blood tests include CBC; serum chemistry for creatine, albumin, and calcium; serum quantitative immunoglobulins, SPEP, and SIFE; and serum FLC assay. Testing for LDH levels and β₂-microglobulin may be useful under some circumstances. The urine tests include 24-hour urine assay for total protein, UPEP, and UIFE.

Bone marrow aspirate and biopsy, and imaging studies using MRI and/or CT and/or PET/CT are recommended as clinically indicated. PET imaging may detect early bone marrow involvement in patients with solitary plasmacytoma.^30,39 Bone survey is recommended annually or as clinically indicated.

If progressive disease emerges, then patients should be reevaluated for recurrent extraosseous plasmacytoma or myeloma, and systemic therapy administered as indicated.

Smoldering (Asymptomatic) Myeloma

Smoldering (asymptomatic) myeloma describes a stage of disease at which patients have no symptoms and no related organ or tissue impairment.³² Patients with Durie-Salmon stage I myeloma also have low amounts of M-protein without significant anemia, hypercalcemia, or bone disease, and would be included in this category. Patients with asymptomatic smoldering MM have an indolent course for many years without therapy.

Primary Therapy

Patients with smoldering myeloma, including Durie-Salmon stage I, do not need primary therapy because it may take many months to years before the disease progresses. The risk of transformation to symptomatic myeloma is life-long, and patients should be closely monitored.⁴⁰

The panel recommends that patients with smoldering myeloma should initially be observed at 3 to 6-month intervals (category 1 recommendation) or be enrolled in clinical trials.

Surveillance/Follow-Up Tests

The surveillance/follow-up tests include CBC; serum chemistry for creatine, albumin, LDH, calcium, and β₂-microglobulin; serum quantitative immunoglobulins, SPEP, and SIFE; and serum FLC assay. The urine tests include 24-hour urine assay for total protein, UPEP, and UIFE.

Bone survey is recommended annually or as clinically indicated. Bone marrow aspiration and biopsy, and imaging studies with MRI and/or CT and/or PET/CT are recommended as clinically indicated. PET imaging seems to reliably predict active myeloma through FDG uptake; low-level smoldering myeloma is consistently negative on PET scan.²⁹ PET can also assess the extent of active disease, detect extramedullary involvement, or evaluate treatment response.^30,41-43

Multiparameter flow cytometry is a newly available tool that can help individualize the follow-up/surveillance strategy for patients with smoldering myeloma. It measures abnormal cells in the bone marrow and provides information regarding the risk of progression to active myeloma. A high proportion of abnormal plasma cells within the bone marrow plasma cell compartment (> 95%) has been shown to predict the risk of progression in both patients with smoldering myeloma or MGUS.^44,45 According to the panel, multiple parameter flow cytometry information may be useful to consider in the follow-up/surveillance plan of patients with smoldering myeloma. Because this test is not standardized or widely available, they recommend it only be performed in laboratories with experience.

If the disease progresses to symptomatic myeloma then patients should be treated according to the guidelines for symptomatic MM. The IMWG definition for progressive disease is on page 1155.

Active (Symptomatic) MM

Primary Therapy

Patients presenting with active (symptomatic) myeloma are initially treated with primary therapy and, in selected patients, primary therapy is followed by high-dose chemotherapy with autologous stem cell support. Stem cell toxins, such as nitrosoureas or alkylating agents, may compromise stem cell reserve, and regimens with these agents (notably melphalan) should be avoided in patients who are potential candidates for stem cell transplant (SCT). Therefore, one of the first steps in evaluating patients with advanced MM is to determine whether they would be considered candidates for high-dose therapy and transplant based on age and comorbidities. However, advanced age and renal dysfunction are not absolute contraindications to transplant. It is also important to consider supportive care for all patients at the time of diagnosis. For example, 80% of patients have bone disease and up to 33% have renal compromise. Bone disease, renal dysfunction, and other complications, such as hypercalcemia, hyperviscosity, and coagulation/thrombosis, should be treated with appropriate adjunctive measures (see Adjunctive Treatment for MM, page 1157). In all patients, careful attention to supportive care is critical to avoid early complications that may compromise therapeutic outcome.

Page 1157 presents a list of primary therapy regimens recommended by the panel for transplant and nontransplant candidates, and also lists drugs recommended for maintenance therapy. The list is selected and does not include all regimens. The panel has classified the regimens as either “preferred regimens” or “other regimens” based on a balance of efficacy and toxicity. Research into various primary regimens has focused on improving the complete response rates in both transplant and nontransplant candidates. The panel has noted the importance of assessing for response to primary therapy after 2 cycles.

Lenalidomide is a potent analogue of thalidomide. Both lenalidomide and thalidomide possess immunomodulatory properties.⁴⁶ Prophylaxis with an anticoagulation agent is recommended for patients receiving thalidomide-based or lenalidomide-based therapy.

Bortezomib-based regimens may be of value in patients with renal failure and those with certain adverse cytogenetic features.⁴⁷ Although bortezomib treatment has been associated with an incidence of herpes zoster,⁴⁸ this may be reduced with the use of prophylactic acyclovir.⁴⁹ The risk of deep vein thrombosis (DVT) is low with bortezomib; however, peripheral neuropathy and gastrointestinal disturbance can be higher. Bortezomib-related adverse events are predictable and managed with patient monitoring and appropriate supportive care.⁵⁰

Preferred Primary Therapy Regimens for Transplant Candidates

Bortezomib/Dexamethasone: Bortezomib is a proteasome inhibitor that not only directly targets the myeloma cell but also targets the interaction between the tumor cell and the bone marrow microenvironment. Bortezomib targets both intrinsic and extrinsic signaling pathways, whereas dexamethasone targets only the intrinsic pathway. This emerging understanding of the bone marrow microenvironment provides the rationale for combining these drugs.

In the Intergroupe Francophone du Myélome (IFM) cooperative group trial, 482 patients were randomized to one of the following arms: vincristine/doxorubicin/dexamethasone (VAD; n = 121) alone, VAD plus consolidation therapy with dexamethasone/cyclophosphamide/etoposide/cisplatin (DCEP; n = 121), bortezomib/dexamethasone alone (n = 121), or bortezomib/dexamethasone plus consolidation with DCEP (n = 119), followed by autologous SCT.⁵¹ The primary end point after primary therapy was CR/near CR rate. The investigators evaluated the response according to modified EBMT criteria,³⁴ including additional categories of near CR (CR but immunofixation-positive)⁵² and VGPR (serum M-protein reduction ≥ 90%; urine light chain < 100 mg over 24 hours).⁷

After primary therapy, the rates of CR/near CR (14.8% vs. 6.4%), of at least a VGPR (37.7% vs. 15.1%), and of overall response (78.5% vs. 62.8%) were significantly higher with bortezomib plus dexamethasone versus VAD.⁵¹ At a median follow-up of 32.2 months, median progression-free survival (PFS) was modest and not statistically significant (36.0 vs. 29.7 months for bortezomib/dexamethasone vs. VAD, respectively).⁵¹ Use of DCEP as consolidation therapy after primary therapy did not have a significant impact on response rates.⁵¹ Bortezomib/dexamethasone was equally effective in patients with high-risk MM, including those with ISS stage III disease and poor-risk cytogenetic abnormalities.

Another trial analyzed a large series of patients (< 65 years of age) with newly diagnosed MM who were treated with primary therapy of bortezomib/dexamethasone versus VAD before high-dose melphalan treatment with hematopoietic stem cell support.⁴⁷ The results showed that bortezomib improved the prognosis (in terms of both event-free and overall survivals) of patients with t(4;14) compared with those treated with VAD primary therapy. Also, primary therapy with bortezomib/dexamethasone significantly improved the outcome of patients, including those with t(4;14), compared with VAD.⁴⁷

Based on these data and the uniform consensus among the panel, bortezomib/dexamethasone is a category 1 option as primary therapy for transplant candidates. Because bortezomib treatment has been associated with an incidence of herpes zoster,^53,54 herpes prophylaxis is recommended for patients receiving this agent and in the posttransplant setting.⁴⁸

Bortezomib/Doxorubicin/Dexamethasone: The updated results from the Dutch-Belgian Hemato-Oncology Cooperative Group HOVON-65/GMMG-HD4 phase III trial of patients with newly diagnosed stage II/III myeloma showed high response rates with bortezomib/doxorubicin/dexamethasone versus VAD, and this superior response rate was maintained even after SCT with a significantly higher overall response rate.⁵⁵ No unexpected toxicities occurred, and deletion of chromosome 13q did not have a significant impact on response. Responses improved with bortezomib maintenance.⁵⁵ The PFS at 36 months was 46% for patients treated with bortezomib/doxorubicin/dexamethasone as primary therapy followed by SCT and bortezomib maintenance, versus 42% for patients treated with VAD followed by SCT and maintenance with thalidomide.⁵⁵

Based on data from the HOVON-65/GMMG-HD4 trial and the uniform consensus among the panel, bortezomib/doxorubicin/dexamethasone is a category 1 option as primary therapy for transplant candidates.

Bortezomib/Thalidomide/Dexamethasone: The GIMEMA Italian Multiple Myeloma Network reported results of a phase III trial investigating bortezomib/thalidomide/dexamethasone (n = 241) versus thalidomide/dexamethasone (n = 239) as primary therapy, followed by tandem autologous SCT with high-dose melphalan and then consolidation therapy with the same primary regimen.⁵⁶ The addition of bortezomib to thalidomide and dexamethasone significantly improved overall response rate after primary treatment. After primary therapy, CR/near CR was seen in 73 patients (31%; 95% CI, 25.0-36.8) receiving bortezomib/thalidomide/dexamethasone and 27 (11%; 95% CI, 7.3-15.4) on thalidomide/dexamethasone.⁵⁷ Rates of CR/near CR and VGPR or better continued to be significantly higher in the bortezomib/thalidomide/dexamethasone group than in the thalidomide/dexamethasone group after the first and second autologous SCT, and subsequent consolidation therapy.⁵⁷ Patients receiving the bortezomib containing regimen experienced grade 3/4 peripheral neuropathy.

Data from a single-institution retrospective study are similar to the interim data from the GIMEMA trial.⁵⁸ The findings of this analysis show that the overall response rate after primary therapy with bortezomib/thalidomide/dexamethasone was 94% (32 patients of 34 showed some response, including a VGPR rate ≥ 56%).⁵⁸

The results of the randomized phase III trial by the Spanish Myeloma Group (PETHEMA/GEM) also showed a significantly higher CR rate with bortezomib/thalidomide/dexamethasone as primary therapy in both the overall series and in patients with high-risk cytogenetics. After autologous SCT, the CR rate continued to be significantly higher with bortezomib/thalidomide/dexamethasone than with thalidomide/dexamethasone.⁵⁹

Based on these data and uniform consensus among the panel, bortezomib/thalidomide/dexamethasone is a category 1 option as primary therapy for transplant candidates.

Bortezomib/Lenalidomide/Dexamethasone: Phase I/II study results have shown that primary therapy with bortezomib/lenalidomide/dexamethasone is very active and well tolerated in patients with newly diagnosed MM.^60-62 The response rate is 100%, with 74% VGPR or better and 52% CR/near CR. Given this high extent and frequency of response, a randomized trial is now evaluating this regimen with or without high-dose melphalan and stem cell support in newly diagnosed transplant candidates.

The benefits of bortezomib/lenalidomide/dexamethasone as primary therapy were also seen in the results of the phase II EVOLUTION trial⁶³ and the phase II IFM 2008 trial.^64,65 In the EVOLUTION study, the overall response rate after primary treatment was 83% (14% stringent CR; 38% CR+ near CR; and 50% ≥ VGPR),⁶¹ and in the phase II IFM 2008 trial, the overall response rate after primary treatment was 97% (13% stringent CR; 16% CR; and 54% ≥ VGPR).⁶⁴

Bortezomib/lenalidomide/dexamethasone is included as a category 2A recommendation to the list of primary treatment options available for transplant candidates in the guidelines.

Cyclophosphamide/Bortezomib/Dexamethasone: Data from 3 phase II studies involving patients with newly diagnosed MM (n = 495) has shown high response rates with cyclophosphamide/bortezomib/dexamethasone (CyBorD) as primary treatment.^66-68 The trial by Reeder et al.⁶⁶ performed in the United States and Canada showed an overall response rate of 88%, including a 61% rate of VGPR or greater and a 39% rate of CR/near CR with CyBorD as the primary regimen. The depth of response seen after primary treatment was also maintained after transplant, in those who underwent transplantation (70% rates of CR/near CR; rate of at least VGPR or better 74%).⁶⁶

Analysis of the German DSMM XIa study also showed high responses with CyBorD as primary treatment (the overall response rate was 84%, with a PR rate of 74% and a CR rate of 10%). High response rates were also seen in patients with unfavorable cytogenetics.⁶⁷ In the updated results of the phase II EVOLUTION study, primary treatment with CyBorD showed an overall response rate of 78% (3% stringent CR; 31% CR + near CR; and 41% ≥ VGPR).⁶³ Based on data from these 3 phase II studies, the panel added the combination of cyclophosphamide/bortezomib/dexamethasone as a category 2A recommendation to the list of primary treatment options available for transplant candidates.

Lenalidomide/Dexamethasone: Lenalidomide is a potent analogue of thalidomide. Like thalidomide, it is believed to attack multiple targets in the microenvironment of the myeloma cell, producing effects such as apoptosis and inhibition of angiogenesis and cytokine circuits. Lenalidomide received approval from the FDA for the treatment of relapsed/refractory MM in combination with dexamethasone (discussed further in Salvage Therapy, page 1172). However, lenalidomide and dexamethasone have been investigated as primary therapy. The SWOG phase III randomized controlled study S0232 compared dexamethasone alone with a combined therapy of dexamethasone plus lenalidomide for patients with newly diagnosed MM.⁶⁹ This trial was halted at interim analysis and patients on dexamethasone alone were allowed to switch to lenalidomide with dexamethasone. The SWOG data and safety monitoring committee decided to permanently close enrollment based on the preliminary 1-year survival results from the ECOG phase III study (E4A03).^70,71 At the time the SWOG trial was halted, the lenalidomide plus dexamethasone arm showed improved CR rate compared with dexamethasone alone (22% vs. 4%).⁶⁹

In a recent open-label trial, Rajkumar et al.⁷² randomized 445 patients with newly diagnosed MM to either high- or low-dose regimens, with results showing that response was superior with high-dose dexamethasone. Complete or partial response were experienced within 4 cycles by 169 (79%) of 214 patients receiving high-dose therapy and 142 (68%) of 205 patients receiving low-dose therapy.⁷² However, the high response rates did not result in superior time to progression, PFS, or overall survival compared with low-dose dexamethasone. The trial was stopped after 1 year and patients on high-dose therapy were allowed to cross over because the overall survival rate was significantly higher in the low-dose arm. At 1-year interim analysis, the overall survival rate was 96% in the low-dose dexamethasone group compared with 87% in the high-dose group (P = .0002), and 2-year overall survival rates were 87% versus 75%, respectively.

The cause of inferior overall survival with high-dose dexamethasone seems to be related to increased deaths from toxicity. More patients on the high-dose regimen than those on the low-dose regimen (52% vs. 35%) experienced grade 3 or worse toxic effects in the first 4 months, including DVT (26% vs. 12%), infections including pneumonia (16% vs. 9%), and fatigue (15% vs. 9%). The 3-year overall survival of patients who received 4 cycles of primary treatment with either dose followed by autologous SCT was 92%, suggesting that lenalidomide/dexamethasone is reasonable for primary therapy before SCT.

A retrospective analysis of 411 patients with newly diagnosed MM treated with either lenalidomide/dexamethasone (n = 228) or thalidomide/dexamethasone (n = 183) was performed at the Mayo Clinic.⁷³ In a matched-pair analysis, the differences between the arms were similar for age, sex, transplantation status, and dexamethasone dose. The proportion of patients experiencing at least a PR to lenalidomide/dexamethasone was 80.3% versus 61.2% with thalidomide/dexamethasone; VGPR rates were 34.2% versus 12.0%, respectively. Patients receiving lenalidomide/dexamethasone had a longer time to progression (median, 27.4 vs. 17.2 months; P = .019), longer PFS (median, 26.7 vs. 17.1 months; P = .036), and better overall survival (median not reached vs. 57.2 months; P = .018).⁷³ Grade 3 or 4 adverse events (57.5% vs. 54.6%; P = .568) were seen in a similar proportion of patients in both groups. Main grade 3 or 4 toxicities of lenalidomide/dexamethasone were hematologic, mainly neutropenia (14.6% vs. 0.6%; P < .001). The most common toxicities associated with thalidomide/dexamethasone were venous thromboembolism (15.3% vs. 9.2%; P = .058) and peripheral neuropathy (10.4% vs. 0.9%; P < .001). Based on the results of this metaanalysis, lenalidomide/dexamethasone seems to be well tolerated and more effective than thalidomide/dexamethasone.⁷³ However, randomized prospective trials are needed to confirm these results.

A decrease in CD34-positive cells collected after prolonged lenalidomide treatment has been reported.^74,75 Guidelines by the IMWG suggest that patients on lenalidomide in combination with dexamethasone should have stem cells collected within the first 4 cycles of therapy.⁷⁶

The panel recommends harvesting peripheral blood early in the course of primary treatment with lenalidomide. Lenalidomide/dexamethasone is listed as a category 1 primary treatment option in the guidelines. The panel recommends appropriate prophylaxis for patients undergoing this therapy.

The incidence of DVT is low with single-agent lenalidomide or lenalidomide plus low-dose dexamethasone, but risk rises when combined with high-dose dexamethasone. According to a recent report, patients treated with lenalidomide and high-dose dexamethasone who developed a venous thromboembolism did not experience shorter overall survival or time to progression.⁷⁷ Prophylactic anticoagulation is recommended in patients receiving this therapy.^50,78

Other Primary Therapy Regimens for Transplant Candidates

Thalidomide/Dexamethasone: Thalidomide attacks multiple targets in the microenvironment of the myeloma cell, producing effects such as apoptosis and inhibition of angiogenesis and cytokine circuits. Rajkumar et al.⁷⁹ reported the results of a study involving 207 patients with newly diagnosed MM randomized to receive thalidomide/dexamethasone or dexamethasone alone. The response rate to the combined therapy was significantly higher compared with that for dexamethasone alone (63% vs. 41%, respectively). Stem cells for subsequent transplant were also successfully collected. However, increased toxicity is associated with thalidomide, specifically DVT, and therefore prophylactic anticoagulation is recommended if thalidomide and dexamethasone are given.⁷⁸ Other side effects of thalidomide included rash, gastrointestinal disturbance, peripheral neuropathy, or somnolence.⁵⁰ The use of thalidomide requires individual patient consideration, and the higher response rate of the thalidomide/dexamethasone combination must be weighed against the increased side effects. Thalidomide in combination with dexamethasone as a primary regimen is a category 2B recommendation in the guidelines. The panel recommends appropriate thromboprophylaxis for patients undergoing this therapy.

Single-Agent Dexamethasone: Dexamethasone alone may be an option as short-term primary therapy for a highly selected group of patients (e.g., those with renal failure, hypercalcemia, cord compromise requiring radiation therapy, cytopenia). Single-agent dexamethasone as primary treatment is a category 2B recommendation in the guidelines.

Liposomal Doxorubicin/Vincristine/Dexamethasone Regimen: In a noninferiority trial, patients with newly diagnosed, active MM (n = 192) were randomized to receive a pegylated liposomal doxorubicin/vincristine/dexamethasone regimen or a VAD regimen.⁸⁰ The primary end points were response and toxicity. Objective response, PFS, and overall survival were similar between the treatment groups. However, pegylated liposomal doxorubicin/vincristine/dexamethasone was associated with less toxicity than VAD.⁸⁰ Data from recent studies suggest that VAD should no longer be recommended, because most patients experience response to induction regimen based on novel drug combinations. The guidelines list liposomal doxorubicin/vincristine/dexamethasone regimen as a category 2B recommendation for primary treatment.

Preferred Primary Therapy Regimens for Nontransplant Candidates

All of the regimens described for transplant candidates are also options for nontransplant candidates. The regimens containing melphalan compromise stem cell reserve, and thus are options only for nontransplant candidates.

Melphalan/Prednisone/Thalidomide: MP has been a standard treatment of MM since 1960. A review of the clinical trials reported that MP results in a 60% response rate with duration of 18 months and an overall survival of 24 to 36 months.⁸¹ Palumbo et al.⁸² were the first to report that when thalidomide was combined with MP (MPT), combined CR and near CR rates were 27.9% for MPT compared with 7.2% for MP.⁸² Subsequently, several phase III trials have reported significant higher overall response rate with MPT versus MP (57%-76% vs. 31%-48%), including a higher CR or VGPR rate (7%-15.5%).^83-88 The impact of MPT on survival is unclear, because only the IFM studies^83,84 have reported a survival advantage in patients on MPT. The HOVON group performed a phase III study to compare the standard MP regimen versus MPT in 333 elderly patients with newly diagnosed MM.⁸⁹ Significantly higher response rates were seen among patients treated with MPT than with MP, and these response rates were comparable with those seen in the French⁵¹ and Italian⁵⁶ trials described earlier. Overall response rate with MPT (CR + VGPR + PR) was 66% versus 45% with MP. The number of patients experiencing no response to therapy or progressive disease was 55% with MP and 34% with MPT. The event-free survival was 13 months with MPT versus 9 months with MP, and overall survival was 40 months with MPT versus 31 months with MP.⁸⁹ Comparisons among these studies are difficult because of differences in patient populations, duration of treatment, and use of maintenance regimens.

Because of the significantly higher overall response rate consistently seen in all of these studies, MPT is a category 1 recommendation as primary treatment in patients ineligible for transplant. A significant risk of DVT is associated with thalidomide-based therapy, therefore the use of prophylaxis in patients on MPT therapy is highly recommended.

Melphalan/Prednisone/Bortezomib: Addition of bortezomib to MP (MPB) was investigated in a large randomized international phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial.⁹⁰ The trial evaluated MP (n = 338) versus MPB (n = 344) in previously untreated patients with MM aged 65 years or older, or patients younger than 65 years and ineligible for transplant. The addition of bortezomib resulted in highly significant increases in time to disease progression, PFS, overall survival, time to next treatment, and complete response. Importantly, adverse cytogenetics, advanced age, and renal function had no impact on the efficacy of the bortezomib-containing regimen, which was well tolerated.

Updated results from the phase III VISTA trial, with a median follow-up of 36.7 months, show a 35% reduced risk of death associated with MPB compared with MP.⁹¹ The 3-year overall survival rate was 68.5% in the MPB arm compared with 54% in the MP arm. With MPB, time to progression and overall survival were unaffected by advanced age, renal impairment, and adverse cytogenetics [t(4;14), t(14;16), del(17p)]. The adverse events were higher in the MPB arm; however, discontinuation of treatment because of adverse events was reported to be similar in both arms. Improvement in peripheral neuropathy in patients treated with MPB was seen within a median of 1.9 months; 60% completely resolved within a median of 5.7 months.⁹¹

Another interesting finding from this study was that patients experiencing relapse after bortezomib-based therapy are not more resistant to subsequent therapies and can be as successfully treated with subsequent immunomodulatory drug-based therapies. The median survival from start of subsequent therapy was 30.2 months for those treated initially with MPB, compared with 21.9 months for those treated with MP.⁹¹ Response rates to second-line bortezomib, thalidomide, and lenalidomide-based therapies were 41%, 37%, and 73%, respectively, after MPB, and 59%, 47%, and 67%, respectively, after MP.⁹¹ This finding supports the strategy of using bortezomib-based treatment as first-line therapy instead of reserving it as salvage after up-front conventional therapy. Based on the VISTA trial results, the MPB regimen is now a category 1 recommendation as primary treatment in patients ineligible for transplant.

Advantages of MPB over MPT include more rapid response and higher rates of CR, which is associated with improved survival in the nontransplant setting.^92,93 Results of VISTA also support use of MPB in patients with high-risk cytogenetics and/or impaired renal function. No randomized head-tohead study has compared MPT and MPB; however, a meta-analysis of the phase III studies has shown that better response rates could be expected with MPB than with MPT.⁹⁴ Yeh et al.⁹⁴ compared the existing data (on MP, MPT, and MPB) and calculated an 81% probability that MPB was the most efficacious among the 3 regimens in terms of overall response rate and a greater than 99% probability that it was also the most efficacious in terms of CR. No difference was seen in overall survival and PFS between the MPB and MPT regimens.

Melphalan/Prednisone/Lenalidomide: Melphalan and prednisone in combination with lenalidomide (MPL) was studied in 54 patients with newly diagnosed MM.⁹⁵ Although myelosuppression was a concern with lenalidomide, therapy with oral MPL produced very high response rates, with 81% of patients experiencing at least a PR, 47.6% experiencing a VGPR, and 24% having a complete immunofixation-negative response. The 1-year event-free survival rate in all patients was 92% and the overall survival rate was 100%. Common grade 3/4 toxicities seen were neutropenia (in 52%), thrombocytopenia (in 24%), and anemia (in 5%).

A subsequent analysis of the kinetics of neutropenia and thrombocytopenia and the safety and efficacy of MPL showed that the hematologic toxicities were manageable, and that the median PFS was 28.5 months and the 2-year overall survival was 91%.⁹⁶ The investigators suspect that cytoxicity of bone marrow is related to melphalan in the regimen.

In another phase I/II trial of patients with newly diagnosed MM who were ineligible for autologous SCT (median age, 74 years), the MPL regimen showed substantial activity (CR was 12%, overall response rate was 69%) with a manageable toxicity profile.⁹⁷ The most common grade 3/4 toxicities were neutropenia (58% of patients) and thrombocytopenia (27%).⁹⁷

The phase III MM-015 study is evaluating 459 patients (median age, 65 years) with newly diagnosed MM randomly assigned to either MPL followed by lenalidomide maintenance, MPL followed by placebo maintenance, or MP followed by placebo maintenance.⁹⁸ The updated results show that overall, MPL plus lenalidomide maintenance reduced the risk of disease progression by 58% compared with MP, with a higher 2-year PFS rate (55% vs. 16%).⁹⁹ The MPL regimen is a category 1 option as primary treatment option for patients ineligible for transplant in the guidelines.

Lenalidomide/Low-Dose Dexamethasone: The results of the SWOG S0232 trial,⁶⁹ which included nontransplant candidates, and those of the ECOG E4A03 trial,⁷⁰ which also included elderly patients, showed that lenalidomide in combination with low-dose dexamethasone is a well-tolerated and effective regimen for elderly patients. In the study by Rajkumar et al.⁷² discussed earlier, the overall survival rate was significantly higher in the lenalidomide plus low-dose dexamethasone arm than in the lenalidomide plus high-dose dexamethasone arm.⁷² The inferior survival outcome seen with high-dose dexamethasone was greatest in patients 65 years and older. At 2 years, patients who did not proceed to transplant had an overall survival rate of 91% with lenalidomide and low dose dexamethasone.⁷² Therefore, the panel considers lenalidomide in combination with low-dose dexamethasone a category 1 option for nontransplant candidates. The panel recommends appropriate thromboprophylaxis for patients undergoing this therapy.

Bortezomib/Dexamethasone: A United States community-based, randomized, open-label, multicenter phase IIIb UPFRONT trial is comparing safety and efficacy of 3 highly active bortezomib-based regimens, one of which is bortezomib/dexamethasone.

Bortezomib/thalidomide/dexamethasone, bortezomib/dexamethasone, and MPB are being compared in elderly patients with previously untreated MM who are ineligible for SCT.¹⁰⁰ The updated results show that all 3 regimens are active with good response rates, and predictable and similar rates of toxicities are reported for all arms.^100,101 The study also showed that bortezomib maintenance was well tolerated and resulted in increased rates of VGPRs in all 3 arms. The panel included bortezomib/dexamethasone as a category 2A primary therapy option for patients ineligible for transplant.

Other Primary Therapy Regimens for Nontransplant Candidates

Superior responses have been reported for both MPT and MPB regimens compared with MP. However, MP may still have a role in patients who do not have access to novel agents. According to the panel, MP is a category 2A recommendation. The other category 2B options for patients ineligible for SCT include thalidomide/dexamethasone, single-agent dexamethasone, liposomal doxorubicin/vincristine/dexamethasone, and VAD.

Follow-up After Primary Therapy for Transplant and Nontransplant Candidates

After primary therapy, patients are reevaluated (after 2 cycles) with the laboratory tests, bone survey, and bone marrow aspiration and biopsy to determine whether a treatment response has occurred, or whether primary progressive disease is present. Potential transplant candidates undergo a stem cell harvest, collecting enough stem cells for 2 transplants in anticipation of a tandem transplant or a second transplant as salvage therapy. Autologous and allogeneic transplants are discussed further in the next section. Alternatively, all patients may consider continuation of primary therapy until the best response is reached. The optimal duration of primary therapy after maximal response is unknown, and therefore maintenance therapy or observation can be considered 2 cycles beyond maximal response.

SCTs

High-dose therapy with stem cell support is a critical component in the treatment plan for eligible patients with newly diagnosed MM. The types of SCT may be single autologous SCT, a tandem SCT (a planned second course of high-dose therapy and SCT within 6 months of the first), or an allogeneic SCT. An allogeneic SCT can either be performed after prior myeloablative therapy or after nonmyeloablative therapy. Nonmyeloablative therapy, also referred to as “mini transplant,” has been investigated as a technique to decrease toxicity of the allotransplant while preserving the alloimmune graft-versus-myeloma effect.^102,103 An allogeneic SCT may also follow an autologous SCT.

The guidelines indicate that all types of SCT are appropriate in different clinical settings; these indications are discussed further in the following sections. However, in general, all candidates for high-dose chemotherapy must have sufficient liver, renal, pulmonary, and cardiac function. Earlier studies of autologous transplant included total body irradiation (TBI) as a component of the preparative regimen. Regimens with chemotherapy only recently were shown to have equivalent efficacy and less toxicity than TBI. TBI regimens have now been abandoned,¹⁰⁴ but newer, potentially less-toxic radiation techniques with the goal of delivering total marrow irradiation (TMI) while reducing toxicities to non-target organs are currently undergoing evaluation in clinical trials.¹⁰⁵

Autologous SCTs

Autologous SCT results in high response rates and remains the standard of care after primary therapy for eligible patients. In 1996, the IFM reported results of the first randomized trial, showing that autologous SCT was associated with statistically significant higher response rates and increased overall and event-free survivals compared with conventional therapy in similar patients.¹⁰⁶ In 2003, results of a second trial comparing high-dose and standard therapy showed an increase in the complete response rate and an improvement in overall survival (54 months in the high-dose group compared with 42 months for those undergoing standard therapy).¹⁰⁷ The benefit was more pronounced for higher-risk patients. Barlogie et al.¹⁰⁸ reported on the results of an American trial randomizing 510 patients to either high-dose therapy with autologous stem cell support or standard therapy.¹⁰⁸ With a median follow-up of 76 months, no differences were seen in response rates, PFS, or overall survival between the groups. The reason for the discrepant results is unclear, but may be related to differences in the specific high-dose and conventional regimens used in the American and French¹⁰⁶ studies. For example, the American study included TBI as part of the high-dose regimen; TBI was subsequently found to be inferior to high-dose melphalan.¹⁰⁶

Another trial included 190 patients aged 55 to 65 years who were randomized to standard- or high-dose therapy.¹⁰⁹ This study was specifically designed to include older patients, because the median age of the participants in other trials ranged from 54 to 57 years, whereas the median age in this trial was 61 years. After 120 months of follow-up, no significant difference in overall survival was seen, although a trend was seen toward improved event-free survival in the high-dose group (P = .7). Additionally, the time without symptoms of treatment or treatment toxicity was significantly longer in the high-dose group. The study concluded that the equivalent survival suggests that the treatment choice between high- and conventional-dose chemotherapy should be based on personal choice in older patients. For example, an early transplant may be favored because patients can enjoy a longer symptom-free interval. However, this study⁵⁶ also showed that a transplant performed at relapse (as salvage therapy) is associated with a similar overall survival as an early transplant. The choice of early versus late transplant was examined in a randomized French trial, and the results in both arms are comparable with respect to overall survival.¹¹⁰ However, early SCT was superior in terms of quality of life, assessed as time without symptoms and side effects from therapy.¹¹⁰

Notably, all randomized studies of autologous SCT after primary therapy were designed and implemented before the availability of thalidomide, lenalidomide, or bortezomib. Therefore, the role of transplant may evolve in the future. Results from the IFM 2005/01 study of patients with symptomatic myeloma undergoing primary therapy with either bortezomib/dexamethasone versus VAD showed a marked improvement in overall response rate with bortezomib/dexamethasone over VAD (discussed earlier).¹¹¹ After the first autologous SCT, CR/near CR rates were 40% in the bortezomib plus dexamethasone arm, compared with 22% in the VAD arm (P = .0001).¹¹¹ In the bortezomib plus dexamethasone arm, 34% required a second SCT, compared with 47% of patients in the VAD arm.¹¹¹ With a median follow-up of 32.2 months, PFS after primary treatment with bortezomib and dexamethasone versus VAD group was 36.0 and 29.7 months, respectively.¹¹¹ Responses were evaluated after primary treatment and after autologous SCT. PFS was significantly longer in patients experiencing greater than or equal to a VGPR after autologous SCT than in the 188 patients experiencing less than VGPR (median, 41.1 vs. 33.5 months). PFS was also significantly longer in patients experiencing greater than or equal to a VGPR after primary treatment than in those experiencing less than a VGPR (median, 41.1 vs. 29.0 months).¹¹²

In another study, 474 patients were randomized to primary therapy with bortezomib/dexamethasone/thalidomide (n = 236) or thalidomide/dexamethasone (n = 238) before double autologous SCT.¹¹³ The 3-drug regimen yielded high response rates compared with the 2-drug regimen, with a CR rate of 19% (vs. 5%) and a VGPR or greater of 62% (vs. 31%). After SCT, improved incremental responses were still seen with bortezomib/dexamethasone/thalidomide compared with thalidomide plus dexamethasone. Taken together, these studies suggest that improved responses with the primary regimen result in improved outcomes after transplantation.

Studies have found that progressive disease emerging after primary therapy does not preclude a good response to autologous SCT.^108,114,115 For example, Kumar et al.¹¹⁵ reported on a case series of 50 patients with primary progressive MM undergoing an autologous SCT.¹¹⁵ Results were compared with those from 100 patients with responsive disease undergoing autologous SCT. The 1-year PFS from the time of transplant was 70% in the primary progressive group compared with 83% in the chemosensitive group. For this reason, the guidelines list autologous SCT as a category 1 option for treatment of primary progressive or refractory disease after primary treatment.

Tandem SCTs

Tandem SCT refers to a planned second course of high-dose therapy and SCT within 6 months of the first. Planned tandem transplants have been studied in several randomized trials. The IFM94 trial reported by Attal et al.¹¹⁶ randomized patients with newly diagnosed myeloma to single or tandem autologous transplants. A total of 78% of patients assigned to the tandem transplant group received the second transplant at a median of 2.5 months after the first. A variety of options for salvage therapy were provided. For example, patients experiencing relapse in either group underwent either no therapy, additional conventional therapy, or another SCT. The probability of surviving event-free for 7 years after the diagnosis was 10% in the single-transplant group compared with 20% in the double-transplant group.

An accompanying editorial by Stadtmauer¹¹⁷ questions whether the promising results might be related to regimens used, rather than the effect of 2 courses of high-dose therapy. For example, patients in the single-transplant arm received 140 mg/m² melphalan plus TBI, whereas those in the tandem arm received the same dose without TBI for the initial transplant and with TBI for the second transplant. TBI has been shown to be more toxic without providing additional benefit. Based on this, the editorial suggests that the increased survival in IFM94's tandem arm may have resulted from greater cumulative exposure to melphalan (280 vs. 140 mg/m²). In a subset analysis, patients who did not experience a CR or a VGPR within 3 months after the first transplant seemed to benefit most from a second transplant. The authors of the IFM94 study suggested that the improvement in projected survival associated with tandem transplant is related not to improved response rates but rather to longer durations of response. Four other randomized trials have compared single versus tandem transplant.^109,118-120 None of these trials showed a significant improvement in overall survival. However, because the median follow-up in these trials ranged from 42 to 53 months, the lack of significant improvement is not surprising. The Italian trial by Cavo et al.¹¹⁸ found that patients not in CR or near CR after the first transplant benefited most from a second transplant. This confirms the observations of the IFM94 trial using non-TBI-based high-dose regimens.

In both the French and Italian trials, the benefit of a second autologous SCT was seen in patients who did not experience a CR or VGPR (> 90% reduction in M-protein level) with the first procedure. These studies were not adequately powered to evaluate the equivalence of 1 versus 2 transplants in patients experiencing a CR or VGPR after the first transplantation.

A review of long-term outcomes of several trials of autologous transplantation by Barlogie et al.¹²¹ found that tandem transplantations were superior to both single transplantations and standard therapies. Also, postrelapse survival was longer when event-free survival was sustained for at least 3.5 years after tandem transplantation.¹²¹ The panel recommends collecting enough stem cells for 2 transplants in all eligible patients. According to the panel, a tandem transplant can be considered for all patients who are candidates for SCT, and is an option for patients who do not experience at least a VGPR after the first autologous SCT. The benefit from the second transplant in patients who experience a CR or VGPR, and also in those who experience less than VGPR, after the first SCT should preferably be determined in a clinical trial. In fact, a randomized prospective National Institutes of Health and Intergroup-supported trial is currently ongoing. Other options for this group of patients include maintenance therapy or observation.

The algorithm identifies 2 situations in which a repeat autologous SCT as salvage therapy may be considered either on or off clinical trial, depending on the interval between the preceding SCT and documented progression. The first is in patients initially treated with primary therapy alone who received the first autologous SCT performed on disease relapse, and then experience progressive disease (category 2A recommendation on or off a clinical trial). The second is in patients who experience progressive disease after the first autologous transplant (category 2A recommendation on or off a clinical trial). A retrospective case-matched control analysis was performed comparing patients who underwent a second autologous SCT to those treated with conventional chemotherapy for relapsed MM.¹²² Similar to previously published smaller studies,^123-125 this retrospective analysis showed that a second autologous SCT is associated with superior relapse-associated mortality compared with conventional chemotherapy (68% vs. 78%), along with improved overall survival (32% vs. 22%) at 4 years. In this analysis, factors associated with improved overall survival and PFS included younger age (< 55 years), β₂-microglobulin less than 2.5 mg/L at diagnosis, a remission duration of more than 9 months, and a greater than PR to their first autologous SCT. Indicating that a second autologous transplant after relapsed or progressive MM occurs may be an option for carefully selected patients. The third instance is in patients with initial CR or near CR to an initial single/tandem autologous SCT who then develop progressive disease. Some of these patients can achieve durable complete or partial remission^125-126 and for this reason the panel members consider it category 2A and recommend it in the setting of standard therapy or as part of clinical trial.

Allogeneic SCT

Allogeneic SCT includes either myeloablative or nonmyeloablative transplants (also called a “mini transplant”). Allogeneic SCT has been investigated as an alternative to autologous SCT both to avoid the contamination of reinfused autologous tumor cells and to take advantage of the beneficial graft-versus-tumor effect associated with allogeneic transplants. However, lack of a suitable donor and increased morbidity has limited this approach, particularly for the typical older MM population. Non-myeloablative transplants are designed to decrease the morbidity of the high-dose chemotherapy but preserve the beneficial graft-versus-tumor effect. Therefore, the principle difference between myeloablative and nonmyeloablative transplants relates to the chemotherapy regimen used. Specific preparatory regimens have not been a focus of these guidelines, and therefore a distinction is not made between these approaches.

Given the small candidate pool, it is not surprising that no randomized clinical trials have compared myeloablative allogeneic with autologous SCT, but multiple case series have been published describing allogeneic SCT as an initial or salvage therapy for MM. In a 1999 review, Kyle¹²⁷ reported a mortality rate of 25% within 100 days and an overall transplant-related mortality rate of approximately 40%, and few patients were cured. Other reviews have also reported increased morbidity without convincing proof of improved survival.^114,128 However, intriguing data were reported from the SWOG randomized trial of autologous transplant versus conventional chemotherapy.¹⁰⁸ The original trial had an ablative, allogeneic transplant group in which patients with HLA-identical siblings were assigned. Only 36 patients received allografts, and because of the high 45% 6-month mortality rate, the allogeneic arm was closed. With 7 years of follow-up, the overall survival rates of the conventional chemotherapy, autologous SCT, and allogeneic SCT arms are identical at 39%. The autologous SCT and conventional chemotherapy arms do not show a plateau, however, whereas the allogenic curve is flat at 39%. This suggests that a proportion of these patients are long-term survivors. Thus, interest in myeloablative allogeneic SCT is ongoing, particularly given the lack of a significant cure rate for single or tandem autologous SCT. Therefore, the guidelines consider myeloablative allogeneic SCT an accepted option, only in the setting of a clinical trial in patients experiencing response to primary therapy or primary progressive disease, or as salvage therapy in patients with progressive disease after an initial autologous SCT.

Another strategy that has been investigated is initial autologous SCT followed by a mini-allogeneic transplant. In a prospective trial, Bruno et al.¹²⁹ showed that, among patients (< 65 years of age) with HLA-matched siblings who received an autograft-allograft regimen, CR rate after allografting was 55%, compared with 26% after double autograft in patients without HLA-matched siblings. Median overall survival was higher (80 vs. 54 months). In the prospective PETHEMA trial, in patients for whom a first autologous SCT failed to produce at least a near CR, a trend toward a longer PFS was observed, although no significant difference in overall survival was observed between patients who had double-autologous SCT and those who had autologous SCT followed by mini-allogeneic transplant.¹³⁰ In contrast, the IFM trial (9903) by Garban et al.¹³¹ and the BMT-CTN 0102 trial by Stadtmauer et al.¹³² reported no overall survival or PFS with autologous transplant followed by mini-allogeneic transplant in patients with high-risk myeloma.

Mini-allogeneic transplants have also been investigated as salvage therapy because of their graftversus-myeloma effect. Responsive disease to prior transplantation and younger age are associated with better response and overall survival rates.^133-136 In a case series report, 54 patients with previously treated relapsed or progressive disease were treated with an autologous SCT followed by a mini-allogeneic transplant.¹³⁴ An overall survival rate of 78% was seen at a median 552 days after the mini-allogeneic transplant, with a 57% complete response rate and an 83% overall response rate. This study concluded that this approach reduced the acute toxicities of a myeloablative allogeneic SCT while preserving anti-tumor activity. The largest case series was reported by the EBMT.¹³⁵ In this heterogeneous population of 229 patients, the 3-year overall survival and PFS rates were 41% and 21%, respectively. Adverse overall survival was associated with chemoresistant disease, more than one prior transplant, and improved overall survival was associated with graft-versus-host disease, confirming the importance of a graft-versus-leukemia effect. This study concluded that mini-allogeneic transplantation is feasible, but heavily pretreated patients and patients with progressive disease are unlikely to benefit.

Patients whose disease either does not respond to or relapses after allogeneic stem cell grafting may receive donor lymphocyte infusions to stimulate a beneficial graft-versus-myeloma effect,^137-144 or salvage therapy on or off a clinical trial.

Maintenance Therapy

Thalidomide as Maintenance Therapy After Autologous SCT: Thalidomide as maintenance therapy after a prior autologous SCT has been studied in retrospective and independent randomized trials. In a retrospective review of 112 patients undergoing autologous SCT, Brinker et al.¹⁴⁵ reported on the outcomes of 36 patients who received thalidomide as maintenance or salvage therapy compared with 76 patients who received no posttransplant therapy.¹⁴⁵ The median survival in the thalidomide group was 65.5 months compared with 44.5 months in the no-treatment group (P = .9). Attal et al.¹⁴⁶ randomized 597 patients to either no maintenance, pamidronate alone, or pamidronate combined with thalidomide after tandem autologous SCT and found a highly significant event-free and overall survival advantage in the thalidomide and pamidronate arm. The group that seemed to benefit most included patients who experienced only a partial response after transplantation. However, peripheral neuropathy is a challenge with low-dose thalidomide, and may preclude long-term maintenance.

An Australian study comparing thalidomide plus prednisone and prednisone alone as maintenance therapies after autologous SCT confirmed that thalidomide added to maintenance is superior to prednisone alone.¹⁴⁷ In another randomized trial, thalidomide maintenance induced improvement in PFS in patients experiencing less than a VGPR after autologous SCT with no survival benefit.¹⁴⁸

Thalidomide has also been used before, during, and after tandem autologous SCT.^108,149 In a randomized study of 668 patients with newly diagnosed MM, half received thalidomide throughout the course of the tandem autologous SCT (i.e., thalidomide was incorporated into primary therapy, continued between the tandem autologous SCT, and was incorporated into consolidation therapy and continued as maintenance therapy).¹⁴⁹ The group that was not treated with thalidomide received the same core therapy. After a median follow-up of 42 months, the group that received thalidomide had improved CR (62% vs. 43%) and 5-year event-free survival rates (56% vs. 44%). However, the overall survival rate was approximately 65% in both groups. Patients who did not receive thalidomide throughout therapy benefited from thalidomide at relapse. The results of this study suggest that sequencing drugs may be important. For example, if thalidomide is used as part of up-front therapy, another drug should be considered for maintenance therapy.

Based on the above evidence, the panel lists thalidomide alone as a category 1 recommendation and one of the preferred maintenance regimens. Thalidomide in combination with prednisone is a category 2A recommendation as maintenance therapy. Concerns exist about the cumulative toxicity with thalidomide. For example, peripheral neuropathy observed with thalidomide is related to the duration of treatment and is cumulative. The benefits and risks of maintenance therapy with thalidomide should be discussed with patients.

Lenalidomide as Maintenance Therapy After Autologous SCT: Lenalidomide has been evaluated in 2 independent randomized phase III studies as maintenance after autologous transplant. The CALGB 100104 trial compared lenalidomide versus placebo as maintenance therapy after prior autologous SCT.¹⁵⁰ The encouraging preliminary interim results led to unblinding of this trial. The updated interim results show that patients receiving lenalidomide maintenance after an autologous SCT had a significant reduction in the risk of disease progression or death compared with patients receiving placebo.¹⁵¹ The benefit of lenalidomide maintenance therapy was observed among those who experienced a complete response after autologous SCT and those who did not.

Data from the international, randomized, double-blind phase III IFM 2005-02 trial show that after autologous SCT, patients treated with lenalidomide as consolidation therapy followed by lenalidomide as maintenance therapy had upgraded responses. The final analysis of the IFM 2005-02 trial performed after a median follow-up of 34 months from randomization and 44 months from diagnosis showed that maintenance with lenalidomide improved PFS. The median PFS was 24 months from randomization in patients with lenalidomide maintenance, versus 42 months from randomization in the placebo arm.¹⁵²

Lenalidomide as Maintenance Therapy After Nontransplant Active Primary Treatment: Data from the phase III MM-015 study show that lenalidomide maintenance after melphalan/prednisone/lenalidomide primary therapy significantly reduced the risk of disease progression and also increased PFS.⁹⁹ In this study, newly diagnosed patients with MM (n = 459) aged 65 years or older were randomized to receive MP followed by placebo until progression, or MPL followed by placebo until progression, or MPL followed by lenalidomide maintenance. The primary comparison for this trial was the MPL followed by lenalidomide maintenance arm versus the MP followed by placebo arm. The MPL followed by lenalidomide maintenance arm resulted in rapid and higher rates overall response rate (77% vs. 50%; P < .001) compared with MP alone. Maintenance with lenalidomide also reduced the risk of disease progression by 58% compared with MP alone, with a higher 2-year PFS rate (55% vs. 16%).

The analysis comparing MPL followed by lenalidomide maintenance with MPL followed by placebo at the beginning of cycle 10 showed that maintenance lenalidomide resulted in a 69% reduced risk of progression compared with placebo (hazard ratio [HR], 0.314; P < .001).⁹⁹

Based on this evidence, the panel listed single-agent lenalidomide as one of the preferred maintenance regimens. However, pending peer-reviewed publications of the phase III trial results discussed earlier and the safety/efficacy data of lenalidomide in this setting, lenalidomide as maintenance therapy is currently a category 2A recommendation. Lenalidomide lacks the neurologic toxicity seen with thalidomide. However, its use seems to be associated with an increased risk for secondary cancers, especially for lenalidomide maintenance therapy after SCT. The benefits and risks of maintenance therapy with lenalidomide, including its possible association with secondary cancers, should be discussed with patients. A recent report from the HOVON 76 trial indicates that lenalidomide maintenance may not be a feasible option after mini-allogeneic SCT.¹⁵³

Bortezomib as Maintenance Therapy After Autologous SCT: Bortezomib as maintenance therapy is being investigated in phase III trials. The preliminary results from the HOVON study show that maintenance with single-agent bortezomib after autologous SCT is well tolerated and associated with improvement of overall response rates.⁵⁵ Patients in the HOVON trial were randomly assigned to 1 of the 2 arms consisting of either primary treatment with VAD followed by autologous SCT and maintenance with thalidomide or with bortezomib/doxorubicin/dexamethasone followed by autologous SCT and bortezomib as maintenance therapy. Maintenance therapy in both arms was given for 2 years. The study reported high CR/near CR rates after primary treatment with a bortezomib-based regimen. Bortezomib as maintenance therapy was well tolerated and associated with additional improvement of response rates.⁵⁵

Bortezomib as Maintenance Therapy After Nontransplant Active Primary Treatment: Preliminary results of the phase III UPFRONT study also show that maintenance with single-agent bortezomib is well tolerated when administered after treatment with bortezomib-based primary therapy.¹⁰⁰ Patients with newly diagnosed MM and ineligible for high-dose therapy and SCT enrolled in the UPFRONT trial were randomized (1:1:1) and treated with one of the following bortezomib-based primary regimens: bortezomib/dexamethasone, bortezomib/thalidomide/dexamethasone, or MPB, followed by maintenance treatment with bortezomib. The updated results show that the response rates, including CR and a VGPR or greater, improved after bortezomib maintenance in all arms, with no concomitant increase in the incidence of peripheral neuropathy.¹⁰⁰

The panel has added bortezomib to the list of preferred maintenance regimens with a category 2A designation.

Other Maintenance Therapy Regimens After Autologous SCT: Several other maintenance therapies, such as steroids (dexamethasone) and interferon, have been investigated in patients whose disease responds to high-dose therapy followed by autologous or allogeneic SCT.¹⁵⁴ Currently, the role of interferon¹⁵⁵ or steroid maintenance therapy¹⁵⁶ in general is uncertain, and for this reason the guidelines list these as category 2B recommendations for maintenance therapy.

Treatment of Progressive or Relapsed Myeloma

Salvage Therapy

Salvage therapy is considered in the following clinical situations: in patients with relapsed disease after allogeneic or autologous SCT, those with primary progressive disease after initial autologous or allogeneic SCT, and those ineligible for SCT with progressive or relapsing disease after initial primary therapy.

A variety of therapies are available as options for salvage therapy. If the relapse occurs more than 6 months after completion of the initial primary therapy, patients may be re-treated with the same primary regimen.

The phase III APEX trial compared bortezomib with high-dose dexamethasone as salvage therapy.⁵⁴ Among the 669 participants, those randomized to bortezomib had a combined CR and PR rate of 38% (vs. 18% for those receiving dexamethasone), improved median time to progression (6.22 vs. 3.49 months), and greater 1-year survival rate (80% vs. 66%). When combined with dexamethasone, bortezomib is considered a category 2A recommendation. In an updated efficacy analysis,¹⁵⁷ the response rate was 43% with bortezomib versus 18% with dexamethasone (P < .0001). Among patients experiencing relapse, those treated with bortezomib had a 16% CR or near CR rate compared with 0% among those treated with dexamethasone. Median overall survival of patients treated with bortezomib was 29.8 months versus 23.7 months for dexamethasone, despite nearly two-thirds of patients crossing over to bortezomib. Survival rates after 1 year were 80% and 67%, respectively (P = .00002). Patients with poor prognostic factors also benefited from bortezomib. Patients with deletion of chromosome 13 had worse survival when treated with dexamethasone than those without the deletion. However, for bortezomib-treated patients, the outcome was the same for those with and those without the deletion.¹⁵⁸ Based on the phase III trial data described earlier, the panel included bortezomib monotherapy as a category 1 salvage therapy option for patients with relapsed/refractory myeloma. Results of the MMY-3021 trial, which randomized 222 patients to either intravenous or subcutaneous single-agent bortezomib, showed no significant differences in time to progression or 1-year overall survival.¹⁵⁹ However, patients receiving bortezomib subcutaneously had a significant reduction in peripheral neuropathy.

The FDA approved the regimen of bortezomib combined with pegylated liposomal doxorubicin as a treatment option for patients with MM who have not previously received bortezomib and have received at least one prior therapy. The approval was based on a priority review of data from an international phase III trial (n = 646), showing that the combination significantly extended the median time to disease progression compared with bortezomib alone (9.3 vs. 6.5 months).¹⁶⁰ Median duration of response increased from 7.0 to 10.2 months with the combination therapy. Based on these results, the panel considers the regimen of bortezomib combined with pegylated liposomal doxorubicin a category 1 salvage therapy option for patients with relapsed or refractory myeloma.

The addition of dexamethasone to bortezomib resulted in improved response in 18% to 34% of patients with relapsed or refractory myeloma who experienced progressive disease during bortezomib monotherapy.^161-163 The panel included the bortezomib/dexamethasone regimen as a category 1 salvage therapy option for patients with relapsed or refractory myeloma.

Lenalidomide combined with dexamethasone received FDA approval as a treatment option for patients with MM who had received at least one prior treatment. This was based on the results of 2 studies of 692 total patients randomized to receive dexamethasone either with or without lenalidomide. The primary efficacy end point in both studies was time to progression. A preplanned interim analysis of both studies reported that the median time to progression was significantly longer in the lenalidomide arm than in the control group.^164,165 The updated clinical data from the pivotal North American phase III trial (MM-009) in 353 patients with previously treated MM reported increased overall survival and median time to disease progression in those receiving lenalidomide plus dexamethasone compared with those receiving dexamethasone plus placebo.¹⁶⁵ Similar results were seen in the international trial MM-010.¹⁶⁴ Patients in both of these trials had been heavily treated before enrollment, many of whom had experienced no response to 3 or more rounds of therapy with other agents, and more than 50% of patients had undergone SCT.^164,165 Adverse events and grade 3 or 4 adverse events occurred more frequently in patients treated with lenalidomide/dexamethasone than in those treated with placebo and dexamethasone. Thrombocytopenia (61.5%) and neutropenia (58.8%) were the most frequently reported adverse events. The panel now considers this regimen a category 1 option as salvage therapy for patients with relapsed or refractory myeloma. Lenalidomide monotherapy has also been investigated and found to be effective in patients with relapsed or refractory myeloma.¹⁶⁶ The panel suggests that lenalidomide monotherapy be considered for steroid-intolerant individuals.

Data from preclinical studies showed that lenalidomide sensitizes myeloma cells to bortezomib and dexamethasone. The results of phase I and II studies show that bortezomib/lenalidomide/dexamethasone is well tolerated and very active, with durable responses seen in patients with heavily pretreated relapsed and/or refractory myeloma, including those who have had prior lenalidomide, bortezomib, thalidomide, and SCT.^167,168 The updated data after more than 2 years of follow-up report a median PFS of 9.5 months and median overall survival of 26 months, with 12- and 24-month overall survival rates of 86% and 55%, respectively.¹⁶⁹ The panel has now included bortezomib/lenalidomide/dexamethasone as category 2A option for relapsed or refractory myeloma.

The effects of adding of an alkylating agent (e.g., cyclophosphamide) and a novel agent (e.g., lenalidomide, bortezomib) to dexamethasone have been investigated in patients with relapsed or refractory myeloma. A retrospective analysis to assess the efficacy of lenalidomide in combination with cyclophosphamide and dexamethasone showed that this regimen is effective in heavily pretreated patients, with manageable adverse effects.¹⁷⁰ The combination of bortezomib, dexamethasone, and cyclophosphamide was found effective in patients with relapsed or refractory myeloma, with an acceptable toxicity profile.^171,172 The panel has included cyclophosphamide/dexamethasone in combination with either lenalidomide or bortezomib to the list of options for relapsed or refractory myeloma.

In patients with relapsed or refractory myeloma, dexamethasone added to thalidomide for has been reported to have higher response rates of approximately 50% compared with thalidomide alone.^173-176 Furthermore, combination therapy of dexamethasone/thalidomide along with infusional chemotherapy, such as cisplatin, doxorubicin, cyclophosphamide, and etoposide (DT-PACE regimen), was also found to be effective, especially in patients with progressive disease.¹⁷⁷ Both of these regimens are included in the guidelines as category 2A options for relapsed or refractory myeloma. Thalidomide monotherapy has also been shown to be effective in refractory or relapsed myeloma, with 20% to 48% of patients experiencing at least a PR.^178-182 Because thalidomide-based combination regimens are more effective than thalidomide monotherapy, the panel suggests thalidomide monotherapy be considered for steroid-intolerant individuals.

A trial by Knop et al.¹⁸³ enrolled 31 patients who had experienced relapse after high-dose chemotherapy and autologous transplantation to receive increasing doses of bendamustine. The overall response rate was 55%, with a median PFS of 26 weeks for all patients and 36 weeks for patients who received higher doses of bendamustine (90-100 mg/m²). Toxicity was mild and mainly hematologic. A retrospective analysis of 39 patients reported that bendamustine is effective and tolerable in patients with advanced progressive myeloma, with an overall response rate of 36%.¹⁸⁴ Bendamustine is currently a category 2A treatment option for relapsed or refractory myeloma.

Other salvage options in the guidelines, include high-dose (non-marrow ablative) cyclophosphamide¹⁸⁵; DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin)^186,187; and VTD-PACE (bortezomib/thalidomide/dexamethasone with cisplatin, doxorubicin cyclophosphamide, and etoposide).¹⁷

Adjunctive Treatment for MM

Important advances have been made in adjunctive treatment/supportive care of patients with MM. This aspect of treatment involves careful patient education about the probable side effects of each drug and the drug combinations being used, and the supportive care measures required. Supportive care can be categorized into measures required for all patients and those that address specific drugs.

Bony manifestations of myeloma, in the form of diffuse osteopenia and/or osteolytic lesions, develop in 85% of patients. Related complications are the major cause of limitations in quality of life and performance status in patients with MM. A large, double-blind, randomized trial has shown that monthly use of intravenous pamidronate (a bisphosphonate) can decrease pain and bone-related complications, improve performance status, and, importantly, preserve quality of life in patients with Durie-Salmon stage III myeloma and at least one lytic lesion.^188,189 Zoledronic acid is more potent, can be administered more rapidly, and has equivalent benefits.¹⁹⁰ Results from the study conducted by Zervas et al.¹⁹¹ show a 9.5-fold greater risk for the development of osteonecrosis of the jaw with zoledronic acid compared with pamidronate. Patients who are on bisphosphonates should have their renal function monitored and should be monitored for osteonecrosis of the jaw.

The MRC Myeloma IX study examined effects of zoledronic acid versus clodronate (a bisphosphonate not currently FDA approved) in patients with MM initiating chemotherapy regardless of whether they had bone disease. The patients were randomized to receive zoledronic acid (n = 981) or clodronic acid (n = 979). Zoledronic acid was reported to reduce mortality and significantly improve PFS.¹⁹² Although both groups of patients had similar occurrence of acute renal failure and treatment-emergent serious adverse events, zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw compared with clodronic acid.^192-194

The NCCN Guidelines now recommend bisphosphonates for all patients receiving myeloma therapy for symptomatic disease (category 1 recommendation).

In patients with smoldering or stage I MM, bisphosphonates may be considered, but preferably in a clinical trial. Skeletal survey annually or as clinically indicated is recommended for these patients. Bone densitometry or other metabolic studies should be reserved for clinical trials.

Low-dose radiation therapy (10-30 Gy) is used for the palliative treatment of uncontrolled pain, impending pathologic fracture, or impending spinal cord compression.³⁸ Limited involved fields should be used to limit the effect of irradiation on stem cell harvest or its effect on potential future treatments. The radiation doses administered should not preclude stem cell collection in potential candidates for high-dose therapy and hematopoietic SCT. Orthopedic consultation should be obtained for impending or actual fractures in weight-bearing bones, bony compression of the spinal cord, or vertebral column instability. Either vertebroplasty or kyphoplasty should be considered for symptomatic vertebral compression fractures.

Excess bone resorption from myeloma bone disease can lead to excessive release of calcium into the blood, contributing to hypercalcemia. Symptoms include polyuria and gastrointestinal disturbances, with progressive dehydration and decreases in glomerular filtration rate. Hypercalcemia should be treated with hydration and furosemide, bisphosphonates, steroids, and/or calcitonin. Among the bisphosphonates (zoledronic acid, pamidronate, and ibandronate), the panel prefers zoledronic acid for this treatment.^195-197

Plasmapheresis should be used as adjunctive therapy for symptomatic hyperviscosity.¹⁹⁸ Institutions differ in their use of plasmapheresis for adjunctive treatment of renal dysfunction.

Erythropoietin therapy should be considered for anemic patients, especially those with renal failure. Measuring endogenous erythropoietin levels may also be helpful in treatment planning^199,200 (see NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines] for Cancer- and Chemotherapy-Induced Anemia; to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).

To prevent infection, 1) intravenous immunoglobulin therapy should be considered in the setting of recurrent, life-threatening infections; 2) pneumococcal and influenza vaccine should also be considered; and 3) Pneumocystis carinii pneumonia, herpes, and antifungal prophylaxis is recommended, if a high-dose regimen is used. Bortezomib treatment has been associated with an incidence of herpes zoster,^53,54 and therefore herpes prophylaxis is recommended in patients receiving bortezomib and in the posttransplant setting⁴⁸ (see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections; to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).

Thrombosis is relatively common when thalidomide or lenalidomide is used with steroids, and is particularly frequent when treating patients with newly diagnosed MM. Use of prophylactic anticoagulation agents (see NCCN Guidelines for Venous Thromboembolic Disease; to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org) is recommended when immunomodulatory drugs are used in combination therapy during induction.^78,201,202

Hydration should be maintained and NSAIDs should be avoided to decrease the chances of renal dysfunction. According to the panel, the use of plasmapheresis to improve renal function is a category 2B recommendation. The use of intravenous contrast media and NSAIDs should also be avoided in patients with renal impairment.

Individual Disclosures of the NCCN Guidelines Panel for Multiple Myeloma

Please Note

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines™ is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representation or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their applications or use in any way.

© National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

Disclosures for the NCCN Guidelines Panel for Multiple Myeloma

At the beginning of each NCCN Guidelines panel meeting, panel members disclosed any financial support they have received from industry. Through 2008, this information was published in an aggregate statement in JNCCN and online. Furthering NCCN's commitment to public transparency, this disclosure process has now been expanded by listing all potential conflicts of interest respective to each individual expert panel member.

Individual disclosures for the NCCN Guidelines for Multiple Myeloma panel members can be found on page 1183. (The most recent version of these guidelines and accompanying disclosures, including levels of compensation, are available on the NCCN Web site at www.NCCN.org.)

These guidelines are also available on the Internet. For the latest update, visit www.NCCN.org.

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NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

Version 1.2012, 07-26-11 ©2011 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

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NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

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Multiple Myeloma

NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma

Overview

Multiple Myeloma

Initial Diagnostic Workup

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

Additional Diagnostic Tests

Diagnostic Categories

Response Criteria

Solitary Plasmacytoma

Primary Therapy

Surveillance/Follow-Up Tests

Smoldering (Asymptomatic) Myeloma

Primary Therapy

Surveillance/Follow-Up Tests

Active (Symptomatic) MM

Primary Therapy

Preferred Primary Therapy Regimens for Transplant Candidates

Other Primary Therapy Regimens for Transplant Candidates

Preferred Primary Therapy Regimens for Nontransplant Candidates

Other Primary Therapy Regimens for Nontransplant Candidates

Follow-up After Primary Therapy for Transplant and Nontransplant Candidates

SCTs

Autologous SCTs

Tandem SCTs

Allogeneic SCT

Maintenance Therapy

Treatment of Progressive or Relapsed Myeloma

Salvage Therapy

Adjunctive Treatment for MM

References

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NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma Version 1:2012

References