Antigenic Stimulation and Immunosuppression

MGUS is characterized by evidence of genomic instability on molecular genetic testing. The trigger for this genomic instability is not well understood, but current evidence suggests that antigenic stimulation may be a key factor (Fig. 104-1). Unlike normal plasma cells, human myeloma cell lines and primary myeloma cells express a broad range of Toll-like receptors (TLRs). TLRs are normally expressed by B lymphocytes and are essential for these cells to recognize infectious agents and pathogen-associated molecular patterns (PAMP), which then initiates the host-defense response.^18–18 The aberrant expression of TLRs by plasma cells may enable them to respond to TLR-specific ligands, resulting in an abnormal and perhaps sustained response to infection. It has been shown that TLR-specific ligands cause increased myeloma cell proliferation, survival, and resistance to dexamethasone-induced apoptosis. These effects are mediated in part by autocrine interleukin (IL)-6 production.^16,17

IL-6 is a major growth factor for plasma cells,¹⁹ and there is overexpression of CD126 (IL-6 receptor α-chain) in MGUS compared with normal plasma cells.^20,21 Thus, abnormal TLR expression and/or overexpression of IL-6 receptors in plasma cells may be early, initiating events that lead to an abnormal response to infection and act as sustained, autocrine IL-6–dependent, proliferative triggers for plasma cells. During this process, plasma cells may acquire one of various cytogenetic alterations that result in a limited clonal plasma cell proliferative process, namely MGUS.

Immunosuppression either by promoting evasion of tumor surveillance or by promoting antigenic stimulation may also contribute to the initiation of monoclonal gammopathies. Monoclonal proteins have been reported in the context of immunosuppressive states such as bone marrow/stem cell transplantation, organ transplantation, and human immunodeficiency virus (HIV) infection.22–25 Patients undergoing renal transplantation develop M proteins depending on the level of immunosuppression to which they are subjected.²⁵

Cytogenetic Changes

Over 90% of MGUS is associated with cytogenetic changes possibly precipitated by infection or immune dysregulation as discussed earlier, likely during IgH switch recombination or somatic hypermutation.²⁶ Approximately 50% of patients with MGUS have primary translocations in the clonal plasma cells involving the immunoglobulin heavy chain (IgH) locus on chromosome 14q32 (IgH-translocated MGUS/SMM) (see Fig. 104-1).^5,26 The most common partner chromosome loci and genes dysregulated in these translocations are 11q13 (CCND1 [cyclin D1 gene]), 4p16.3 (FGFR3 and WHSC1), 6p21 (CCND3 [cyclin D3 gene]), 16q23 (MAF), and 20q11 (MAFB).^29–29 It is likely that these translocations play an important pathogenetic role in the resultant limited clonal proliferation that is clinically manifested as MGUS.

Approximately 45% of cases of MGUS are associated with trisomies, usually of the odd numbered chromosomes with the exception of 13; and the origin of the remaining 5% or fewer of MGUS is not clear.26,30 These categories of MGUS that lack evidence of IgH translocations are referred to as non–IgH-translocated MGUS. In one recent study it was shown that there is a small overlap wherein a subset of patients has both types of translocations as well as trisomies; this condition is likely present at the MGUS stage, but the sequence and prevalence are not well known (Table 104-2).³¹

Deletion of chromosome 13, a major prognostic factor in multiple myeloma, is seen in up to 50% of patients with MGUS by interphase fluorescent in-situ hybridization (FISH); hence, the presence of this abnormality cannot be used to differentiate MGUS from multiple myeloma.²⁹

Progression of MGUS to Malignancy

The constant rate of progression of MGUS to myeloma, macroglobulinemia, or related malignancy in a recent epidemiological study over a period spanning 30 to 35 years strongly suggests a simple, random, two-hit genetic model of malignancy.¹³ The risk of progression is similar regardless of the known duration of antecedent MGUS, suggesting that the second-hit responsible for progression is a random event, not cumulative damage.

The specific second-hit that initiates the cascade of events associated with progression is unknown. Several abnormalities have been detected with progression in both the plasma cell and its microenvironment that likely play a role in the progression of MGUS, but little is known about the sequence of events (see Fig. 104-1). RAS mutations, CDKN2A methylation, abnormalities involving the MYC family of oncogenes, secondary translocations, and TP53 mutations have all been identified in clonal plasma cells in association with progression to the symptomatic stage.²⁷ It is possible that the second-hit responsible for disease progression may be different in IgH-translocated versus non–IgH-translocated MGUS, and even within the various subtypes of IgH-translocated MGUS, depending on the partner chromosome involved. For example, amplification of chromosome 1q21 has been noted in over 40% of patients with SMM and myeloma compared with 0% in MGUS,³² suggesting that such amplification (e.g., by trisomy 1) may play a role in progression, perhaps in non–IgH-translocated MGUS.

The bone marrow microenvironment undergoes marked changes with progression, including induction of angiogenesis,³³ suppression of cell-mediated immunity,³⁴ and paracrine loops involving cytokines such as interleukin-6 and vascular endothelial growth factor (VEGF).³⁵ As in solid tumors, the transition from MGUS to multiple myeloma may involve an angiogenic switch. In solitary plasmacytoma, which can be considered to be analogous to localized stage I solid tumor, induction of angiogenesis at the time of diagnosis has been shown to be a predictor of progression to myeloma, suggesting a pathogenetic role for the process in disease progression.³⁶ Furthermore, there is a gradual increase in degree of bone marrow angiogenesis along the disease spectrum from MGUS to SMM to symptomatic myeloma.³³ In one study, approximately 60% of myeloma bone marrow plasma samples stimulated angiogenesis in an in vitro angiogenesis assay, compared with 0% of SMM and 7% of MGUS (P < .001).³⁷

Pathogenesis of Bone Lesions

The progression of MGUS to myeloma is characterized by the development of bone lesions. The pathogenetic mechanisms involved are complex and involve a combination of osteoclast activation coupled with osteoblast inhibition. Understanding these mechanisms has resulted in clinical trials with specific agents to prevent or delay the formation of bone lesions in myeloma.

There are several important mechanisms that mediate increased osteoclast activation.³⁸ There is an increase in the receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) expression by osteoblasts and possibly plasma cells. This is accompanied by decreased stromal cell secretion of the RANKL decoy receptor osteoprotegerin (OPG).^39,40 In addition, the binding of OPG to RANKL is also inhibited by syndecan-1 (CD138) secreted and or shed by myeloma cells. The net result of these facts is an increase in the RANKL/OPG ratio. This causes increased osteoclast activation mediated through the NF-κB pathway. A second factor governing the activation of osteoclasts is the release of macrophage inflammatory protein (MIP)-1α and MIP-1β by myeloma cells. Both these cytokines cause osteoclast activation primarily by increasing RANKL expression in stromal cells. Finally, there is increased expression of stromal derived factor-1α (SDF-1α) by stromal cells and myeloma cells. SDF-1α causes osteoclast activation by binding to chemokine (C-X-C motif) receptor 4 (CXCR4) on osteoclast precursors. In addition to these three factors, several other cytokines such as IL-1β and IL-6 are also thought to play a role in osteoclast activation and bone resorption.

Osteoblast inhibition in myeloma is believed to be primarily related to increased dickkopf 1 (DKK1) expression by myeloma cells.⁴¹ DKK1 binds to Wnt receptors and inhibits the Wnt signaling pathway by preventing the normal binding of Wnt glycoproteins to Wnt receptors.³⁸ The inhibition of Wnt signaling prevents the intracellular stabilization of β-catenin, leading to the phosphorylation and degradation of β-catenin through the proteasome pathway. Normally, β-catenin plays an important role in osteoblast activation and its absence reduces the activity of osteoblasts. In addition to its key role in causing osteoblast inhibition, increased levels of DKK1 may also contribute in some measure to osteoclast activation. Other factors such as IL-3 and IL-7 may contribute to osteoblast inhibition. The combination of osteoclast activation and inhibition of osteoblast differentiation is believed to be the mechanism behind the development of osteolytic lesions in myeloma.

Identification of Monoclonal Proteins

Myeloma is characterized by the presence of monoclonal immunoglobulins in the serum and/or urine. Monoclonal immunoglobulins are commonly referred to as monoclonal proteins, M proteins, or paraproteins. The presence of M proteins is indicative of a clonal plasma cell proliferative disorder such as myeloma, MGUS, Waldenström macroglobulinemia, and so on; additional tests are required to distinguish between the various plasma cell disorders.

M proteins can be detected by serum protein electrophoresis (SPEP) in 82% of patients with myeloma and by serum immunofixation (IFE) in 93% of patients.¹⁰ Up to 20% of patients with myeloma lack heavy-chain expression in the M protein and are considered to have light-chain myeloma. The M protein in these patients is always detected in the urine but can be absent in the serum even by immunofixation, making it imperative that protein electrophoresis and immunofixation are always done on both the serum and urine in all patients in whom myeloma is suspected. Addition of urine protein electrophoresis (UPEP) and urine IFE will increase the sensitivity of detecting M proteins in patients with myeloma to 97%. Most (60%) of the remaining patients who are negative for M proteins on serum and urine electrophoresis and immunofixation studies will have evidence of clonal paraproteins on the serum free light chain (FLC) assay. Currently, only 1% to 2% of patients with myeloma will have no detectable M proteins on any of these tests. These patients have true nonsecretory myeloma.

Serum Protein Electrophoresis and Immunofixation

Agarose gel SPEP and immunofixation are the preferred methods of detection of serum M proteins (Fig. 104-5). M proteins appear as a localized band on SPEP.⁴² After recognition of a localized band suggestive of an M protein on SPEP, immunofixation is necessary for confirmation and to determine the heavy- and light-chain class of the M protein. In addition, immunofixation is more sensitive than SPEP and allows detection of smaller amounts of M protein and should therefore be performed whenever myeloma, amyloidosis, macroglobulinemia, or a related disorder is suggested. The size of the M protein is measured using SPEP. For purposes of clinical trials and monitoring, the M protein is considered to be “measurable” if it is 1 g/dL or more in the serum and or greater than or equal to 200 mg/d in the urine.

Identification of Bone Disease

Plain radiographic examination of all bones including long bones (skeletal survey) is the preferred method of detecting lytic bone lesions in myeloma. Conventional radiographs show skeletal abnormalities in almost 80% of patients with myeloma; often these lesions have a characteristic punched-out appearance. Osteoporosis and/or fractures are also detected by conventional radiography. Occasionally osteosclerotic lesions can occur. CT and MRI are more sensitive than conventional radiography in detecting bone disease. Among asymptomatic multiple myeloma patients with normal radiographs, up to 50% have tumor-related abnormalities on MRI of the lower spine. FDG-PET/CT is are useful in the evaluation of bone disease, in staging, and in assessing response to therapy in myeloma (Fig. 104-6).⁵³ It is not necessary in all patients with myeloma but is of value in patients in whom there is uncertainty about the extent of bone disease. It is also of value in monitoring response to therapy in patients with oligosecretory myeloma. In most cases, if there is uncertainty about the extent of disease, FDG-PET/CT is preferable to MRI or CT because the whole body can be imaged. However, if more detailed imaging is required, as in the case of spinal cord compression, MRI or detailed CT may be preferable. The role of bone mineral density studies in myeloma and the use of these studies in identifying patients at risk for pathological fractures and prophylactic bisphosphonate therapy remain unresolved. However, if these studies have been done, the results can be used to guide the frequency of bisphosphonate administration.

Bone Marrow Studies

A unilateral bone marrow aspiration and biopsy is indicated in all patients with myeloma. Almost all patients with myeloma will have 10% or more clonal bone marrow plasma cells. If a lower extent of involvement is detected, one is either dealing with an erroneous diagnosis or there is a sampling error due to patchy marrow involvement, in which case a repeat marrow biopsy is indicated. Occasionally an entity called “multiple” solitary plasmacytomas has been described in which there are clearly multiple plasmacytomas on clinical and radiographic examination but marrow involvement is either minimal or absent. In these patients, the diagnosis of myeloma is based on biopsy of one or more of these lesions. The monoclonal (or more accurately monotypic) nature of bone marrow plasma cells is established by the demonstration of an abnormal κ/λ ratio by immunohistochemistry or flow cytometry. On flow cytometry, plasma cells in multiple myeloma typically stain positive for CD38, CD56, and CD138 and are usually negative for surface immunoglobulin and CD19. Up to 20% stain positively for CD20. Morphologically, the presence of immature “blast”-like plasma cells (plasmablastic morphology) carries an adverse prognosis.

Given their impact on prognosis (see later discussion), bone marrow samples should be studied with conventional karyotyping studies and/or FISH to detect specific abnormalities such as t(4;14), t(14;16), and 17p−. The bone marrow plasma cell proliferative rate should be estimated by multiparametric flow cytometry, if available. Gene expression profiling studies, if done, can provide additional prognostic information.54,55

Host Factors

Age, performance status, and extent of comorbidities are important prognostic factors.¹⁰ In addition, they affect choice of therapy. In most countries, only patients younger than the age of 65 are considered candidates for ASCT. Performance status is of critical importance but is not reflected in results of clinical trials, which systematically exclude patients with poor performance status from trial entry.¹⁰ Renal function is another host factor that plays a role in outcome and also plays a role in choice of initial therapy. For example, patients who have acute renal failure due to light-chain cast nephropathy require a bortezomib-containing regimen; lenalidomide is not preferred in this setting because the optimum dosing schedule for this agent in renal failure is not well studied.

Stage

Since 1975, the Durie-Salmon staging system (DSS) has been used to stratify patients with multiple myeloma.⁵⁸ The DSS provides a good estimate of tumor burden but has some limitations, especially in the categorization of bone lesions.^59,60 Greipp and colleagues subsequently developed an International Staging System (ISS), a collaborative effort by investigators from 17 institutions worldwide with data on 11,171 patients.⁶¹ The ISS overcomes the limitations of the DSS and divides patients into three distinct stages and prognostic groups based solely on the β₂-microglobulin and albumin levels in the serum (see Box 104-1). However, the ISS cannot be considered a true staging system, because it is influenced by overall health and comorbidities, tumor burden, as well as renal function.

In general, staging of myeloma is not helpful in making therapeutic choices because the risk groups are heterogeneous. For example, stage 3 ISS consists of a mixture of patients, some with renal failure, some with high tumor burden, and some with both. Thus, the ISS is useful for prognosis but not particularly useful in deciding choice of therapy in multiple myeloma. The one exception to this rule is stage 1 Durie-Salmon disease, which consists of patients with either SMM (no therapy needed) or solitary plasmacytoma (typically treated with radiation alone).

Disease Biology and Risk Stratification

Myeloma is a cytogenetically heterogenous condition. A revised molecular cytogenetic classification that takes into account overlapping categories is provided in Table 104-2.³¹ Most patients can be subdivided into at least three distinct primary cytogenetic categories: presence of immunoglobulin heavy-chain (IgH) translocations, trisomies of odd-numbered chromosomes, or both. These abnormalities originate at the MGUS stage and are readily recognized on bone marrow FISH studies. In addition, other cytogenetic abnormalities occur during disease progression, including 17p deletion and secondary MYC translocations.

Newly diagnosed myeloma can be stratified into standard-, intermediate-, and high-risk disease using the Mayo stratification for myeloma and risk-adapted therapy classification (mSMART) (Box 104-2).^3,62 Patients with standard-risk myeloma have a median overall survival (OS) of 6 to 7 years, whereas those with high-risk disease have a median OS of less than 2 to 3 years despite tandem ASCT.² Patients with intermediate-risk disease have traditionally had significantly inferior outcome but now can achieve survival similar to patients with standard-risk myeloma when treated with bortezomib-containing regimens and ASCT.^63–66 Other promising biomarkers that may further assist in risk stratification include 1q amplification, 1p deletion, MYC translocations, plasma cell immunophenotyping, detection of minimal residual disease by allele-specific oligonucleotide polymerase chain reaction (ASO-PCR), and identification of circulating plasma cells by multiparametric flow cytometry.²

Thalidomide-Dexamethasone

The Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial comparing TD with dexamethasone alone.⁷³ The best response within four cycles of therapy was significantly higher with TD compared with dexamethasone alone: 63% versus 41%, respectively, P = .0017. Deep vein thrombosis was more frequent with TD (17% vs. 3%). Based on this trial, the U.S. Food and Drug Administration granted accelerated approval for TD for the treatment of newly diagnosed myeloma. A separate randomized, double-blind, placebo-controlled study compared TD versus dexamethasone alone as primary therapy in 470 patients with newly diagnosed myeloma.⁷⁵ As in the ECOG trial, response rates were significantly higher with TD compared with placebo/dexamethasone, and time to progression was also superior, 22.6 versus 6.5 months, respectively (P < .001).

The incidence of deep vein thrombosis is 1% to 3% in patients receiving thalidomide alone but rises to 15% to 20% in patients receiving thalidomide in combination with high-dose dexamethasone and to over 25% in patients receiving the agent in combination with other cytotoxic chemotherapeutic agents, particularly doxorubicin. Patients receiving thalidomide in combination with high-dose corticosteroids or chemotherapy need routine thromboprophylaxis with warfarin (Coumadin) (target international normalized ratio [INR] 2 to 3) or low-molecular weight heparin (equivalent of enoxaparin 40 mg once daily). Aspirin can be used instead in patients receiving only low doses of dexamethasone (40 mg once a week or lower) or prednisone in combination with thalidomide, provided no concomitant erythropoietic agents are used.

Lenalidomide-Dexamethasone

Lenalidomide belongs to a class of thalidomide analogs termed immunomodulatory drugs (ImiDs). Although thalidomide and lenalidomide are considered “immunomodulatory,” more recent studies show that the mechanism of action of these drugs may be mediated through cereblon, the putative primary teratogenic target for thalidomide.76,77 In newly diagnosed myeloma, a phase II trial conducted at the Mayo Clinic demonstrated remarkably high activity with lenalidomide and low-dose dexamethasone (Rd).^78,79 A Southwest Oncology Group (SWOG)–randomized trial showed that the Rd regimen was superior to high-dose dexamethasone alone in newly diagnosed myeloma.⁸⁰ An ECOG trial done in parallel demonstrated superior OS with lower toxicity with Rd compared with lenalidomide plus high-dose dexamethasone.⁸¹ In Rd, dexamethasone is administered at a dose of 40 mg once a week. Based on this trial, the use of high-dose dexamethasone is no longer recommended in newly diagnosed myeloma. The toxicity of dexamethasone also makes it difficult to incorporate into multiple-agent combination regimens. Almost all recent trials in newly diagnosed myeloma now incorporate low-dose dexamethasone (40 mg once a week or equivalent). Rd is also an attractive option for the treatment of elderly patients with newly diagnosed myeloma because of its excellent tolerability, convenience, and efficacy. The 3-year OS rate with Rd in patients 70 and older who did not receive ASCT is 70% and is comparable to results with melphalan-prednisone-thalidomide (MPT) and bortezomib-melphalan-prednisone (VMP). An ongoing phase III trial is currently comparing MPT versus Rd for 18 months versus Rd until progression.

The incidence of deep vein thrombosis is low with single-agent lenalidomide or Rd but rises markedly when the agent is combined with high-dose dexamethasone. As with TD, all patients treated with Rd require anti-thrombosis prophylaxis with aspirin, low-molecular weight heparin, or warfarin.84–84 Rd may impair collection of peripheral blood stem cells for transplant in some patients when mobilized with granulocyte colony-stimulating factor (G-CSF) alone.⁸⁵ Stem cell mobilization in these patients is usually successful with a chemotherapy-containing mobilization regimen such as cyclophosphamide and G-CSF. Plerixafor, a CXCR4 inhibitor–mobilizing agent, also usually allows adequate stem cell collection in the subset of patients who have difficulty with stem cell mobilization with G-CSF alone.

Bortezomib-Dexamethasone

Bortezomib is a novel proteasome inhibitor approved for the treatment of patients with relapsed and refractory multiple myeloma. In newly diagnosed patients, treatment with bortezomib-dexamethasone (VD) produces response rates of 70% to 90%.86,87 Harousseau and colleagues compared VD versus VAD as pretransplant induction therapy.⁸⁸ The response rate before and after transplant was better with VD versus VAD. The postinduction very good partial response (VGPR) was 38% versus 15%, respectively. Corresponding posttransplant VGPR rates were 54% versus 37%, respectively. There was a modest improvement in PFS of 36 months versus 30 months, respectively. No OS benefit was noted. The main toxicity with bortezomib is neurotoxicity, which can be severe (grade 3 or higher) in approximately 15% of patients. However, recent studies show that the neurotoxicity of bortezomib can be greatly diminished by administering bortezomib using a once-weekly schedule^89,90 and by administering the drug subcutaneously.⁹¹

Bortezomib-Thalidomide-Dexamethasone

VTD has been compared with TD in a randomized trial.⁶⁵ VTD results in better response rates and PFS, but no OS benefit has been noted. Nevertheless, one of the most compelling findings in this study was the ability of VTD plus double ASCT followed by bortezomib-based consolidation to overcome the poor prognostic effects of t(4;14) translocation. In another randomized trial, VTD was found to produce better response rates and PFS compared with VD; no significant differences in OS rates were reported.⁹² VTD is particularly useful in the setting of acute renal failure because it acts rapidly and can be used without dose modification.

Bortezomib-Lenalidomide-Dexamethasone

VRD produces remarkably high overall response (OR) and complete response (CR) rates in newly diagnosed myeloma.74,93 A SWOG randomized trial has compared VRD with Rd in the United States, but results from this study are not yet available. An international phase III trial is ongoing, comparing VRD followed by early transplant versus VRD alone in newly diagnosed myeloma. Although response rates and CR rates are very high with VRD, it must be noted that there are no data from randomized trials comparing the safety and efficacy of this rather expensive regimen compared with other less expensive, equally effective and possibly less toxic regimens. However, in the subset of patients with high-risk myeloma in whom all of the current options appear inadequate, it may be a reasonable treatment option to consider.

Bortezomib-Cyclophosphamide-Dexamethasone

VCD (also commonly known as CyBorD) has significant activity in newly diagnosed multiple myeloma⁹⁴ and is less expensive than either VTD or VRD. It represents a variation of the VMP regimen with substitution of cyclophosphamide for melphalan to improve tolerability. A randomized phase II EVOLUTION trial in newly diagnosed myeloma showed that VCD is well tolerated and has similar activity compared with VRD.⁹³ CR was achieved in 22% and 47% of patients treated with two different schedules of VCD, versus 24% of patients treated with VRD. Based on efficacy, ease of use, safety, and cost, VCD is an excellent choice when considering a bortezomib-containing regimen for front-line therapy. VCD can also be used in patients who are not candidates for ASCT.

Bortezomib-Dexamethasone-Cyclophosphamide-Lenalidomide

This new quadruplet regimen of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide (VDCR) has shown high response rates in patients with newly diagnosed myeloma.⁹⁵ The randomized phase II EVOLUTION trial compared VDCR with VRD and VCD.⁹³ Although the regimen was highly active, CR rates with VDCR were similar compared with either VCD or VRD. Additional studies are needed.

Multiple-Drug Combinations

Besides the regimens just discussed, multiple-agent combination chemotherapy regimens such as VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) have been tested extensively at the Myeloma Institute for Research and Therapy at the University of Arkansas for Medical Sciences by Barlogie and colleagues.63,96 VDT-PACE is particularly useful in patients with aggressive disease such as plasma cell leukemia or multiple extramedullary plasmacytomas.

Melphalan-Prednisone-Thalidomide

Six randomized studies have shown that melphalan-prednisone-thalidomide (MPT) improves response rates compared with MP.98–103 A significant prolongation of PFS with MPT has been seen in four trials,^98–100,102 and an OS advantage has been observed in three.^98,99,102 The trial by Facon and colleagues comparing MPT versus MP versus tandem ASCT with reduced dose melphalan (100 mg/m²) was the first trial to show a clear survival advantage of any combination regimen to the simple oral regimen of MP.⁹⁸ Two meta-analyses of these randomized trials have been conducted, and they show a clear superiority of MPT over MP.^104,105 Grade 3/4 adverse events occur in approximately 55% of patients treated with MPT, compared with 22% with MP.¹⁰⁰ As with TD, there is a considerable (20%) risk of deep vein thrombosis with MPT in the absence of thromboprophylaxis.

Bortezomib-Melphalan-Prednisone

In phase II studies, VMP was remarkably active with a response rate of almost 90% and a CR rate of approximately 30%.¹⁰⁶ In a phase III trial comparing VMP with MP, the CR rate was 30% versus 4%, respectively.^107,108 The time to progression was also significantly superior at 24 versus 17 months respectively. VMP was also associated with significantly improved OS compared with MP, which persisted with long-term follow-up.^107,108 In a subsequent randomized trial there was no significant advantage of bortezomib-thalidomide-prednisone (VTP) over VMP.⁸⁹ Neuropathy is a significant risk with VMP therapy but can be lowered substantially by using a once-weekly regimen.^89,90 VCD, discussed earlier, is a minor variation of VMP and is often used instead of VMP to minimize melphalan-related toxicity.

Melphalan-Prednisone-Lenalidomide

The regimen of melphalan, prednisone, and lenalidomide (MPR) has shown high activity in phase II studies in newly diagnosed patients 65 years or older.¹⁰⁹ MPR has been recently compared with MP in a randomized trial among patients 65 years or older with newly diagnosed multiple myeloma.¹¹⁰ Unlike with MPT and VMP, neuropathy is not a major adverse effect but major grade 3/4 adverse events are hematologic and include neutropenia, thrombocytopenia, and anemia. The median PFS was similar between MPR and MP at 14 months versus 13 months, respectively. The disappointing lack of improvement in PFS with MPR compared with MP may be related to the fact that dose reductions of both melphalan and lenalidomide are often required when the two agents are combined. In addition, the incidence of second primary tumors in this trial was 7% with MPR compared with 3% for MP alone. An ECOG randomized trial (E1A06) compared MPR with MPT, and results are awaited.

Bortezomib-Melphalan-Prednisone-Thalidomide

The quadruplet regimen of bortezomib, melphalan, prednisone, and thalidomide (VMPT) has been tested against VMP in a randomized phase III trial.⁹⁰ The 3-year PFS rate was 56% with VMPT compared with 41% with VMP. However, patients in the VMPT study arm received maintenance therapy with bortezomib and thalidomide (VT), whereas patients in the VMP study arm did not receive any additional therapy beyond 9 months. Furthermore, no differences in OS rates were seen; the 3-year OS rate was 89% with VMPT and 87% with VMP. Until differences in OS rates emerge, there does not appear to be any advantage of using VMPT as initial therapy compared with VMP or other similar regimens.

Autologous Stem Cell Transplantation

Although not curative, ASCT improves CR rates and prolongs median OS in myeloma by approximately 12 months (Table 104-6).^116–119 The mortality rate is 1% to 2%. Approximately 50% of transplants can be done on an outpatient basis.¹²⁰ Melphalan 200 mg/m² is the most widely used preparative (conditioning) regimen for ASCT. Studies are ongoing to determine if the conditioning regimen can be improved with the addition of bortezomib.

Although the efficacy of ASCT in prolonging median OS prior to the arrival of thalidomide, lenalidomide, and bortezomib is not in doubt, its timing (early vs. late) has always been questioned.⁷⁰ Three randomized trials show that survival is similar whether ASCT is done early (immediately after four cycles of induction therapy) or delayed (at the time of relapse as salvage therapy).^123–123There are also doubts about whether ASCT is necessary in patients who achieve an excellent response to induction. The only randomized trial to test that question, a Spanish PETHEMA group study, found that patients responding to induction therapy had similar OS and PFS with either ASCT or eight additional courses of chemotherapy,¹²⁴ suggesting that the greatest benefit from ASCT may be in patients with disease refractory to induction therapy.^125,126 More recently, there is a debate about whether ASCT has the same value as it did before the arrival of thalidomide, lenalidomide, and bortezomib.

Overall, ASCT, especially for patients younger than 65 years of age with adequate renal function, still remains an important treatment option.¹¹⁸ However, given effective new agents to treat myeloma, some patients with standard-risk disease can be given the option of delaying the procedure until first relapse based on their preference. An ongoing trial is comparing VRD versus VRD followed by ASCT.

Tandem Transplantation

With tandem (double) ASCT, patients receive a second planned ASCT after recovery from the first procedure.127,128 A French randomized trial found significantly better event-free survival (EFS) and OS in recipients of double versus single ASCT (Table 104-7).¹²⁹ So far, three randomized trials including the French trial suggest superior PFS and OS with tandem ASCT.^131–131 In the French and Italian trials, the benefit of a second ASCT was restricted to patients failing to achieve a CR or VGPR with the first procedure. Based on these results, it is preferable to collect enough stem cells for two transplants in patients younger than 65 years. Patients achieving a CR or VGPR with the first transplant can delay possible consideration of second ASCT until relapse. On the other hand, those who fail to achieve a VGPR and those with intermediate-risk myeloma can be considered for tandem ASCT. Patients not achieving such a response are offered a second ASCT.

Allogeneic Transplantation

The advantages of allogeneic transplantation are lack of graft contamination with tumor cells and presence of a graft versus myeloma effect.132,133 However, only 5% to 10% of patients are candidates because of age, availability of a human leukocyte antigen (HLA)-matched sibling donor, and adequate organ function. Furthermore, the high TRM, mainly related to graft-versus-host disease (GVHD) has made conventional allogeneic transplants unacceptable for most patients with myeloma. Recent studies have tried to reduce TRM by using nonmyeloablative allografting regimens (mini-allogeneic transplantation; reduced-intensity–conditioning allogeneic transplantation) in myeloma. In the newly diagnosed setting, such transplants usually occur after optimal disease control with induction therapy and ASCT. The TRM is lower than with myeloablative transplants and is 10% to 15%, but grade 2/4 acute GVHD occurs in approximately 40% and extensive chronic GVHD can occur in over 50%.¹³⁴ Unfortunately, the occurrence of GVHD appears to be tied to disease control.

Bruno and colleagues found a significant OS advantage with a strategy of ASCT followed by nonmyeloablative allograft compared with tandem ASCT.¹³⁵ Björkstrand and associates have also reported a survival benefit,¹³⁶ but other trials have not shown such a benefit.^137,138 A recent trial in the United States found no benefit with nonmyeloablative allogeneic transplantation compared with ASCT in either high-risk or standard-risk patients.¹³⁹ At this time, mini-allogeneic transplantation remains investigational for patients with newly diagnosed myeloma, and its use should be restricted primarily to clinical trials.

Glucocorticoids and Alkylating Agents

Dexamethasone or intravenous methylprednisolone are reasonable options for palliation of symptoms in patients in whom other options have been exhausted.150,151 Patients experiencing relapse more than 6 to 12 months after an ASCT may note a response to melphalan-containing regimens such as VCD, MPT, or VMP because most would not have been exposed to these regimens as induction therapy. Intravenous melphalan at a dose of 25 mg/m² is another active regimen but usually requires transfusion and growth factor support. Patients who have cryopreserved stem cells early in the disease course can derive significant benefit from ASCT as salvage therapy.¹⁵²

Thalidomide and Thalidomide-Based Regimens

As a single-agent, thalidomide has a response rate of 25% in heavily pretreated patients with relapsed and refractory disease.¹⁵³ The median duration of response is approximately 1 year. Thalidomide is usually given in a daily dosage of 100 to 200 mg. After a response is achieved, the dose should be adjusted to the lowest dose that can achieve and maintain a response so as to minimize long-term toxicity. A TD regimen or TD in combination with cyclophosphamide (CTD) has significant activity in the treatment of relapsed multiple myeloma. Studies show that response rates in relapsed disease are about 50% with TD and over 65% with CTD.^156–156 Several other combination chemotherapy regimens containing thalidomide are being studied, including DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin [Adriamycin], cyclophosphamide, and etoposide), BLT-D (clarithromycin, low-dose thalidomide, and dexamethasone), and MTD (melphalan, thalidomide, and dexamethasone).¹⁵⁷

The use of thalidomide in pregnancy is absolutely contraindicated, and the System For Thalidomide Education and Prescribing Safety Program (S.T.E.P.S.) must be followed to prevent teratogenicity.¹⁵⁸ The incidence of deep vein thrombosis is only 1% to 3% in patients receiving thalidomide alone but rises to 10% to 15% in patients receiving thalidomide in combination with dexamethasone and to about 25% in patients receiving the agent in combination with other cytotoxic chemotherapeutic agents, particularly doxorubicin.^159–163 The management of thalidomide toxicity has been reviewed.¹⁶⁴

Bortezomib and Bortezomib-Based Regimens

Bortezomib is a proteasome inhibitor approved for the treatment of patients with relapsed and refractory multiple myeloma.165,166 In the first phase II trial conducted in 202 patients with relapsed/refractory multiple myeloma, approximately one third responded to bortezomib therapy, with an average response duration of 1 year.¹⁶⁷ These results were confirmed in a randomized phase II trial in patients who failed to respond or experienced relapse after front-line therapy for myeloma.¹⁶⁸ Although initial trials only allowed a maximum of eight cycles of bortezomib, additional data indicate that it is safe to give additional cycles of therapy, without undue toxicity.¹⁶⁸ In a randomized trial, PFS was superior with bortezomib compared with dexamethasone alone in patients with relapsed, refractory multiple myeloma.¹⁶⁹ The dose used in initial trials was 1.3 mg/m² given twice weekly on days 1, 4, 8, and 11 every 21 days. However, bortezomib is now administered subcutaneously in a once-weekly schedule to minimize neurotoxicity. The dosage may need to be further decreased to 1.0 mg/m² or 0.7 mg/m² if toxicity arises.

VD, VTD, VCD, and VRD are all active regimens that can be used in the treatment of relapsed disease.¹⁷⁰ Patients who fail bortezomib alone and cyclophosphamide alone may respond to the two drugs administered in combination as in the VCD regimen. Similarly, responses occur with VRD even when patients are refractory to lenalidomide and bortezomib administered separately.

Lenalidomide

Two large phase III trials have shown superior time to progression and OS with lenalidomide plus dexamethasone compared with placebo plus dexamethasone in relapsed multiple myeloma.171,172 In these trials grade 3/4 neutropenia was more frequently seen with the combination of lenalidomide plus dexamethasone; the frequency of grade 3/4 infections were similar in both study arms. Typical dosing of lenalidomide for myeloma is 25 to 30 mg/d on days 1 to 21 of a 28-day cycle, with dose adjustments based on toxicity.

Liposomal Doxorubicin

A phase III randomized trial found that median time to progression was superior with bortezomib plus pegylated liposomal doxorubicin (PLD) compared with bortezomib alone: 9.3 months versus 6.5 months, respectively (P < .001).¹⁷³ OS at 15 months was also superior: 76% compared with 65%, respectively (P = .03). Based on this study, liposomal doxorubicin appears to have modest activity in relapsed myeloma and can be considered as an option for the treatment of relapsed myeloma.

Pomalidomide

Pomalidomide is a new immunomodulatory analog of thalidomide and lenalidomide that is approved for the treatment of relapsed and refractory myeloma in patients who have been previously treated with bortezomib and lenalidomide.¹⁷⁵ Schey and colleagues showed remarkable single-agent activity of pomalidomide (CC-4047) in a small phase I trial in patients with relapsed, refractory multiple myeloma.¹⁷⁶ Lacy and colleagues later established that the combination of pomalidomide (2 mg/d given orally) plus low-dose dexamethasone (40 mg once weekly given orally) is remarkably active in relapsed multiple myeloma, with response rates of over 60%.¹⁷⁵ It is also active in patients with myeloma refractory to lenalidomide¹⁷⁷ as well as disease refractory to both lenalidomide and bortezomib.¹⁷⁸ Given its single-agent activity and excellent tolerability, pomalidomide is approved for the treatment of relapsed refractory myeloma.

Carfilzomib

Carfilzomib is a novel keto-epoxide tetrapeptide proteasome that has potent single-agent activity in relapsed refractory myeloma.¹⁷⁹ Unlike bortezomib, which has a slowly reversible effect on the proteasome and some cross-reactivity with serine proteases, carfilzomib is a highly selective irreversible proteasome inhibitor, binding specifically to the N-terminal threonine active sites of the proteasome. Whereas bortezomib inhibits both chymotrypsin-like and caspase-like activities of the proteasome, carfilzomib is more selective for the chymotrypsin-like active site within the proteasome, which may result in greater specificity and lower toxicities. In a phase II study, partial response or better was achieved in 23 of 51 patients with relapsed multiple myeloma (45%) who were bortezomib naïve.¹⁸⁰ Response rates are lower in patients previously treated with bortezomib (approximately 20%) or refractory to bortezomib (approximately 15%). Carfilzomib has promise because the rate of severe neuropathy is low. A phase III trial is comparing carfilzomib plus Rd to Rd alone in relapsed myeloma. Carfilzomib is also being investigated for the treatment of newly diagnosed myeloma. Carfilzomib is approved for the treatment of relapsed myeloma in patients who have been previously treated with lenalidomide and bortezomib.

Other Promising Drugs

The most promising drugs in advanced clinical trials in multiple myeloma include histone deacetylase inhibitors (vorinostat and panobinostat) and the anti–CS-1 antibody elotuzumab.¹⁸¹ However, none of these appears to have significant single-agent activity and their long-term impact is unclear. More promising drugs that have clear single-agent activity include ARRY-520 (a kinesin spindle protein inhibitor), anti-CD 38 monoclonal antibodies, and cyclin dependent kinase inhibitors.

Treatment of Anemia

Iron, folate, or vitamin B₁₂ deficiency may also be responsible for the anemia, and must be recognized and treated. Treatment of the underlying disease and renal failure often leads to improvement in the hemoglobin level. Erythropoietin 40,000 units subcutaneously weekly or darbepoietin 200 µg subcutaneously every 2 weeks are both useful treatments in patients with persistent symptomatic anemia.201,202 These treatments should be restricted, however, because of a higher risk of deep vein thrombosis when used in combination with thalidomide or lenalidomide. Blood transfusions are indicated for patients with symptomatic anemia who do not obtain benefit from other therapies.

Prevention of Infections

Patients should receive pneumococcal and influenza vaccinations. The optimal use of prophylactic antibiotics in patients receiving chemotherapy for myeloma has not been confirmed. A small randomized placebo-controlled trial of trimethoprim-sulfamethoxazole in 57 patients with newly diagnosed myeloma demonstrated benefit with routine prophylaxis administered with the first two cycles of chemotherapy.²⁰³ In a more recent randomized trial, significant benefit was noted with prophylactic antibiotics administered during initial therapy.²⁰⁴ Nevertheless, prophylaxis against Pneumocystis jiroveci (formerly P. carinii) pneumonia should be considered in all patients receiving long-term corticosteroid therapy. Because of the risk for serious skin toxicity, use of trimethoprim-sulfamethoxazole should be avoided in patients receiving TD or Rd therapy. In patients receiving TD or Rd, alternative agents for Pneumocystis prophylaxis should be considered. Acyclovir or valacyclovir should be administered routinely for patients receiving bortezomib-based therapy as prophylaxis against herpes zoster. Intravenously administered gamma globulin is not indicated unless patients have recurrent serious infections associated with severe hypogammaglobulinemia.

Bone Lesions, Fractures, and Spinal Cord Compression

Surgical fixation of fractures or impending fractures of long bones may be needed. Local radiation should be limited to patients with disabling pain who have a well-defined focal process that has not responded to analgesics and/or chemotherapy.

Both vertebroplasty (injection of methylmethacrylate into a collapsed vertebral body) and kyphoplasty (introduction of an inflatable bone tamp into the vertebral body and after inflation the injection of methylmethacrylate into the cavity) have been used to decrease pain in patients with vertebral fractures.²⁰⁷ Pain relief is usually rapid and can be long lasting. However, two recent randomized trial found no significant benefit of vertebroplasty compared with a sham procedure.^208,209

Spinal cord compression from an extramedullary plasmacytoma should be suspected in patients with severe back pain, weakness or paresthesias of the lower extremities, or bladder or bowel dysfunction or incontinence. The standard treatment of cord or cauda equina compression includes corticosteroids (dexamethasone 10 mg to 40 mg intravenously followed by 4 mg orally/intravenously four times daily) and radiation therapy. In selected patients, rapidly acting chemotherapy such as VCD can be used in addition to or in place of irradiation. On rare occasions, surgical decompression may be necessary.

Renal Insufficiency

Nonsteroidal anti-inflammatory agents can precipitate renal failure and should generally be avoided.210,211 Dehydration, hypercalcemia, infection, and radiographic contrast media may also contribute to acute renal failure. The most important cause of acute renal failure in myeloma is light-chain cast nephropathy, also referred to as “myeloma kidney.” Maintenance of a high urinary output (3 L/day) is important in preventing renal failure in those with high levels of monoclonal light chains in the urine. Light-chain cast nephropathy is a risk in patients with serum FLC levels greater than 150 mg/dL and is typically uncommon in patients with FLC levels less than 50 mg/dL. Persons with acute or subacute renal failure that is due to light-chain cast nephropathy should be treated with rapidly acting chemotherapy such as VCD or VTD to reduce light-chain production as quickly as possible. A trial of plasmapheresis should be considered in these patients in an attempt to prevent irreversible renal damage.²¹² Studies show that prompt plasma exchange coupled with effective therapy can reverse renal failure in a substantial proportion of patients.²¹³

Hyperviscosity Syndrome

Infrequently, patients with multiple myeloma develop hyperviscosity syndrome. Plasmapheresis promptly relieves the symptoms and should be done regardless of the viscosity level if the patient has signs or symptoms of hyperviscosity.²¹⁴