Challenges in multiple myeloma diagnosis and treatment

Abstract

Although multiple myeloma (MM) remains an incurable disease, the advent of novel treatment paradigms has improved survival outcomes in the past two decades. This includes widespread use of high-dose chemotherapy with autologous stem cell transplantation (HDT–ASCT) and the development of the novel agents thalidomide, lenalidomide and bortezomib. The efficacy and tolerability of these novel agents have allowed for the exploration of continuous therapy approaches. Maintenance therapy after HDT–ASCT, for example, may help prolong progression-free survival by providing sustained control of residual disease. Trials are also under way to evaluate lenalidomide in patients with high-risk smoldering MM, with the aim of delaying progression to symptomatic MM. Other research is focusing on improving HDT–ASCT protocols and integrating novel agents, such as bortezomib, as an induction or consolidation therapy. Despite these advances, more effective strategies are needed, particularly for the management of older, less fit patients who are ineligible for HDT–ASCT. Preliminary results on the use of lenalidomide maintenance therapy in elderly patients are encouraging. Taken together, these observations indicate that in this era of novel agents, optimal treatment of MM requires a long-term perspective that focuses on providing sustained disease control while maintaining quality of life.

Introduction

Multiple myeloma (MM) is an incurable plasma cell neoplasm accounting for 1% of all malignancies and 10% of hematologic malignancies.^{1, 2} In 2011, the estimated annual incidence of new cases of MM was 20 520.³ The incidence is 5.7 per 100 000 population, with rates almost twice as high among African Americans.³ MM affects a higher proportion of elderly patients with an age-adjusted incidence rate of 30.3 per 100 000 population aged >65 years. The median age at diagnosis is 70 years, and with the aging US demographic, the overall incidence of MM is expected to rise.

The advent of novel treatment paradigms has improved survival over the past two decades. The first major therapeutic milestones were autologous stem cell transplantation (ASCT) in the 1980s and the introduction of novel agents, such as thalidomide in 1999, and bortezomib and lenalidomide in 2003 and 2005, respectively. The Surveillance, Epidemiology and End Results (SEER) database showed a modest increase in 5-year relative survival rates from 1975 to 2000 (from 25 to 32%).³ However, from 2001 to 2007, the 5-year relative survival rate increased to 41.1% this benefit was seen primarily in younger patients.⁴ Life expectancy in younger patients with standard-risk MM is now 7–10 years.⁵ In patients aged >70 years, there was no statistically significant difference in 5- or 10-year estimates of overall survival (OS) from 1990 and 2002. However, a trend towards improved 5-year survival in patients aged 60–69 years has been observed (P=0.09).⁴ Median survival in patients with newly diagnosed MM (NDMM) improved from 29.9 months in those diagnosed between 1971 and 1996 to 44.8 months for those diagnosed in the following decade (P<0.001).⁶ These studies followed cohorts until the mid 2000s; hence, the effects of novel agents had not yet been maximized. In this review, we will discuss the use of novel agents in the treatment of MM and long-term strategies to provide sustained disease control, maintain good quality of life and optimize outcomes.

Diagnosis

MM is typically detected on routine blood work, or by characteristic symptoms caused by infiltration of myeloma cells or end-organ damage related to effects of secreted and/or deposited immunoglobulins. Patients can present with bone pain—often precipitated by movement (58%)—fatigue (32%) or weight loss (24%).⁷ Fatigue correlates with anemia (median hemoglobin of 9.9 g/dl). The majority of patients with MM have a localized band on a serum protein electrophoresis, a monoclonal protein detected by immunofixation or abnormal light chains in the urine or serum.

Plasma cell dyscrasia encompasses a spectrum of disorders, from monoclonal gammopathy of unknown significance (MGUS) to smoldering MM, to symptomatic MM. The International Myeloma Working Group Consensus Panel provided diagnostic criteria for plasma cell disorders.⁸ Differentiation among MGUS, smoldering MM and symptomatic MM is based on the level of serum monoclonal protein, the percentage of clonal plasma cells in bone marrow and the presence or absence of end-organ damage, such as hypercalcemia, renal insufficiency, anemia or bone lesions. In addition, consideration and evaluation for amyloid light-chain amyloidosis or light-chain deposition disease is recommended, especially in patients fitting the criteria for MGUS.⁹

Staging and risk stratification

Significant heterogeneity in the natural history and response to treatment has been observed in MM. Even in 2007, 24% of NDMM patients died within 1 year of diagnosis, whereas a small percentage of patients will live for longer than a decade now.³ Several prognostic factors have been established to identify patients with high-risk disease. The International Staging System (ISS) classifies patients with MM into one of three stages based on serum β₂-microglobulin and albumin levels: stage I is characterized by serum β₂-microglobulin <3.5 mg/l and serum albumin >3.5 g/dl; stage II patients do not meet the criteria for stage I or III; and stage III is characterized by serum β₂-microglobulin ⩾5.5 mg/l.¹⁰ In the era before the approval of bortezomib and lenalidomide, median survival for stages I, II and III MM disease were 62, 44 and 29 months, respectively. The ISS was validated and found to be significant irrespective of age, conventional versus high-dose treatment and geographical location. Although platelet count had a higher hazard ratio (HR) than serum albumin, it occurred less frequently and was not incorporated into the ISS. Elevated serum lactate dehydrogenase also correlated with high tumor mass, decreased response rate and shorter median survival.¹¹

Cytogenetic abnormalities

Detection of certain cytogenetic abnormalities carries a poor prognosis, but standard karyotyping is hindered by the low proliferative index of myeloma cells and the difficulty in aspirating malignant clones.¹² More recently, fluorescence in situ hybridization has been incorporated into standard workup, as it can detect chromosomal abnormalities in non-mitotic cells. In particular, the del(17p) and t(4;14) abnormalities are associated with shorter event-free survival (EFS; HR 3.29 and 2.79, respectively) and OS (HR 3.93 and 2.78, respectively).¹² The presence of these two cytogenetic abnormalities predicts significantly worse EFS and OS (P⩽0.001) across all three ISS stages. In patients with a low β₂-microglobulin level and without del(17p) and t(4;14), the expected 4-year survival rate is 83%. In comparison, median OS in patients with either a cytogenetic abnormality or an elevated β₂-microglobulin level is 19 months. Another cytogenetic abnormality linked with worse outcome is t(14;16).¹³ Del(13) also has a high incidence in MM and a negative impact on EFS and OS, but its effect is not significant in the absence of del(17p) and/or t(4;14).¹² Overall, the consensus recommendation is to perform cytogenetics and fluorescence in situ hybridization for the 17p13, t(4;14) and t(14;16) abnormalities. However, the optimal treatment approach for patients with high-risk MM based on the presence of ⩾1 cytogenetic abnormality has not been established as prospective, randomized studies are lacking. In one study, 100 consecutive patients, of which 16% had high-risk cytogenetics, received lenalidomide plus dexamethasone.¹⁴ At a median follow-up of 36 months, the group with high-risk cytogenetics had worse progression-free survival (PFS; 18.5 versus 36.5 months; P<0.001), but similar response rates (P=0.36) and OS as those with a standard-risk cytogenetic profile (P=0.4); the median OS was not reached in either arm. Half of the high-risk patients who relapsed received bortezomib as a salvage therapy. Longer follow-up and a larger series are necessary to determine whether novel agents may overcome high-risk cytogenetic features in MM.¹⁵

Serum free light-chain assay

Importantly, measurement of serum free light chains (FLCs) has become integral to screening for plasma cell dyscrasia, risk stratification of patients with MGUS and smoldering MM, disease staging and response assessment. The serum FLC immunoassays have a very low limit of detection (<1 mg/l) compared with serum protein electrophoresis (1–2 g/l) or immunofixation electrophoresis (150–500 mg/l).¹⁶ The sensitivity and specificity of serum FLCs alone are 0.76 and 0.96, respectively.¹⁷ However, the addition of serum FLCs to serum immunofixation electrophoresis and serum protein electrophoresis improved the sensitivity for detecting paraproteinemia to 99.5%.¹⁸ Serum FLCs are still insufficient in certain cases of MM with light-chain excretion in the urine and in detecting amyloid light-chain amyloidosis; thus, a 24-hour urine immunofixation electrophoresis is necessary in the initial workup and when considering amyloid light-chain amyloidosis.¹⁶

Serum FLCs have been incorporated into models predicting progression of MGUS or smoldering MM to symptomatic MM, or related disorders such as amyloid light-chain amyloidosis or light-chain deposition disease. In a single-institution retrospective study, multivariate analysis showed that an abnormal serum FLC ratio increased the risk of progression from MGUS to MM by an HR of 2.6 (P<0.001).¹⁹ This study concluded that three risk factors could predict progression from MGUS to MM or a related disorder: (a) an abnormal serum FLC ratio; (b) a serum monoclonal protein level >15 g/l; and (c) non-immunoglobulin G subtype. The same group investigated prognostic factors for progression of smoldering MM. Multivariate analysis showed that an abnormal FLC ratio of <0.125 or >8 increased the risk of progression by an HR of 1.9 (P<0.01).²⁰

The use of serum FLCs for staging has been proposed. Van Rhee et al.²¹ have reported that patients with FLCs >75 mg/dl had more aggressive disease features with more renal failure, higher percentages of bone marrow plasma cells, higher values of β₂-microglobulin and lactate dehydrogenase, higher proportion of light-chain disease and higher proportion of ISS stage III disease, all of which correlate with worse OS and EFS.²¹ In fact, Snozek et al.²² have reported improved prognostic capacity of ISS, with inclusion of FLCs in the staging system, especially in patients with stage II disease.²² The most recent International Myeloma Working Group Consensus Panel recommendations did not incorporate serum FLC in staging.²³

Management

Smoldering MM

Smoldering MM presents with a higher burden of disease than MGUS and has a higher rate of progression to MM or related diseases. The risk of progression is 10% annually for the first 5 years, or 51% at 5 years.²⁴ The rate of progression decreases to 3% annually for the next 5 years, and the 15-year risk is 73%. A multivariate analysis showed three risk factors for progression: (a) bone marrow plasma cells ⩾10% (b) a serum monoclonal protein level ⩾3 g/dl; and (c) a serum FLC ratio of <0.125 or >8. The 5-year rate of progression was 15, 43 and 69%, and the median time-to-progression was 19, 8 and 2 years, for patients with one, two and three risk factors, respectively. Flow cytometry assessment of the bone marrow aspirate to stratify progression has been proposed.²⁵ Immunoparesis and >95% of clonal or abnormal plasma cells on flow cytometry have also been identified as risk factors. With this method, the 5-year progression rate was 4, 46 and 72% for patients with no, one and two risk factors, respectively. Another risk factor for early progression of asymptomatic MM is occult bone disease detectable by magnetic resonance imaging.²⁶

Several clinical trials are investigating the role of preventative chemotherapy to delay the onset of symptomatic MM. A study of asymptomatic stage I MM treated with early or deferred melphalan plus prednisone (MP) in the mid 1980s did not show a difference in response rate, duration of response or OS.²⁷ A randomized controlled study showed that zoledronic acid decreased skeletal-related events, but did not change time-to-progression.²⁸ Those studies preceded newer agents and improved risk stratification. More recently, several studies have looked at lenalidomide in high-risk smoldering MM. In an ongoing phase III, randomized multicenter trial conducted by Mateos et al.,²⁹ 118 patients with high-risk smoldering MM received nine 4-week cycles of induction lenalidomide plus dexamethasone treatment, followed by maintenance lenalidomide therapy or observation. The overall response rate was 75% in the intent-to-treat population and 91% in those who completed induction. With a 16 month follow-up, 23% (13/57) of patients receiving lenalidomide plus dexamethasone progressed to active MM compared with 34% (21/61) in the observation arm. The estimated HR was 6.7 (95% confidence interval 2.3–19.9). The median time-to-progression in the lenalidomide plus dexamethasone arm was not reached compared with 25 months in the observation arm (P<0.0001); there was no statistically significant difference in mortality. In the United States, an ongoing Eastern Cooperative Oncology Group trial (ClinicalTrials.gov: NCT01169337) is comparing six cycles of lenalidomide to observation in patients with high-risk smoldering MM, but preliminary results are not yet available. Despite identification of a subset of smoldering MM patients with a high-risk of progression, the data for preventive chemotherapy are promising but have not matured sufficiently.

Symptomatic MM—goals of therapy

More aggressive treatment of NDMM with combination novel agents has increased complete response (CR) rates and PFS, although its long-term impact on improvement in OS remains to be confirmed.³⁰ The debate regarding the best treatment objectives (cure versus control) continues.³¹ Supporters of the curative approach believe that MM is more sensitive to therapy early in the disease course, and thus recommend aggressive therapy at diagnosis. Alternatively, those espousing the control approach prefer sequential therapy that minimizes adverse events and improves quality of life, as cure is unlikely. Use of aggressive combination approaches, such as stem cell transplantation in the ‘Total Therapy' program, has led to long-term sustainment of CR indicative of a possible cure in a fraction of patients with MM.

Transplantation-eligible patients

The standard of care for patients aged <65 years with NDMM, with no comorbidity, includes high-dose chemotherapy followed by ASCT. Several studies have compared conventional chemotherapy with ASCT;³² two of these showed improvement in OS with ASCT.^{33, 34} A meta-analysis of nine studies with a total of 2411 patients showed that ASCT improved PFS, but did not show an OS benefit.³⁵ The improvement seen in PFS was also applicable in chemorefractory disease. In high-risk disease, the median OS is 2–3 years, compared with 5 years in standard-risk myeloma.⁹ More recently, use of novel agents before ASCT (induction) or after ASCT (maintenance), tandem transplantations and allogeneic stem cell transplantation are being reinvestigated to improve survival.

Induction therapy

The goal of induction therapy is to achieve a minimal disease status that allows for successful use of ASCT. It also reduces plasma viscosity and provides symptom control.⁹ Compared with a historical combination, such as vincristine, doxorubicin and dexamethasone, which produces response rates of 40–70%,⁹ novel agents can achieve impressive response rates. As CR after induction therapy correlates with CR after ASCT, novel agents have been examined for induction chemotherapy.³⁶

Thalidomide was the first novel agent used as an induction therapy. Regimens such as thalidomide and dexamethasone, and thalidomide, doxorubicin and dexamethasone have been evaluated.^{37, 38, 39} Lenalidomide, a second-generation immunomodulator with a different toxicity profile to thalidomide, has also been evaluated in patients with NDMM.⁴⁰ In a randomized trial, the combination of lenalidomide and low-dose dexamethasone produced superior survival outcomes compared with lenalidomide and standard-dose dexamethasone.⁴¹ A short induction course of lenalidomide plus standard-dose dexamethasone does not hamper stem cell collection, with 91% of patients obtaining a sufficient yield with one or two collections.⁴² With a novel and different mechanism of action, bortezomib has also been explored as an induction therapy. In a phase III, multicenter European study that randomized 482 patients to induction chemotherapy with vincristine, doxorubicin and dexamethasone, or bortezomib plus dexamethasone (VD), the VD cohort had a better CR rate (5.8% versus 1.4% P=0.012), CR plus very good partial response rate (37.7% versus 15.1% P<0.001) and overall response rate (78.5 versus 62.8% P<0.001).⁴³ Survival data in this study are difficult to interpret since 88% of patients were then enrolled in a lenalidomide consolidation study. Nonetheless, there was a trend towards improved PFS in the VD group (36.0 versus 29.7 months; P=0.064).

Multidrug approaches, especially bortezomib-based, for induction chemotherapy are being explored. The combination of lenalidomide, bortezomib and dexamethasone (RVD) has produced an overall response rate of 100%, including 74% of patients achieving a very good partial response or better, making this combination a standard of care in NDMM.⁴⁴ The 18-month PFS and OS were 75% and 97%, respectively. The multicenter, phase I EVOLUTION (Evaluation of Velcade, dexamethasOne and Lenalidomide with or without cyclophosphamide Using Targeted Innovative ONcology strategies in the treatment of frontline MM) study evaluated the safety and efficacy of combination cyclophosphamide, lenalidomide, bortezomib and dexamethasone, and reported results that were not significantly superior to the RVD regimen.⁴⁵ Other induction regimens, such as bortezomib, cyclophosphamide and dexamethasone, and bortezomib, thalidomide and dexamethasone have also been assessed.^{46, 47}

It should be noted that a post-transplantation CR correlates with prolonged PFS and OS, especially if sensitive CR criteria, such as molecular remission or multiparameter flow cytometry, are used.³² However, the data on thalidomide predated serum FLC; hence, one must be cautious concluding that an improved response rate will result in improved survival. The data on bortezomib and lenalidomide included serum FLC, but reported primarily response rates to induction chemotherapy. Further refinement of CR assessment using newer technologies is needed, and assessment of the impact of CR on survival outcomes is warranted.

Allogeneic stem cell transplantation

Because of graft-versus-myeloma effect, allogeneic stem cell transplantation is currently the only curative therapy for MM. The prospect of curative treatment is seductive, but the treatment-related mortality from myeloablative conditioning in a heavily pretreated patient is 41%.⁵ Because of this high treatment-related mortality, survival in allogeneic stem cell transplantation is inferior to ASCT. Reduced-intensity conditioning with allogeneic stem cell transplantation is associated with lower treatment-related mortality and has, therefore, been compared with tandem ASCT. Several multicenter trials conducted in Europe and the United States, however, have failed to show a survival benefit with reduced-intensity conditioning with allogeneic stem cell transplantation and, in fact, showed a trend towards improved PFS with tandem ASCT.⁵

Maintenance therapy

Novel agents have been used as maintenance therapy after ASCT. Several previous studies have evaluated the role of maintenance therapy in MM using interferon, steroids, thalidomide, lenalidomide and bortezomib. Two studies have recently evaluated lenalidomide maintenance therapy after ASCT^{48, 49} and both the studies demonstrated a significant improvement in PFS, and one found an improvement in OS with lenalidomide maintenance compared with placebo.⁴⁹ However, the incidence of the second primary malignancy was reported to be increased in the group receiving lenalidomide maintenance compared with placebo. Nevertheless, currently, the significant benefit observed with lenalidomide maintenance suggests that continued use of lenalidomide maintenance may be warranted after careful discussion with patients. These trials are ongoing and continue to collect OS information.

Transplantation-ineligible patients

Historically, the MP regimen was the standard of care in patients who were not transplantation candidates. Frontline therapies are evolving, as multiple new agents and combinations are explored. In a meta-analysis, thalidomide-based regimens such as MP plus thalidomide showed superior efficacy to MP, but increased the risk of adverse events.^{50, 51}

Lenalidomide-based regimens have also been evaluated in transplantation-ineligible patients. These regimens include lenalidomide plus dexamethasone,^{52, 53} MP plus lenalidomide (MPR), with or without single-agent lenalidomide maintenance,^{52, 54} and the BiRD (clarithromycin, lenalidomide and dexamethasone) regimen.^{53, 55}

Lastly, bortezomib was found to prolong PFS and OS when combined with MP in the phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) trial.⁵⁶ Total grade 3 or 4 adverse event rates were similar across both the MP group and the bortezomib plus MP group, and the peripheral neuropathy associated with bortezomib was reversible. Longer follow-up confirmed improved survival (HR 0.653; P<0.001).⁵⁷ In summary, novel agents have been incorporated into the management of patients with NDMM, including transplantation-eligible and -ineligible patients. Although this has improved response rates and PFS, it remains to be seen how this will affect OS. We believe that a bortezomib-based regimen is the standard of care because of the associated rapid response, improved response rate, prolonged survival and excellent response to other agents after relapse. However, the optimal sequence of chemotherapies remains to be determined.

Elderly patients

Although significant progress has been made in the management of MM, the benefit has been seen primarily in younger patients. With an average age of diagnosis at 70 years, most MM patients are elderly, which generates several challenges (Table 1). Many patients have comorbidities that frequently preclude aggressive therapies, such as ASCT. Reduced-intensity ASCT can be offered in younger patients, which is associated with a longer EFS (28 versus 15.6 months; P<0.0001) and OS (not reached at 41 months follow-up versus 42.5 months; P<0.0005) when compared with MP. ASCT was associated with higher early mortality, greater transfusion requirements and fevers of unknown origin.⁵⁸

Table 1. Challenges in treating elderly patients.

Challenges	Considerations
Comorbidities
Renal	Lenalidomide may need dose adjustment and close monitoring
Hepatic	Dose reduction of bortezomib
Cardiac	More sensitive to fluid status, may need to reduce dexamethasone
Bone marrow insufficiency	Exacerbation of treatment-related cytopenias
Polyneuropathy	Avoid bortezomib or thalidomide
Venous thromboembolic events	Requires full-dose anticoagulation
Decreased functional capacity and frailty	Correlates with increased toxicity from chemotherapy
Low performance status	Require dose attenuation and close monitoring
Cognitive dysfunction	Higher risk for delirium, increased caregiver support
Fear of falling	Provide preventative measure
Slow gait speed	Consider neuropathy, proximal myopathy—dose or regimen modification
Impaired ambulation	May need to consider transportation needs, oral versus intravenous therapy and scheduling
Polypharmacy	Need to consider interactions
Decreased capacity to tolerate toxicity	Dose modifications

In patients who are ineligible for ASCT, standard treatment typically includes the MP regimen, combined with either thalidomide or bortezomib, or lenalidomide and low-dose dexamethasone.⁵⁹ It is important to remember that all the options available to younger transplantation-eligible patients are also available and effective in older patients. This includes bortezomib plus dexamethasone and three-drug combinations, such as bortezomib, cyclophosphamide and dexamethasone or RVD. The treatment should be tailored to the individual. Bortezomib should be avoided in patients with neuropathies, although once-weekly dosing can potentially reduce additional neuropathy.⁶⁰ As lenalidomide is excreted renally, doses of lenalidomide should be adjusted in patients with renal insufficiency to avoid adverse effects. Thalidomide can increase the risk of venous thromboembolism.⁶¹ Thus, systemic anticoagulation or a low-dose aspirin regimen are necessary to reduce the risk of venous thromboembolism.⁶² In patients aged >75 years, doses of chemotherapy should be reduced (Table 2).^{41, 56, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75} Additional reductions may be necessary, especially in frail individuals.

Table 2. Suggested dose reductions for elderly patients.

Drug	Aged 65–75 years	Aged >75 years	Further dose reduction
Dexamethasone	40 mg/day given orally on days 1–4 and 15–18 of each 28-day cycle, or 40 mg/day given orally on days 1, 8, 15 and 22 of each 28-day cycle41	40 mg/day given orally on days 1, 8, 15 and 22 of each 28-day cycle41	20 mg/day given orally on days 1, 8, 15 and 22 of each 28-day cycle64
Melphalan	0.25 mg/kg given orally on days 1–4 every 6 weeks65	0.25 mg/kg given orally on days 1–4 every 6 weeks;65 or 0.18 mg/kg given orally on days 1–4 of each 28-day cycle66	0.18 mg/kg given orally on days 1–4 every 6 weeks, or 0.13 mg/kg given orally on days 1–4 of each 28-day cycle
Cyclophosphamide	300 mg/m2 given orally on days 1, 8, 15 and 22 of each 28-day cycle67	300 mg/m2 given orally on days 1, 8 and 15, of each 28-day cycle;68 or 50 mg/day given orally on days 1–21 of each 28-day cycle	50 mg/day given orally on days 1–21 of each 28-day cycle, or 50 mg every other day given orally on days 1–21 of each 28-day cycle
Thalidomide	200 mg/day given orally continuously65	100 mg/day69 or 200 mg/day65, 70 given orally continuously	50 mg/day68 to 100 mg/day69, 71 given orally continuously
Lenalidomide	25 mg/day given orally on days 1–21 of each 28-day cycle41, 72, 73	15–25 mg/day given orally on days 1–21 of each 28-day cycle41, 72, 73	10–25 mg/day given orally on days 1–21 of each 28-day cycle41
Bortezomib	1.3 mg/m2 given as bolus intravenous infusion on days 1, 4, 8 and 11 every 3 weeks56, 74	1.3 mg/m2 given as bolus intravenous infusion on days 1, 4, 8, and 11 every 3 weeks;56, 74 or 1.3 mg/m2 given as bolus intravenous infusion on days 1, 8, 15, and 22 every 5 weeks75	1.0–1.3 mg/m2 given as bolus intravenous infusion on days 1, 8, 15 and 22 every 5 weeks75

From Palumbo A, Anderson K. Multiple myeloma, New England Journal of Medicine, 364, 1046–1060. Copyright (2011) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.⁶³

Some evidence now suggests that continuous therapy may improve survival in the elderly. In the MM-015 phase III trial, patients (aged >65 years) received MP, MPR, or MPR followed by lenalidomide maintenance (10 mg/day, days 1–21 of a 28-day cycle).⁵⁴ The addition of lenalidomide maintenance to MPR significantly reduced the risk of progression (HR 0.34; P<0.001). Similar results were seen in patients aged >75 years, although the number of patients in this subgroup was small.⁷⁶ A second study compared bortezomib plus prednisone with bortezomib plus thalidomide maintenance therapy after induction with the three-drug combinations, bortezomib plus thalidomide and prednisone, or bortezomib plus MP in patients aged ⩾65 years.⁷⁷ Both therapies were well tolerated, with no grade ⩾3 hematologic toxicities, and 2% and 7% grade 3 peripheral neuropathy in the bortezomib plus prednisone and bortezomib plus thalidomide cohorts, respectively. There was no difference between the two cohorts in terms of PFS (median 35 months) and 3-year survival (70%). Thus, maintenance therapy with novel agents is tolerable and may improve outcomes in elderly patients.

Conclusion

Significant advances have been made in the prognosis, monitoring and treatment of MM. Novel agents have shown improved rates of response, PFS and, in some circumstances, OS. Many current studies show promising results, but the data are still maturing. The best combinations and sequences of therapies are still disputed, although lenalidomide- and bortezomib-based therapies have been extremely promising in the initial management of both transplantation-eligible and -ineligible patients. Extended treatment with novel agents may provide sustained disease control and delay relapse while maintaining quality of life. Promising strategies include consolidation or maintenance therapy following ASCT, or maintenance monotherapy for transplantation-ineligible patients. Use of novel agents to delay progression from smoldering MM to symptomatic MM is another promising strategy for optimizing outcomes through continuous therapy. Additional work is needed to determine the benefit of these approaches. Each of the three novel agents has a distinct safety profile that must be taken into consideration, although most adverse events can be managed with some combination of prophylaxis (for example, thromboprophylaxis for thalidomide and lenalidomide), dose modifications (for example, for lenalidomide-related myelosuppression) and careful patient selection (for example, avoiding use of thalidomide or bortezomib in patients with existing neuropathy). Another major concern, especially in the current political and economic climate, is the cost-effectiveness of novel agents when compared with early therapies. A balance between efficacy, safety and health-care costs needs to be reached, especially as the next generation of proteasome inhibitors and immunomodulators are being developed.

SG has no conflicts of interest to report. NM serves on advisory committees for Millenium, Celgene, Onyx and Merck. NM also owns equity in OncoPep.