“Evaluating the Role of Maintenance Therapy in the Management of Multiple Myeloma”

 
 
 
  TABLE OF CONTENTS
Evaluating the Role of Maintenance Therapy in the Management of Multiple Myeloma
Ashraf Badros, MD
April 11, 2011


Introduction

Multiple myeloma (MM) is a molecularly heterogeneous disease with a high degree of genomic instability in which specific genetic changes can be linked to clinical presentation and prognosis. Despite recent improvement of event-free survival and overall survival with the use of high-dose chemotherapy and stem cell support, and the development of novel agents such as thalidomide, lenalidomide, and bortezomib, MM remains an incurable disease for the majority of patients.1-7 Until a cure is found that can eliminate the malignant clone, the goal of maintenance therapy in MM is to achieve and maintain a durable remission.8

Maintenance therapy in MM has been studied for more than 30 years9; however, its role remains controversial.1,3,10 There is no consensus on the optimal regimen or duration, and many authorities question the advantages of the continuation of therapeutic agents as maintenance therapy, with all their side effects, over observation followed by treatment reimplementation at the time of relapse.1,5,9-12 Indeed, alternatives to prolonged treatment with alkylating agents, which increases the likelihood of acute myeloid leukemia, were already being assessed with interferon alfa, corticosteroids (with or without interferon alfa), and recently, novel agents after conventional chemotherapy or autologous stem cell transplantation (ASCT).9


 

At present, NCCN guidelines recommend the following agents as maintenance therapy in MM: interferon alfa (category 2B); corticosteroids (category 2B); thalidomide (category 1) with or without prednisone (category 2B); and lenalidomide (category 2A).3 In addition, bortezomib is currently under investigation in the maintenance setting, but the NCCN panel has deemed current data inadequate to make a recommendation.3


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...the criteria used to determine whether maintenance therapy is an appropriate strategy in a patient with MM.


0:43


Interferon Alfa as Maintenance Therapy
  

Interferon alfa as maintenance therapy in MM has been investigated in several clinical trials, but the findings have been inconsistent.9,13

Data from two meta-analyses showed that interferon alfa produced a statistically significant (albeit small) survival advantage when used after conventional therapy.9 In one meta-analysis, based on 1615 patients with MM in 13 trials, interferon alfa maintenance therapy, compared with no treatment, prolonged relapse-free and overall survival by 4.4 and 7.0 months, respectively (P<.01).13 In the second meta-analysis, based on 1543 patients with MM in 12 trials, response duration was better with interferon alfa maintenance therapy (27% vs 19%, respectively, at 3 years; log rank P<.00001); furthermore, interferon alfa prolonged median time to progression by approximately 6 months.14

A clinical trial in 101 patients with MM who had responded to conventional induction chemotherapy showed that maintenance therapy with interferon alfa, compared with no treatment, significantly improved duration of response (26 vs 14 months, respectively; P=.0002)15; median overall survival in the two groups was 52 vs 39 months, respectively (P=.0526).15 In a prospective randomized trial conducted by the Spanish Society of Hematology in 92 patients with MM who had responded to VCMP/VBAP (vincristine, cyclophosphamide, melphalan, prednisone/vincristine, carmustine, doxorubicin, prednisone) chemotherapy, median duration of response from time of randomization until relapse was 13 months in the interferon alfa group and 7.7 months in the no-treatment group (P=.042)16; median survival from time of randomization was 38.8 and 32.7 months, respectively (P=.12).16

A study conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) in 176 patients with MM who had responded to melphalan and prednisone found that interferon alfa maintenance therapy was associated with a statistically significant improvement in duration of response and overall survival, compared with no treatment12; however, maintenance therapy with interferon alfa also led to considerable toxicity that resulted in a dose reduction in 58% of patients and treatment discontinuation in 14% of patients.12 In two small studies—US Intergroup Trial S9321 (n=242) and SWOG 8624 (n=193)—no difference in progression-free survival (PFS) or overall survival was noted with interferon alfa maintenance therapy versus observation only in patients with MM who had attained a reduction in tumor burden of ≥75% after initial treatment.10,17

In general, interferon alfa has been associated with modest improvement in remission duration, and in a few studies, overall survival; however, this therapy has been associated with high toxicity and poor tolerability and, therefore, interferon maintenance is rarely used today.10,18,19



Corticosteroids as Maintenance Therapy
  

Several clinical trials have investigated the use of corticosteroids as maintenance therapy, but definitive conclusions cannot be drawn from the findings.9 SWOG 9210 was the first study to investigate the role of glucocorticoids used alone as maintenance therapy in MM.5 In the study, which compared two doses of alternate-day prednisone (10 mg vs 50 mg) as remission maintenance therapy in 126 patients with MM who had responded to induction therapy (either vincristine, doxorubicin, dexamethasone with prednisone [VAD-P] or VAD-P with quinine [VAD-P/Q]),5 median PFS was significantly longer with high-dose than low-dose prednisone (14 vs 5 months, respectively; P=.003), as was median overall survival (37 vs 26 months, respectively; P=.05).5 Adverse events were similar in the two treatment arms (ie, 13 patients experienced toxicity of ≥3 grade in each arm).5

In a randomized trial comparing dexamethasone versus interferon alfa as maintenance therapy in 84 patients who had responded to primary therapy with oral melphalan and intermittent high-dose dexamethasone, median remission was 10 months with both regimens, and side effects were rare and mild18; median survival from initiation of maintenance therapy was 52 and 58 months with interferon alfa and dexamethasone, respectively.18 In the NCIC CTG MY.7 study comparing dexamethasone versus observation as maintenance therapy in 292 patients with MM who had responded to induction therapy with melphalan plus dexamethasone or melphalan plus prednisone, median PFS was 2.8 versus 2.1 years, respectively (hazard ratio [HR] = 0.61; 95% confidence interval [CI], 0.47-0.79; P=.0002); however, no difference was observed in median overall survival (4.1 vs. 3.8 years, respectively; HR, 0.88; 95% CI, 0.65-1.18; P=.4).20

Combination maintenance therapy consisting of a glucocorticoid plus interferon alfa has been shown to improve both progression-free and overall survival in patients with MM compared with interferon alfa alone.5 In SWOG 9028—a study in 89 patients with MM who had attained complete or partial remission after VAD induction—PFS with prednisone plus interferon alfa versus interferon alfa alone was 19 and 9 months, respectively (P=.008); median survival was 57 and 46 months, respectively (P=.36).19 In general, maintenance therapy was well tolerated, and toxicity of ≤3 grade, which included malaise and leukopenia, was usually correlated with interferon alfa administration.19

Again, tolerability and toxicity have prevented widespread use of steroids as maintenance therapy. This, and the recent recognition of the negative impact steroids have in the newly diagnosed setting, especially in combination with novel agents, limits the use of steroids in myeloma therapy in general.10,18,19


Thalidomide as Maintenance Therapy
  
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...the use of thalidomide as induction therapy, as well as in relapsed and refractory MM, and summarize the rationale for its use as maintenance therapy.


2:33

Thalidomide was the first novel agent to be studied in the maintenance setting.9 In a recent meta-analysis of three randomized controlled trials, the use of thalidomide maintenance therapy following ASCT in patients with previously untreated MM was associated with a significant overall survival advantage (HR, 0.49; 95% CI, 0.32-0.74),21 but also an increased relative risk (RR) of venous thromboembolism (RR, 1.95; 95% CI, 1.15-3.30).21

Most studies investigating thalidomide maintenance therapy have focused on younger patients who have completed ASCT, a setting in which such therapy has led to improvement in PFS and mixed results with regard to overall survival (see Table 1).

In the Intergroupe Francophone du Myélome (IFM) 99-02 trial in 708 patients with MM (aged 65 years or younger) who were nonprogressing after high-dose therapy followed by double ASCT, maintenance therapy with pamidronate plus thalidomide led to a complete or very good partial response in 67% of patients, compared with rates of 55% and 57% in patients receiving no maintenance and pamidronate alone, respectively.1 Of interest, the benefit of thalidomide in terms of event-free survival was substantial in patients who did not have a deletion of chromosome 13; in contrast, thalidomide was not effective in patients who had a deletion of chromosome 13.1 The main adverse events associated with thalidomide included neuropathy (68%), fatigue (34%), and constipation (20%); adverse events led to discontinuation of thalidomide in 39% of patients.1

Table 1

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In another study—243 patients (median age, 57 years) who had achieved stable disease or better with induction chemotherapy, high-dose melphalan therapy, and ASCT—were assigned to either maintenance prednisolone only or maintenance prednisolone plus consolidation thalidomide.22 At median follow-up of 3 years, estimated PFS was 42% versus 23% in the thalidomide and control arms, respectively (P=.001),22 and estimated overall survival was 86% and 75%, respectively (P=.004).22

In the NCIC CTG MY.10 study, a randomized trial comparing daily thalidomide plus alternate-day prednisone (T/P) as maintenance therapy versus observation only following ASCT in 332 patients with MM (median age, 58 years), T/P did not significantly prolong overall survival (HR, 0.77; 95% CI, 0.53-1.13; P=.18); the 4-year overall survival rate was 68% and 60%, respectively.23 Although median PFS was significantly improved in the T/P versus observation-only arm (28 and 17 months, respectively; HR, 0.56; 95% CI, 0.43-0.73; P<.0001), grade 3/4 nonhematologic toxicity and common toxicities of all grades were higher with treatment; the 4-year PFS rate was 32% versus 14%, respectively.23

Another study investigated the efficacy of thalidomide as maintenance or salvage therapy versus no treatment in 112 patients with MM (median age, 53 years) who had undergone ASCT.24 Patients receiving thalidomide post-transplantation had improved median survival, compared with those in the no-treatment group (65.5 vs. 44.5 months, respectively; P=.09); additionally, overall survival was longer in patients who received thalidomide as maintenance therapy than as salvage therapy (65 vs. 54 months, respectively; P=.05).24

In contrast to the above randomized trials, where thalidomide was given after ASCT, the Total Therapy 2 (TT2) trial randomized newly diagnosed MM (n=668) to thalidomide upfront and through various stages of induction, tandem transplants, consolidation and maintenance; about 80% of the patients were younger than 65 years. At median follow-up of 42 months, complete response was 62% in patients receiving thalidomide and 43% in those not receiving thalidomide (P<.001); however, 5-year overall survival was about 65% in both study arms (P=.90). The incidence of severe peripheral neuropathy and deep vein thrombosis was higher in the thalidomide group than in the control group. Also of note, an update to the TT2 trial showed that thalidomide improved survival and duration of complete remission in patients with high-risk cytogenetics. At 7 years from onset of complete remission, 45% of patients with cytogenetic abnormalities who received thalidomide versus 20% of patients in the control arm remained relapse free (P=.05).25

The role of thalidomide as maintenance therapy in older patients who are ineligible for ASCT remains to be clearly elucidated.11 One recent study assessed the effect of thalidomide plus interferon alfa versus interferon alfa alone as maintenance therapy in 128 elderly patients with MM who had stable disease or better after induction therapy with either thalidomide plus dexamethasone or melphalan plus prednisolone.11 PFS was significantly longer in patients receiving thalidomide plus interferon alfa than interferon alfa alone (27.7 vs. 13.2 months; P=.0068)11; however, overall survival was similar in the two groups (52.6 vs. 51.4 months; P=.81) and did not differ between older and younger patients (P=.39).11

In a study in 103 elderly patients with MM who had achieved at least a minor response after conventional induction therapy with thalidomide, dexamethasone, and pegylated liposomal doxorubicin, PFS and overall survival were significantly better with thalidomide plus dexamethasone (TD) than interferon alfa plus dexamethasone (ID) maintenance therapy.6 Two-year PFS was 63% in patients in the TD arm versus 32% in the ID arm (P=.024); overall survival was 84% versus 68%, respectively (P=.030).6 Main adverse events were peripheral neuropathy and constipation in the TD arm and fatigue, anorexia, and hematological toxicity in the ID arm.6

Investigators have also studied the effectiveness and tolerability of different doses of thalidomide used as maintenance therapy. In a phase 2 study in 100 patients with nonprogressive MM investigating thalidomide maintenance therapy in five dose-escalating cohorts (ie, 50, 100, 200, 250, and 300 mg) after high-dose melphalan-based ASCT, dosage did not affect disease outcome, but had a substantial effect on toxicity.26 At median follow-up of 32.3 months, 77 patients had discontinued thalidomide because of side effects (n=53), disease progression (n=23), or financial reasons (n=1).26 The main toxicity, peripheral neuropathy, led to discontinuation of maintenance therapy in nearly one-third of patients.26 At 3 years, PFS and overall survival were 41% and 76%.26 Thalidomide maintenance doses >200 mg were mostly unattainable.26

A study in 31 patients with MM who were nonprogressing after ASCT examined the tolerability and efficacy of maintenance therapy with thalidomide, starting with 50 mg/day and escalating in 50-mg increments, as tolerated, to a maximum dose of 200 mg/day.27 At 1 and 2 years, complete or very good partial response was reported in 65% and 42% of patients, respectively27; median PFS was 20.8 months, and median overall survival was longer than 5 years.27 The median tolerated dose of thalidomide was 100 mg/day27; only 17 patients attained dosing at 200 mg/day.27 The main reason for intolerance to thalidomide was sensory neuropathy.27

A major limitation of thalidomide maintenance is the toxicity profile of the drug, as mentioned above, and its association with poor compliance. Lower doses of thalidomide are better tolerated and can be given for prolonged periods of time; however, data for differences between dose/duration and outcome are lacking.27 More importantly, with the recent data for lenalidomide in the maintenance setting, thalidomide is falling out of favor as a therapy for MM patients, as lenalidomide has demonstrated an acceptable tolerability and ease of long-term use.28


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...a short case study of a patient with MM who could potentially be a candidate for maintenance therapy.


1:30


Lenalidomide as Maintenance Therapy
  

Lenalidomide as maintenance therapy has been investigated in 3 key randomized phase 3 studies, 2 of which were for transplant-eligible patients (CALGB 100104 and IFM 2005-02) and produced results that led to a category 2A recommendation by the NCCN panel (see Table 2).3 The third trial, MM-015, included ASCT-ineligible patients.3

The first trial, CALGB 100104, compared maintenance lenalidomide (10 mg daily escalated to 15 after 3 months) versus placebo after ASCT in 460 patients (age, 70 years or younger) with stable disease or better and showed a median time to progression of 42.3 in lenalidomide-treated patients and 21.8 months in the placebo arms29,30; that resulted in unblinding of the results by the Data Safety Monitoring Committee (DSMC) and crossover for those receiving placebo.29,30 A recent update showed that lenalidomide was associated with a 61% reduction in risk of disease progression or death (estimated HR, 0.39; 95% CI, 0.27-0.56; P<.0001) at median post-ASCT follow-up of 17.5 months.29 Pooled grade 3 and higher adverse events attributed to lenalidomide included: thrombocytopenia (11% vs. 3%, respectively; P=.01), neutropenia (44% vs. 8%, respectively; P<.0001), anemia (5% vs. 1%, respectively; P=.0082), and all infections (16% vs. 3%, respectively, P<.0001).29


Table 2

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In the IFM 2005-02 trial, 614 patients with MM (age, younger than 65 years) who had nonprogressive disease after ASCT received consolidation therapy with lenalidomide (25 mg daily) for 2 months, followed by maintenance therapy with either lenalidomide (10-15 mg daily) or placebo.31,32 Median PFS from time of randomization and diagnosis was 24 and 34 months, respectively, in patients receiving placebo, compared with 42 and 52 months, respectively, in patients receiving lenalidomide maintenance therapy (HR = 0.5; P<10-8).32 The study was stopped by the DSMC, but with no crossover for placebo patients.32

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...the use of lenalidomide as maintenance therapy in MM.


1:14

The third trial, MM-015, from Italy, randomized 459 ASCT-ineligible patients with newly diagnosed MM (aged 65 years or older) to receive one of three regimens: (1) melphalan, prednisone, and lenalidomide (MPR) induction therapy followed by continuous lenalidomide maintenance therapy; (2) fixed duration MPR; or (3) fixed duration MP.33,34 Two-year PFS was 55% and 16% with MPR-R versus MP, respectively.34 Overall response rates with MPR followed by continuous lenalidomide maintenance therapy versus fixed duration MP were 77% and 50%, respectively (P<.001); complete response rates were 16% versus 4%, respectively (P<.001).34 In addition, overall risk of disease progression was reduced by 58% with MPR followed by continuous lenalidomide maintenance therapy versus fixed duration MP (HR, 0.423; P<.001), and 2-year PFS was 55% versus 16%, respectively.34 Grade 3/4 neutropenia, thrombocytopenia, and anemia were reported in 71%, 38%, and 24% of patients, respectively, receiving MPR followed by continuous lenalidomide maintenance therapy versus 30%, 14%, and 17% of patients, respectively, receiving fixed duration MP.34 All 3 trials have not matured enough to establish survival benefits for patients. Additionally, in all 3 trials, there was an increased risk of second cancers (Table 3) including breast, prostate, colon, as well as leukemia and Hodgkin and non-Hodgkin lymphomas in patients receiving lenalidomide compared with those on placebo.29-34



Table 3

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Bortezomib as Maintenance Therapy
  
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...the mechanism of action of bortezomib and compare its side effect profile with that of standard chemotherapeutic agents.


0:45

The use of the proteasome inhibitor bortezomib35,36 as maintenance therapy is currently under investigation in several clinical trials (see Table 4).3

In the US community-based, randomized, open-label, multicenter, phase 3b UPFRONT study, 300 elderly patients who were ineligible for high-dose therapy and ASCT were randomized to one of three bortezomib-based induction therapies (bortezomib-dexamethasone, bortezomib-thalidomide-dexamethasone, or bortezomib-melphalan-prednisone) followed by 5 cycles of bortezomib maintenance (bortezomib 1.6 mg/m2 days 1, 8, 15, and 22 of a 35-day cycle).37 After eight cycles of induction therapy, overall response in the bortezomib-dexamethasone, bortezomib-thalidomide-dexamethasone, and bortezomib-melphalan-prednisone groups was 68%, 78%, and 71%, respectively; after five cycles of bortezomib maintenance therapy, overall response increased to 71%, 79%, and 73%, respectively, with no increase in the frequency of peripheral neuropathy.37

Table 4

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The randomized phase 3 HOVON-65/GMMG-HD4 trial compared the efficacy of induction therapy with standard VAD followed by high-dose melphalan with ASCT and maintenance therapy with 50 mg daily of thalidomide for 2 years (arm A) versus induction therapy with bortezomib, doxorubicin, and dexamethasone followed by high-dose melphalan with ASCT and maintenance therapy with 1.3 mg/m2 of bortezomib twice weekly for 2 years (arm B) in 613 evaluable patients with newly diagnosed MM.38 Maintenance therapy was started by 67% of patients in arm A versus 57% of patients in arm B; protocol deviations occurred in 64% and 47% of patients, respectively, because of toxicity, progression, or other reasons.38 At 36 months, PFS was 42% in arm A and 46% in arm B.38

A randomized phase 3 study in 511 patients with MM (aged 65 years or older) who were ineligible for high-dose therapy plus ASCT found that treatment with bortezomib-melphalan-prednisone-thalidomide (VMPT) followed by maintenance therapy with bortezomib-thalidomide (VT) was superior to VMP without maintenance therapy.39 At 3 years, overall survival was 89% and 87% with VMPT followed by maintenance therapy with VT versus VMP without maintenance therapy (HR, 0.92; 95% CI, 0.53-1.60; P=.77)39; estimated 3-year PFS was 56% and 41%, respectively (HR, 0.67; CI, 0.50-0.90; P=.008).39 Grade 3 to 4 neutropenia occurred in 38% and 28% of patients receiving VMPT followed by maintenance VT versus VMP, respectively (P=.02).39

A prospective, multicenter, randomized trial recently investigated induction therapy with VMP versus VTP followed by maintenance therapy with VT versus VP in elderly patients (older than 65 years of age) with MM.40 In 143 evaluable patients after maintenance therapy, complete response in the VT and VP arms was 46% and 38%, respectively.40 The trend in terms of time to progression at median duration of maintenance therapy (13 months) favored the VT arm over the VP arm (84% vs. 71%, respectively; P=.05); 1-year overall survival was 92% versus 89%, respectively.40

In a study in 49 patients with advanced MM (median age, 71 years) who were responsive to salvage bortezomib-containing regimens and had measurable disease, the use of bortezomib plus dexamethasone as maintenance therapy was shown to be effective and well tolerated. Median time to progression was 17 months; at 1 year, PFS and overall survival were 61% and 79%, respectively.36 Three patients experienced grade 2 neuropathy, which led to bortezomib dose reduction; no grade 3 or 4 neuropathy or hematologic adverse events were reported.36

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...the rationale for the use of maintenance therapy in appropriate patients with MM.


1:28


The Use of Novel Agents as Consolidation Therapy
  

Consolidation therapy is maintenance given after induction therapy, but the doses are higher and are usually given for a defined period that varies from 4 cycles in one year to 2 intensive cycles over 2 months.

In a randomized phase 3 study in 474 newly diagnosed patients with MM, investigators compared VTD with TD as induction (three 21-day cycles) and consolidation therapy (two 35-day cycles) before and after double ASCT to analyze response after all phases of treatment and survival.1,3,41 The centrally reassessed complete response/near complete response rate was significantly higher in patients receiving VTD than TD after induction therapy (30% vs. 10%; P<.0001), double ASCT (54% vs. 42%, respectively; P=.008), and consolidation therapy (60% vs. 44%, respectively; P=.001).42 A per-protocol analysis in 323 patients showed that overall upgraded response with VTD and TD as consolidation therapy was observed in 55% versus 37% of patients, respectively (odds ratio, 1.15-3.77; P=.01).42 At median follow-up of 31 months, median PFS was 42 months in patients receiving TD and was not yet reached in those receiving VTD.42 Furthermore, a molecular substudy using qualitative and quantitative polymerase chain reaction analysis in 67 and 45 evaluable patients, respectively, showed that two 35-day cycles of VTD consolidation after double ASCT versus TD consolidation was associated with a significant increase in the rate of molecular remission and a significant reduction in the burden of residual myeloma cells.43

In another study—in 46 evaluable patients younger than age 65 years with de novo MM—early consolidation with VTD after thalidomide and/or bortezomib induction therapy improved response in nearly 40% of patients.44 Overall, consolidation therapy with two cycles of VTD, started within 3 months of ASCT, led to complete response in 36% of patients, complete response/near complete response in 68% of patients, and very good partial response in 91% of patients.44

Data from the open-label, phase 2 IFM 2008 study in 31 evaluable patients younger than age 65 years with newly diagnosed MM showed that induction therapy with bortezomib/lenalidomide/dexamethasone (VRD) followed by ASCT and VRD consolidation therapy yielded responses of high quality.45 After consolidation, stringent complete response was achieved in 5 patients, and complete response was achieved in 5 patients.45 The overall response rate after consolidation was 94%.45

A recent study assessing the prognostic implications of cumulative dosing and premature discontinuation of the components of VTD from the outset of protocol therapy into maintenance therapy supports the upfront usage of all active agents in a dose-dense and dose-intense manner, as in the Total Therapy 3 (TT3) protocol.46 In TT3, the addition of bortezomib, plus the shortening of induction and consolidation therapies to 2 cycles (from 4 cycles in TT2),47 led to superior outcomes.48



Summary
  

The role of maintenance therapy after conventional chemotherapy or high-dose therapy followed by ASCT in patients with MM is evolving.1,5,9,10 At present, clinical trials established improvement of PFS and, in many studies, OS with the use of thalidomide; the data for lenalidomide is immature to show OS difference, but established an impressive improvement of EFS.9 The addition of bortezomib in consolidation/limited maintenance therapy has shown improvement in the depth of response, including in many cases of molecular remission, which may establish a role for such intervention in eliminating minimal residual disease, a goal that is rarely obtained in MM patients.44

Additional studies are needed to determine optimal dose and duration of any maintenance therapy and to identify patients who would most benefit from such treatment. Additionally, more research is needed to determine the impact of such therapy on the pattern of relapse and the response to salvage therapy.9

The current NCCN recommendations for maintenance therapy in MM include interferon alfa (category 2B); corticosteroids (category 2B); thalidomide (category 1) with or without prednisone (category 2B); and lenalidomide (category 2A). All are rarely used today because of side effects, as they are replaced mostly by lenalidomide (category 2A).3 Use of the proteasome inhibitor bortezomib as maintenance therapy lacks a formal NCCN recommendation.3



References
  
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