Multiple myeloma (MM) is a neoplasm typical of the elderly, with median age at diagnosis of 70 years, and approximately 65% of patients older than 65 years. Many advances have been made thanks to the use of autologous hematopoietic stem cell transplantation (AHSCT) and the introduction of the immunomodulatory drugs and the proteasome inhibitors. Incorporation of novel agents into induction has resulted in improved overall survival. Optimal MM maintenance therapy should maintain or increase response after induction and, when possible, AHSCT. Optimal maintenance therapy must be effective with minimal toxicity and should be easily administered.
Key points
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Maintenance therapy with novel agents prolonged remission duration in both transplant-ineligible and transplant-eligible patients with multiple myeloma.
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The appropriate maintenance strategy should be not only effective but also well tolerated.
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In transplant-ineligible patients, single-agent thalidomide or lenalidomide showed positive results after thalidomide-based and lenalidomide-based induction therapies, respectively. Bortezomib in association with thalidomide is also a valid strategy.
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In transplant-eligible patients, single-agent thalidomide resulted in improved progression-free survival (PFS) but was not well tolerated and in high-risk cytogenetic patients may lead to inferior survival, whereas bortezomib as part of induction and maintenance improves PFS in all patients and overall survival in patients with the del 17 cytogenetic abnormality and those who present in renal failure.
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In transplant-eligible patients, single-agent lenalidomide is effective as demonstrated in improved PFS and, in 2 of 3 studies, in improved OS.
Introduction
Multiple myeloma (MM) is a neoplasm typical of the elderly, with median age at diagnosis of 70 years, and approximately 65% of patients older than 65 years. Many advances have been made thanks to the use of autologous hematopoietic stem cell transplantation (AHSCT) and the introduction of the immunomodulatory drugs and the proteasome inhibitors. Incorporation of novel agents into induction has resulted in improved overall survival (OS) over the past decade. Indeed, in a large group of 2981 patients with newly diagnosed MM, OS significantly improved from 29.9 to 44.8 months in patients diagnosed in the last decade ( P <.001). The agents that have most impacted on progression-free survival (PFS) and OS are thalidomide, lenalidomide, and bortezomib. The alkylating agent cyclophosphamide, in combination with bortezomib and dexamethasone generated comparable deep responses to bortezomib, lenalidomide, and dexamethasone in a phase 2 study. These combination induction regimens improve the overall response and the depth of response by increasing the percentage of patients achieving complete responses (CR). Many MM patients will have disease progression or relapse and die of MM within 10 years of the initiation of therapy. Thus, there is a pressing need for improved induction regimens and for strategies to control disease with the long-term goal of cure. Of note, sequential approaches consisting of induction followed by consolidation and maintenance with novel agents have been recently tested with the attempt of improving the clinical benefit of current treatments. Consolidation improves responses after induction therapy (and transplantation when applicable), and maintenance further delays relapse/progression with the ultimate goal of improving OS. Consolidation consists of 2 to 4 cycles of combination therapies and maintenance of continuous therapy, usually with single agents, until disease progression. Maintenance therapy is suggested for both transplant-ineligible patients (usually elderly patients 65 years of age and over) and transplant-eligible ones (patients younger than 65 years of age). However, no specific guidelines are available, and the optimal duration of maintenance remains to be established.
Optimal MM maintenance therapy should maintain or increase response after induction and, when possible, AHSCT. Maintenance therapy should be easily given (preferably orally) and, if administered intravenously, convenient for the patient. Because of the lack of long-term efficacy and tolerability, agents such as melphalan, interferon-α, and glucocorticoids have not become widely used for maintenance. Newer agents are more attractive as maintenance therapies because of improved efficacy and better tolerability. Most maintenance studies have used thalidomide and, more recently, bortezomib and lenalidomide. Different studies have assessed the benefits associated with maintenance treatment incorporating thalidomide, lenalidomide, and bortezomib, yet no clinical study has directly compared the advantages of one approach over the other. Despite the benefits associated with continuous novel-agent–based therapy, prolonged exposure to new drugs may increase toxicities and cause treatment discontinuation. Therefore, the optimal maintenance therapy must be effective with minimal toxicity and should be easily administered.
Introduction
Multiple myeloma (MM) is a neoplasm typical of the elderly, with median age at diagnosis of 70 years, and approximately 65% of patients older than 65 years. Many advances have been made thanks to the use of autologous hematopoietic stem cell transplantation (AHSCT) and the introduction of the immunomodulatory drugs and the proteasome inhibitors. Incorporation of novel agents into induction has resulted in improved overall survival (OS) over the past decade. Indeed, in a large group of 2981 patients with newly diagnosed MM, OS significantly improved from 29.9 to 44.8 months in patients diagnosed in the last decade ( P <.001). The agents that have most impacted on progression-free survival (PFS) and OS are thalidomide, lenalidomide, and bortezomib. The alkylating agent cyclophosphamide, in combination with bortezomib and dexamethasone generated comparable deep responses to bortezomib, lenalidomide, and dexamethasone in a phase 2 study. These combination induction regimens improve the overall response and the depth of response by increasing the percentage of patients achieving complete responses (CR). Many MM patients will have disease progression or relapse and die of MM within 10 years of the initiation of therapy. Thus, there is a pressing need for improved induction regimens and for strategies to control disease with the long-term goal of cure. Of note, sequential approaches consisting of induction followed by consolidation and maintenance with novel agents have been recently tested with the attempt of improving the clinical benefit of current treatments. Consolidation improves responses after induction therapy (and transplantation when applicable), and maintenance further delays relapse/progression with the ultimate goal of improving OS. Consolidation consists of 2 to 4 cycles of combination therapies and maintenance of continuous therapy, usually with single agents, until disease progression. Maintenance therapy is suggested for both transplant-ineligible patients (usually elderly patients 65 years of age and over) and transplant-eligible ones (patients younger than 65 years of age). However, no specific guidelines are available, and the optimal duration of maintenance remains to be established.
Optimal MM maintenance therapy should maintain or increase response after induction and, when possible, AHSCT. Maintenance therapy should be easily given (preferably orally) and, if administered intravenously, convenient for the patient. Because of the lack of long-term efficacy and tolerability, agents such as melphalan, interferon-α, and glucocorticoids have not become widely used for maintenance. Newer agents are more attractive as maintenance therapies because of improved efficacy and better tolerability. Most maintenance studies have used thalidomide and, more recently, bortezomib and lenalidomide. Different studies have assessed the benefits associated with maintenance treatment incorporating thalidomide, lenalidomide, and bortezomib, yet no clinical study has directly compared the advantages of one approach over the other. Despite the benefits associated with continuous novel-agent–based therapy, prolonged exposure to new drugs may increase toxicities and cause treatment discontinuation. Therefore, the optimal maintenance therapy must be effective with minimal toxicity and should be easily administered.
Maintenance approaches for patients ineligible for transplantation
Patients 65 years of age and older do not tolerate intensive therapy and are usually ineligible for high-dose melphalan (MEL200; melphalan 200 mg/m 2 ) and AHSCT. For these patients, gentler strategies should be used. Combinations with novel agents, such as thalidomide, lenalidomide, and bortezomib, are widely adopted, for both newly diagnosed and relapsed patients with MM. In the 1970s, maintenance treatment of this subset of patients consisted of prolonging chemotherapy after successful induction treatment with melphalan-prednisone (MP). Other attempts of maintenance therapies consisted of using single-agent interferon.
Thalidomide
Thalidomide can be a suitable option for prolonged use because of the oral administration. Nevertheless, the neurologic toxicity associated with this drug is a major concern and should be carefully considered. To date, continuous thalidomide after melphalan-prednisone-thalidomide (MPT) induction has been evaluated in 4 trials ( Table 1 ). In one study, 100 mg/d thalidomide was given continuously. The median PFS was 25 months for patients who received thalidomide and 15 months for those who did not ( P <.001). The median OS was 48 months and 45 months for the 2 arms, respectively ( P = .79). The incidence of grade 3 to 4 neurologic toxicity was 10% in patients receiving thalidomide therapy and 1% in those receiving no maintenance. In another study, thalidomide was administered at 200 mg/d at induction and was reduced to 50 mg/d during maintenance. The median event-free survival (EFS) time was 13 months for patients who received thalidomide and 9 months for those who did not ( P <.001). A marginally significant OS advantage favoring thalidomide maintenance was also detected, with a median of 40 months versus 31 months ( P = .05). The incidence of grade 3 to 4 neurologic toxicities was particularly higher with thalidomide (23%) than no thalidomide (4%). In another study, thalidomide at a dose of 200 mg/d was administered continuously until relapse. The median PFS (15 months vs 14 months, P = .84) and OS (29 months vs 32 months, P = .16) was similar between patients who received thalidomide and those who did not. The incidence of grade 3 to 4 peripheral neuropathy was quite low in both arms, 6% versus 1%, respectively. These findings support the concept that thalidomide maintenance should be administered at the minimal effective dose associated with the lowest toxicity (50–100 mg/d) to avoid early discontinuation.
| Drug | Study | Schedule | Response | Median PFS/TTP/EFS | Median OS | Previous Induction |
|---|---|---|---|---|---|---|
| Thalidomide | Palumbo et al, 2006, 2008 | T: 100 mg/d until relapse | 16% CR | 22 mo | 45 mo | MPT |
| Wijermans et al, 2010 | T: 50 mg/d until relapse | 23% ≥VGPR | 13 mo | 40 mo | MPT | |
| Waage et al, 2010 | T: 200 mg/d until progression | 13% CR | 15 mo | 29 mo | MPT | |
| Beksac et al, 2011 | T: 100 mg/d until relapse | 9% CR | 21 mo | 26 mo | MPT | |
| Ludwig et al, 2010 | T: 200 mg/d until progression or intolerance; I: 3 Mega units 3 times a wk | — | 28 mo | 53 mo | MP or TD | |
| Morgan et al, 2012 | T: 50 mg/d increased to 100 mg/d after 4 cycles (if tolerated) until progression | — | 23 mo | — | MP or CTDa | |
| Lenalidomide | Palumbo et al, 2012 | R: 10 mg day 1–21 until disease progression | 33% ≥VGPR | 31 mo | 70% @ 36 mo | MPR |
| Gay et al, 2013 | R: 25 mg d 1–21; P: 50 mg qod for four 28-d cycles followed by | 48% CR | 48 mo | 63% @ 60 mo | PAD-MEL100 a | |
| R: 25 mg days 1–21 until disease progression | 53% CR | |||||
| Bortezomib | Mateos et al, 2010 | V: 1.3 mg/m 2 twice weekly, on days 1, 4, 8, 11, every 3 mo; P: 50 mg qod for up to 3 y | 39% CR | 32 mo | — | VMP or VTP |
| Mateos et al, 2010 | V: 1.3 mg/m 2 twice weekly, on days 1, 4, 8, 11, every 3 mo; T: 50 mg/d for up to 3 y | 44% CR | 24 mo | — | VMP or VTP | |
| Palumbo et al, 2014 | V: 1.3 mg/m 2 every 14 d; T: 50 mg/d for 2 y | 42% CR b | 56% @ 36 mo | 61% @ 60 mo | VMPT |
a Treatment approach incorporating transplantation before consolidation and maintenance, enrolling patients 65–75 years.
b By exploratory analysis performed on the 82 patients treated with VMPT induction who received at least 6 months of maintenance with VT.
Another randomized trial assessed the role of thalidomide-interferon or interferon alone as maintenance therapy after induction with either thalidomide-dexamethasone (TD) or MP. The median PFS was 28 months for patients who received thalidomide maintenance and 13 months for those who received interferon alone ( P = .007). The median OS was similar in the 2 groups (53 months vs 51 months, P = .81). The rate of grade 3 to 4 neuropathy was 7% versus 0%, respectively ( P = .002). Finally, in another study, a total of 820 patients, both eligible and ineligible for AHSCT, were randomized to thalidomide maintenance or no maintenance. Patients ineligible for AHSCT had received MP or cyclophosphamide-TD induction. In these patients, thalidomide maintenance improved PFS (23 vs 15 months, P <.001), and the advantage was more evident in patients who had received thalidomide also at induction. The median OS was not significantly different between the 2 arms ( P = .40). In patients with adverse interphase Fluorescence In Situ Hybridization (iFISH), thalidomide maintenance had a negative impact on OS ( P = .009).
All the studies including thalidomide maintenance reported an improvement in terms of PFS, although longer follow-up is needed to detect an OS benefit. The risk of peripheral neuropathy after long-term thalidomide exposure is a major limitation to its routine use. To avoid excessive neurologic toxicity and consequently treatment discontinuation, the preferred dose of thalidomide maintenance should range between 50 and 100 mg/d. In case of occurrence of grade 3 to 4 neurotoxicity, it is highly recommended to temporarily interrupt treatment until resolution to at least grade 1; otherwise treatment should be stopped.
Lenalidomide
Lenalidomide, similarly to thalidomide, is administered orally and has the additional advantage of lower neurologic toxicity.
A phase 3 study evaluated the role of lenalidomide at 10 mg on days 1–21 of each 28-day cycle after melphalan-prednisone-lenalidomide (MPR-R) versus MPR versus MP. The median PFS was 31 months with MPR-R, 14 months with MPR, and 13 months with MP. In a landmark analysis from start of lenalidomide maintenance, lenalidomide after MPR significantly prolonged the median PFS from 7 to 26 months ( P <.001). No particular advantage was seen in terms of OS, and the 4-year OS was approximately 58% in the 3 treatment groups. One of the major toxicities associated with lenalidomide is neutropenia, which was reported in 7% of patients in the MPR-R arm. Some concerns about the increased risk of second primary malignancies (SPM) with prolonged exposure to lenalidomide were raised. In this study, the rate of SPM was 7% for both MPR-R and MPR, and 3% for MP. Nevertheless, the benefits associated with lenalidomide treatment outweigh the increased risk of SPM. A recent meta-analysis on 3218 patients found that patients treated with lenalidomide had an increased risk of developing hematologic SPM (hazard ratio [HR] 1.55; P = .037). Of note, the risk was increased when lenalidomide was given with melphalan compared with melphalan alone (HR 4.86; P <.0001), whereas exposure to lenalidomide plus cyclophosphamide (HR 1.26; P = .75) or lenalidomide plus dexamethasone (HR 0.86; P = .76) did not increase hematologic SPM risk versus melphalan alone. Thus, the use of alternative alkylating agents can be a possible option.
A phase 2 study evaluated a sequential approach consisting of lenalidomide-prednisone (RP) induction followed by MPR consolidation and subsequent RP maintenance (lenalidomide 10 mg/d on days 1–21 of each 28-day cycle; prednisone 25 mg 3 times/wk). Median age was 75 years; 59% of patients had at least one comorbidity and 35% at least 2 comorbidities. Median PFS was 18.4 months and 2-year OS was 80%. Grade 4 neutropenia occurred in 12% of patients. Therefore, this study demonstrated that the addition of prednisone increases the efficacy of lenalidomide alone in unfit elderly MM patients, with the advantage of a low toxicity and consequently improved quality of life.
A recent large phase 3 study compared lenalidomide plus low-dose dexamethasone (Rd) until relapse versus Rd for 18 cycles (72 weeks) versus MPT for 12 cycles (72 weeks). Median age was 73 years. After a median follow-up of 37 months, Rd significantly improved PFS compared with MPT (HR 0.72; P = .00006) and marginally OS (HR 0.78, P = .01685). Relevant grade 3 to 4 adverse events with Rd until relapse versus MPT were neutropenia (28% vs 45%), thrombocytopenia (8% vs 11%), febrile neutropenia (1% vs 3%), infection (29% vs 17%), neuropathy (5% vs 15%), and deep vein thrombosis (5% vs 3%). The respective incidence of hematologic SPM was 0.4% versus 2.2%; the overall incidence of solid tumors was identical (2.8%). These results suggest the need for prolonging therapy until progression, because outcome after 18 cycles of therapy was similar between Rd and MPT. Continuous Rd is therefore a valid option in transplant-ineligible patients and may be preferred to the standard MPT with no maintenance.
Although elderly patients are usually not able to tolerate MEL200 and AHSCT, reduced intensity transplantation with melphalan 100 mg/m 2 (MEL100) can be safely adopted for fit elderly patients. A phase 2 study assessed bortezomib-adriamycin-dexamethasone (PAD) induction followed by tandem MEL100, AHSCT, RP consolidation, and lenalidomide maintenance in patients aged 65 to 75 years. This approach induced a median PFS of 48 months and a 5-year OS of 63%. Consolidation and maintenance with lenalidomide considerably increased responses, mostly in subjects who had achieved a very good partial response after transplantation. During consolidation and maintenance, the main toxicities were hematologic; in particular, neutropenia (19% after consolidation and 23% after maintenance) and thrombocytopenia (15% after consolidation and 3% after maintenance).
Based on the data available, lenalidomide seems to be the most suitable choice for maintenance and can be preferred to thalidomide because of the higher efficacy and the lack of neurologic toxicity.
Bortezomib
Bortezomib is another possible option as maintenance therapy. Peripheral neuropathy associated with this drug may be a limitation, yet its incidence is lower than that reported with thalidomide.
In one study, bortezomib plus either thalidomide (VT) or prednisone (VP) was given after induction with either VMP or bortezomib-thalidomide-prednisone. The median PFS was longer with VT (32 months) than VP (24 months), yet this difference was not statistically significant ( P = .1). No OS advantage favoring one of the 2 options was detected, and the incidence of peripheral neuropathy was slightly higher with VT (7%) than VP (2%).
In another study, bortezomib-melphalan-prednisone-thalidomide (VMPT) induction followed by VT maintenance (VMPT-VT) was compared with VMP followed by no maintenance. VT consisted of bortezomib at 1.3 mg/m 2 every 15 days and thalidomide at 50 mg per day for 2 years or until progression or relapse. The median PFS was significantly longer with VMPT-VT (35.3 months) than with VMP (24.8 months; HR 0.58; P <.001). The 5-year OS was greater with VMPT-VT (61%) than with VMP (51%; HR 0.70; P = .01). Of note, the use of once-weekly bortezomib instead of twice-weekly administration seemed to be an appropriate strategy to improve tolerability and decrease discontinuation. During the maintenance phase with VT, the incidence of new or worsened grade 3 to 4 toxicities was low (less than 5%). Grade 3 to 4 neutropenia was reported in 4 patients (3%), peripheral neuropathy in 6 patients (4%), and cardiologic adverse events in 2 patients (1%).
Another study assessed the role of bortezomib alone as maintenance therapy (1.6 mg/m 2 , days 1, 8, 15, 22 for five 35-day cycles) after induction with bortezomib-dexamethasone (VD), bortezomib-thalidomide-dexamethasone (VTD), or VMP. The median PFS was 14.7 months with VD, 15.4 months with VTD, and 17.3 months with VMP. The respective median OS was 49.8, 51.5, and 53.1 months. Grade 3 to 4 adverse events were lower with VD (78%) than VTD (87%) and VMP (83%). Bortezomib maintenance was associated with limited additional toxicity compared with induction.
A recent study evaluated the role of a sequential strategy with VMP followed by Rd versus the same regimens in an alternating approach. A total of 18 cycles was planned for both approaches. After a median follow-up of 12 months, the 18-month time to progression was 83% with the sequential strategy and 89% with the alternating approach. A trend in favor of the alternating approach was seen in patients with a high-risk cytogenetics profile (84% vs 94%). The respective 18-month OS was 83% and 93%. Nevertheless, the difference between the 2 options was not statistically significant. Hematologic toxicities were lower in the sequential strategy (neutropenia: 16% vs 23%; thrombocytopenia: 16% vs 20%). Nonhematologic toxicities were low, with infections being the most common (5% vs 4%, respectively). Both the sequential and the alternating approaches proved to be feasible and well tolerated.
In conclusion, bortezomib induces a lower rate of peripheral neuropathy than thalidomide, and maintenance with VT is effective and safe in patients ineligible for MEL200 and AHSCT. The lack of SPM and the possibility of the subcutaneous administration make bortezomib an advantageous strategy for maintenance. Although combining 2 agents associated with a potential risk of neurotoxicity can be a concern, the use of reduced dose intensities makes VT a valid maintenance option. Alternating VMP and Rd is an appealing option, particularly in high-risk patients, but further investigation is needed.
Maintenance approaches for patients eligible for transplantation
The paradigm in 2014 for transplant-eligible patients consists of induction, stem-cell mobilization, AHSCT, followed by consolidation, and/or maintenance. Recent studies have demonstrated improved outcomes in transplant-eligible patients receiving maintenance therapy, and new approaches to consolidation and maintenance are currently being investigated for transplant-eligible patients. This portion of the review focuses on maintenance therapy following AHSCT for transplant-eligible MM patients.
Thalidomide
The maintenance thalidomide studies resulted in improved EFS or PFS with OS that were improved, no different from maintenance, or worse for selected high-risk patients ( Table 2 ). Four phase 3 studies looked at thalidomide maintenance until progression (see Table 2 ). The Intergroupe Francophone du Myelome (IFM) randomized 400 patients after AHSCT to thalidomide versus no maintenance and demonstrated an improved 3-year EFS (52% vs 37%, P <.009) and an improved 4-year OS (87% vs 75%, P <.04). A US single-institution study from the Arkansas group demonstrated a significant benefit for thalidomide versus no thalidomide maintenance. The 5-year EFS was 64% for thalidomide and 43% for no maintenance ( P <.001), and the 8-year OS was 57% for thalidomide versus 44% for no maintenance ( P = .09). A Stichting Hemato-Oncologie voor Volwassensen Nederland (Dutch-Belgian Cooperative Trial Group for Hematology Oncology; HOVON) compared thalidomide and interferon-α maintenance and demonstrated that thalidomide improved the median EFS (34 vs 22 months, P <.001) and resulted in a nonsignificant increase in median OS (73 vs 60 months, P = .77). The Medical Research Council of the United Kingdom (MRC UK) Myeloma IX study examined intensive (transplant) and nonintensive (nontransplant) approaches for the treatment of newly diagnosed MM patients. For the transplant arm, thalidomide maintenance resulted in a median PFS of 22 months versus 15 months for the no-maintenance arm ( P <.0001). The median OS was 60 months in both groups ( P = .70). The median PFS benefit due to thalidomide maintenance was seen only in the patients with low-risk cytogenetics analyses at diagnosis (29 vs 18 months, P = .01) but without OS benefit. For patients with high-risk cytogenetic analyses, the OS was inferior for patients receiving thalidomide maintenance when compared with no maintenance (35 vs 47 months, P = .01).
| Study | Number of Patients | Initial Dose, mg | Maintenance vs No Maintenance | |
|---|---|---|---|---|
| EFS or PFS | OS | |||
| Attal et al, 2006 | 597 | 400 | 3-y EFS 52 vs 37% ( P <.009) | 4-y OS 87 vs 75% ( P <.04) |
| Barlogie et al, 2008 | 668 | 400 | 5-y EFS 64 vs 43% ( P <.001) | 8-y OS 57 vs 44% ( P = .09) |
| Lokhorst et al. | 556 | 50 | Median EFS 43 vs 22 mo ( P <.001) | Median OS 73 vs 60 mo ( P = .77) |
| Morgan et al. 2012, 2013 | 820 a | 50 | Median PFS (HSCT) 30 vs 23 mo ( P = .003) | 3 y OS 75 vs 80% ( P = .26) |
| Spencer et al, 2009 | 243 | 200 and prednisolone | 3-y PFS 42 vs 23% ( P <.001) | 3-y OS 86 vs 75% ( P = .004) |
| Krishnan et al, 2011 | 436 b | 200 and dexamethasone | 3 y PFS 49 vs 43% ( P = .08) | 3 y OS 80 vs 81% ( P = .817) |
| Maiolino et al, 2012 | 108 | 200 and dexamethasone | 2 y PFS 64 vs 30% ( P = .002) | 2 y OS 85 vs 70% ( P = .27) |
| Stewart et al, 2013 | 332 | 200 and prednisone | 4 y PFS 32 vs 14% ( P <.0001) | 4 y OS 68 vs 60 ( P = .18) |
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