Have drug combinations supplanted stem cell transplantation in myeloma?

Multiple myeloma (MM) is a plasma cell malignancy, accounting for 1% of all cancers and 10% of hematologic neoplasms. Incidence increases greatly with age: the median age at diagnosis is 70 years, with 35% of patients younger than 65 years.¹  In the Western countries, the annual age-adjusted incidence has reached 5.6 cases per 100 000 persons because of the aging of the general population. In the 1990s, treatment efficacy was improved by the use of autologous stem cell transplantation (ASCT) and subsequently by the introduction of proteasome inhibitors and immunomodulatory agents (IMiDs). In the last decade, survival of patients younger than 50 years with newly diagnosed MM has significantly improved, with 10-year survival rate increasing from 24.5% to 41.3%.²  However, MM is characterized by multiple relapses. Genomic instability and clonal heterogeneity cause the selection of more aggressive subclones responsible for drug resistance and finally dismal outcome.³  For these reasons, effective treatment should be concentrated at the early phases of disease, when clones are more drug sensitive, long-lasting remissions are more frequent, and serious adverse events are less prominent. This approach significantly improves quality of life and may ultimately prolong overall survival (OS).

The efficacy of treatment is mainly related to the achievement of a durable response. The achievement of a complete response (CR) is associated with prolongation of progression-free survival (PFS) and OS in both young and elderly patients.^4,5  Before the introduction of bortezomib and IMiDs, an analysis of 4990 patients with MM receiving ASCT, including 2991 patients in prospective studies, showed that patients achieving CR after transplantation had longer event-free survival (EFS) and OS compared with patients achieving partial response (PR) only: median OS was 59-88.6 months in patients with CR compared with 39-68 months in patients with PR (P < .001).⁴  Of note, a recent study reported that 35% of patients attaining CR were alive at 12 years after a median follow-up of 153 months.⁶  In the elderly patients treated with either conventional chemotherapy or combinations, including thalidomide or bortezomib, the achievement of CR confirmed to be an independent predictor of longer outcome: the 3-year OS rose from 67% in patients in PR to 91% in patients in CR (P < .001), regardless of age, International Staging System stage, and treatment received.⁵  Conventional chemotherapy, including thalidomide or bortezomib, has shown similar results to high-dose therapy and ASCT. In MM, CR is defined by negative serum and urine immunofixation, disappearance of any soft tissue plasmacytoma, and < 5% plasma cell on bone marrow examination. This definition has low sensitivity and is somehow inappropriate, because residual tumor is always present despite the achievement of CR. More sensitive techniques are now showing better correlation between a deeper response level and an improved outcome.^7,8  In patients with immunofixation-negative CR the 3-year PFS was 50% as opposed to 95% in patients with immunophenotypic CR (P = .02).⁷  However, even in patients with stringent, immunophenotypic, or molecular CR, late relapses occur, showing the need for adequate biomarkers to detect the eradication of the tumor clone in vivo. In a recent analysis, after a median follow-up of 65 months, the 6-year PFS was 46%, despite the previous achievement of a molecular CR. It is important not only to achieve CR but also to maintain a sustained CR. Patients with sustained CR for ≥ 3 years had a longer OS than patients who had unsustained CR (5-year OS, 82% vs 24%; P < .001).⁹  These data support a treatment strategy tailored to increase both CR rates and duration of response.

Excessive toxicities are the main cause of early discontinuation that significantly affect cumulative dose intensity and efficacy. In the Total Therapy 3 (TT3) program, the premature discontinuation of bortezomib increased the risk of progression by 6 times (P < .001).¹⁰  In the exploratory analysis of 134 patients receiving twice-weekly bortezomib compared with 369 patients on the once-weekly schedule, the twice-weekly bortezomib schedule resulted in a higher rate of nonhematologic grade 3-4 adverse events (51% vs 36%; P = .003), mainly peripheral neuropathy (16% vs 3%; P = .001). The twice-weekly schedule had a higher rate of discontinuation (15% vs 5%; P < .001), consequently the cumulative delivered dose of bortezomib was similar (40.1 mg/m² for twice-weekly schedule and 39.4 mg/m² for once-weekly schedule) and so was the 3-year PFS rate (47% vs 50%; P value is not significant).¹¹ 

Low-dose dexamethasone in combination with lenalidomide (Ld) reduced the frequency of adverse events and improved treatment adherence compared with high-dose dexamethasone with lenalidomide (LD): 30% of patients in the Ld group remained on treatment for > 1 year compared with 14% in the LD group. The 1-year OS was 96% for the Ld group compared with 87% for the LD group (P < .001).¹²  In a randomized trial, the cumulative dose intensity of the combination melphalan-prednisone-lenalidomide followed by lenalidomide maintenance (MPL-L) was 88% in patients younger than 75 years but only 56% in those older than 75 years, with a negative effect on median PFS.¹³  These data clearly show the need to avoid excessive toxicities, to reduce discontinuation rate to < 20%, and to maintain cumulative dose intensity to ≥ 80%, delivering the appropriate treatment to the appropriate patient subgroups.

Before the introduction of bortezomib and IMiDs, a meta-analysis performed on 9 randomized trials confirmed a PFS benefit with upfront ASCT in comparison with conventional chemotherapy combinations.¹⁴  Three randomized studies showed that OS was similar whether ASCT was done early or as salvage therapy at relapse.¹⁵  Interestingly, in one trial early ASCT improved median EFS (39 vs 13 months), as well as the average time without symptoms (27.8 vs 22.3 months) compared with late ASCT, but OS was unchanged (64.6 vs 64 months). The early approach was also associated with lower rate of relapse, reduced treatment-related toxicities, and discontinuation. Another trial detected no significant PFS improvement with early ASCT (42 vs 33 months; P = .57) and suggested that the greatest benefit from early ASCT was among patients with disease refractory to induction therapy.¹⁵ 

In elderly patients with newly diagnosed MM, the combination melphalan-prednisone-thalidomide (MPT) was compared with an intermediate-dose melphalan 100 mg/m² (Mel 100) followed by ASCT.¹⁶  The MPT regimen significantly reduced the risk of progression by 46% (P < .001) and the risk of death by 31% (P = .027). This study questioned the role of ASCT in the era of bortezomib and IMiDs. In recent years the efficacy of both ASCT and combination chemotherapy has been improved by the introduction of more effective induction, consolidation, and maintenance schedules that prolong duration of response.

Bortezomib-dexamethasone (BD) induction regimen significantly increased CR/near CR (nCR) rate after ASCT (39.5%) in comparison with dexamethasone-vincristine-adriamicyn (VAD; 39.5% vs 22.5%; P < .001; Table 1).¹⁷  However, the PFS improvement induced by BD was modest (36 vs 29.7 months; P = .064). Better results were obtained with 3-drug combinations.^18,20,30,31  The addition of cytotoxic drugs such as doxorubicin or cyclophosphamide to both thalidomide (TAD, CTD)^30,31  or bortezomib (PAD, BCD)^18,20  improved response rate. The TAD regimen prolonged PFS in comparison with VAD (34 vs 22 months; P < .001), whereas the PFS induced by CTD was similar to cyclophosphamide-VAD (median, 27 vs 25 months; P = .59). The regimen of BCD led to 70% CR/nCR rate after ASCT.²⁰  The combination of PAD significantly improved PFS compared with VAD (35 vs 28 months; P = .002).¹⁸  The combination of bortezomib and IMiDs has shown similar results.^21,32  Bortezomib-thalidomide-dexamethasone (BTD) was superior to thalidomide-dexamethasone (TD).²¹  The CR/nCR rate was increased with BTD induction compared with TD (55% vs 41%; P = .002) and so was also the 3-year PFS (68% vs 56%; P < .006).^21,32  Grade 3-4 neuropathy was higher with BTD (10% vs 2%; P < .001). The TT program consisted of induction, consolidation with combination chemotherapy plus thalidomide (TT2) or bortezomib (TT3), and double ASCT. In the TT3 program the cumulative frequency of CR increased with time and reached 56% at 2 years, with a 5-year EFS of 69%.^10,22 

In several studies, the double ASCT extended PFS in comparison with single ASCT, but OS benefit was found in only 2 of them.³³  The role of the double ASCT is being questioned by the availability of novel effective combinations, although it is currently recommended in patients who fail to achieve VGPR or better after the first ASCT. In a recent study, tandem ASCT improved OS in comparison with single ASCT (5-year OS, 70% vs 55%; P = .03), the treatment regimen included PAD as induction and bortezomib or thalidomide as maintenance; unfortunately, the tandem versus single ASCT option was not randomized and only depended on insurance reimbursement.¹⁸  Consolidation with bortezomib and IMiDs is currently under evaluation. BTD consolidation increased CR from 15% to 49% in patients who achieved VGPR after double ASCT.⁸  Recently, the role of BTD versus TD consolidation after double ASCT was assessed. BTD consolidation increased the CR/nCR rate from 63% to 73%, but 3-year PFS was marginally improved (60% vs 48%; P = .042).³²  Four cycles of lenalidomide-prednisone have been adopted as consolidation after double ASCT; this approach increased the CR rate from 38% to 66%.

After ASCT, thalidomide maintenance therapy improved the quality of response and increased PFS. In a recent meta-analysis, maintenance therapy with thalidomide reduced both the risk of progression (36%) and death (27%).³⁴  However a significant rate of grade 3-4 polineuropathy (7%-19%) was reported, and the rate of discontinuation reached 52.2%.³⁵  Median time on therapy was ∼ 1 year.³⁶  The role of lenalidomide maintenance after ASCT was assessed.^27,28  In one study, lenalidomide reduced the risk of progression by 50% (P < .001), whereas OS was similar to the placebo group (P = .29).²⁷  In another study, lenalidomide reduced the risk of progressive disease by 52% (P < .001) and the risk of death by 38% (P < .03; Figure 1A-B).²⁸  In both studies, the most frequent grade 3-4 adverse events were neutropenia (45%-51%) and infections (1%-13%), and a higher incidence of second primary cancers in the lenalidomide arm was detected (7.8%-8.5% at 3 years; Table 2). Despite the high toxicities associated with this approach, a PFS improvement was detected. Median time on treatment was ∼ 2 years. Data on single-agent bortezomib maintenance are available in one trial only. Patients who were randomly assigned to PAD or VAD induction followed by ASCT received bortezomib or thalidomide as maintenance therapy, respectively. Bortezomib maintenance significantly improved CR/nCR, from 31% to 49%, and reduced the risk of progression on a landmark analysis (P = .04). With bortezomib maintenance, grade 3-4 peripheral neuropathy was 5% and grade 3-4 infections were 24%. The median time on therapy was ∼ 2 years in the bortezomib group and 1 year in the thalidomide group.¹⁸ 

The 3-drug combinations, such as BCD, BTD, or BRD inductions, improved response rate. These results might be further improved with the introduction of novel proteasome inhibitors as shown by the combination of carfilzomib-lenalidomide-dexamethasone. The role of the second ASCT has been questioned and is currently limited to patients who do not reach VGPR after a single ASCT. Future trials to assess the role of single versus double ASCT are warranted. Consolidation with BTD improved CR rates and PFS, but data are limited and randomized studies for consolidation regimens are lacking. Maintenance therapy with IMiDs reduced the risk of progression by ∼ 50%. In patients aged 65-75 years, PAD induction followed by tandem Mel 100, ASCT, lenalidomide-prednisone consolidation, and lenalidomide maintenance induced a CR rate of 40%, 3-year PFS of 66%, and 3-year OS of 85%.¹⁹  Overall, the available data show that effective induction, consolidation, and maintenance therapy have greatly improved the efficacy of high-dose therapy and ASCT. With these approaches the CR/nCR rates are ranging from 36% to 70%, the 5-year PFS from 62% to 69%, and the 5-year OS from 61% to 72%.

A meta-analysis of the 6 randomized controlled trials that compared MPT with MP showed that MPT improved both PFS and OS of ∼ 6 months.²³  Peripheral neuropathy (6%-23%) and venous thromboembolism (3%-12%) were the main adverse events associated with thalidomide. The combination bortezomib-melphalan-prednisone (BMP) improved the median time to next therapy by 8 months (P < .001) and reduced the risk of death by 32% in comparison with MP.²⁴  Grade 3-4 peripheral neuropathy was 13%.

BMP plus thalidomide followed by bortezomib-thalidomide maintenance (BMPT-BT) was compared with BMP alone. BMPT-BT significantly increased the CR rate (38% vs 24%; P < .001) and prolonged the 3-year PFS (56% vs 41%; P = .008), but the 3-year OS was similar (89% vs 87%; P = .77).¹¹  The median PFS for BMPT-BT was 37.2 months. Thalidomide did not increase the hematologic toxicity of BMP, and the weekly dose of bortezomib plus 50 mg/d thalidomide did not increase the risk of grade 3-4 peripheral neuropathy (4%). In another study BTP versus BMP inductions were followed by BT or bortezomib-prednisone (BP) maintenance. From start of maintenance, the median PFS was 32 months for patients receiving BT and 24 months for those receiving BP (P = .1).²⁹ 

In a randomized phase 2 study, bortezomib-lenalidomide-dexamethasone (BLD), bortezomib-cyclophosphamide-dexamethasone (BCD) or bortezomib-cyclophosphamide-lenalidomide-dexamethasone (BCLD) was tested. The regimens were equally effective; CR rate was 24% with BLD, 22% with BCD, and 25% with BCLD, and the corresponding 1-year PFS was 83%, 93%, and 86%, respectively. BCLD increased the frequency of hematologic toxicities and the discontinuation rate (21%); the excessive toxicities did probably reduce the efficacy of the 4-drug combination.³⁷  In another study, BLD induced 100% at least PR, including 37% of CRs; the 1.5-year PFS rate was 75% and the 1.5-year OS rate was 97%; the frequency of grade 3-4 neuropathy was 3%.²⁵ 

MPL-L prolonged the median PFS of 17 months in comparison with MPL and MP alone (31 vs 14 vs 13 months; P < .001).¹³  The 3-year OS was similar (70% vs 62% vs 66%). The most common adverse events were hematologic, with grade 4 neutropenia reported in 35% and 32% patients in the MPL-L and MPL groups, respectively. The 3-year rate of second primary cancers was 7% with MPL-L.

The combination of the new proteasome inhibitor carfilzomib with lenalidomide and low-dose dexamethasone was effective and well tolerated. Responses were rapid, with 46 of 49 patients achieving PR after 1 cycle; after 4 cycles, the PR rate was 100%; after 12 cycles, the VGPR rate was 100%, including 79% CR/nCR. No overlapping toxicities were recorded, with no grade 3-4 peripheral neuropathy.²⁶ 

In conclusion, MPT or BMP has improved median PFS of ∼ 6-8 months in comparison with MP. The latest 3- or 4-drug combinations, and particularly maintenance therapy, have further prolonged PFS approximately by another 10-17 months. OS advantage will require longer follow-up to be clearly assessed. Drug combinations, including proteasome inhibitors and IMiDs, have led to at least PR of 100% and high rates of CRs (24%-38%). Maintenance therapy with bortezomib or lenalidomide induced a median PFS of ∼ 31-37 months and 3-year OS of ∼ 70%-89% (Figure 1C-D). Despite these improvements and the difficult comparison of studies conducted in patients younger than 65 years versus studies conducted in patients older than 65 years, ASCT still seems to add clinical value to current induction, consolidation, and maintenance regimens.

In a retrospective analysis, OS was evaluated in patients receiving lenalidomide-dexamethasone followed by ASCT or lenalidomide-dexamethasone as continuous treatment, the 3-year OS was 94% in patients receiving early ASCT and 78% in those receiving lenalidomide-dexamethasone. Although this trial was not designed to assess early ASCT versus drug combination, OS with early ASCT appeared to be superior.³⁸  In a posthoc landmark analysis of 53 patients who received BLD induction at diagnosis, PFS was unchanged in patients treated with early ASCT or continuous treatment (P = .38).²⁵  In a retrospective analysis of 290 patients who received early versus delayed ASCT after IMiD-based initial therapy, the 4-year OS rate was 73% in both groups (P = .03).³⁹ 

In the first prospective randomized trial, patients received Ld induction therapy and were then randomly assigned to tandem ASCT or MPL. After a median follow-up of 26 months, the CR rate was 25% for ASCT and 20% for MPL (P = .49). ASCT reduced the risk of progression by ∼ 50% (P < .001). The 2-year PFS was 73% for ASCT and 54% for MPL. The 2-year OS was comparable in the 2 groups (90% vs 87%; P = .19).⁴⁰  In a similar study, 390 patients received Ld induction regimen and were then randomly assigned to receive tandem ASCT or cyclophosphamide-lenalidomide-dexamethasone, followed by lenalidomide maintenance therapy. Patient accrual was completed in May 2011, and preliminary data should be available soon (NCT01091831 at www.clinicaltrials.gov).

Two ongoing large studies are currently enrolling patients. The IFM/DFCI2009 study addresses the question of whether high-dose therapy and ASCT or conventional chemotherapy should be preferred. In this trial 1000 patients are receiving BLD induction and are then randomly assigned to continue BLD treatment or to receive ASCT plus BLD consolidation. Afterward, the role of fixed-duration maintenance therapy will be investigated, and patients will receive lenalidomide maintenance for 1 year (NCT01191060 and NCT01208662 at www.clinicaltrials.gov). The EMN02 study not only aims to compare ASCT with conventional chemotherapy, but it also investigates the role of second ASCT and the advantages associated with consolidation therapy after transplantation. In this study, 1500 patients are receiving BCD induction and are then randomly assigned to BMP or ASCT and further randomly assigned to receive consolidation or no consolidation with BLD. The benefits of maintenance therapy will be assessed as well, but, compared with the previous study, patients will receive lenalidomide maintenance until disease progression (NCT01208766 at www.clinicaltrials.gov).

The introduction of effective regimens, including bortezomib and IMiDs, has greatly improved the outcome observed with ASCT in young patients with MM. The achievement of CR is an independent predictor of prolonged PFS and OS. Despite the improvement reported with conventional chemotherapy plus IMiDs, ASCT remains a necessary component of therapy to attain CR and consequently superior PFS. The data from prospective trials performed so far suggest that the best available strategy to achieve high CR rates and to prolong their duration includes induction with 3-drug bortezomib-based combinations followed by ASCT and consolidation/maintenance with IMiDs. This sequential approach seems the most appropriate strategy to upgrade response and prolong survival. Longer follow-up is needed to evaluate whether the timing of ASCT is relevant for OS. Results from ongoing large collaborative studies that compare effective drug combinations with stem cell transplantation are awaited and will shed further light on this important clinical question.

The authors thank the editorial assistant Giorgio Schirripa.

Contribution: A.P. and F.C. collected and analyzed the data and wrote the manuscript.

Conflict-of-interest disclosure: A.P. has received honoraria from Celgene, Janssen-Cilag, Bristol-Myers Squibb, Millennium, Merck, and Onyx and has served on the advisory boards of Celgene and Janssen-Cilag. F.C. has received honoraria from Celgene, Janssen-Cilag, and Onyx and has served on the advisory committee of Celgene.

Correspondence: Antonio Palumbo, Divisione di Ematologia dell'Università di Torino, Azienda Ospedaliera S. Giovanni Battista, Via Genova 3, 10126 Torino, Italy; e-mail: appalumbo@yahoo.com.