Abstract

Survival rates of young patients with myeloma have increased markedly in the last decade, mainly due to the use of autologous stem cell transplantation (ASCT) and new, highly efficient rescue treatments. In order to improve the survival of newly diagnosed young patients further, the next steps need to focus on increasing the activity of upfront or debulking regimens, improving the efficacy of ASCT, mainly through the conditioning regimen, and increasing the duration of responses through more effective maintenance or consolidation therapies. Nevertheless, this approach is being challenged by the favorable results obtained with long-term treatment with novel agents and the possibility of reserving the ASCT until relapse. Allogeneic transplantation in newly diagnosed patients should be considered as an investigational procedure and used only in well-designed clinical trials. This review covers the new strategies that are currently under investigation with the aim of optimizing the outcome for newly diagnosed young patients with myeloma.

By the term “young myeloma patient” we understand not only people younger than 65 or 70 years old, but also those fit enough (that is, without severe comorbidities) to be able to endure intensive treatments and the inconveniences of some intravenous (IV) or repetitive therapies. What should the aim of treatment be in these patients? Ideally it should be to provide a cure or at least ensure long-term survival (> 10 or 20 years) with good quality of life. Achieving such a goal implies the eradication, or at least a major reduction, of the tumor cell clone in most patients. Here we review the current data concerning the treatment of newly diagnosed young patients with myeloma. For this purpose we have divided the discussion into three phases, each with its particular burning question: (1) Induction treatment phase: what is the optimal induction regimen? (2) Intensification phase with autologous stem cell transplantation (ASCT): should ASCT be used upfront or at the time of relapse? and (3) Maintenance or consolidation phase: do we have enough reliable data with which to make general recommendations? We will also address the role of allogeneic transplant and the treatment of high-risk patients, and, first of all, try to shed some light into the controversial matter of determining the value of complete response (CR) as a treatment endpoint.

Should CR Be a Treatment Endpoint?

There is a large body of evidence showing an association between optimal response to ASCT therapy and long-term outcomes such as progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma (MM).1,2 This association is not so well established for elderly patients mainly because in the era of melphalan-prednisone (MP) few patients achieved CR. However, the current definition of CR in MM is far from optimal since it is based only on the disappearance of the monoclonal component by immunofixation and the presence of fewer than 5% plasma cells in bone marrow (BM); the incorporation of new criteria, such as the normal free light chain ratio and the absence of clonal plasma cells by immunohistochemistry (stringent CR), though representing a step forward, has not greatly increased its low sensitivity.3 In order to improve the assessment of treatment efficacy at the BM level, more sensitive tools are currently being investigated. These include multiparametric flow cytometry and RT-PCR, which may help to define immunophenotypic and molecular remission, respectively. These techniques can detect a single clonal cell among between 10−4 and 10−5 normal cells, which is a sensitivity at least two orders of magnitude greater than that of immunohistochemistry. Nevertheless, it is important to understand that, in contrast to acute leukemia, the BM pattern of infiltration in MM is not uniform; therefore, negative results from immunophenotyping or molecular techniques do not rule out the possibility that residual tumor cells are present at another BM location. In spite of this drawback, recent data indicate that these new tools are more sensitive and provide more accurate prognostic information than the conventional CR definition.4,5 Another limitation of these BM investigations is the occurrence of extramedullary relapses, which is an emerging problem that is probably associated with the prolonged survival of MM patients and the capacity of plasma cells to escape the BM milieu. Accordingly, the use of imaging techniques, such as magnetic resonance imaging (MRI) and computed tomography–positron emission tomography (CT-PET) with (18F)2-fluoro-2-deoxy-D-glucose (PET-FDG), should be investigated in order to detect residual disease outside the BM.6,7 Once the patient achieves CR, this must be lasting; in fact, duration of CR is the best predictor of OS.8 Finally, it is important to emphasize that the prognostic impact of CR should only be evaluated within uniformly treated cohorts of patients, since differences in treatment duration and the use of consolidation or maintenance therapies may greatly modify the value of CR. For example, it is well established that maintenance treatment in acute lymphocytic leukaemia (ALL) or non-Hodgkin lymphoma (NHL) has a marked impact on the duration of CR and, eventually, on the probability of cure.

Despite these observations about the value of CR and how its assessment might be improved, it should be noted that within an apparently uniform diagnosis of myeloma, together with a large group of patients who may represent two thirds of all MMs, and whose quality of response is clearly associated with survival, three other small subgroups can be distinguished on the basis of their response pattern: (1) rapidly responding but early relapsing. This pattern is also observed in other hematological malignancies such as NHL, and these patients probably harbor distinct genotypic features that would require a different treatment approach; (2) non-responding, non-progressive patients; and (3) those that revert to an MGUS profile after treatment. The final goal would be the design of “risk-adapted” treatment strategies for these singular patient subgroups.9 Thus, while rapidly responding but early relapsing patients may benefit from intensive-sequential therapy, those developing a monoclonal gammopathy of unknown significance (MGUS) profile and non-responding, non-progressing patients should probably not be over-treated. An additional treatment endpoint is to pay more attention to the individual response obtained with each line of therapy in order to avoid using consolidation or maintenance approaches with drugs that had low efficacy in that particular patient during previous treatment phases.

Induction Treatment: Will Novel Drug Combinations Replace the VAD Regimen?

For the answer to this question to be affirmative, novel drug combinations would need to demonstrate higher efficacy than VAD (vincristine, adriamycin, dexamethasone), in terms of response rate, both before and after ASCT, and this must also result in the prolongation of PFS. However, we do not think it would be so easy to demonstrate the impact on OS, since the heterogeneity of treatments at relapse precludes statistically sound analysis.

The VAD combination has long been the gold standard as a preparatory regimen for young patients who are candidates for ASCT. The efficacy of VAD results in a partial response (PR) rate of 52% to 63%, with 3% to 13% CR rates. The new alternative debulking treatment strategies are based on thalidomide, lenalidomide and bortezomib in combination with well-established anti-myeloma agents such as dexamethasone, adriamycin and cyclophosphamide, or even the combination of two novel agents plus corticosteroids. The results so far obtained with these regimens will be discussed in detail in the next paragraphs.

Thalidomide-based Induction Regimens

The use of thalidomide plus dexamethasone (TD) has been extensively studied (Table 1 ), and several pilot studies have shown 48% to 80% ≥ PR, including CR rates of 4% to 16%. Rajkumar et al10 compared TD with dexamethasone alone in two randomized phase III studies and both showed a significantly superior results for the TD arm. As shown in Table 1 , TD also proved to be superior to VAD as an induction regimen.11 Two other randomized trials showed that the addition of adriamycin to TD (TAD)12 or thalidomide to VAD (T-VAD) resulted in an increase in the response rate (RR) (72% and 81%, respectively) that was significantly greater than that obtained with VAD (54% and 66%, respectively). The CR rate was relatively low (4%–7%) in these two studies, but the CR plus very good PR (VGPR) was 32% and 38%, respectively, which are significantly higher values than those obtained with VAD (15% and 19%, respectively). The British group has compared cyclophosphamide + TD (CTD) with cyclophosphamide + VAD (CVAD) as induction regimens before transplant, and found the thalidomide arm to be significantly superior, with RRs of 87% and 75%, including 19% and 9% CR, for CTD and CVAD, respectively.13 

To define the current role of novel agents as induction regimens, it is important to determine whether the apparent initial benefit is maintained after ASCT. In the study of Macro et al, which compared TD and VAD, the difference in VGPR was no longer evident following ASCT (44% vs 42%). In the Hovon study of TAD vs VAD,12 the benefit in favor of TAD remained after ASCT when considering the VGPR rate (49% vs 32%; P = .01) but not for the CR rate (16% vs 11%). This translates into a superior PFS for TAD-compared with VAD-treated patients (33 vs 25 months, respectively; P < .001) but a similar OS (59 vs 62 months). Finally, in the UK trial, the CR rate after transplant also remained favourable for the thalidomide arm (51% vs 40% for CTD vs CVAD, respectively; P = .08).

The most relevant thalidomide-related side effects are peripheral neuropathy and deep venous thrombosis (DVT). Peripheral neuropathy (12%–17% of patients) limits the dose and duration of treatment.12,14 The overall incidence of DVT ranged from 8% to 23%, and the greatest risk of its occurrence is when thalidomide is combined with chemotherapy, especially with adriamycin. Accordingly, in this setting, anticoagulant prophylaxis with low molecular weight heparin (LMWH) or aspirin is mandatory. Warfarin has been considered as an alternative in DVT risk-reduction strategies. However, therapeutic-dose warfarin is associated with an increased risk of severe hemorrhage, as well as reduced effectiveness in cancer patients receiving chemotherapy. In contrast, low-dose warfarin may not be efficacious in this setting.

Lenalidomide-based Induction Regimens

Lenalidomide is also undergoing first-line evaluation, although the information is more scarce (Table 1 ). Two large randomized trials, one conducted by ECOG15 and the other by SWOG, have shown that the majority of patients respond to induction with lenalidomide plus dexamethasone (RR of 82 and 85% with a CR rate of 4% and 22%, respectively). In the ECOG trial, 90 of the initial 431 patients went off therapy after the initial 4 cycles and received an ASCT; information about CR rate after ASCT is not available, but the 3-year OS of this cohort of patients was 92% (Rajkumar SV et al, personal communication). Niesvizky et al,16 in a pilot study of 72 patients, showed that the combination of lenalidomide plus dexamethasone plus clarithromycin was associated with an RR of 90%, including 41% CR (most of which qualified as stringent CR), although after 4 to 6 cycles the CR rate was in the range of 5% to 10%. In this study, 30 patients underwent ASCT and achieved a median EFS of 37 months. Finally, lenalidomide plus dexamethasone has been combined with cyclophosphamide in a dose-finding pilot study that produced a RR of 83% (Table 1 ).

With respect to toxicity, lenalidomide is better tolerated than thalidomide from several perspectives: it does not usually produce clinically significant somnolence, constipation or neuropathy, although the incidence of myelosuppression is higher, mainly neutropenia and thrombocytopenia, which are manageable with dose reduction and growth factor support. Lenalidomide is also associated with risk of DVT and anticoagulant prophylaxis with LMWH or aspirin is also mandatory.

Bortezomib-based Induction Regimens

Numerous phase II clinical trials have been designed to assess the activity of bortezomib-based combinations as frontline therapy in transplant candidate patients. As shown in Table 1 , the RR ranges from 60% to 95% with 10% to 32% CRs. In all these pilot studies the CR markedly increased after transplant (31%–54%). Results from two large phase III randomized trials have recently been reported. The IFM trial compared bortezomib plus dexamethasone with VAD.17 After 4 cycles the RR with bortezomib plus dexamethasone was significantly higher than that with VAD (82% vs 65%, including 15% vs 7% CR/nCR) and this benefit remained after transplant (CR/nCR: 40% vs 22%). A significant prolongation of PFS had already been observed for bortezomib plus dexamethasone relative to the VAD arm (69% vs 60% at 2 years, respectively; P < .01), although no significant differences in OS have been detected so far. This trial also explored the value of two consolidation DCEP cycles before ASCT, and concluded that this strategy apparently has no benefit since the CR rate did not increase. The Hovon group is currently comparing the combination of bortezomib plus adriamycin and dexamethasone (PAD) vs VAD. The bortezomib arm induced a significantly higher VGPR rate (42% vs 15%) but few CRs (5% vs 1%); nevertheless, the CR significantly increased after transplant, particularly in the PAD arm (23% vs 9% P < .001).18 

The most frequent side effects of bortezomib included gastrointestinal symptoms, cyclical thrombocytopenia and, in particular, peripheral neuropathy. This latter side effect is less frequent in newly diagnosed patients (6%–7%) than reported in previously treated patients, probably because only 3 or 5 cycles are administered as induction therapy.

Bortezomib in Combination with Thalidomide or Lenalidomide

Several pilot studies have explored the feasibility and efficacy of the combination of bortezomib with thalidomide (Table 1 ) in untreated MM patients. The high and rapid response rate (88%–92% ≥ PR, with 18%–22% CR) prompted the design of phase III trials. Thus, the Italian group compared bortezomib plus thalidomide and dexamethasone (VTD) with thalidomide-dexamethasone (TD) and again found the first option to be significantly superior both before ASCT (RR: 94% vs 79% with 32% vs 12% CR/nCR) and after ASCT (55% vs 32% CR/nCR; P < .001).19 In addition this translated into a significantly longer PFS (90% vs 80% at 2 years for VTD vs TD, respectively; P < .009), but no significant differences in OS have yet been observed (96 vs 91% at 2 years). The Spanish group has performed a similar comparison (VTD vs TD), but in addition a third arm, based on chemotherapy (VBCMP/VBAD plus bortezomib), was included in the trial.20 Preliminary results indicate that the TD arm is inferior to the two others in terms of CR rate both before (30%, 6%, 20%) and after (49%, 34%, 43%) ASCT.

The combination of bortezomib with lenalidomide and dexamethasone has also been investigated in a phase I/II trial in which 68 patients were enrolled. All patients responded, including 74% ≥ VGPR and 44% CR/nCR. Moreover, responses were independent of cytogenetics and toxicities were manageable with an incidence of only 3% of grade 3 peripheral neuropathy and DVT. Kumar et al have explored the same combination but with the addition of cyclophosphamide in 25 patients; all responded with 20% of stringent CR plus additional 16% of CR (Table 1 ).21 Taken together, these data suggest that the upfront combination of a proteasome inhibitor plus one immunomodulatory drug (IMID) is highly effective, although longer follow-up is needed to define the effect on survival and, in particular, to exclude the possibility of inducing more resistant relapses or to burn out drugs that could be very valuable at relapse.

These data lead us to conclude that VAD is no longer the gold-standard induction regimen. TD is probably suboptimal and higher response rates could be achieved if adriamycin or cyclophosphamide were added to TD. A similar possibility may exist for Len-based induction regimens. Bortezomib-dexamethasone +/− thalidomide has proved to be highly effective as a debulking treatment and is significantly superior to VAD or TD before and after ASCT. A similar pattern would be expected for bortezomib + lenalidomide + dexamethasone.

Rationale for Autologous Stem Cell Transplantation

High-dose therapy (HDT) (usually based on melphalan 200 mg/m2) followed by ASCT prolonged OS as compared with standard-dose therapy (SDT) in prospective randomized trials conducted by the French (IFM) and English (MRC) groups and has provided evidence for longer than 10-year survivorship in at least a subset of patients.22,23 Nevertheless, the US (SWOG 9321) and French (MAG91) studies and the Spanish (PETHEMA-94) trial, though confirming the benefit of ASCT in terms of RR and event-free survival (EFS), found no greater OS than with SDT24,26 (Table 2 ). These discrepancies can at least be partly explained by differences in (1) the study designs (the Spanish study randomized only patients who responded to initial therapy while randomization was performed upfront in the others), (2) in the conditioning regimens and, particularly, and (3) the intensity and duration of the chemotherapy arm (the dose of alkylating agents and steroids were higher in the SWOG and Spanish trials, which may explain why OS for conventionally treated patients was longer in these two studies than in the IFM and MRC trials).

In spite of these discrepancies, ASCT is currently considered to be the standard care for younger patients with multiple myeloma, mainly because of its low treatment mortality rate (1%–2%), the benefit in response rate, and, particularly in EFS, which ranges between 25 and 42 months, representing a prolongation of 9 to 12 months compared with conventional chemotherapy. Moreover, soon after ASCT, patients enjoy an excellent quality of life with a long treatment-free interval, which also makes ASCT a cost-effective therapy. In fact, compared with the cost of novel agents, ASCT is no longer an expensive treatment.

Unfortunately, efforts directed towards improving the efficacy of the conditioning regimen have been very limited, and melphalan 200 mg/m2 (Mel200) continues to be the gold standard. Nevertheless, unpublished data from the Spanish group suggest that the combination of melphalan and busulfan (particularly in its IV formulation) may be superior to Mel200. In addition, the possibility of adding new agents (such as bortezomib) to the conditioning regimen is also under investigation. The IFM Group conducted a pilot study of Mel200 plus Bz (1 mg/m2 on days −6, −3, +1, +4).27 Three months after ASCT, 70% of patients achieved VGPR or better, including 34% with CR. Kaufman et al conducted another pilot study of Mel200 plus Bz, administered as a single dose 24 hours before or after Mel200.28 The VGPR rate was 53% and the PR rate was 94%.

When considering novel agents it is also important to determine whether ASCT enhances the high response rates already obtained with these new induction regimens. As mentioned above, studies with bortezomib-based combinations, including four randomized trials,17,20 as well as data from thalidomide (TAD regimen)12 and probably from Len,15,16 indicated an improved CR rate following ASCT (Table 1 ), which already translates into prolonged PFS. These data imply that induction with novel agents and ASCT are complementary rather than alternative treatment approaches.

The use of tandem ASCT will decrease for two reasons. First, according to the experience of the IFM and Italian groups, only patients achieving less than a VGPR with the first transplant benefit from the second29,30 (Table 2 ). Second, a similar benefit accrues when using thalidomide as a consolidation/maintenance therapy.31,32 Moreover, a second transplant at relapse may be performed increasingly often, providing that the duration of the response to the first transplant has lasted for more than 2 or 3 years.

Autologous Stem Cell Transplantation Upfront or at the Time of Relapse?

The favorable results obtained with long-term treatment with novel combinations (for example, the 79% 3-year OS for patients treated with Len-Dex beyond 4 cycles)15 are challenging the role of upfront ASCT. In fact, one of the current major debates surrounding the treatment of young MM patients concerns whether to use high-dose chemotherapy followed by ASCT upfront or to reserve this treatment until relapse. In other words, the debate is between a more intensive approach with an induction debulking scheme (3–6 cycles) followed by ASCT plus the possibility of a consolidation treatment or a more gentle approach based on an optimized treatment with novel agents until relapse or disease progression occurs, at which time ASCT would be performed. Several groups are currently evaluating these two approaches and it is hoped that these randomized trials will clarify the utility of ASCT.

The “total therapy (TT) programs” are the opposite of the “gentle approach.” In TT2, the addition of thalidomide to induction therapy and its use in consolidation and maintenance therapy produced a significantly higher rate of CR compared with that in patients not receiving thalidomide (62% vs 43%) and a significantly greater 5-year EFS rate (56% vs 45%).33 Although there were no significant differences in the 8-year OS rate, a significant survival advantage was apparent among the group of patients who had cytogenetic abnormalities (46% vs 27%). Overall post-relapse survival was significantly shorter in the group of patients who were randomly assigned to receive thalidomide than in those of the control group, whereas this was not the case among the patients with cytogenetic abnormalities.34 In the TT 3 program the addition of bortezomib to the previous TT2 approach yielded a higher CR rate (63%), sustained at 4 years from response onset in 87%, with a 4-year estimated OS and EFS of 78% and 71%, respectively. The superiority of the TT3 program over its predecessor, TT2, was also noted in the low-risk subgroup of patients; nevertheless, in the high-risk MM group, outcomes also remained poor with TT3. Based on these results, the Arkansas group has developed a gene-expression profile (GEP)-risk-based algorithm for assigning separate therapies to good-risk (TT4) and poor-risk (TT5) MM.35 

Maintenance or Consolidation Treatment

Maintenance treatment with interferon and/or corticosteroids has been employed for many years after ASCT. Two extensive meta-analyses showed a median prolongation of both PFS and OS of 4 to 8 months for patients receiving interferon maintenance. However, this approach has been abandoned due to its side effects and what was considered to be only a modest survival advantage. The availability of novel agents (particularly those in oral formulations: thalidomide and lenalidomide) has renewed the concept of maintenance in an attempt to prolong the duration of the responses after transplant. The IFM group was the first to show that thalidomide as maintenance after tandem ASCT was superior to no maintenance or pamidronate alone,31 and the Australian group obtained similar results upon comparing thalidomide (for 12 months) plus prednisone (until progression) with prednisone alone.32 In total, 3 of 5 randomized trials showed a benefit in PFS and OS with thalidomide maintenance (Table 3 ). In spite of these positive results there are several caveats that currently preclude a general recommendation about maintenance with thalidomide outside of clinical trials. Thus, although the Australian trial indicated that maintenance for only one year did not adversely affect the outcome after relapse, two studies33,35 suggested that the long-term use of thalidomide may induce more resistant relapses. Moreover, the benefit of thalidomide maintenance to patients with poor cytogenetics is not well established. Thus, while the French group found no benefit to patients with 13q deletion31 and the MMRC found a negative influence of thalidomide treatment in patients with 17p,36 the TT2 program revealed a survival advantage for patients with abnormal cytogenetics.34 Finally, there is no consensus about the benefit to patients who are already in CR. Considering all this information together, maintenance with thalidomide could only currently be recommended for less than 12 months and for patients who do not achieve CR after ASCT. The more favorable toxicity profile of lenalidomide makes it an ideal maintenance agent and has prompted several ongoing trials designed to compare continuous treatment until relapse with non-maintenance or treatment for only a short period after ASCT.

The alternative would be to use 3 or 4 courses of consolidation therapy after ASCT. The Italian group showed that the combination of Bz-T-Dex upgraded the responses obtained with ASCT (36% converted from VGPR to CR and 22% became PCR-negative).37 The Hovon group is currently investigating the role of bortezomib, given every 15 days after ASCT; preliminary results suggest an improvement in CR rate from 23% to 37%.18 

Allogeneic Transplantation

Allogeneic transplantation (Allo-trx) offers the possibility of a curative approach in MM patients. However, it is associated with high transplant-related mortality (TRM) of up to 30%–50%) and morbidity (mainly due to chronic graft-versus-host disease). Accordingly, it should be only used in carefully defined situations and, preferably, in the context of clinical trials. In order to decrease TRM, various reduced-intensity conditioning regimens (RIC) have been developed (mainly based on fludarabine and melphalan or fludarabine plus radiotherapy [2 Gy]). With this approach the TRM decreased to 12% to 25% but this was associated with a higher incidence of relapses. To try to overcome this problem, several tandem “auto-allo” programs, summarized in Table 4 , have been employed. In a prospective randomized trial, the French group compared double ASCT with ASCT followed by Allo-RIC among patients displaying poor prognostic features [high β2-microglobulin and del(13q)]. Unfortunately, there were no event-free survivors at 5 years either after double ASCT or after ASCT followed by Allo-RIC.38 By contrast, the Italian group described an improvement in terms of OS among patients receiving ASCT followed by Allo-RIC compared with double autologous transplant.39 The Spanish group recently reported on a similar comparison but in patients failing to achieve at least near-complete remission (nCR) after a first ASCT. Although there was a greater increase in CR rate and a trend towards a longer PFS in favor of Allo-RIC, this was associated with a trend towards a higher TRM (16% vs 5%, P = .07), and there were no statistically significant differences in EFS and OS.40 The Hovon group found these two approaches equivalent,41 while recent results from an EBMT study showed a significant advantage of the Allo-RIC approach, whereby at 6 years the PFS was 36% and 15% and the OS was 65% and 50% for the Allo-RIC and double Auto groups, respectively.42 

Differences in patient characteristics, graft-versus-host disease prophylaxis and conditioning regimens may help to explain these discrepant results. An emerging problem with Allo-RIC is the large proportion of patients who develop extramedullary relapses without bone marrow involvement, indicating that although the disease may be under control in the bone marrow milieu, extramedullary spread may occur. Regarding the use of Allo-trx as rescue therapy, CR or a VGPR is a prerequisite for transplantation, since otherwise patients with active disease will not benefit from this procedure. Once again, these transplants should be performed by experienced groups and within clinical trials. Donor lymphocyte infusions (DLI) given for relapsed myeloma following allogeneic transplantation induce responses in 30% to 50% of patients, but unfortunately the long-term efficacy is limited. Interestingly, the combination of DLI with thalidomide, lenalidomide or bortezomib may improve the response rate and contribute to modulate the immune response, although further studies are required to confirm this.

In summary, due to the high morbidity and mortality incurred, Allo-trx should still be considered as an investigational approach and performed in well-controlled trials. Our current policy is not to use it upfront but at relapse in high-risk patients (including early relapses after ASCT), providing the disease is under control before the allo-transplant is performed.

Can Novel Drugs Overcome the Adverse Prognosis of the High-risk Patients?

We could include several cohorts of patients in the high-risk category: (1) those with poor cytogenetics (particularly p53(17p13), t(4;14); t(14;16) or complex karyotype), (2) those with early disease progression under induction therapy, and (3) those presenting with plasma cell leukemia. Recent data indicate that bortezomib combinations can overcome the adverse prognosis of the aforementioned cytogenetic abnormalities.17,19,20 Nevertheless, both the number of patients with these signatures and their follow-up is still very short. As far as thalidomide is concerned, as previously discussed in the maintenance section, the results are contradictory, since while the TT2 program developed by the Arkansas group suggests that its use throughout the entire treatment programme mainly favors patients with cytogenetic abnormalities,34 the data from IFM and MMRC suggest no benefit from thalidomide treatment,31,36 and in the HOVON study patients with del(13q) detected by FISH or conventional karyotyping, had not different outcome. Lenalidomide apparently also overcomes the prognostic influence of del(13q), t(4;14) but not that of 17p deletion.9 On the basis of these data we would not at this time propose a risk-stratification programme for these patients, but we would favor enrolling them in large clinical trials providing that these include one or two novel agents (particularly bortezomib) plus corticosteroids and/or one alkylating agent. Combinations such as Bz-T-Dex, Bz-Len-Dex or Bz-Len-Dex+ cyclophosphamide are very attractive.

A second possibility, for patients with specific genetic lesions, is to include them in experimental pilot studies in which a targeted therapy (such as FGFR kinase inhibitors in t(4;14) or cyclin-dependent kinase inhibitors) is added to a scheme such as VRD. A third possibility for these patients, particularly those with primary refractory disease, would be to add novel drugs with a complementary mechanism of action (eg, proteasome inhibitors and/or IMIDs plus Hsp90 or HDAC inhibitors). If CR or VGPR is achieved, patients should be exposed to high-dose therapy (ASCT) or to the experimental possibility of a tandem ASCT plus Allo-trx with a reduced-intensity conditioning regimen (Allo-RIC). However, we must emphasize that the choice of option should be made in the context of controlled clinical trials.9 

Table 1.

Results of novel agent-based combinations used as induction therapy: responses before and after autologous stem cell transplantation (ASCT).

Pre-trxPost-trx
Treatment schedulePtsPR (%)CR +nCR (%)PR (%)CR + nCR (%)Reference
*Including VGPR 
**4-year OS after 4 cycles and trx: 92% in both arms 
†Median EFS for patients receiving trx after Len-Dex clarithromycin: 37 months 
Trx indicates transplantation; PR, partial response; CR, complete response; nCR, near CR; Thal, thalidomide; Len, lenalidomide; Dex, dexamethasone; Cy, cyclophosphamide; Bz, bortezomid; Doxil, doxorubicin; VAD, vincristine, adriamycin, dexamethasone; TAD, thalidomide, adriamycin, dexamethasone; CTD, cyclophosphamide, thalidomide, dexamethasone; CVAD, cyclophosphamide, VAD; VBCMP, vincristine, bleomycin, chlorambucil, melphalan, prednisone; VBAD, vincristine, bleomycin, adriamycin, dexamethasone; DTPACE, cisplatin, cyclophosphamide, dexamethasone, doxorubicin, etoposide, thalidomide. 
Thalidomide-based combinations 
    Thal-Dex vs Dex 207 63 vs 41 – – – Rajkumar V et al. J Clin Oncol. 2006;24:431–436 
    Thal-Dex vs Dex 470 63 vs 46 7.7 vs 2.6 – – Rajkumar V et ak. J Clin Oncol. 2008;26:2171–2177 
    Thal-Dex vs VAD 200 76 vs 52 10 vs 8 – – Cavo M et al. Blood. 2005;106:35–39 
    Thal-Dex vs VAD 204 65 vs 47 35 vs 13* – 44 vs 42* Macro M et al. Blood. 2006:108:57a 
    TAD vs VAD 400 72 vs 54 4 vs 2 87 vs 79 30 vs 21 Lokhorst HM et al. Haematologica2008;93:124–127. 
    T+VAD vs VAD 230 81 vs 66 38 vs 19* – – Zervas K et al. Ann Oncol. 2007;18:1369–1375 
    CTD vs CVAD 254 87 vs 75 19 vs 9 88 vs 76 51 vs 40 Morgan G et al. Blood. 2007;110:3593a 
Lenalidomide-based combinations 
    Len-Dex vs Len-Dex 445 81 vs 70 17 vs 14 –** –** Rajkumar V et al. J Clin Oncol. 2008;26:8504a 
    Len-Dex vs Dex 198 85 vs 51 22 vs 4 – – Zonder J et al. Blood. 2007;110:77a 
    Len-Dex-Clarithromycin 72 90 46 –† –† Niesvizky R et al. Blood. 2008;111:1101–1109. 
    Len-Cy-Dex 53 83 – – Kumar S et al. Blood. 2008;112:91a 
Bortezomib-based combinations 
    Bz-Dex 48 66 21 90 33 Harousseau JL et al. Haematologica. 2006;91:1498–1505 
    Bz-Dex (alt) 40 60 13 88 30 Rosiñol L et al. J Clin Oncol. 2007;25:4452–4458 
    Bz-Doxil 63 79 28 – – Orlowski R et al. Blood. 2006;108:797a 
    Bz-Doxil-Dex 36 89 32 96 54 Jakubowiak AJ et al. Blood. 2006;11:3093a 
    Bz-Adriamycin 21 95 24 95 57 Oakervee HE et al. Br J Haematol. 2005;129:755–762 
    Bz-Cy-Dex 100 79 11 – – Knopp S et al. Blood. 2008;112:2776a 
    Bz-Cy-Dex 33 100 64 – – Reeder CB et al. J Clin Oncol. 2008;26:8517a 
    Bz-Dex vs VAD 482 82 vs 65 15 vs 7 91 vs 91 40 vs 22 Harousseau JL et al. J Clin Oncol. 2008;26:8505a 
    Bz-Adriamycin-Dex vs VAD 300 83 vs 59 5 vs 1 93 vs 80 23 vs 9 Sonneveld P et al. Blood. 2008;112:653a 
Bortezomib and IMID-based combinations 
    Bz-Thal-Dex 38 92 18 – – Wang M et al. Hematology. 2007;235–239 
    Bz-DTPACE 12 83 17 92 58 Badros A et al. Clin Lymph Myeloma. 2006;7:210–216 
    Bz-Thal-Dex vs Thal-Dex 460 94 vs 79 32 vs 12 – 55 vs 32 Cavo M et al. Blood. 2008;112:158a 
    VBCMP/VBAD-Bz vs Thal-Dex vs Bz-Thal-Dex 183 72 vs 66 vs 80 28 vs 12 vs 41 97 vs 97 vs 97 54 vs 53 vs 64 Rosiñol L et al. Blood. 2008;112:654a 
    Bz-Len-Dex 68 100 44 – – Richardson P et al. Blood. 2008;112:92a 
    Bz-Len-Cy-Dex 25 100 36 – – Kumar S et al. Blood. 2008;112:93a 
Pre-trxPost-trx
Treatment schedulePtsPR (%)CR +nCR (%)PR (%)CR + nCR (%)Reference
*Including VGPR 
**4-year OS after 4 cycles and trx: 92% in both arms 
†Median EFS for patients receiving trx after Len-Dex clarithromycin: 37 months 
Trx indicates transplantation; PR, partial response; CR, complete response; nCR, near CR; Thal, thalidomide; Len, lenalidomide; Dex, dexamethasone; Cy, cyclophosphamide; Bz, bortezomid; Doxil, doxorubicin; VAD, vincristine, adriamycin, dexamethasone; TAD, thalidomide, adriamycin, dexamethasone; CTD, cyclophosphamide, thalidomide, dexamethasone; CVAD, cyclophosphamide, VAD; VBCMP, vincristine, bleomycin, chlorambucil, melphalan, prednisone; VBAD, vincristine, bleomycin, adriamycin, dexamethasone; DTPACE, cisplatin, cyclophosphamide, dexamethasone, doxorubicin, etoposide, thalidomide. 
Thalidomide-based combinations 
    Thal-Dex vs Dex 207 63 vs 41 – – – Rajkumar V et al. J Clin Oncol. 2006;24:431–436 
    Thal-Dex vs Dex 470 63 vs 46 7.7 vs 2.6 – – Rajkumar V et ak. J Clin Oncol. 2008;26:2171–2177 
    Thal-Dex vs VAD 200 76 vs 52 10 vs 8 – – Cavo M et al. Blood. 2005;106:35–39 
    Thal-Dex vs VAD 204 65 vs 47 35 vs 13* – 44 vs 42* Macro M et al. Blood. 2006:108:57a 
    TAD vs VAD 400 72 vs 54 4 vs 2 87 vs 79 30 vs 21 Lokhorst HM et al. Haematologica2008;93:124–127. 
    T+VAD vs VAD 230 81 vs 66 38 vs 19* – – Zervas K et al. Ann Oncol. 2007;18:1369–1375 
    CTD vs CVAD 254 87 vs 75 19 vs 9 88 vs 76 51 vs 40 Morgan G et al. Blood. 2007;110:3593a 
Lenalidomide-based combinations 
    Len-Dex vs Len-Dex 445 81 vs 70 17 vs 14 –** –** Rajkumar V et al. J Clin Oncol. 2008;26:8504a 
    Len-Dex vs Dex 198 85 vs 51 22 vs 4 – – Zonder J et al. Blood. 2007;110:77a 
    Len-Dex-Clarithromycin 72 90 46 –† –† Niesvizky R et al. Blood. 2008;111:1101–1109. 
    Len-Cy-Dex 53 83 – – Kumar S et al. Blood. 2008;112:91a 
Bortezomib-based combinations 
    Bz-Dex 48 66 21 90 33 Harousseau JL et al. Haematologica. 2006;91:1498–1505 
    Bz-Dex (alt) 40 60 13 88 30 Rosiñol L et al. J Clin Oncol. 2007;25:4452–4458 
    Bz-Doxil 63 79 28 – – Orlowski R et al. Blood. 2006;108:797a 
    Bz-Doxil-Dex 36 89 32 96 54 Jakubowiak AJ et al. Blood. 2006;11:3093a 
    Bz-Adriamycin 21 95 24 95 57 Oakervee HE et al. Br J Haematol. 2005;129:755–762 
    Bz-Cy-Dex 100 79 11 – – Knopp S et al. Blood. 2008;112:2776a 
    Bz-Cy-Dex 33 100 64 – – Reeder CB et al. J Clin Oncol. 2008;26:8517a 
    Bz-Dex vs VAD 482 82 vs 65 15 vs 7 91 vs 91 40 vs 22 Harousseau JL et al. J Clin Oncol. 2008;26:8505a 
    Bz-Adriamycin-Dex vs VAD 300 83 vs 59 5 vs 1 93 vs 80 23 vs 9 Sonneveld P et al. Blood. 2008;112:653a 
Bortezomib and IMID-based combinations 
    Bz-Thal-Dex 38 92 18 – – Wang M et al. Hematology. 2007;235–239 
    Bz-DTPACE 12 83 17 92 58 Badros A et al. Clin Lymph Myeloma. 2006;7:210–216 
    Bz-Thal-Dex vs Thal-Dex 460 94 vs 79 32 vs 12 – 55 vs 32 Cavo M et al. Blood. 2008;112:158a 
    VBCMP/VBAD-Bz vs Thal-Dex vs Bz-Thal-Dex 183 72 vs 66 vs 80 28 vs 12 vs 41 97 vs 97 vs 97 54 vs 53 vs 64 Rosiñol L et al. Blood. 2008;112:654a 
    Bz-Len-Dex 68 100 44 – – Richardson P et al. Blood. 2008;112:92a 
    Bz-Len-Cy-Dex 25 100 36 – – Kumar S et al. Blood. 2008;112:93a 
Table 2.

Results of randomized trials comparing autologous stem cell transplantation (ASCT) with chemotherapy.

StudyEFS/PFSOSPReference
EFS indicates event-free survival; PFS, progression-free survival; OS, overall survival; SDT, standard-dose therapy; S indicates significant P-value; NS, non-significant P-value; NR, not reached 
SDT vs ASCT 
 IFM    Attal M et al. N Engl J Med. 1996;335:91–97 
 SDT 18 m (10% 5 y) 37 m (12% 5 y)  
 HDT 27 m (28% 5 y) NR (52% 5 y)   
 MRC    Child JA et al. N Engl J Med. 2003;348:1875–1883 
 SDT 19 m 42 m  
 HDT 31 m 54 m   
 SWOG    Barlogie B et al. J Clin Oncol. 2006;24:929–936 
 SDT 14% 7 y 39% 7 y NS  
 HDT 17% 7 y 38% 7 y   
 PETHEMA    Blade J et al. Blood. 2005;106:3755–3759 
 SDT 33 m 66 m NS  
 HDT 42 m 61 m   
 MAGG    Fermand JP et al. J Clin Oncol. 2005;23:9227–9233 
 SDT 19 m 47 m NS  
 HDT 25 m 47 m   
Single vs Double ASCT 
 IFM   NS Attal M. N Engl J Med. 2003;349:2495–2502 
 Single 25 m (10% 7 y) 48 m (21% 7 y)   
 Double 30 m (20% 7 y) 58 m (42% 7 y)   
 GIMEMA    Cavo M. J Clin Oncol. 2007;25:2434–2441 
 Single 23 m 46 m NS  
 Double 35 m 43 m   
StudyEFS/PFSOSPReference
EFS indicates event-free survival; PFS, progression-free survival; OS, overall survival; SDT, standard-dose therapy; S indicates significant P-value; NS, non-significant P-value; NR, not reached 
SDT vs ASCT 
 IFM    Attal M et al. N Engl J Med. 1996;335:91–97 
 SDT 18 m (10% 5 y) 37 m (12% 5 y)  
 HDT 27 m (28% 5 y) NR (52% 5 y)   
 MRC    Child JA et al. N Engl J Med. 2003;348:1875–1883 
 SDT 19 m 42 m  
 HDT 31 m 54 m   
 SWOG    Barlogie B et al. J Clin Oncol. 2006;24:929–936 
 SDT 14% 7 y 39% 7 y NS  
 HDT 17% 7 y 38% 7 y   
 PETHEMA    Blade J et al. Blood. 2005;106:3755–3759 
 SDT 33 m 66 m NS  
 HDT 42 m 61 m   
 MAGG    Fermand JP et al. J Clin Oncol. 2005;23:9227–9233 
 SDT 19 m 47 m NS  
 HDT 25 m 47 m   
Single vs Double ASCT 
 IFM   NS Attal M. N Engl J Med. 2003;349:2495–2502 
 Single 25 m (10% 7 y) 48 m (21% 7 y)   
 Double 30 m (20% 7 y) 58 m (42% 7 y)   
 GIMEMA    Cavo M. J Clin Oncol. 2007;25:2434–2441 
 Single 23 m 46 m NS  
 Double 35 m 43 m   
Table 3.

Studies evaluating the role of maintenance therapy with thalidomide in newly diagnosed patients with multiple myeloma (MM).

Maintenance vs No Maintenance
Cooperative GroupNInitial dose (mg)Duration of T-maintenanceCR+ VGPR, %EFS or PFS, %OS, %Reference
CR indicates complete response; VGPR, very good partial response; EFS, event-free survival; PFS, progression-free survival; OS, overall survival; PD, progression of disease; NA, not available. 
IFM 597 400 Until PD 67 vs 55 3-y EFS 4-y OS Attal et al. Blood. 2006;108:3289–3294 
     52 vs 36 87 vs 77  
Australian 243 200 12 months 63 vs 40 3-y PFS 3-y OS Spencer et al. J Clin Oncol. 2009;27:1788–1793 
     42 vs 23 86 vs 75  
Arkansas 668 400 Throughout study 62 vs 43 5-y EFS 5-y OS Barlogie et al. Blood. 2008;112:3115–3121 
     56 vs 45 67 vs 65  
MRC (UK) 820 100 Until PD NA HR:1.9 Similar OS Morgan et al. Blood. 2008;112:656a 
     P =.007   
Maintenance vs No Maintenance
Cooperative GroupNInitial dose (mg)Duration of T-maintenanceCR+ VGPR, %EFS or PFS, %OS, %Reference
CR indicates complete response; VGPR, very good partial response; EFS, event-free survival; PFS, progression-free survival; OS, overall survival; PD, progression of disease; NA, not available. 
IFM 597 400 Until PD 67 vs 55 3-y EFS 4-y OS Attal et al. Blood. 2006;108:3289–3294 
     52 vs 36 87 vs 77  
Australian 243 200 12 months 63 vs 40 3-y PFS 3-y OS Spencer et al. J Clin Oncol. 2009;27:1788–1793 
     42 vs 23 86 vs 75  
Arkansas 668 400 Throughout study 62 vs 43 5-y EFS 5-y OS Barlogie et al. Blood. 2008;112:3115–3121 
     56 vs 45 67 vs 65  
MRC (UK) 820 100 Until PD NA HR:1.9 Similar OS Morgan et al. Blood. 2008;112:656a 
     P =.007   
Table 4.

Results of the trials evaluating the role of tandem autologous stem cell transplantation (ASCT) versus ASCT followed by allogeneic reduced-intensity chemotherapy (Allo-RIC).

Tandem Auto vs Auto/Allo-RIC
Cooperative GroupPatientsCR, %EFS, moOS, moPRef.
*Only high-risk patients (high β2-microglobulin and/or del(13q); worse survival for patients with del(13q) 
**Only patients with < CR/nCR after first ASCT 
†Patients after first ASCT were randomized to receive maintenance versus Allo-RIC 
S indicates significant P-value; NS, non-significant P-value 
IFM* 166 vs 46 37 vs 55 25 vs 21 57 vs 41 NS 35  
GIMEMA 82 vs 80 26 vs 55 33 vs 37 64 vs NR 36  
PETHEMA** 82 vs 25 11 vs 40 20 vs 26 58 vs 60 NS 37  
HOVON† 101 vs 115 42 vs 45 34 vs 39 63 vs 56 NS 38  
EBMT 250 vs 110 41 vs 52 15 vs 36 50 vs 65 39  
Tandem Auto vs Auto/Allo-RIC
Cooperative GroupPatientsCR, %EFS, moOS, moPRef.
*Only high-risk patients (high β2-microglobulin and/or del(13q); worse survival for patients with del(13q) 
**Only patients with < CR/nCR after first ASCT 
†Patients after first ASCT were randomized to receive maintenance versus Allo-RIC 
S indicates significant P-value; NS, non-significant P-value 
IFM* 166 vs 46 37 vs 55 25 vs 21 57 vs 41 NS 35  
GIMEMA 82 vs 80 26 vs 55 33 vs 37 64 vs NR 36  
PETHEMA** 82 vs 25 11 vs 40 20 vs 26 58 vs 60 NS 37  
HOVON† 101 vs 115 42 vs 45 34 vs 39 63 vs 56 NS 38  
EBMT 250 vs 110 41 vs 52 15 vs 36 50 vs 65 39  

Disclosures
 Conflict-of-interest disclosures: JFS-M received honoraria and serves on advisory committees/boards of directors of Celgene, Millennium, and Janssen-Cilag. M-VM received honoraria from Janssen Cilag and Celgene Corporation. Off-label drug use: Lenalidomide is not approved for the treatment of patients with untreated multiple myeloma who are candidates for autologous stem cell transplantation, and for this indication bortezomib is not approved in the EU.

Acknowledgments

This work was partially supported by RTICC (Red Temática Cooperativa en Cáncer)(RD06/0020/0006).

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Author notes

1

University Hospital of Salamanca, Salamanca, Spain

2

CIC, IBMCC (USAL-CSIC), Salamanca, Spain