The treatment approaches, goals of therapy, and underlying philosophy for how to approach the treatment of a patient with newly diagnosed myeloma have dramatically shifted over the past 20 years. This shift has occurred partly as a consequence of the development of more effective antimyeloma agents and renewed emphasis on maintenance therapies. The combination of these 2 factors has allowed patients to benefit from disease burden levels at lower thresholds than were previously achieved with conventional therapy. Although myeloma was historically presumed to be an incurable disorder for which the primary goal was to obtain partial responses with the intent of disease control for a limited period (the “do no harm” approach), it is now incumbent on treating clinicians to treat to maximal response, and consider long-term treatment strategies rather than a piecemeal treatment strategy. This is particularly important because current treatments have been shown to improve outcomes for patients, as measured by overall survival, with the result that median survival for many patients will exceed 8 to 10 years.
Who Needs Therapy?
Currently, the criteria for initiating induction therapy are largely based on a clinical assessment of symptomatic disease. It is important to recall that the diagnosis of multiple myeloma requiring therapy is not a pathologic decision but rather a clinical decision that requires the assessment of end organ damage. This is defined practically as the presence or absence of “CRAB” criteria, which consist of hyperCalcemia, Renal insufficiency, Anemia, and Bone disease. The presence of any of these factors, which are thought to be related to the plasma cell clone, constitutes the definition of symptomatic myeloma and indicates that therapy should begin.1 However, there is a growing movement to potentially identify and modify these criteria to include patients who have a high risk of conversion from asymptomatic to symptomatic myeloma in a short time frame. A randomized clinical trial from the PETHEMA group demonstrated that the use of lenalidomide/dexamethasone versus observation improved not only the time to developing symptomatic myeloma but also overall survival for this cohort of patients with asymptomatic myeloma with a high risk of progression to symptomatic myeloma.2 A current ECOG trial is further testing this observation in a randomized phase III trial, the results of which are pending (ECOG-E3A06; ClinicalTrials.gov identifier: NCT01169337). Despite these early data from the Spanish group, it remains the recommendation of the International Myeloma Working Group that patients without evidence of end organ damage as described earlier continue with observation and are not treated early.
Treatment of Newly Diagnosed Transplant Candidates
For suitable patients who are fit and with reasonable performance status, the use of high-dose therapy (HDT) and autologous stem cell transplant (ASCT) remains a standard part of the treatment approach.3 In most European series, the cutoff age of eligibility for ASCT is 65 years, although most transplant centers in the United States will consider ASCT an option for patients older than 65 years. Typically ASCT has no specific age exclusion, although a reduced melphalan dose is commonly used for patients older than 70 years.4 Thus, fit patients should be considered and referred to an appropriate transplant/myeloma center early in their treatment for consideration of stem cell collection and ASCT.
Before initiation of stem cell collection, patients undergo induction therapy for 3 to 6 cycles- to attempt to debulk disease and improve the end organ damage that was the reason for initiation of therapy.5 The combination of vincristine, doxorubicin, and dexamethasone (VAD) has long been the gold standard as a preparatory regimen for young patients with newly diagnosed multiple myeloma who are candidates for ASCT, with partial response rates around 60% and complete response rates less than 10%. However, novel drug combinations are significantly superior to VAD and have replaced its use.6 Regimens with phase III data supporting their use as initial therapy for these patients include VTD (bortezomib, thalidomide, and dexamethasone),7 PAD (bortezomib, doxorubicin, and dexamethasone),8 Rd (lenalidomide with low-dose dexamethasone),9 VD (bortezomib and dexamethasone),10 TD (thalidomide and dexamethasone),11 and vTD12 (Table 1).
Notably, the VTD study from Cavo et al7 required that all patients undergo tandem autologous transplant, whereas in the HOVON study from Sonnenveld et al,8 133 patients in the VAD arm and 142 patients in the PAD arm underwent planned tandem transplantation. In the Intergroupe Francophone du Myelome (IFM) study12 comparing VD with VAD, 41 patients in the VD arm versus 50 patients in the VAD arm underwent a second autologous transplant, both because of inadequate response. Regimens with phase II data supporting their use include VRD (bortezomib, lenalidomide, and dexamethasone), CyBorD (cyclophosphamide, bortezomib, and dexamethasone), the alternating VCD (bortezomib, cyclophosphamide, and dexamethasone)/VTD regimen,13 and several combinations of bortezomib and lenalidomide (Table 2).
Although considerable controversy exists about whether a doublet regimen (VD, Rd, TD) or a triplet regimen (VTD, VRD,14 CyBorD15) should be used, most investigators agree that the use of TD is suboptimal, as defined by a lower very good partial response/complete response rate after induction, and has largely been replaced with either lenalidomide- or bortezomib-based inductions.16 In the setting of randomized clinical trials, the use of VTD was superior to TD in terms of progression-free survival post-transplant, and this was associated with a higher very good partial response/complete response rate after induction therapy.7 Additionally, although the most recent IFM trial testing the combination of vTD versus VD showed superiority of the triplet regimen in the context of pre- and posttransplant very good partial response but, unlike the trial by Cavo et al,7 did not result in an improvement in progression-free survival posttransplant. In the context of data from the IFM and other groups suggesting that achieving a very good partial response or better after induction therapy but before HDT is associated with improved overall survival,17 it seems that a major goal for induction regimens should include the achievement of a very good partial response after therapy, and in this context triplets are preferred over doublets. The reason why results of the vTD versus VD trial followed the emerging pattern of superiority in terms of posttransplant progression-free survival may be related to the fact that dose-reduced bortezomib did not confer the same complete response rate seen with VTD in the trial by Cavo et al7 and, rather than very good partial response, the more suitable end point for postinduction therapy may be complete response. This does not necessarily mean that if patients do not achieve a very good partial response after induction the treatment should be changed before proceeding to transplant (with the exception of those that achieve less than a partial response, who should be considered to be primary refractory, and may benefit from an alternative regimen before high-dose melphalan), but rather that one should choose the induction regimen with the highest likelihood of producing a very good partial response or better. The impact of 3 versus 2 drug combinations is likely most important for the high-risk patient population (as evidenced by the elimination of the poor risk t(4;14) phenotype in the VTD vs. TD study7); however, it also results in significant benefit for the standard-risk patient population, and this population may be one in which long-term durable remissions or even cures can be induced.18
Phase III Trials of Novel Agents in Transplant-Eligible Patients
Phase II Trials With Novel Agents in Transplant-Eligible Patients
A discussion of ASCT remains important, because transplantation is one of the major treatment approaches that has shown a survival benefit. The timing of ASCT is now being challenged by the efficacy of continuous treatment with novel agents. A recent study from the Italian myeloma group comparing lenalidomide/dexamethasone induction followed by transplant versus low-dose melphalan-based therapy in combination with lenalidomide showed a major improvement in progression-free survival favoring the transplant arm.19 In the E4A03 clinical trial testing the use of lenalidomide with either high- or low-dose dexamethasone, the patients who proceeded to ASCT achieved a superior overall survival compared with those who did not.20 Thus, considerable evidence remains favoring the use of ASCT even in the novel agent era.
Although retrospective studies are fraught with selection bias issues, the ongoing IFM/DFCI trial is addressing the question of timing of transplant (early vs. late) for patients receiving VRD-based induction in a prospective fashion, but results are still pending (ClinicalTrials.gov identifier: NCT01191060). What is known from an IFM pilot study is that the use of VRD induction, HDT consolidation, and lenalidomide maintenance results in one of the longest progression-free survival experiences patients with myeloma have experienced in clinical trials, suggesting that the benefits of induction therapy and transplant are likely additive, and thus should continue to be considered a standard approach for most patients.21 Moreover, this is consistent with data from phase III trials conducted by the Italian7 (VTD vs. TD), Spanish22 (VTD vs. TD vs. vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone/bortezomib [VBMCP/VBAD/B]), and Hovon8 (PAD vs. VAD) groups showing that novel agent-based induction followed by HDT and maintenance is associated with prolonged progression-free survival.
Nevertheless, data sets now exist suggesting that there is no difference between early or late HDT in terms of overall survival, and this may be the case for standard-risk patients if they are willing to undergo HDT at first relapse. Whether the benefit of HDT remains for patients who use “delayed” transplant in the setting of subsequent relapses (ie, relapses occurring after a first relapse) is unknown. Until results from randomized trials comparing early versus late HDT become available, it is recommended that patients and physicians consider up-front transplantation, because it is complementary with novel drug induction in terms of inducing a high complete response rate, and patients can have an excellent quality of life. Additionally, after short-course induction, it is known that at relapse after ASCT, patients typically experience response to rescue therapies or retreatment, whereas the efficacy of HDT after long-term exposure to novel agents remains unknown.
Regarding tandem ASCT, its use has significantly decreased in favor of consolidation or maintenance therapies. By contrast, a second transplant at later relapse is being increasingly used, provided that the response to first transplant has lasted for at least 2 years.23 This consideration, in addition to reconstitution of normal hematopoiesis after extensive therapy, supports the continued collection of sufficient cells for multiple transplants at initial harvest.
Treatment of Newly Diagnosed Transplant-Ineligible Patients
Melphalan with prednisone (MP) has been the gold standard for more than 40 years; however, recent results based on the combination of MP with either thalidomide or bortezomib, and probably also with lenalidomide, indicate new standards of care now exist for elderly patients with multiple myeloma.24
Six randomized trials have compared thalidomide plus MP (MPT) versus MP, showing a significantly higher relative risk in the MPT arm (59% vs. 37%; complete response, 10% vs. 2.5%) and longer progression-free survival/time to progression (prolongation of progression-free survival of 5.4 months). However, only in 3 studies was treatment with MPT associated with a significant prolongation in overall survival (Table 3). The toxicity associated with the high dose of thalidomide used in some of these trials may explain the differences in overall survival between trials, because they used different doses and duration of thalidomide. Preliminary data from the Medical Research Council Myeloma IX trial show that the combination of cyclophosphamide, thalidomide, and dexamethasone is superior to MP in terms of relative risk (82% vs. 49%) but not overall survival.25 MP has also been compared with TD, and although the relative risk was higher in the experimental arm, the overall survival was shorter again,26 suggesting that thalidomide has a major toxicity issue that may limit not only duration of therapy but also the ability to give subsequent therapy.
Lenalidomide has also been combined with MP. A large randomized trial has recently been completed comparing MP alone versus MP with lenalidomide used only as part of the induction or also as maintenance. The results show a significantly longer progression-free survival for the maintenance approach (31 vs. 14 and 12 months, respectively); however, no differences in overall survival have so far been observed.27 Notably, the MP plus lenalidomide arms were initially associated with an increased incidence of secondary malignancies, although longer follow-up indicates that the incidence has not increased further.
The proteasome inhibitor bortezomib has been tested in combination with MP in a pilot study conducted by the Spanish group. The positive results were confirmed in a large randomized study comparing bortezomib plus MP versus MP alone,28,29 which showed a relative risk of 71% versus 35%, respectively, and complete response rates of 30% and 4%, respectively. Bortezomib plus MP treatment was associated with a longer time to progression (24 vs. 16.6 months) and more than a 1-year prolongation in overall survival (median, 56.4 vs. 43.1 months). In an attempt to optimize the treatment of elderly patients with untreated multiple myeloma using bortezomib plus MP, the Spanish and Italian myeloma groups (GEM/PETHEMA and GIMEMA) reported on 2 randomized trials evaluating the efficacy of weekly bortezomib dosing in combination with MP-based inductions.30,31 Results indicate that efficacy is maintained with the reduced-dose bortezomib schedule, whereas tolerability is increased substantially. Notably, grade 3/4 peripheral neuropathy was only 2% or 5% with the reduced-dose bortezomib/MP regimen in the 2 studies, and this was associated with a lower rate of treatment discontinuations (8% and 10%). The recent approval of subcutaneous bortezomib as an alternative route of administration has provided additional options to reduce the adverse event profile of the bortezomib/MP regimen, because the use of subcutaneous bortezomib is associated with a significant reduction in overall neuropathy,32 and when given weekly, probably has an improved adverse event profile over the most recent published reports using intravenous weekly therapy.
The historical approach of melphalan-based inductions for older patients is currently being challenged by regimens using either lenalidomide- or bortezomib-based inductions even for elderly patients. Data from the E4A03 trial testing lenalidomide with either high- or low-dose dexamethasone showed that among those who received low-dose dexamethasone, the 2-year survival probability was 82% in patients aged 65 years or older, and the regimen was associated with very good tolerability.9 In the phase III UPFRONT trial, reported by Niesvizky et al,33 among patients who received either VD, bortezomib/MP, or VTD no difference in progression-free or overall survival was seen among the 3 treatment arms, suggesting that non-melphalan-based regimens are associated with similar efficacy as melphalan-based regimens.33 Although these data are not conclusive, the FIRST trial has been completed comparing lenalidomide with MPT, and may shed additional light on the necessity of melphalan as part of the induction regimen for older patients.
Phase III Trials of Novel Agents in Transplant-Ineligible Patients
Among the average patient, no uniform consensus exists regarding which of the 3 novel MP combinations is best. An individualized treatment approach would probably be valuable: 1) for patients with antecedent or risk of deep venous thrombosis, bortezomib/MP could be the preferable option; 2) in patients with antecedent peripheral neuropathy, lenalidomide/MP or simply lenalidomide/dexamethasone should be the choice; 3) in patients with renal insufficiency, bortezomib/MP is safe; 4) in patients living long distances from hospital, oral treatment (MPT, lenalidomide/MP, or lenalidomide/dexamethasone) would be preferable; and 5) in patients with poor compliance with treatment, bortezomib/MP could be better.
In patients older than 75 years or in fragile condition, modified regimens would be recommended, with a lower dose of thalidomide (100 mg), lenalidomide (15-20 mg), or bortezomib (weekly schedule with dose reduction at 1 mg/m2 if required).34 One additional possibility in these patients is to substitute melphalan with cyclophosphamide (50 mg/d or 1 g per 21 days), because this latter agent is less myelotoxic. In very elderly patients (age >75 years), special attention must be paid to infectious episodes (may require prophylaxis) and renal function (appropriate hydration), particularly during the first 3 months of treatment when these conditions are responsible for the high incidence of early deaths. Ongoing studies will establish optimal dosing and treatment schedules for different populations with the aim of maximizing efficacy and improving tolerability.
Initial Therapy for High-Risk Patients
The management of high-risk patients at the time of presentation is a critical point of current clinical investigation. Although no consensus exists regarding the optimal induction regimen, combinations that include either the proteasome inhibitor bortezomib or lenalidomide are clearly needed in this situation. Data from the Spanish trial comparing VTD with TD and a chemotherapy-based approach suggest that the response rates are highest when thalidomide is combined with bortezomib, and this is further supported by the very high overall response rate for the VRD regimen among patients with standard- and high-risk myeloma.22 However, achieving a complete response is not sufficient in this setting, and the use of prolonged maintenance is likely necessary to best improve complete response duration. The HOVON study suggested improved progression-free and overall survivals for patients who received bortezomib maintenance compared with thalidomide among the high-risk cohorts,8 and additional data from Cavo et al7 suggest that the use of VTD induction and VTD consolidation may eliminate the t(4:14) as a poor prognostic marker.
Data from the authors’ group suggested that the use of combined posttransplant VRD may also help improve outcomes for the highest-risk patients when used as part of a planned treatment strategy.35 Further studies to evaluate optimal duration and combination approaches for high-risk patients are clearly needed, and are being addressed by the cooperative groups going forward.
Maintenance Therapy
Interferon and/or corticosteroids have shown little benefit and have been abandoned as maintenance therapy. The availability of novel agents, particularly those with oral formulations, has renewed the concept of maintenance in an attempt to prolong the duration of responses after transplant.36 Six randomized trials using thalidomide or TD have shown a significant prolongation in progression-free survival, but only 3 of these have resulted in prolonged overall survival compared with pamidronate, corticosteroids, or interferon, and are discussed in more detail elsewhere in this issue. However, the toxicity and possibility of inducing more resistant relapses are important concerns and have led to the limited use of thalidomide in the maintenance setting. Two randomized trials recently reported a significant benefit for lenalidomide maintenance in terms of progression-free survival (42 vs. 24 months in the placebo arm), with only one showing a benefit in overall survival, but methodological differences between the trials may explain why this benefit is not seen in both.37,38 Results have also shown a higher incidence of second primary malignancies among the patients randomized to maintenance lenalidomide, yet there remains an improvement in overall survival in the US trial, and several other retrospective analyses suggest the risk of second malignancy is far outweighed by the risk of death from the primary malignancy. These issues require in-depth discussion between physicians and their patients when considering maintenance after autologous transplant. The role and approaches for maintenance are discussed in greater detail elsewhere in this issue.
Allogeneic Transplant
Allogeneic transplantation remains the only curative therapeutic approach in patients with multiple myeloma. However, it is associated with a high transplant-related mortality (TRM; up to 15%-30% at 1 year and higher for 2- and 3-year follow-up) and morbidity (mainly because of chronic graft-versus-host disease), and an ongoing risk of relapse. Accordingly, it should be considered only in carefully defined situations and within the context of clinical trials. To decrease TRM, different reduced-intensity conditioning regimens (RICs) have been developed (allogeneic RIC [allo-RIC]), mainly based on fludarabine and melphalan or fludarabine plus radiotherapy (2 Gy). The TRM decreases in the short term, but remains high over 1 and 2 years, and is associated with a higher rate of relapse. Six randomized trials have compared the up-front use of double ASCT versus ASCT followed by allo-RIC,39 with only 2 of them showing superiority of the allogeneic approach in terms of progression-free and overall survival.40,41 Most recently, the Blood and Marrow Clinical Trials Network trial evaluated standard- and high-risk patients with a tandem ASCT versus ASCT/allo-RIC from matched related siblings,42,43 with similar data from the HOVON group.44 In this analysis, no subset of patients seemed to benefit from the use of early allo-RIC, with a relatively short follow-up. Moreover, a high proportion of patients develop extramedullary relapses without bone marrow involvement, indicating that, although the disease may be under control in the bone marrow, extramedullary escape may occur. The high treatment mortality, exceptional outcomes for standard-risk patients using available novel agents, and lack of demonstrated benefit among any trial evaluating high-risk patients further support the highly experimental nature of this treatment approach, and the fact that it should only be performed at specialized centers in the context of clinical trials. The use of allogeneic transplantation in the setting of relapsed disease has even poorer outcomes data, and again is only recommended within designed clinical trials, even among patients with short durations of response to initial therapy.45
Conclusions
Treatment options for patients with newly diagnosed myeloma continue to evolve, as does the treatment paradigm for young, older, and frail patients. It is clear now that nearly all patients will achieve at least a partial response, and increasing numbers of patients will achieve a complete response using conventional criteria. With the demonstration that patients develop numerous new genomic mutations with subsequent relapses, the use of combination therapy and attempts to prolong duration of first remission remain important priorities. Newer definitions of complete response, including the addition of molecular and flow cytometric studies, will help further define which patients are able to achieve even lower levels of minimal residual disease, a clinical status associated with improved progression-free and overall survival in many studies. Additional focus on risk stratification, particularly in the setting of maintenance therapy, will help further improve the frequency and incidence of sustained complete response, and thus move closer to the goal of cure. Continued clinical trial participation in therapeutic and now in tumor sequencing protocols at the time of diagnosis and relapse will further aid in understanding mechanisms of high-risk disease, drug resistance, and clonal evolution, and remain a high priority for all patients with newly diagnosed myeloma.
Dr. Lonial has disclosed that he is a consultant for Millennium Pharmaceuticals, Inc.; Celgene Corporation; Novartis AG; Bristol-Myers Squibb Company; Onyx Pharmaceuticals, Inc.; and Merck & Co., Inc. Dr. San Miguel had disclosed that he has received honoraria from Celgene Corporation, Millennium Pharmaceuticals, Inc., and Janssen.
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