Current Treatment Strategies

Current Multiple Myeloma Treatment Strategies with Novel Agents: A European Perspective

Heinz Ludwig, Meral Beksac, Joan Bladé, Mario Boccadoro, Jamie Cavenagh, Michele Cavo, Meletios Dimopoulos, Johannes Drach, Hermann Einsele, Thierry Facon, Hartmut Goldschmidt, Jean-Luc Harousseau, Urs Hess, Nicolas Ketterer, Martin Kropff, Larisa Mendeleeva, Gareth Morgan, Antonio Palumbo, Torben Plesner, Jesús San Miguel, Ofer Shpilberg, Pia Sondergeld, Pieter Sonneveld, Sonja Zweegman

Wilhelminenspital, Vienna, Austria; Ankara University School of Medicine, Department of Haematology, Ankara, Turkey; Department of Hematology, Hospital Clinic, Barcelona, Spain; Divisione di Ematologia dell’Università di Torino, Azienda Ospedaliera S. Giovanni Battista, Ospedale Molinette, Turin, Italy; Department of Haematology, St. Bartholomew’s Hospital, London, U.K.; Institute of Hematology and Medical Oncology, Seragnoli, Bologna, Italy; Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece; Department of Oncology, University Clinic Vienna, Vienna, Austria; Universitätsklinik Würzburg, Medizinische Klinik und Poliklinik II, Würzburg, Germany; Service d’Hématologie, Centre Hospitalier Universitaire (CHU), Lille, France; Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; Centre René Gauducheau Nantes, Nantes, France; Division of Oncology/Hematology, Kantonsspital St. Gallen, St. Gallen, Switzerland; Department of Oncology, University Hospital CHUV, Lausanne, Switzerland; Department of Medicine/Hematology and Oncology, University of Münster, Münster, Germany; Hematology Scientific Center, Russian Academy of Medical Sciences, Moscow, Russia; Institute of Cancer Research, Royal Marsden Hospital, London, U.K.; Department of Haematology, IRS-CSFU, University of Southern Denmark, Vejle Hospital, Vejle, Denmark; Department of Hematology, University Hospital of Salamanca, Salamanca, Spain; Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petah-Tiqva, Israel; Ammonite Systems Ltd., Faringdon, U.K.; Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands; VU University Medical Center, Department of Haematology, Amsterdam, The Netherlands

Key Words. Multiple myeloma, Thalidomide, Bortezomib, Lenalidomide

Disclosures: Heinz Ludwig: Consultant/advisory role: ESMO; Honoraria: Amgen, Ortho Biotech; Research funding/contracted research: Mundipharma, Janssen-Cilag; Meral Beksac: Honoraria: Celgene, Janssen-Cilag; Joan Bladé: Honoraria: Celgene, Janssen-Cilag; Mario Boccadoro: Consultant/advisory role: Celgene, Janssen-Cilag; Research funding/contracted research: Celgene, Janssen-Cilag; Jamie Cavenagh: None; Michele Cavo: Honoraria: Celgene, Janssen-Cilag, Novartis; Meletios Dimopoulos: Honoraria: Ortho-Biotech, Millennium, Celgene; Johannes Drach: Honoraria: Celgene, Janssen-Cilag; Hermann Einsele: Honoraria: Celene, Ortho-Biotech; Thierry Facon: Consultant/advisory role: Janssen-Cilag, Celgene; Honoraria: Janssen-Cilag, Celgene; Hartmut Goldschmidt: Research funding/contracted research: Ortho-Biotech; Jean-Luc Harousseau: Honoraria: Celgene, Janssen-Cilag; Urs Hess: None; Nicolas Ketterer: None; Martin Kropff: Honoraria: Ortho-Biotech, Celgene; Larisa Mendeleeva: None; Gareth Morgan: None; Antonio Palumbo: Honoraria: Celgene, Janssen-Cilag; Torben Plesner: Honoraria: Janssen-Cilag; Research funding/contracted research: Janssen-Cilag; Jesús San Miguel: Honoraria: Millennium, Celgene, Janssen-Cilag; Ofer Shpilberg: None; Pia Sondergeld: None; Pieter Sonneveld: Consultant/advisory role: ASH, Celgene, Janssen-Cilag; Sonja Zweegman: None.
The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.

Abstract

0533faThe treatment of multiple myeloma (MM) has undergone significant developments in recent years. The availability of the novel agents thalidomide, bortezomib, and lenalidomide has expanded treatment options and has improved the outcome of patients with MM. Following the introduction of these agents in the relapsed/refractory setting, they are also undergoing investigation in the initial treatment of MM. A number of phase III trials have demonstrated the efficacy of novel agent combinations in the transplant and nontransplant settings, and based on these results standard induction regimens are being challenged and replaced. In the transplant setting, a number of newer induction regimens are now available that have been shown to be superior to the vincristine, doxorubicin, and dexamethasone regimen. Similarly, in the front-line treatment of patients not eligible for transplantation, regimens incorporating novel agents have been found to be superior to the traditional melphalan plus prednisone regimen. Importantly, some of the novel agents appear to be active in patients with high-risk disease, such as adverse cytogenetic features, and certain comorbidities, such as renal impairment. This review presents an overview of the most recent data with these novel agents and summarizes European treatment practices incorporating the novel agents.

Introduction

Multiple myeloma (MM) is the second most frequent hematological malignancy. It is characterized by malignant plasma cell infiltration of the bone marrow and is associated with an increased level of monoclonal protein in the blood and/or urine. The uncontrolled growth of myeloma cells has many consequences, including skeletal destruction, bone marrow failure, suppression of normal immunoglobulin production, and renal insufficiency. Although the disease remains incurable, outcomes have improved substantially over recent years as a result of advances in therapy, including high-dose therapy and the availability of novel agents, as well as improvements in supportive care strategies [1,2 ].

In parallel with advances in treatment options, the goals of therapy have also evolved. Although prolongation of disease-free survival and overall survival (OS) times remain the ultimate goal, newer, effective therapies are making it possible to aim for a complete response (CR) in a larger proportion of patients than previously possible. The importance of achieving a CR for overall outcome has recently been the subject of discussion. In the transplant setting, the association between best response and OS has been noted in a number of analyses [3,4 ]. A study by the Spanish myeloma group in patients undergoing high-dose therapy showed that, within the group of patients who achieve disappearance of monoclonal protein, a distinction between CR and near-CR (nCR) may be important because the event-free survival (EFS) and OS times were significantly longer for patients in CR than for patients achieving a nCR or a partial response (PR) [5 ]. Moreover, it is not only the achievement of a CR, per se, but the maintenance of a durable CR that appears to influence outcome, as demonstrated in a study by Barlogie et al. [6 ], which showed that survival was significantly longer in patients who had a durable CR than in those who did not achieve a CR or in those who achieved CR but subsequently lost their CR status. In addition, achievement of a CR was found to be particularly important for patients with high-risk disease by gene-expression profiling. Interestingly, in a number of trials, a higher CR rate was not found to correlate with longer survival [7,8 ]. Similarly, CR was not a surrogate marker for survival in patients whose disease had evolved from monoclonal gammopathy of undetermined significance (MGUS) or smoldering MM [9 ], although newer data indicate that all or almost all myelomas arise from a MGUS precursor state. These results highlight the fact that other considerations need to be taken into account, such as toxicity, and that CR may not be the goal in all patients. Although an association between CR and OS has not been observed in all trials, achievement of a durable complete remission is an important treatment goal that has to be balanced with acceptable toxicity.

This review aims to provide a summary of recent data with the novel agents, thalidomide (Thalomid®; Celgene Corporation, Warren, NJ), bortezomib (Velcade®; Millennium Pharmaceuticals, Inc., Cambridge, MA), and lenalidomide (Revlimid®; Celgene Corporation, Warren, NJ), as well as an overview of current European treatment strategies, with a focus on these novel agents. There are substantial differences in treatment practices as well as approval status of these novel agents in the U.S. and Europe (Table 1), and even within Europe the availability of the different novel agents varies substantially. The manuscript is therefore focused on the review of recent data and includes a discussion of off-label use of these novel agents.

Front-Line Treatment

Transplant-Eligible Patients

Induction

For young patients, high-dose therapy with autologous stem cell support is still considered the standard treatment following the results of several randomized studies that demonstrated a survival advantage for patients given this treatment, compared with conventional chemotherapy [10,11,12 ]. During the 1990s, vincristine, doxorubicin, and dexamethasone (the VAD regimen) was considered the standard induction chemotherapy for MM patients undergoing stem cell transplantation in most European centers [13 ]. Responses to VAD are in the range of 55%-60%; however, CRs are achieved in only a small number of patients [14 ], and moreover, the response to VAD induction has no impact on the outcome after autologous stem cell transplantation (ASCT) and CRs are typically achieved only post-transplant.

Recent efforts have focused on improving response rates, and in particular CR rates, by including novel agents in induction treatments. Increasing the rate of CRs pretransplant may result in higher rates of CR post-transplant and superior long-term outcomes. A number of studies, which will be summarized in the following, are investigating induction regimens incorporating novel agents.

Thalidomide.

Thalidomide as short upfront therapy (4-month duration) was initially administered in combination with dexamethasone (TD) and was found to be superior to VAD or dexamethasone alone in terms of the overall response rate (ORR); however, the CR rate with the combination is low, at 4%-10% [15,16 ] (Table 2). In addition, TD has been administered until second ASCT, after initial treatment with the combination during the induction phase. A recently reported case-matched analysis found that patients who underwent this treatment had better clinical outcomes in terms of a higher CR plus very good partial response (VGPR) rate, longer time to progression (TTP), and longer progression-free survival (PFS) time than those assigned to receive VAD induction plus double ASCT [17 ] (Table 2). Thalidomide has also been investigated as part of three-drug regimens. The Dutch-Belgian Cooperative Trial Group for Hematology-Oncology (Stichting Hemato-Oncologie voor Volwassenen Nederland [HOVON]) investigated thalidomide in combination with doxorubicin and dexamethasone (TAD) and found that TAD resulted in significantly higher response rates than VAD postinduction [18,19 ]. In addition, in contrast to the results described by Macro et al. [20 ] for TD, the CR+VGPR rate remained significantly higher for TAD after stem cell transplantation. Furthermore, there were significantly longer EFS and PFS times in the TAD arm; however, there was no difference in terms of OS between the two arms (Table 2).

Another thalidomide-containing three-drug regimen was investigated in the Medical Research Council (MRC) Myeloma IX trial, which was designed to compare cyclophosphamide, thalidomide, and dexamethasone (CTD) with cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) as induction therapy, followed by a second randomization step between thalidomide maintenance and no maintenance [21,22 ]. CTD treatment resulted in a significantly higher ORR and CR rate than CVAD both pre- and post-transplant (Table 2).

Taken together, the results suggest that the combination TD is suboptimal, but that the addition of another chemotherapy agent, such as cyclophosphamide or an anthracycline, may improve the outcome.

Bortezomib.

Bortezomib has been investigated as part of a number of different induction regimens. A randomized phase III study by the French Myeloma Study Group (Intergroupe Francophone du Myélome [IFM]) examined the combination of bortezomib plus dexamethasone and found this to be significantly superior to the comparator arm, which consisted of VAD, with respect to response rates postinduction and post-transplant, as well as the 2-year PFS rate (Table 3) [23 ].

In addition, a number of studies are examining bortezomib as part of three-drug induction regimens. For example, the Italian Myeloma Network (Gruppo Italiano Malattie Ematologiche dell’Adulto [GIMEMA]) is investigating bortezomib in combination with thalidomide and dexamethasone (VTD) compared with TD given before and after double ASCT. At an interim analysis, VTD was found to be significantly superior to TD in terms of the CR+nCR and CR+VGPR rates pre- and post-transplant, as well as the PFS rate [24 ] (Table 3). The combination VTD as induction therapy was also found to be superior in terms of the postinduction CR rate in a phase III trial investigating the combination in comparison with TD or VBMCP/VBAD (vincristine, carmustine, melphalan, cyclophosphamide; prednisone/vincristine, carmustine, doxorubicin, and dexamethasone) plus two cycles of bortezomib, which is being conducted by the Spanish Myeloma Group (Programa para el Estudio y la Terapéutica de las Hemopatías Malignas y Grupo Español de Mieloma [PETHEMA/GEM]) [25 ] (Table 3).

The Arkansas group pioneered the Total Therapy approach, and a recent report of long-term follow-up of the Total Therapy 3 (TT3) regimen, which consists of tandem transplant with melphalan (200 mg/m2), induction and consolidation with bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide, and maintenance with VTD or bortezomib, lenalidomide, and dexamethasone (VRD), demonstrated encouraging results [26 ]. With a median follow-up of 39 months, the 4-year EFS rate was 71% and the 4-year OS rate was 78%. Comparison of the TT3 regimen with that of the predecessor trial, TT2, in which patients were randomized to receive thalidomide throughout or not, revealed that TT3 was significantly superior in terms of CR and nCR duration, EFS, and OS.

Another three-drug combination incorporating bortezomib is being examined by the HOVON and the German-speaking Myeloma Multicenter Group (GMMG). The ongoing phase III HOVON 65 MM/GMMG-HD4 trial is comparing bortezomib, doxorubicin, and dexamethasone (PAD) induction therapy with VAD followed by either bortezomib or thalidomide maintenance treatment post-ASCT [27 ]. In a first analysis of the trial, the PAD combination was found to be significantly superior to VAD in terms of the ≥VGPR and ≥PR rates (Table 3). Finally, an ongoing phase II/III trial by the German Myeloma Group (Deutsche Studiengruppe Multiples Myelom [DSMM]) is investigating bortezomib, cyclophosphamide, and dexamethasone (VCD) as an induction regimen based on positive results with the combination in earlier studies in the relapsed/refractory and upfront settings [28,29 ]. Results of an interim analysis of the ongoing trial demonstrated positive results for the combination [30 ] (Table 3).

In summary, a number of bortezomib induction regimens are now available. The results of the IFM trial indicate that the combination of bortezomib and dexamethasone is an appropriate regimen that is superior to the traditional VAD regimen. The addition of thalidomide may further improve response rates, especially CR and VGPR rates, and possibly the PFS interval. Mature results of the ongoing studies incorporating anthracyclines and alkylating agents are eagerly anticipated and will further define the role for bortezomib-containing induction regimens.

Lenalidomide.

A large phase III Eastern Cooperative Oncology Group (ECOG) trial is investigating lenalidomide in combination with two different doses of dexamethasone in the upfront setting. Patients were randomized to receive lenalidomide at 25 mg on days 1-21 plus high-dose dexamethasone (40 mg on days 1-4, 9-12, and 17-20 every 28 days [RD]) or low-dose dexamethasone (40 mg on days 1, 8, 15, and 22 every 28 days [Rd]) [8 ]. The primary study analysis was to compare the two regimens over four cycles and showed that the RD regimen was associated with a superior ORR and VGPR rate versus Rd (ORR, 79% versus 68%; p = .008 and ≥VGPR, 42% versus 24%; p = .008). Best responses, including the ORR (81% versus 70%; p = .009) and ≥VGPR rate (50% versus 40%; p < .0001), were also significantly better for RD. However, the median PFS time and 2-year OS rate were higher for Rd (median PFS, 25.3 months versus 19.1 months; p = .026 and 2-year OS, 87% versus 75%; p = .0002 for Rd versus RD, respectively), whereas the 3-year OS rate was 75% in both arms [31 ]. Among patients who underwent transplantation after four cycles of primary treatment, the 3-year OS rate was 92%, compared with 55% in those patients who did not undergo transplantation. In addition, among patients who received treatment with RD or Rd beyond 4 months, the 3-year OS rate was 79%. However, it has to be noted that this analysis was not a randomized comparison and that the trial was not designed to evaluate the combination of lenalidomide and dexamethasone as an induction regimen prior to ASCT. The RD regimen was associated with more toxicities than the Rd regimen [8 ]: Grade ≥3 venous thromboembolisms (VTEs) occurred in 26% versus 12% of patients (p = .0003), grade ≥3 infection/pneumonia occurred in 16% versus 9% of patients (p = .04), grade ≥3 nonhematological adverse events (AEs) were seen in 65% versus 48% of patients (p = .0002), and early deaths (75 years old with a poor performance status.

Lenalidomide

Lenalidomide has also been examined in the nontransplant setting for the treatment of elderly patients with newly diagnosed MM. In a phase I/II trial, the combination of lenalidomide with MP (MPR) was found to result in an ORR of 81% and a 24% CR rate [59 ]. With a median follow-up of 29.5 months, the median TTP and PFS times were 28.5 months and the 2-year OS rate was 90.5%. The main AEs included neutropenia, thrombocytopenia, and thromboembolism. These preliminary results suggest that the MPR regimen may be useful in the nontransplant setting; however, confirmation of the results by the ongoing randomized MM015 trial is needed. In addition, the HOVON and the Nordic Myeloma Study Group are conducting a phase III trial in elderly patients comparing melphalan, prednisone, and thalidomide (MPT) plus maintenance thalidomide with MPR followed by maintenance with lenalidomide, which will further clarify the role of lenalidomide in the nontransplant setting.

A subanalysis of the phase III ECOG trial examined the efficacy of RD versus Rd in patients ≥65 years old. The 1-year survival rate was found to be significantly better for patients receiving Rd than for those receiving RD (94% versus 83%, respectively; p = .004) [8 ].

Bortezomib

The combination of bortezomib with MP (VMP) was explored in the large phase III Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone (VISTA) trial and was found to be significantly superior to MP alone for all prespecified endpoints, including the CR rate, ORR, TTP, and OS time (Table 6) [60,61 ]. VMP was also superior to MP regarding two additional parameters that were included in the comparison of the two arms: time to next therapy (TTNT) and treatment-free interval (TFI). The TTNT was 28.1 months for VMP versus 19.2 months for MP (p 60 ml/minute) in 31% of patients.

Thalidomide is also considered a feasible option for the treatment of patients with renal impairment. An analysis of pharmacokinetic data in patients with varying degrees of renal function found that there was no correlation between thalidomide clearance and renal function [73 ]. In addition, clinical studies have shown that response rates and tolerability with thalidomide are similar in patients with renal failure and in those with normal renal function, both in the relapsed/refractory and front-line settings [74, 75 ]. In addition, recovery of renal function was observed in the majority of patients whose disease responded to thalidomide treatment [74 ].

Lenalidomide is primarily excreted by the kidneys and, therefore, careful monitoring of AEs and appropriate dose adjustments in patients with impaired renal function are essential [76,77,78,79 ]. Prospective studies investigating lenalidomide dose adapted to creatinine clearance have been initiated.

Cytogenetic Abnormalities

MM is characterized by various chromosomal changes that carry prognostic information. The deletion of chromosome 17 [del(17)], the translocation of chromosomes 4 and 14 [t(4;14)], the translocation of chromosomes 14 and 16 [t(14;16)], as detected by fluorescence in situ hybridization, the deletion of chromosome 13 [del(13)] by metaphase cytogenetics, and the presence of hypodiploidy are characteristic of high-risk disease [80 ]. Novel agents may offer the possibility of improving outcomes in patients with these adverse prognostic factors.

Bortezomib appears to be effective in patients with cytogenetic abnormalities, as observed in a number of studies. In the relapsed/refractory setting, the ORR, duration of response, and OS time were not found to be different between patients with and without del(13) [81,82 ]. In elderly patients with newly diagnosed disease, the response rate, TTP, and OS time were not negatively affected by the presence of t(4;14), t(14;16), or del(17p) [60 ]. In the transplant setting, bortezomib induction regimens were also found to remain effective in patients with cytogenetic abnormalities. In the IFM bortezomib plus dexamethasone versus VAD study, the combination of bortezomib plus dexamethasone resulted in a significantly higher ≥VGPR rate than VAD in patients with t(4;14) and/or del(17p) [23 ]. Similarly, in an Italian trial investigating a bortezomib-based induction regimen, the combination of VTD was significantly superior to TD in patients with t(4;14) and in those with del(17p) in terms of the CR+nCR rate [83 ].

The addition of thalidomide to the TT2 regimen was found to result in significantly longer survival in patients with cytogenetic abnormalities than in patients who did not receive thalidomide [46 ]. On the other hand, Cavo et al. [84 ] showed that TD resulted in a significantly lower probability of response in patients with co-existing del(13) and t(4;14), but not in those with a single abnormality. Moreover, a recent examination of thalidomide maintenance therapy in the MRC Myeloma IX trial found that, in patients with del(17), thalidomide treatment was unfavorable [22,47 ].

Lenalidomide has also been investigated in patients with cytogenetic abnormalities. Results from a study by Reece et al. [85 ] in patients with relapsed/refractory MM indicated that t(4;14) did not influence the response rate, TTP, or OS time, whereas in patients with del(17), the TTP and OS time were significantly shorter. A recent report by the IFM suggested that, in heavily pretreated patients with relapsed or refractory MM, the presence of t(4;14) resulted in a significantly lower response rate and shorter PFS and OS times than in patients without cytogenetic abnormalities [86 ]. Finally, a report by Kapoor et al. [87 ] showed that lenalidomide treatment resulted in comparable response rates in patients with newly diagnosed high-risk and standard-risk disease; however, responses were less durable in patients with high-risk disease and the PFS interval was significantly shorter in those patients. However, the OS time was not significantly different between the high-risk and standard-risk groups.

For all novel therapies, there is a lack of prospective data in patients with cytogenetic abnormalities. Currently available results are obtained from reports with small patient numbers and are often derived from subanalyses of trials. Overall, prospective studies with larger patient numbers and longer follow-up are needed to establish the role of novel agents in this setting to enable a risk-adapted approach.

Treatment Decisions for Newly Diagnosed Disease

Decision trees for the front-line treatment of MM have been developed, and Figure 1 shows a possible treatment tree based on available data from novel agents. The initial decision in newly diagnosed disease is whether the patient is eligible for transplantation or not. In patients 62% of patients in the dexamethasone arm crossing over to receive bortezomib [90 ] (Table 7). In another phase III trial, the addition of pegylated liposomal doxorubicin (PegLD) (Doxil®; Ortho Biotech Products, L.P., Bridgewater, NJ) to bortezomib was found to lead to a significantly longer TTP and OS time versus bortezomib alone [91 ]. A large number of studies have examined bortezomib in combination with steroids, conventional chemotherapy, or other novel agents and have demonstrated superior efficacy resulting from additive or synergistic effects [92,93,94,95 ]. Major toxicities with bortezomib in the relapsed setting include thrombocytopenia, neutropenia, PN, and gastrointestinal AEs. In the relapsed setting, bortezomib is indicated in the European Union for the treatment of MM at first relapse as a single agent, but clinically, it is almost universally used in combination.

Retreatment with bortezomib was examined in the prospective phase II Retreatment after Initial Response to Velcade® (RETRIEVE) study, in which patients whose disease had responded to previous bortezomib treatment and relapsed after ≥6 months could be retreated with bortezomib (with or without dexamethasone) [96 ]. Preliminary results of that study indicate that responses were achieved in approximately two thirds of patients and that retreatment is well tolerated with no evidence of cumulative toxicity. In addition, an analysis of response to treatment at relapse in the phase III VISTA trial demonstrated that retreatment with bortezomib appears feasible and that patients can also be effectively treated with immunomodulatory drugs (IMiDs) following front-line bortezomib [61 ].

Lenalidomide is licensed for the treatment of relapsed/refractory disease in combination with dexamethasone, based on two phase III studies (the MM009 and MM010 studies) that demonstrated a significantly greater ORR, CR rate, TTP, and OS time for the combination versus dexamethasone alone, despite 47.6% of patients in the dexamethasone group crossing over to receive lenalidomide plus dexamethasone (Table 7) [97,98,99 ]. The main toxicities reported with the combination of lenalidomide plus dexamethasone include neutropenia, thrombocytopenia, VTE, and infection [97,98 ]. An analysis of the effects of prior thalidomide exposure on response, TTP, and OS with lenalidomide plus dexamethasone revealed that the combination remained significantly superior to dexamethasone alone regardless of prior thalidomide [100 ]. In patients who were refractory to thalidomide, treatment with lenalidomide plus dexamethasone was associated with a lower CR rate and ORR and shorter TTP and PFS time than in those with thalidomide-sensitive disease.

Lenalidomide is also being investigated in combination with other agents, such as doxorubicin, cyclophosphamide, and bortezomib and also in combination with thalidomide. In general, response rates with these combination regimens are superior to those seen with lenalidomide plus dexamethasone alone. For example, the combination of lenalidomide, doxorubicin, and dexamethasone, which was investigated in a phase I/II study in 69 patients, resulted in an ORR of 73% in the overall population, including a 14.5% CR rate and 43% VGPR rate [101 ]. The median TTP was 10.4 months and the 1-year survival probability was 88%. Longer follow-up is needed to assess the effects on OS in this and other combination studies.

SCT at Relapse

The use of ASCT at relapse has been investigated in a number of studies [102,103,104,105,106,107 ] and is considered a useful option in selected patients [107 ]. Its success appears to be influenced by the efficacy of the previous transplant, the number of prior therapies, as well as the time between the initial and the second transplant step.

Furthermore, allogeneic stem cell transplantation (allo-SCT) may also be feasible in the relapsed setting, and this approach was investigated in a number of recent studies [108,109,110 ]. It has been suggested that allo-SCT may be valuable in patients with high-risk disease, but that it currently remains an investigational approach [111 ].

Treatment Decisions at Relapse

Figure 2 shows a possible treatment decision tree for the treatment of MM at relapse, with a focus on incorporating novel agents into the treatment. It is notable that, although novel agents are widely incorporated into treatment at relapse, data supporting their use does not always stem from randomized studies. Nevertheless, their use is associated with better outcomes [2 ], and at relapse after front-line treatment with one of the “older” agents, administration of a novel agent should be considered.

Increasingly, novel agents are being incorporated into front-line treatments, which will significantly influence the choices available at relapse and may also influence the efficacy of the different treatments.

A decision to be made at relapse is whether to repeat the initial front-line treatment or switch to a therapy different from that used previously. The decision will be influenced by the duration of remission to initial therapy as well as by the presence of or risk for toxicities. If a long remission was obtained (≥12 months) following a distinct short course of treatment and AEs were acceptable, then rechallenge with the front-line regimen may be possible. On the other hand, if only a short remission (≤6 months) was obtained and the duration of the initial therapy was long, then it may be advisable to switch to a different treatment. For example, transplant at relapse is feasible if a long remission was achieved with the initial transplant. Increasingly, novel agents are being incorporated into front-line therapies, and treatment at relapse has to consider the appropriate treatment sequence. If the relapse happened after long-term thalidomide treatment, then it would be advisable to change treatment and consider a bortezomib-based regimen with the potential addition of alkylating agents. If the disease recurred after front-line treatment with bortezomib, a switch to an IMiD-containing regimen may be indicated. Alternatively, retreatment with bortezomib may be considered if a good response to the initial bortezomib therapy was obtained and if the treatment-free interval was long.

The presence of toxicities will influence the choice of treatment at relapse and may necessitate a change from the front-line treatment. For example, if PN is present from front-line treatment, a switch to a non-neurotoxic agent, such as lenalidomide, may be necessary. The combination of lenalidomide and dexamethasone can be considered a reasonable treatment in thalidomide-refractory patients if PN is present. A history of or high risk for thromboembolic events may indicate a switch from an IMiD-based regimen to a bortezomib combination and the use of low molecular weight heparin (LMWH) thrombophylaxis to avoid further complications.

Specific disease characteristics also influence treatment decisions at relapse, for example, in cases of an aggressive relapse and the presence of poor-risk cytogenetics, treatment with bortezomib or lenalidomide may be indicated. In the presence of renal impairment, a bortezomib-containing regimen may be useful.

In choosing the optimal treatment at relapse, the decision should be individualized based on patient-specific characteristics such as age, presence of comorbidities, type of previous therapy, quality and duration of response, tolerance of therapy, and time without treatment. In addition, decisions have to be made regarding the sequential use of different agents versus combination treatment with simultaneous administration of several agents. Novel agents that have been shown to offer better outcomes than traditional regimens should, whenever feasible, be incorporated into the treatment strategy.

Managing AEs Associated with Novel Agent Use

Thromboembolic events are one of the most significant side effects associated with thalidomide or lenalidomide when these agents are used in combination with steroids or chemotherapy. The risk for developing thromboembolic events appears to be greater when erythropoiesis-stimulating agents (ESAs) are added to IMiDs [112 ].

Thromboprophylaxis consists of aspirin, LMWH, or warfarin given at either the full dose or a fixed low dose. In a phase III study, fixed low-dose warfarin was not inferior to LMWH or aspirin in patients with a low risk for developing thromboembolic events [113 ]. On the other hand, LMWH may be recommended in patients at higher risk for developing this complication and in those receiving concomitant high-dose dexamethasone or doxorubicin [114 ]. Studies are needed to define the optimal agent in the different settings. Prior history or a risk for developing thromboembolic events will require the use of thromboprophylaxis in combination with the chosen IMiD. Alternatively, bortezomib may be useful in this setting because this agent is not associated with a higher risk for thromboembolic events [115 ], even with the use of ESAs [116 ].

Both bortezomib and thalidomide can lead to PN, which can be debilitating in some patients. It has been observed that patients who do not develop PN during the first four to six cycles of bortezomib treatment are unlikely to develop this complication during further bortezomib treatment cycles. Notably, bortezomib-associated PN is reversible in the majority of patients. In the APEX trial, grade ≥2 PN resolved or improved in 64% of patients, whereas in the VISTA trial improvement by at least one grade was observed in 79% of patients in a median of 1.9 months [61,117 ]. Complete resolution was seen in 60% of patients within a median of 5.7 months. Close monitoring of patients and dose reduction at the first sign of a worsening of the tingling sensation are important. It may be useful to employ a specific questionnaire to help patients recognize the symptoms and to detect the early signs of PN [118 ].

The risk for developing PN while receiving thalidomide increases with prolonged administration [89 ]. Dose reduction or discontinuation of treatment is necessary to manage the complication [89 ]. Lenalidomide is not associated with PN and it may therefore be useful for the treatment of patients with pre-existing PN.

Bortezomib therapy can be associated with reactivation of varicella zoster virus (herpes zoster) [61,119 ]; however, the use of antiviral prophylaxis has been shown to successfully prevent this AE [120 ], and the routine use of antiviral prophylaxis in patients receiving a bortezomib-containing regimen should therefore be considered [119 ].

Neutropenia is frequently observed with lenalidomide treatment and may necessitate dose reduction, discontinuation of treatment, or administration of growth factors [59,79,121,122 ]. Bortezomib treatment can lead to thrombocytopenia, which may require dose reduction or temporary treatment discontinuation. However, bortezomib-induced thrombocytopenia is cyclical and platelets typically recover during the rest period of a treatment cycle, so that intervention may not be necessary [66,115 ].

MM is characterized by bone disease, and bisphosphonates play an important role in the management of skeletal events. Expert recommendations regarding the use of bisphosphonates have been formulated and were recently published [123 ]. In patients suffering from lytic bone disease, the use of bisphosphonates is recommended. Treatment should be administered for 2 years and proactive management is needed to avoid renal impairment and osteonecrosis of the jaw.

Clinical Gaps and Ongoing Research

A number of questions surrounding the use of novel agents in the treatment of MM remain. For example, long-term follow-up of the front-line trials is needed so that treatment decisions can be made based on robust survival data. Long-term data will provide answers to questions such as the optimal induction treatment and the appropriate sequencing of agents. Furthermore, new classes of antimyeloma agents, such as heat shock protein-90 and histone deacetylase inhibitors, have shown promising results in preclinical studies and are currently undergoing investigation in the clinical setting. The combination of these newer agents with the agents discussed herein appears attractive and may offer better outcomes.

Studies are needed to further explore the role of transplantation and of consolidation and maintenance therapy. Regarding risk-adapted treatment approaches, large trials or systematic reviews of the available data are needed to define the role of the different agents in the setting of high-risk disease and provide treatment recommendations according to risk factors, such as cytogenetic abnormalities. In addition, further advances in techniques, such as gene-expression profiling and single-nucleotide polymorphism analysis, are eagerly anticipated to further individualize treatment approaches for patients. Moreover, there may be a role for minimal residual disease detection in deciding on the intensity of induction therapy and on the duration of maintenance therapy. Finally, assessment of quality of life has so far been given insufficient attention in MM studies and future studies will help to close this gap.

Acknowledgments

The meeting of the authors and the contribution of Pia Sondergeld were supported by an educational grant from Ortho Biotech, a division of Janssen-Cilag Europe.

Author Contributions

Conception/Design: Heinz Ludwig, Meral Beksac, Joan Bladé, Mario Boccadoro, Jamie Cavenagh, Michele Cavo, Meletios Dimopoulos, Johannes Drach, Hermann Einsele, Thierry Facon, Hartmut Goldschmidt, Jean-Luc Harousseau, Urs Hess, Nicolas Ketterer, Martin Kropff, Larisa Mendeleeva, Gareth Morgan, Antonio Palumbo, Torben Plesner, Jesús San Miguel, Ofer Shpilberg, Pieter Sonneveld, Sonja Zweegman

Collection and/or assembly of data: Heinz Ludwig, Meral Beksac, Joan Bladé, Mario Boccadoro, Jamie Cavenagh, Michele Cavo, Meletios Dimopoulos, Johannes Drach, Hermann Einsele, Thierry Facon, Hartmut Goldschmidt, Jean-Luc Harousseau, Urs Hess, Nicolas Ketterer, Martin Kropff, Larisa Mendeleeva, Gareth Morgan, Antonio Palumbo, Torben Plesner, Jesús San Miguel, Ofer Shpilberg, Pieter Sonneveld, Sonja Zweegman

Data analysis and interpretation: Heinz Ludwig, Meral Beksac, Joan Bladé, Mario Boccadoro, Jamie Cavenagh, Michele Cavo, Meletios Dimopoulos, Johannes Drach, Hermann Einsele, Thierry Facon, Hartmut Goldschmidt, Jean-Luc Harousseau, Urs Hess, Nicolas Ketterer, Martin Kropff, Larisa Mendeleeva, Gareth Morgan, Antonio Palumbo, Torben Plesner, Jesús San Miguel, Ofer Shpilberg, Pieter Sonneveld, Sonja Zweegman

Manuscript writing: Heinz Ludwig, Meral Beksac, Joan Bladé, Mario Boccadoro, Jamie Cavenagh, Michele Cavo, Meletios Dimopoulos, Johannes Drach, Hermann Einsele, Thierry Facon, Hartmut Goldschmidt, Jean-Luc Harousseau, Urs Hess, Nicolas Ketterer, Martin Kropff, Larisa Mendeleeva, Gareth Morgan, Antonio Palumbo, Torben Plesner, Jesús San Miguel, Ofer Shpilberg, Pia Sondergeld, Pieter Sonneveld, Sonja Zweegman

Final approval of manuscript: Heinz Ludwig, Meral Beksac, Joan Bladé, Mario Boccadoro, Jamie Cavenagh, Michele Cavo, Meletios Dimopoulos, Johannes Drach, Hermann Einsele, Thierry Facon, Hartmut Goldschmidt, Jean-Luc Harousseau, Urs Hess, Nicolas Ketterer, Martin Kropff, Larisa Mendeleeva, Gareth Morgan, Antonio Palumbo, Torben Plesner, Jesús San Miguel, Ofer Shpilberg, Pia Sondergeld, Pieter Sonneveld, Sonja Zweegman

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Mehta J, Tricot G, Jagannath S et al. Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft? Bone Marrow Transplant 1998;21:887-892.

103

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104

Mikhael J, Samiee S, Stewart AK et al. Second autologous stem cell transplantation as salvage therapy in patients with relapsed multiple myeloma: Improved outcomes in patients with longer disease free interval after first autologous stem cell transplantation. Biol Blood Marrow Transplant 2006;12(1 suppl.):117.

105

Simpson L, Verma R, Kumar S et al. Outcome after second stem cell transplantation for relapsed multiple myeloma [abstract 8118]. J Clin Oncol 2007;25(18 suppl):470s.

106

Olin RL, Vogl DT, Porter DL et al. Second auto-SCT is safe and effective salvage therapy for relapsed multiple myeloma. Bone Marrow Transplant 2009;43:417-422.

107

Alvares CL, Davies FE, Horton C et al. The role of second autografts in the management of myeloma at first relapse. Haematologica 2006;91:141-142.

108

de Lavallade H, El-Cheikh J, Faucher C et al. Reduced-intensity conditioning allogeneic SCT as salvage treatment for relapsed multiple myeloma. Bone Marrow Transplant 2008;41:953-960.

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Minnema MC, van Dorp S, van de Donk N et al. Non-myeloablative allo-SCT for relapsed myeloma: A single-center experience [abstract 288]. Clin Lymphoma Myeloma 2009;9(1 suppl):42.

110

Elliott B, Osman K, Mandeli J et al. Nonmyeloablative conditioning and allogeneic transplantation for multiple myeloma [abstract 621]. Clin Lymphoma Myeloma 2009;9(1 suppl):87.

111

San-Miguel J, Harousseau JL, Joshua D et al. Individualizing treatment of patients with myeloma in the era of novel agents. J Clin Oncol 2008;26:2761-2766.

112

Niesvizky R, Spencer A, Wang M et al. Increased risk of thrombosis with lenalidomide in combination with dexamethasone and erythropoietin [abstract 7506]. J Clin Oncol 2006;24(18 suppl):423s.

113

Cavo M, Palumbo A, Bringhen S et al. A phase III study of enoxaparin versus low-dose warfarin versus aspirin as thromboprophylaxis for patients with newly diagnosed multiple myeloma treated up-front with thalidomide-containing regimens [abstract 3017]. Blood 2008;112:1038.

114

Palumbo A, Rajkumar SV, Dimopoulos MA et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008;22:414-423.

115

Lonial S, Richardson PG, San Miguel J et al. Characterisation of haematological profiles and low risk of thromboembolic events with bortezomib in patients with relapsed multiple myeloma. Br J Haematol 2008;143:222-229.

116

Richardson P, Schlag R, Khuageva NK et al. Erythropoiesis-stimulating agents do not adversely affect long-term outcomes nor increase the risk of thromboembolic events in multiple myeloma patients treated in the phase III VISTA trial [abstract 1741]. Blood 2008;112:614.

117

Richardson PG, Sonneveld P, Schuster MW et al. Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: Impact of a dose-modification guideline. Br J Haematol 2009;144:895-903.

118

Colson K, Doss DS, Swift R et al. Expanding role of bortezomib in multiple myeloma: Nursing implications. Cancer Nurs 2008;31:239-249.

119

Chanan-Khan A, Sonneveld P, Schuster MW et al. Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol 2008;26:4784-4790.

120

Vickrey E, Allen S, Mehta J et al. Acyclovir to prevent reactivation of varicella zoster virus (herpes zoster) in multiple myeloma patients receiving bortezomib therapy. Cancer 2009;115:229-232.

121

Mateos MV, García-Sanz R, Colado E et al. Should prophylactic granulocyte-colony stimulating factor be used in multiple myeloma patients developing neutropenia under lenalidomide-based therapy? Br J Haematol 2008;140:324-326.

122

Richardson P, Jagannath S, Hussein M et al. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood 2009;114:772-778.

123

Terpos E, Sezer O, Croucher PI et al. The use of bisphosphonates in multiple myeloma: Recommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol 2009;20:1303-1317. This review presents an overview of the most recent data using the novel agents thalidomide, bortezomib, and lenalidomide in the treatment of multiple myeloma and summarizes European treatment practices incorporating these novel agents.

A position paper of the European Myeloma Network (EMN). Correspondence: Heinz Ludwig, M.D., Department of Medicine, Wilhelminenspital, Montleartstr. 37, 1160 Vienna, Austria. Telephone: 43-1491502101; Fax: 43-1491502109; e-mail: heinz.ludwig@wienkav.at Received August 26, 2009; accepted for publication December 11, 2009; first published online in The Oncologist Express on January 19, 2010; available online without subscription through the open access option. ©AlphaMed Press 1083-7159/2010/$30.00/0 doi: 10.1634/theoncologist.2009-0203

Figure 1.

MM treatment tree outside clinical trials: front line.

*Indicates data available from a phase III randomized trial.

Abbreviations: CTD, cyclophosphamide, thalidomide, and dexamethasone; CTDa, attenuated cyclophosphamide, thalidomide, and dexamethasone; Cyc, cyclophosphamide; Dex, dexamethasone; IMiD, immunomodulatory drug; Len, lenalidomide; MM, multiple myeloma; MP, melphalan plus prednisone; MPR, melphalan, prednisone, and lenalidomide; MPT, melphalan, prednisone, and thalidomide; PAD, bortezomib, doxorubicin, and dexamethasone; PN, peripheral neuropathy; Pred, prednisone; Rd, lenalidomide plus low-dose dexamethasone; SCT, stem cell transplant; TAD, thalidomide, doxorubicin, and dexamethasone; Thal, thalidomide; TT3, Total Therapy 3; VCD, bortezomib, cyclophosphamide, and dexamethasone; VDT-PACE, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide; VGPR, very good partial response; VMP, bortezomib, melphalan, and prednisone; VRD, bortezomib, lenalidomide, and dexamethasone; VTD, bortezomib, thalidomide, and dexamethasone.

Figure 2.

MM treatment tree outside clinical trials: relapse.

*Indicates data available from a phase III randomized trial.

Abbreviations: allo-SCT, allogeneic stem cell transplantation; auto-SCT, autologous stem cell transplantation; CRD, cyclophosphamide, lenalidomide, and dexamethasone; CTD, cyclophosphamide, thalidomide, and dexamethasone; CVD, cyclophosphamide, bortezomib, and dexamethasone; Cyc, cyclophosphamide; Dex, dexamethasone; Len, lenalidomide; MPT, melphalan, prednisone, and thalidomide; PAD, bortezomib, doxorubicin, and dexamethasone; PegLD, pegylated liposomal doxorubicin; PN, peripheral neuropathy; Thal, thalidomide; VMP, bortezomib, melphalan, and prednisone; VTD, bortezomib, thalidomide, and dexamethasone.

Table 1.

Approved therapeutic indications for the novel agents thalidomide, bortezomib, and lenalidomide
Europe ([External Link: http://www.emea.europa.eu]) U.S. ([External Link: http://www.fda.gov])
Thalidomide Thalidomide in combination with melphalan and prednisone as first-line treatment of patients with untreated multiple myeloma, aged ≥65 years or ineligible for high-dose chemotherapy. Thalidomide in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma.
Bortezomib Bortezomib in combination with melphalan and prednisone is indicated for the treatment of patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with bone marrow transplant. Bortezomib for injection is indicated for the treatment of patients with multiple myeloma.
Bortezomib is indicated as monotherapy for the treatment of progressive multiple myeloma in patients who have received at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplantation.
Lenalidomide Lenalidomide in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Lenalidomide in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy.

Table 2.

Summary of thalidomide induction trials
Regimen n Median follow-up Postinduction
Post-transplant
TTP OS Major AEs during induction Reference
≥PR (%) ≥VGPR (%) ≥nCR (%) ≥PR (%) ≥VGPR (%) ≥nCR (%)
Thal/Dex
versus 100 NA 76a NA 13 NA NA NA NA NA DVT, PE, PN, GI toxicity [15 ]
VAD 100 52 13
Thal/Dex
versus 100 NA NA 35a NA NA 44 NA NA NA DVT, PE, PN, GI toxicity [20 ]
VAD 104 13 42
Thal/Dex
versus 135 NA NA 30a NA NA 68a NA 4-yr, 61%a 5-yr, 69% DVT, PE, PN, GI toxicity [17 ]
VAD 135 15 49 4-yr, 41% 5-yr, 53%
Thal/Dex
versus 235 NA 63a 43.8a CR only, 7.7a NA NA NA 22.6 mosa NA DVT, PE, PN, GI toxicity [16 ]
Dex 235 46 15.8 CR only, 2.6 6.5 mos
TAD versus 267 NA 77a 33a CR only, 4 87a 65a CR only, 30a PFS, 33 mosa 59 mos grade 2-4 neurological, 48% [18,19 ]
VAD 269 54 15 CR only, 2 79 54 CR only, 21 PFS, 25 mos 62 mos grade 2-4 neurological, 29%
CTD versus 1,114 35 mos 87a 39 CR only, 19a 88 67 CR only, 51 NA NA NA [21,22 ]
CVAD 75 27 9 87 53 CR only, 40

aStatistically significant difference between arms.

Abbreviations: AE, adverse event; CR, complete response; CTD, cyclophosphamide, thalidomide, and dexamethasone; CVAD, cyclophosphamide, vincristine, doxorubicin, and dexamethasone; Dex, dexamethasone; DVT, deep vein thrombosis; GI, gastrointestinal; NA, not available; nCR, near complete response; OS, overall survival; PE, pulmonary embolism; PFS, progression-free survival; PN, peripheral neuropathy; PR, partial response; TAD, thalidomide, doxorubicin, and dexamethasone; Thal, thalidomide; TTP, time to progression; VAD, vincristine, doxorubicin, and dexamethasone; VGPR, very good partial response.

Table 3.

Summary of bortezomib induction trials
Regimen n Median follow-up Postinduction
Post-transplant
TTP OS Major AEs during induction (grade 3 or 4) (%) Reference
≥PR (%) ≥VGPR (%) ≥nCR (%) ≥PR (%) ≥VGPR (%) ≥nCR (%)
Bortezomib + Dex
versus 240 2 yrs 82a 39a 15a 91 61a 40a Median, NR; 2-yr PFS, 69%a 2-yr, 90% PN (grade 3 only), 7 [23 ]
VAD 242 65 16 7 91 44 22 Median, 28 mos; 2-yr PFS, 60% 2-yr, 88% PN (grade 3 only), 2
VTD versus 226 15 mos 94a 62a 32a 76a 55a 2-yr PFS, 90%a 2-yr, 96% PN, 9; skin rash, 7.5 [24 ]
TD 234 79 29 12 58 32 2-yr PFS, 80% 2-yr, 91% PN, 2.5; skin rash, 1
VBMCP/VBAD +
bortezomib
versus 64 NA 72 NA 28 97 NA 54 NA NA PN, 0 Thrombotic events, 5 [25 ]
VTD versus 56 80 41 97 64 PN, 16 Thrombotic events, 1.7
TD 63 66 12 97 53 PN, 1.5 Thrombotic events, 13
PAD versus 150 NA 79a 45a 7a 91a 71a 26a NA NA PN, 16 [27 ]
VAD 150 57 17 2 79 44 14 PN, 6
VCD 200 NA 84 NA 12.5 (CR only) NA NA NA NA NA PN (overall), 12.5%; PN (grade 3 only), 0.5% [30 ]

aStatistically significant difference between arms.

Abbreviations: AE, adverse event; CR, complete response; Dex, dexamethasone; NA, not available; nCR, near complete response; NR, not reached; OS, overall survival; PAD, bortezomib, doxorubicin, and dexamethasone; PFS, progression-free survival; PN, peripheral neuropathy; PR, partial response; TD, thalidomide and dexamethasone; TTP, time to progression; VAD, vincristine, doxorubicin, and dexamethasone; VBMCP/VBAD, vincristine, carmustine, melphalan, cyclophosphamide, and prednisone/vincristine, carmustine, doxorubicin, and dexamethasone; VCD, bortezomib, cyclophosphamide, and dexamethasone; VGPR, very good partial response; VTD, bortezomib, thalidomide, and dexamethasone.

Table 4.

Summary of thalidomide maintenance studies
Treatment n EFS or PFS OS Survival after relapse Reference
Double ASCT; maintenance:
pamidronate + Thal versus
pamidronate versus none,
until disease progression 597 3-yr EFS, 52% versus 37% versus 36% (p < .009) 4-yr, 87% versus 74% versus 77% (p < .04) Similar in all treatment groups (p = .7) [43 ]
Single ASCT; maintenance: prednisolone + Thal versus prednisolone, 12 mos 243 3-yr PFS, 42% versus 23% (p < .001) 3-yr, 86% versus 75% (p = .004) 79% versus 77% (p = .237) [44 ]
Double ASCT; maintenance:
Thal versus none, until
disease progression 668 Median, 6.0 versus 4.1 yrs (p = .001) 8-yr, 57% versus 44% (p = .09a) Significantly shorter OS from relapse after Thal exposure [45,46 ]
Single or double ASCT; maintenance: Thal versus IFN, until disease progression 556 EFS, 33 versus 22 mos; p < .001. PFS, 33 versus 25 mos (p < .001) 59 versus 62 mos
(p = .96) Significantly shorter OS from relapse after Thal exposure [19 ]
Single ASCT or
nonintensive therapy (MP
versus CTDa); maintenance:
Thal versus none, until
disease progression 820 Significantly longer PFS for <VGPR after ASCT (p = .007); worse outcome for Thal maintenance in patients with del(17p) No significant difference Significantly shorter OS from relapse after Thal exposure [47,48 ]
Thal/Dex versus MP; maintenance: Thal + IFN versus IFN, until disease progression 289 PFS, 24 versus 12.6 mos (p < .024) 52.6 versus 52.2 mos (p = .68) NA [7, 49 ]

aSignificant difference in patients with cytogenetic abnormalities.

Abbreviations: ASCT, autologous stem cell transplantation; CTDa, attenuated cyclophosphamide, thalidomide, and dexamethasone; EFS, event-free survival; IFN interferon; MP, melphalan plus prednisone; NA, not available; OS, overall survival; PFS, progression-free survival; Thal, thalidomide.

Table 5.

Summary of phase III trials investigating thalidomide combinations in the upfront setting in patients not eligible for transplantation
Regimen n Median follow-up CR + PR (%) CR (%) PFS/EFS/TTP (mos) OS (mos) Main reported AEs (grade 3 or 4) (%) Reference
Thal/MP
versus 191 51.5 mos 76a 13a 27.5a 51.6a Thromboembolism, 12 Infection, 13 GI, 11 PN, 6 [53 ]
MP 124 35 2 17.8 33.2 Thromboembolism, 4 Infection, 9 GI, 3 PN, 0
Thal/MP
versus 129 38.1 mos 76a 16a 21.8a 45 Thromboembolism, 12 Infection, 10 GI, 6 PN, 10 [54,55 ]
MP 126 48 4 14.5 47.6 Thromboembolism, 2 Infection, 2 GI, 1 PN, 0
Thal/MPb
versus 363 36 mos 42d 6c,d 20a 29 Markedly higher incidence of constipation with Thal [56 ]
MP 28 3c 18 33 Venous thromboembolism, 8% in both arms
Thal/MP
versus 152 NA 66a 2 EFS 13 versus 9a 37 Thrombosis, 3 Infection, 28 GI, 5 Neurological, 23 [57 ]
MP 149 47 2 PFS 13 versus 10a 30 Thrombosis, 0 Infection, 18 GI, 7 Neurological, 4
Thal/MP
versus 113 47.5 mos 62a 7a 24.1a 44a Thromboembolism, 6 GIe, 20 PN, 2 [58 ]
MP 116 31 1 18.5 29.1 Thromboembolism, 3 GIe, 14 PN, 2
Thal/Dex
versus 145 28.1 mos 68a 2 TTP, 21.2 versus 29.1 41.5a DVT/PE, 13 Infection, 13 Constipation/nausea/vomiting, 13 Neuropathy, 7 [7 ]
MP 143 50 2 PFS, 16.7 versus 20.7 49.4 DVT/PE, 7 Infection, 8 Constipation/nausea/vomiting, 6 Neuropathy, 1
CTDa
versus 856 32 mos 82.5a 22.5 No significant difference for PFS between arms NA VTE, 16 [21,48 ]
MP 48.7 6.2 VTE, 4.5

aStatistically significant difference between arms.

bThal doses, 200-400 mg.

cCR + nCR.

dStatistical information not available.

eGrade 2-4.

Abbreviations: AE, adverse event; CR, complete response; CTDa, attenuated cyclophosphamide, thalidomide, and dexamethasone; Dex, dexamethasone; DVT, deep vein thrombosis; EFS, event-free survival; GI, gastrointestinal; MP, melphalan plus prednisone; nCR, near complete response; OS, overall survival; PE, pulmonary embolism; PFS, progression-free survival; PR, partial response; Thal, thalidomide; TTP, time to progression; VTE, venous thromboembolism.

Table 6.

Summary of bortezomib phase III trials conducted in the upfront setting in patients not eligible for transplantation
Regimen n Median follow-up CR + PR (%) CR (%) TTP OS AEs (grade 3 or 4)c (%) Reference
VMP versus 337 25.9 mos 71a 30a 24 mosa 3-yrb, 72%a Herpes zoster, 4 GI, 20 PN, 14 [60,61 ]
MP 331 35 4 16.6 mos 3-yrb, 59% Herpes zoster, 2 GI, 5 PN, 0
VMP (bortezomib
once weekly) versus 98 NA 81 22 2-yr, 81% 2-yr, 92% Neutropenia, 37 Cardiac toxicity, 0 Infections, 7 PN, 5 [63 ]
VTP (bortezomib
once weekly) 107 81 27 2-yr, 83% 2-yr, 94% Neutropenia, 21 Cardiac toxicity, 8.5 Infections, <1 PN, 9
VMP (bortezomib
once weekly)
versus 229 16.1 mos 78 21a 3-yr PFS, 56% 3-yr, 89% Neutropenia, 28 Thrombocytopenia, 16 Infections, 7 PN, 2 [64 ]
VMPT (bortezomib
once weekly) 221 84 35 3-yr PFS, 71% 3-yr, 90% Neutropenia, 28 Thrombocytopenia, 20 Infections, 12 PN, 2

aStatistically significant difference between arms.

bMedian OS not reached in either arm.

cMajor AEs/AEs that differ between arms.

Abbreviations: AE, adverse event; CR, complete response; GI, gastrointestinal; MP, melphalan plus prednisone; NA, not available; OS, overall survival; PFS, progression-free survival; PN, peripheral neuropathy; PR, partial response; TTP, time to progression; VMP, bortezomib, melphalan, and prednisone; VMPT, bortezomib, melphalan, prednisone, and thalidomide; VTP, bortezomib, thalidomide, and prednisone.

Table 7.

Summary of phase III trials in the relapsed/refractory setting
Treatment n Median follow-up CR + PR (%) CR + nCR (%) TTP (mos) OS Reference
Bortezomib versus 333 22 mos 43a 16a 6.2a 29.8 mosa [90 ]
Dex 336 18 2 3.5 23.7 mos
Bortezomib/pegylated
liposomal doxorubicin
versus 318 NA 52a 17 9.3a 15-mo OS, 76%a [91 ]
Bortezomib 318 44 13 6.5 15-mo OS, 65%
Lenalidomide/Dex versus 353 48 mos 60.6a 15a,b 13.4a 38 mosa [97,98,99 ]
Dex 351 21.9 2 4.6 31.6 mos

aSignificant difference between arms.

bCR only.

Abbreviations: CR, complete response; Dex, dexamethasone; nCR, near complete response; OS, overall survival; PR, partial response; TTP, time to progression.

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