Bortezomib, thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma

A retrospective study

Authors


  • Presented as a poster at the 2007 Annual Meeting of the American Society of Hematology, Atlanta, Georgia, December 8-11, 2007 and also as a poster at the XIth International Myeloma Workshop, Kos Island, Greece, June 25-30, 2007.

Abstract

BACKGROUND:

This single-center retrospective study determined the efficacy of bortezomib, thalidomide, and dexamethasone (BTD) as induction for patients with multiple myeloma (MM) who were eligible for autologous stem cell transplantation (ASCT).

METHODS:

Patients with symptomatic MM who had received BTD induction before stem cell collection at Winship Cancer Institute were included. BTD induction comprised up to 8 3-week cycles of bortezomib 1.3 mg/m2 on Days 1, 4, 8, and 11; thalidomide 100 mg daily; and dexamethasone 40 mg on Days 1 through 4 and Days 9 through 12. Stem cell mobilization involved granulocyte-colony–stimulating factor and/or cyclophosphamide. Response was assessed according to European Group for Blood and Marrow Transplantation criteria.

RESULTS:

Review of medical records identified 44 eligible patients (34 patients who were treated in the front-line setting and 10 patients who were treated for recurrent disease) who received a median of 4 BTD cycles. The overall response rate (ORR) was 91%, which included a greater than or equal to very good partial response (≥VGPR) rate of 57% (including 20% stringent complete responses/complete response [sCR/CR] rate). In front-line patients, the ORR was 94%, which included a 56% ≥VGPR rate (24% sCR/CR). The median CD34-positive stem cell collection was 10.67 × 106/kg. The ORR after ASCT in 34 patients who were evaluable for response was 100%, including a 76% ≥VGPR rate (53% sCR/CR). Among all 44 patients, the median progression-free survival (PFS) was 27.4 months. The median overall survival (OS) was not reached after a median follow-up of 25 months, and the 2-year OS rate was 82%. There were no significant differences in PFS (27.4 months vs 23.5 months) or in 2-year survival (80% vs 90%) between patients who did and did not undergo ASCT, respectively. Twenty patients (45%) developed neuropathy, including 4 (9%) with grade 3 neuropathy episodes, and 1 patient developed deep vein thrombosis.

CONCLUSIONS:

BTD was highly effective and well tolerated as induction for MM patients who were eligible for ASCT. Long-term outcomes appeared to be similar with or without ASCT consolidation. Cancer 2010. © 2010 American Cancer Society.

Over the past 10 years, the introduction of novel agents has markedly changed the treatment of patients with multiple myeloma (MM) in both the frontline and recurrent settings.1-3 Of these novel agents, the proteasome inhibitor bortezomib (VELCADE Millennium Pharmaceuticals, Inc., Cambridge, Mass; and Johnson & Johnson Pharmaceutical Research & Development LLC, Raritan, NJ) is now approved for the treatment of MM based on the results from the phase 3 VELCADE as Initial Standard Therapy in Multiple Myeloma (VISTA) study,4 and thalidomide (Thalomid; Celgene Corporation, Summit, NJ) plus dexamethasone is approved for patients with newly diagnosed MM based on data from 2 phase 3 studies.5, 6 Bortezomib is associated with high rates of overall and complete response (CR) when it is used as induction therapy before high-dose therapy (HDT) plus autologous stem cell transplantation (ASCT),3, 7 which translate into very high overall response and CR/very good partial response (VGPR) rates after transplantation. This is important, because achieving greater than a VGPR both postinduction and post-transplantation is associated with prolonged progression-free survival (PFS) and overall survival (OS) in patients with MM8; therefore, the use of bortezomib-based induction regimens may result in improved outcomes.

Preclinical data indicated the synergistic activity of bortezomib and thalidomide,9 and several studies have since investigated bortezomib and thalidomide combination regimens. Bortezomib plus thalidomide has demonstrated substantial activity in the frontline setting,10, 11 and the triplet combination of bortezomib, thalidomide, and dexamethasone (BTD) has demonstrated notable activity in the setting of recurrent disease.12 BTD is currently being investigated in the frontline setting13-17 and is recommended as an induction treatment option for patients with MM who are eligible for HDT-ASCT according to the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology.18 Here, we report the results of a retrospective, single-center, case-series analysis evaluating BTD as induction therapy before ASCT.

MATERIALS AND METHODS

Patients

This was a retrospective analysis of all patients with symptomatic MM who received BTD as induction before stem cell mobilization at the Winship Cancer Institute between January 2005 and December 2007; 1 patient with advanced renal failure has been described previously.19 Patients with both newly diagnosed and previously treated MM who were not taking part in a clinical trial were included, and the medical records of all eligible patients were reviewed. According to practice guidelines at our center, patients were not excluded from BTD therapy on the basis of creatinine clearance rate or dialysis dependence; patients with grade 2 or worse peripheral neuropathy were offered alternative therapy.

Study Design

A review of medical records indicated that all patients received up to 8 3-week cycles of bortezomib 1.3 mg/m2 on Days 1, 4, 8, and 11; thalidomide 100 mg daily; and dexamethasone 40 mg on Days 1 through 4 and Days 9 through 12. All patients received aspirin for deep vein thrombosis (DVT) prophylaxis and concomitant treatment with antiviral and antibiotic medications. Patients proceeded to stem cell collection after 3 or 4 cycles based on response; patients underwent stem cell mobilization with granulocyte-colony–stimulating factor (G-CSF) 7.5 μg/kg twice daily for 4 days or cyclophosphamide 2 g/m2 to 4 g/m2 at the discretion of the treating physician. After stem cell mobilization and harvesting, patients proceeded to HDT-ASCT or maintenance therapy with thalidomide at the physician's discretion. Patients who proceeded to HDT-ASCT received conditioning with melphalan 200 mg/m2; those with impaired renal function received melphalan 140 mg/m2.

Assessments

Study objectives were to assess response rates after BTD induction and post-ASCT, to assess PFS and OS, and to assess the tolerability of BTD induction. In accordance with clinical practice at our center, all patients were assessed for response and progression according to European Blood and Marrow Transplantation (EBMT) criteria20 every 3 weeks (once per cycle) during BTD therapy and every 2 to 3 months thereafter; patients who proceeded to HDT-ASCT were assessed at 30 days and 100 days after transplantation and every 3 months thereafter. In addition to EBMT criteria, a VGPR was defined as a 90% reduction in serum or urine M-protein according to International Uniform criteria,21 and serum free-light chain data also were reviewed when available. Patient records were reviewed, and all toxicities were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

Statistical Analysis

Response rates to BTD were determined in all patients, in newly diagnosed patients, in patients with elevated (ie, greater than the median) β2-microglobulin, and in patients with high-risk cytogenetics. Patients with cytogenetic abnormalities, which were defined as abnormal conventional cytogenetics in at least 2 metaphases, were considered high risk. Response rates also were determined after ASCT. PFS and OS were evaluated in all patients with the Kaplan-Meier method using SPSS software. PFS and OS also were determined according to transplantation status and cytogenetic risk profile in patients who proceeded to HDT-ASCT. Patients were not censored for HDT-ASCT in analyses of PFS.

RESULTS

Patient Characteristics

An analysis of patient records identified 44 patients with MM who were eligible for inclusion in this retrospective analysis; 3 patients presented with plasma cell leukemia (PCL), 2 at presentation and 1 after receiving lenalidomide (Revlimid; Celgene Corporation) plus high-dose dexamethasone. Patient demographics and disease characteristics are summarized in Table 1. Thirty-four patients received BTD as frontline therapy. Eight patients received BTD as second-line therapy; their prior therapies included vincristine, doxorubicin, and dexamethasone (VAD) (n = 1 patient who had progressive disease [PD]), bortezomib (n = 2 patients who had PD), thalidomide plus dexamethasone (n = 3 patients; 2 who achieved less than a partial response [PR] and 1 who had PD), and lenalidomide plus dexamethasone (n = 2 patients who had PD). Two patients received BTD as third-line therapy after bortezomib and bortezomib plus dexamethasone (1 patient achieved less than a PR and 1 patient had PD). The median duration of BTD therapy was 4 cycles (range, 2-8 cycles). Nine patients, including all 3 patients who had PCL, had abnormal cytogenetics: One patient had deletion of chromosome 13 (del13), 2 patients had hypodiploidy with del13 (including 1 patient with PCL), 3 patients had hypodiploidy without del13 (including 2 patients with PCL), and 3 patients had hyperdiploidy.

Table 1. Patient Baseline Characteristics and Demographics (N=44)
CharacteristicNo. of Patients (%)Median [Range]
  • ISS indicates International Staging System; Ig, immunoglobulin.

  • a

    Patients who had cytogenetic abnormalities identified by conventional cytogenetics.

Age, y 58 [38–71]
No. of men/women23/21 
ISS stage, n=42  
 I15 (36) 
 II17 (40) 
 III10 (24) 
No. previously untreated/treated 34/10 
B2-microglobulin level, mg/L 3.4 [1.3-41.9]
Creatinine level, mg/dL 1.2 [0.5-21.0]
Hemoglobin, g/dL 11.1 [6.0-17.2]
Myeloma type  
 IgG22 (50) 
 IgA7 (16) 
 Free light chain15 (34) 
High-risk cytogeneticsa9 (21) 

Response to Induction Therapy

The response rate to BTD induction was 91% (40 of 44 patients), including a 9% stringent CR (sCR) rate, an 11% CR rate (20% sCR/CR rate), and a 36% VGPR rate, for a ≥VGPR rate of 57%. Table 2 summarizes the responses in all patients, in patients excluding those with PCL (n = 41), in frontline patients (n = 34), in patients with elevated β2-microglobulin (>3.4 mg/L; n = 21), and in patients with high-risk cytogenetics (n = 9). Of the 3 patients with PCL, 1 achieved a PR, and 2 proceeded to salvage therapy with combined bortezomib, thalidomide, and dexamethasone plus cisplatin, doxorubicin, cyclophosphamide, and etoposide (VTD-PACE) chemotherapy.

Table 2. Response to Bortezomib, Thalidomide, and Dexamethasone Induction Therapy in All Patients, in All Patients Except Those With Plasma Cell Leukemia, in Newly Diagnosed Patients, in Patients with Elevated β2-Microglobulin, and in Patients With High-Risk Cytogenetics
ResponseNo. of Patients (%)
All PatientsAll Except Patients with PCLNewly Diagnosed PatientsPatients With β2M >3.4 mg/LPatients With High-Risk Cytogenetics
  1. PCL indicates plasma cell leukemia; β2M, β2-microglobulin; ORR, overall response rate; sCR, stringent complete response; CR, complete response; VGPR, very good partial response; PR, partial response; MR, minimal response; SD, stable disease; PD, progressive disease.

Total no. of patients444134219
ORR40 (91)39 (95)32 (94)20 (95)7 (78)
 sCR 4 (9) 4 (10) 3 (9) 3 (14)1 (11)
 CR 5 (11) 5 (12) 5 (15) 3 (14)1 (11)
 sCR+CR 9 (20) 9 (22) 8 (24) 6 (29)2 (22)
 VGPR16 (36)16 (39)11 (32) 7 (33)3 (33)
 CR+VGPR25 (57)25 (61)19 (56)13 (62)5 (56)
 PR15 (34)14 (34)12 (35) 7 (33)2 (22)
MR/SD 2 (5) 2 (5) 1 (3) 0 (0)0 (0)
PD 2 (5) 0 (0) 1 (3) 1 (5)2 (22)

Stem Cell Collection and ASCT

In accordance with the selection criteria for this retrospective analysis, all 44 patients underwent stem cell mobilization after a median of 4 cycles of BTD. In total, 28 patients received G-CSF alone, 3 patients received G-CSF followed by high-dose cyclophosphamide salvage, and 11 patients received planned mobilization with high-dose cyclophosphamide alone. The remaining 2 patients (both with PCL) underwent mobilization after progression on BTD and after subsequent therapy with VTD-PACE. The overall median collection of CD34-positive stem cells was 10.67 × 106/kg (range, 3.49-130.56 × 106/kg).

In total, 34 patients proceeded to HDT-ASCT, and 3 of those patients received reduced-dose melphalan (140 mg/m2) because of impaired renal function. The median time from the start of BTD induction therapy to ASCT was 4.4 months (133 days). All patients who proceeded to ASCT were evaluable for response. The overall response rate post-ASCT was 100%, including a 53% sCR/CR rate (32% sCR) and a 24% VGPR rate, for a ≥VGPR rate of 76%; Table 3 shows the changes in response status from pretransplantation to post-ASCT. Reasons for not proceeding to ASCT included PD in 2 patients with PCL, peripheral neuropathy in 2 patients, and physician/patient choice for the other 6 patients; 3 patients received thalidomide 100 mg daily as maintenance therapy. Of the 10 patients who did not proceed to ASCT, 4 patients achieved a CR, 4 patients achieved a VGPR, and 2 patients had PD with BTD induction.

Table 3. Responses Before and After Transplantation in 34 of 34 Response-Evaluable Patients Who Proceeded to High-Dose Therapy Plus Autologous Stem Cell Transplantation
ResponseNo. of Patients (%)
Before TransplantationAfter Transplantation
  1. ORR indicates overall response rate; sCR, stringent complete response; CR, complete response; VGPR, very good partial response; PR, partial response; MR, minimal response.

ORR32 (94)34 (100)
 sCR 2 (6)11 (32)
 CR 3 (9) 7 (21)
 VGPR12 (35) 8 (24)
 PR15 (44) 8 (24)
MR 2 (6) 0 (0)

Time-to-Events Data

Among all 44 patients, the median PFS from initiation of BTD induction was 27.4 months. The median OS from initiation of BTD induction had not been reached after a median follow-up of 25 months, and the estimated 1-year and 2-year OS rates were 95% and 82%, respectively. An analysis of time-to-events data according to transplantation status revealed no differences in PFS or OS between patients who underwent ASCT (n = 34) and patients who did not undergo ASCT (n = 10) (Fig. 1). The median PFS was 27.4 months in the ASCT group and 23.5 months in the non-ASCT group (P = .945; Kaplan-Meier estimate). In the ASCT group, the post-transplantation 1-year survival rate was 97% (1 transplantation-related mortality was reported after the patient underwent a second ASCT), and the 2-year survival rate was 80%. In patients who did not proceed to ASCT, the 1-year and 2-year survival rates were both 90%. The median PFS was 14.7 months in patients with high-risk cytogenetics versus 28 months in patients with low-risk cytogenetics (Fig. 2). After ASCT, an analysis of OS according to whether patients achieved a CR/VGPR with BTD induction suggested a trend toward improved survival in patients who achieved at least a VGPR with BTD induction therapy (P = .36) (Fig. 3).

Figure 1.

(A) Progression-free survival and (B) overall survival are illustrated after bortezomib, thalidomide, and dexamethasone induction therapy in all patients (n = 44 patients) and according to whether patients underwent autologous stem cell transplantation (ASCT) (n = 34 patients) or did not undergo ASCT (n = 10 patients).

Figure 2.

(A) Progression-free survival and (B) overall survival are illustrated in patients with high-risk cytogenetics (n = 9 patients) and low-risk cytogenetics (n = 35 patients).

Figure 3.

Overall survival in all patients is illustrated according to whether they achieved a complete response (CR)/very good partial response (VGPR) with bortezomib, thalidomide, and dexamethasone induction therapy.

Safety

A comprehensive summary of all adverse events is provided in Table 4. Twenty-four patients (55%) developed neuropathy during BTD induction therapy, including 20 patients with grade 1/2 neuropathy and 4 patients (9%) with grade 3 neuropathy. Two patients (5%) developed DVT, and 2 patients (5%) developed herpes zoster. No major bleeding episodes occurred.

Table 4. Adverse Events From Combined Bortezomib, Thalidomide, and Dexamethasone Induction Therapy in All Patients (n=44)
EventNo. of Patients (%)
AllGrade 1/2Grade 3Grade 4
  1. DVT/PE indicates deep vein thrombosis/pulmonary embolism.

Peripheral neuropathy24 (55)20 (45)4 (9)0 (0)
Lower extremity edema18 (41)18 (41)0 (0)0 (0)
Fatigue17 (39)15 (34)2 (5)0 (0)
Anemia14 (32)12 (27)2 (5)0 (0)
Constipation14 (32)14 (32)0 (0)0 (0)
Agitation9 (20)9 (20)0 (0)0 (0)
Insomnia9 (20)9 (20)0 (0)0 (0)
Bone pain8 (18)8 (18)0 (0)0 (0)
Transaminitis6 (14)6 (14)0 (0)0 (0)
Thrombocytopenia6 (14)5 (11)1 (2)0 (0)
Gastritis6 (14)6 (14)0 (0)0 (0)
Upper respiratory tract infection5 (11)5 (11)0 (0)0 (0)
Nausea5 (11)5 (11)0 (0)0 (0)
Dyspnea5 (11)5 (11)0 (0)0 (0)
Rash5 (11)5 (11)0 (0)0 (0)
Neutropenia4 (9)4 (9)0 (0)0 (0)
Lack of appetite4 (9)4 (9)0 (0)0 (0)
Cough4 (9)4 (9)0 (0)0 (0)
Limb pain4 (9)4 (9)0 (0)0 (0)
Muscle cramp4 (9)4 (9)0 (0)0 (0)
Head ache2 (5)2 (5)0 (0)0 (0)
Parasthesia2 (5)2 (5)0 (0)0 (0)
Herpes zoster infection2 (5)2 (5)0 (0)0 (0)
DVT/PE2 (5)0 (0)1 (2)1 (2)
Tremor1 (2)1 (2)0 (0)0 (0)
Pyrexia1 (2)1 (2)0 (0)0 (0)
Vomiting1 (2)1 (2)0 (0)0 (0)

DISCUSSION

The findings of this retrospective case-series analysis demonstrate that BTD is highly effective as induction therapy, with 57% of patients achieving a ≥VGPR. It is noteworthy that BTD induction therapy resulted in very high response rates in previously untreated patients with MM (94% overall, including a 56% ≥VGPR rate). Furthermore, the adverse prognostic factors of elevated β2-microglobulin and high-risk cytogenetics appeared to have no substantial effects on the response to BTD induction; however, the effects of high-risk cytogenetics should be interpreted with caution because of the small number of patients in this group. This substantial activity translated into high response rates after ASCT, with all evaluable patients responding, including 53% who achieved a sCR/CR and 76% who achieved a ≥VGPR. Such high CR and ≥VGPR rates are important, because it has been demonstrated that CR rates and a ≥VGPR rates, both postinduction and post-ASCT, are prognostic for improved outcomes.8, 22-27

To date, this is the largest study, with the longest follow-up, to assess BTD induction therapy. The 25-month follow-up allowed an analysis of post-ASCT outcomes to assess the impact of the response and CR rates achieved; and, to our knowledge, this is the first study to report time-to-events data after BTD induction. Reflecting the association between CR and ≥VGPR rates and improved outcomes,8, 22-27 the time-to-events data were promising. In addition, analysis of OS post-transplantation according to response to BTD induction therapy suggested a trend toward improved survival in patients who achieved a ≥VGPR compared with those who did not, although the small number of patients who did not proceed to HDT-ASCT limits interpretation of this result. It is noteworthy that PFS and OS appeared to be the same in patients who did and those who did not proceed to HDT-ASCT, suggesting that BTD may obviate the need for HDT-ASCT in some patients. Together with reports that BTD provides further cytoreduction when administered as maintenance post-ASCT,28 these data add to the debate regarding the use of HDT-ASCT in the era of novel agent-based therapies.3, 29 However, in the current study, further follow-up is needed to assess the long-term outcomes of patients who underwent HDT-ASCT or received maintenance therapy; it is important to note that, because of the retrospective nature of our study, data on minimal residual disease (MRD) status by flow cytometry or PCR were not available for patients who achieved a CR. The use of HDT-ASCT as consolidation for patients who achieve a CR with BTD but remain MRD-positive could result in a further improvement in the depth of response, and it has been demonstrated that MRD status can further stratify outcomes in patients who achieve a CR according to EBMT criteria.30-32 Despite the small number of patients in our series with high-risk cytogenetics (n = 9) among those who proceeded to ASCT, PFS and OS appeared shorter in patients who had high-risk cytogenetics compared with those who had low-risk cytogenetics. On the basis of results produced with other thalidomide-containing regimens in patients with high-risk cytogenetics,33, 34 it is possible, and represents a testable hypothesis, that patients with high-risk cytogenetics may have benefited from a longer duration of BTD therapy either before ASCT13 or as maintenance or consolidation therapy once they were in remission.

The efficacy data reported here are similar to those reported in other studies of BTD induction therapy for patients with MM.13-15, 17, 35 It is noteworthy that our results are very similar to interim data from a phase 3 study by the Italian Group for Adult Hematologic Diseases (GIMEMA), which compared BTD with thalidomide plus dexamethasone as induction therapy in newly diagnosed patients,13 supporting the validity of the findings from our retrospective analysis. In the GIMEMA phase 3 study, BTD produced significantly higher response rates than thalidomide plus dexamethasone both postinduction (94% overall, including a 62% ≥VGPR rate and a 32% CR/near-CR rate, vs 79% overall, including a 29% ≥VGPR rate and a 12% CR/near-CR rate) and post-transplantation (a 76% ≥VGPR rate, including a 55% CR/near-CR rate, vs a 58% ≥VGPR rate, including a 32% CR/near-CR rate).13 These results for BTD and the response rates observed in our analysis similarly appear greater than those reported with thalidomide plus dexamethasone in 2 phase 3 studies in frontline MM.5, 6 Furthermore, the response rates reported with BTD in the current analysis and in the GIMEMA phase 3 study also appear to compare favorably with those reported for bortezomib plus dexamethasone36-39; for example, in the French Myeloma Intergroup (IFM) phase 3 study of bortezomib plus dexamethasone versus VAD as induction therapy, the response rate to bortezomib plus dexamethasone induction was 82%, including a 39% ≥VGPR rate and a 15% CR/near-CR rate, with 68% achieving a ≥VGPR after transplantation, including a 39% CR/near-CR rate38 (updated data presented at the American Society of Hematology [ASH]/American Society of Clinical Oncology Joint Symposium, San Francisco, California, December 7, 2008; part of the 50th ASH Annual Meeting and Exposition, San Francisco, California, December 6-9, 2008).

The approach of combining bortezomib with an immunomodulatory drug and dexamethasone as induction therapy in newly diagnosed patients with MM also has been demonstrated in 2 studies of the combination of bortezomib, the thalidomide analog lenalidomide, and dexamethasone.40, 41 Preliminary results from a phase 1/2 study indicate highly promising activity with this combination, which produced a 100% overall response rate, including a 75% ≥VGPR rate and a 40% CR/near-CR rate.40

BTD is associated with rapid responses. In the current analysis, patients received a median of only 4 3-week cycles; in other studies, similarly high response rates were observed with even shorter durations of BTD therapy.13, 35 The abbreviated number of cycles needed to achieve such high response rates likely contributes to the generally good tolerability of the BTD regimen. In particular, the short duration of therapy may minimize cumulative peripheral neuropathy arising from treatment. Both bortezomib42, 43 and thalidomide44-46 are associated with peripheral neuropathy, so a possible increase in the incidence of peripheral neuropathy when these agents are combined was a concern with BTD therapy. However, the 45% rate of neuropathy reported in our analysis appears similar to that reported with bortezomib plus melphalan and prednisone in previously untreated patients in the VISTA phase 3 study (44%)4 and with single-agent bortezomib in the Assessment of Proteasome Inhibition on Extending Remissions (APEX) phase 3 study (37%)43; the 9% rate of grade 3 events also appears similar to the rates reported in VISTA (13%)4 and APEX (9%),43 in the GIMEMA phase 3 study of BTD (9%),13 in the IFM phase 3 study of bortezomib plus dexamethasone (7%),38 and in phase 3 studies of thalidomide plus dexamethasone (3%-7%).5, 6 Together, these data suggest that the combination of bortezomib and thalidomide in the BTD regimen does not appear to result in additive peripheral neuropathy.

Also noteworthy was the low rate of DVT observed with BTD induction in the current analysis (2%), which, even allowing for the fact that all patients received aspirin prophylaxis, is markedly less than the DVT rates reported in studies of thalidomide plus dexamethasone, a regimen that is associated with an elevated rate of thromboembolic events.5, 6, 47 This difference is supported by preliminary data from the GIMEMA phase 3 study of BTD versus thalidomide plus dexamethasone, which demonstrated a significantly lower rate of DVT with BTD (3.9% vs 5.5%; P = .01) although all patients received prophylaxis.13 These findings, together with the low rates of DVT reported from studies of bortezomib in combination with regimens of known thrombogenic potential, suggest that the addition of bortezomib may mitigate such thrombogenic potential.48

In conclusion, BTD is highly active and well tolerated as induction therapy before ASCT in patients with MM. This translates into very high response rates, very high rates of ≥VGPR after transplantation, and, as reported here for the first time, promising long-term outcomes after BTD induction. In addition, in this retrospective analysis, there was no notable difference in PFS or OS between the ASCT and non-ASCT groups, which suggests that BTD may obviate the need for ASCT in certain patients, although further follow-up would be needed to confirm this possibility. The final results from the GIMEMA phase 3 study of BTD versus thalidomide plus dexamethasone13 likely will provide confirmatory evidence of the impressive efficacy of the BTD regimen in previously untreated patients with MM.

Acknowledgements

We acknowledge the writing assistance of Jane Saunders and Steve Hill of FireKite, UK, during the development of this publication, which was funded by Millennium Pharmaceuticals.

CONFLICT OF INTEREST DISCLOSURES

Ms. Lonial received research funding from Millennium Pharmaceuticals. Ms. Gleason has received honoraria from Celgene Corporation and Millennium Pharmaceuticals. Dr. Heffner has received honoraria from Millennium Pharmaceuticals. Dr. Kaufman has acted as a consultant for Millennium Pharmaceuticals, Celgene Corporation, and Genzyme.

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