ORIGINAL ARTICLE
`LONG-TERM RESULTS OF REV-DEX THERAPY FOR NEWLY DIAGNOSED MYELOMA
`
`Long-term Results of Response to Therapy, Time to Progression,
`and Survival With Lenalidomide Plus Dexamethasone
`in Newly Diagnosed Myeloma
`
`MARTHA Q. LACY, MD; MORIE A. GERTZ, MD; ANGELA DISPENZIERI, MD; SUZANNE R. HAYMAN, MD;
`SUSAN GEYER, PHD; BRIAN KABAT, BS; STEVEN R. ZELDENRUST, MD, PHD; SHAJI KUMAR, MD; PHILIP R. GREIPP, MD;
`RAFAEL FONSECA, MD; JOHN A. LUST, MD, PHD; STEPHEN J. RUSSELL, MD, PHD; ROBERT A. KYLE, MD;
`THOMAS E. WITZIG, MD; P. LEIF BERGSAGEL, MD; A. KEITH STEWART, MD; AND S. VINCENT RAJKUMAR, MD
`
`OBJECTIVE: To determine the long-term effects of a combined
`regimen of lenalidomide and dexamethasone (Rev-Dex) on time to
`progression, progression-free survival, and overall survival (OS) in
`patients with multiple myeloma.
`PATIENTS AND METHODS: From March 2004 through October
`2004, 34 patients were registered for the study. They were
`treated with 25 mg/d of lenalidomide on days 1 through 21 of a
`28-day cycle and 40 mg/d of dexamethasone on days 1 through 4,
`9 through 12, and 17 through 20 of each cycle. After 4 cycles of
`therapy, patients were allowed to discontinue treatment to pursue
`autologous stem cell transplant (SCT). Treatment beyond 4 cycles
`was permitted at the physician s discretion.
`RESULTS: Thirteen patients proceeded to SCT after initial therapy
`and were censored at that time point for purposes of calculation
`of response. Thirty-one patients achieved an objective response,
`defined as a partial response or better (91%; 95% confidence
`interval, 79%-98%), with a complete response plus very good par-
`tial response rate of 56%. The complete response plus very good
`partial response among the 21 patients who received Rev-Dex
`without SCT was 67%. The 2-year progression-free survival rates
`for patients proceeding to SCT and patients remaining on Rev-Dex
`were 83% and 59%, respectively; the OS rates were 92% and 90%
`at 2 years and 92% and 85% at 3 years, respectively. The 3-year
`OS rate for the whole cohort was 88%.
`CONCLUSION: The Rev-Dex regimen is highly active in the treat-
`ment of newly diagnosed multiple myeloma. Responses are du-
`rable with a low progression rate at 2 years. Randomized trials
`that incorporate quality-of-life measures are needed to determine
`if this and other combination regimens are better used early in
`therapy or should be reserved for later interventions.
`Mayo Clin Proc. 2007;82(10):1179-1184
`
`CI = confidence interval; CR = complete response; ECOG = Eastern
`Cooperative Oncology Group; G-CSF = granulocyte colony–stimulating
`factor; OS = overall survival; PFS = progression-free survival; PR = partial
`response; Rev-Dex = lenalidomide and dexamethasone; SCT = stem cell
`transplant; Thal-Dex = thalidomide plus dexamethasone; TTP = time to
`progression; VGPR = very good partial response
`
`Multiple myeloma remains incurable, notwithstanding
`
`recent advances in treatment options. Autologous
`stem cell transplant (SCT) has been shown to be superior to
`conventional dose chemotherapy in 2 randomized trials.1,2
`The standard therapy before SCT was once vincristine,
`doxorubicin, and dexamethasone.3-5 Despite lack of a ran-
`domized phase 3 trial, the combination of thalidomide plus
`dexamethasone (Thal-Dex) is replacing vincristine, doxo-
`
`rubicin, and dexamethasone in newly diagnosed myeloma
`based on efficacy, ease of administration, and low toxicity
`reported in phase 2 clinical trials6-8 and a case control
`study.9 In a recent randomized trial conducted by the East-
`ern Cooperative Oncology Group (ECOG), the response
`rate with Thal-Dex (63%) was significantly higher than
`with dexamethasone alone (41%) (P=.0017).10
`Lenalidomide (CC-5013) belongs to a class of thalido-
`mide analogues that are termed immunomodulatory drugs.
`The safety profile of lenalidomide differs from that of
`thalidomide in preclinical11 and clinical studies.12,13 Data
`from clinical trials in patients with relapsed myeloma sug-
`gest that lenalidomide is less likely to cause peripheral
`neuropathy, constipation, and sedation than thalidomide13-15
`but is more myelosuppressive. The incidence of thromboem-
`bolism is similar for the 2 regimens.16,17 We hypothesized
`that lenalidomide and dexamethasone (Rev-Dex) may be a
`safer and more effective alternative to Thal-Dex in newly
`diagnosed myeloma. The goal of this phase 2 clinical trial
`was to determine the response rate and toxicity of Rev-Dex
`in patients with newly diagnosed multiple myeloma. We
`previously reported the remarkably high response rate
`(91%) seen in this trial with Rev-Dex as frontline therapy
`for myeloma.18 However, that report reflected responses
`seen primarily in the first 4 to 6 months of therapy, and data
`on long-term end points such as time to progression (TTP),
`progression-free survival (PFS), and overall survival (OS)
`were not available. We now present the first data on dura-
`bility of response, TTP, PFS, and OS with the use of Rev-
`Dex as initial therapy for myeloma. Our analysis also in-
`cludes new data regarding the depth and durability of re-
`sponses with this regimen.
`
`From the Division of Hematology (M.Q.L., M.A.G., A.D., S.R.H., S.R.Z., S.K.,
`P.R.G., J.A.L., S.J.R., R.A.K., T.E.W., S.V.R.) and Cancer Center Statistics Unit
`(S.G., B.K.), Mayo Clinic, Rochester, MN; and Division of Hematology/Oncol-
`ogy, Mayo Clinic, Scottsdale, AZ (R.F., P.L.B., A.K.S.).
`
`Address reprint requests and correspondence to Martha Q. Lacy, MD, Division
`of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905
`(lacy.martha@mayo.edu).
`
`© 2007 Mayo Foundation for Medical Education and Research
`
`1179
`Mayo Clin Proc. • October 2007;82(10):1179-1184 • www.mayoclinicproceedings.com
`
`For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
`
`ALVOGEN, Exh. 1038, p. 0001
`
`

`

`LONG-TERM RESULTS OF REV-DEX THERAPY FOR NEWLY DIAGNOSED MYELOMA
`
`PATIENTS AND METHODS
`
`ELIGIBILITY
`Patients who were aged at least 18 years and had previously
`untreated symptomatic multiple myeloma were eligible to
`enroll in the study, provided that they met the following
`conditions. Patients were required to have bone marrow
`plasma of 10% or greater and measurable disease, as de-
`fined by M protein greater than 10 g/L, urine light chain
`excretion greater than or equal to 200 mg/d, or measurable
`soft tissue plasmacytoma that had not been radiated. Pa-
`tients also needed to have hemoglobin levels greater than 8
`g/dL, platelet counts greater than 100 × 109/L, absolute
`neutrophil counts greater than 1.5 × 109/L, and creatinine
`levels less than 2.5 mg/dL (to convert to µmol/L, multiply
`by 76.25). No systemic therapy or prior corticosteroid
`treatment for myeloma was permitted. Prior localized ra-
`diation therapy for solitary plasmacytoma was allowed,
`provided that it occurred at least 4 weeks before the date of
`registration. Patients with smoldering multiple myeloma or
`monoclonal gammopathy of undetermined significance
`were excluded. Also excluded were patients with uncon-
`trolled infection, another active malignancy, deep vein
`thrombosis that had not been therapeutically anticoagu-
`lated, and an ECOG performance score of 3 or 4. Men who
`were unwilling to use a condom, pregnant or nursing
`women, and women of child-bearing age who refused to
`use a dual method of contraception were excluded from the
`study. Overall, 34 patients were registered to the study
`from March 2004 through October 2004, all of whom were
`evaluated for response and toxicity. The study was ap-
`proved by the Mayo Foundation Institutional Review
`Board in accordance with federal regulations and the Dec-
`laration of Helsinki.
`
`TREATMENT SCHEDULE
`On days 1 through 21 of a 28-day cycle, patients received
`25 mg/d of lenalidomide orally. On days 1 through 4, 9
`through 12, and 17 through 20 of each cycle, 40 mg/d of
`dexamethasone was given orally. Patients also received an
`aspirin (81 mg or 324 mg, at the discretion of the physician)
`once daily as thrombosis prophylaxis. Antibiotic and anti-
`viral prophylaxis was not mandated but left to physician
`discretion. Patients were allowed to discontinue treatment
`after 4 cycles of therapy to pursue SCT, but treatment
`beyond 4 cycles was permitted at the physician’s discre-
`tion. Patients who continued therapy beyond 4 months
`received 40 mg/d of dexamethasone only on days 1 through
`4 only of each cycle.
`Dose adjustments were permitted based on toxicity.
`Lenalidomide was permanently discontinued in the event
`of erythema multiforme/Stevens-Johnson syndrome,
`
`desquamating/blistering rash of any grade, any rash of
`grade 4 severity, grade 4 neuropathy or hypersensitivity,
`and grade 3 or higher bradycardia or cardiac arrhythmia. If
`patients experienced other grade 3 or higher adverse events
`that were thought to be related to lenalidomide, the drug
`was withheld until resolution of the adverse event and then
`restarted at the next lower dose level. Lenalidomide was
`progressively reduced for other related grade 3 or higher
`adverse events to dose levels of 15 mg, 10 mg, and 5 mg
`administered on days 1 through 21 of a 28-day cycle,
`except for isolated cases of neutropenia, in which the addi-
`tion of granulocyte colony–stimulating factor (G-CSF) was
`permitted instead of dose reduction. When grade 3 or 4
`adverse events occurred before day 15 of a cycle and
`resolved to a severity of grade 2 or lower before day 21 of
`the cycle, lenalidomide was resumed at the next lower dose
`level until day 21, with the next cycle continuing at the
`reduced dose level. For grade 3 or 4 adverse events that
`occurred on or after day 15 of a given cycle, lenalidomide
`was withheld for the remainder of the cycle and reduced by
`1 dose level beginning with the next cycle. Once the dose
`of lenalidomide was reduced for toxicity, no dose
`reescalation was allowed. The following progressive dose
`reduction was permitted for dexamethasone-related toxic-
`ity: 40 mg/d for 4 days every 2 weeks, then 40 mg/d for 4
`days every 4 weeks, and finally 20 mg/d for 4 days every 4
`weeks. Therapy with lenalidomide or dexamethasone was
`discontinued permanently in patients who were unable to
`tolerate the lowest doses of these agents.
`
`RESPONSE AND TOXICITY CRITERIA
`The primary end point of this trial was the response rate,
`estimated on the basis of the best response to therapy for
`each patient during the course of treatment. The response
`criteria used were standard European Group for Blood and
`Marrow Transplant19 (ie, Bladé criteria). An objective (par-
`tial or better) response was defined as a 50% or greater
`reduction in the level of the serum M protein and/or a
`reduction in 24-hour urinary light chain excretion by 90%
`or greater or to less than 200 mg. No increase in the number
`or size of lytic bone lesions or any other evidence of
`progressive disease by other parameters was allowed. To
`be judged a complete response (CR), the partial response
`(PR) criteria had to be met, no serum or urine M proteins
`could be detected by immunofixation studies, and 5% or
`fewer plasma cells were observed on bone marrow exami-
`nation. Patients were classified as having a very good
`partial response (VGPR) based on the International My-
`eloma Working Group response criteria.20 In addition to
`criteria for PR, VGPR required that serum and urine M
`proteins be detectable only on immunofixation but not on
`electrophoresis, a 90% or greater reduction in serum M
`
`1180
`
`Mayo Clin Proc. • October 2007;82(10):1179-1184 • www.mayoclinicproceedings.com
`
`For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
`
`ALVOGEN, Exh. 1038, p. 0002
`
`

`

`LONG-TERM RESULTS OF REV-DEX THERAPY FOR NEWLY DIAGNOSED MYELOMA
`
`TABLE 1. Patient Characteristics*†
`
`Characteristic
`
`All patients
`(N=34)
`
`No transplant
`(n=21)
`
`Transplant
`(n=13)
`
`Sex, female
`Anemia (hemoglobin <11 g/dL)
`Lytic bone lesions
`β
`2-Microglobulin >2.7 mg/L
`Lactate dehydrogenase (>250 U/L)
`ISS stage 3
`BM plasma cell labeling index >1%§
`
`11 (32)
`15 (44)
`19 (56)
`19 (56)
` 4 (12)
` 4 (12)
`14 (41)
`
` 3 (14)
` 9 (43)
`11 (52)
`11 (52)
` 3 (14)
` 3 (14)
` 9 (43)
`
`8 (62)
`6 (46)
`8 (62)
`8 (62)
`1 (8)
`1 (8)
`5 (38)
`
`*BM = bone marrow; ISS =International Staging System.
`†Data are given as number (percentage) unless indicated otherwise.
`‡Exact P value.
`§Only 32 of the 34 patients had a BM plasma cell labeling index done at baseline.
`
`P value
`(transplant vs
`no transplant)
`
`.01‡
`.85
`.60
`.60
`>.99‡
`>.99‡
`.85
`
`proteins, and a 24-hour urine M protein level of 100 mg/d
`or less. All response categories had to be confirmed by 2
`consecutive measurements at least 4 weeks apart; this was a
`modification of the Bladé criteria that require responses to
`be confirmed at least 6 weeks apart.20
`Disease progression required any 1 of the following
`criteria: (1) increase in serum M protein by 25% or more
`above the lowest response level and an increase in absolute
`level by more than 5g/L, (2) increase in urine M protein by
`25% above the lowest remission value and an absolute
`increase in excretion by 200 mg/d or greater, (3) increase in
`the size of soft-tissue plasmacytoma by more than 50% or
`appearance of a new plasmacytoma, (4) definite appear-
`ance of bone lesions or increase in the size of existing bone
`lesions by more than 50%, and (5) unexplained hypercalce-
`mia greater than 11.5 mg/dL (8.9-10.1 mg/dL) (to convert
`to mmol/L, multiply by 0.25). For patients with CR, relapse
`included reappearance of M protein on immunofixation or
`protein electrophoresis of the serum or urine, or any other
`sign of progression (ie, new plasmacytoma, lytic bone le-
`sion, or hypercalcemia).
`The National Cancer Institute Common Terminology
`Criteria for Adverse Events, version 3, was used to grade
`adverse events as well as to assign perceived attribution of
`these events to the study treatment regimen. By these crite-
`ria, toxicity was defined as an adverse event considered
`possibly, probably, or definitely related to treatment.
`
`STATISTICAL ANALYSES
`The primary end point of this trial was the proportion of
`confirmed responses (patients who achieved CR, VGPR or
`PR), as defined earlier. All patients who met the eligibility
`criteria, signed a consent form, and had begun treatment
`were evaluated for response. Our goal was to assess re-
`sponses in 30 patients with previously untreated symptom-
`atic multiple myeloma; more than 30 patients were accrued
`to account for the possibility of ineligibility, cancellations,
`or major treatment violations. A modified 2-stage Fleming
`
`design, in which accrual was not halted for interim analy-
`sis, was used to evaluate the confirmed response rate. In
`this population, a true response rate of 45% would be
`considered promising vs the 20% true response rate arrived
`at by the null hypothesis. On the basis of these assump-
`tions, 9 or fewer confirmed responses meant that the treat-
`ment regimen was inactive, 10 or more that it was promis-
`ing and recommended for further testing. Interim analysis
`was performed after the 13th patient was accrued; if 2 or
`fewer responses were observed, the treatment regimen was
`considered inactive on the basis of this early evidence and
`accrual was terminated. This study design was powered at
`92% (P=.06) for the detection of a response rate of at least
`45%. To include all evaluated patients in the confidence
`interval (CI), an exact binomial CI was used for the re-
`sponse rate, assuming that the number of patients who
`responded to treatment was binomially distributed. The
`maximum grade for each type of adverse event along with
`perceived causality was recorded and reported for each
`patient.
`
`RESULTS
`
`Patient characteristics at study entry are presented in Table
`1. All patients, including 4 with Durie-Salmon stage I
`myeloma, were symptomatic at study entry. Patients who
`discontinued therapy to proceed to SCT (n=13) received a
`median of 4 cycles of therapy (range, 4-13 cycles), whereas
`those who continued treatment with Rev-Dex (n=21) re-
`ceived a median of 19 cycles of therapy (range, 2-30
`cycles). Median follow-up was 36 months.
`
`RESPONSE TO THERAPY
`Thirty-one of 34 patients (91%; 95% CI, 79%-98%)
`achieved an objective response to therapy. Six patients
`(18%) achieved a CR, 13 patients (38%) a VGPR, and 12
`patients (35%) a PR as their best response to treatment
`(Table 2), with a CR + VGPR rate of 56%. Of the 3 patients
`
`1181
`Mayo Clin Proc. • October 2007;82(10):1179-1184 • www.mayoclinicproceedings.com
`
`For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
`
`ALVOGEN, Exh. 1038, p. 0003
`
`

`

`LONG-TERM RESULTS OF REV-DEX THERAPY FOR NEWLY DIAGNOSED MYELOMA
`
`No transplant
`Transplant
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Time to progression (%)
`
`0
`
`5
`
`10
`
`15
`Months
`
`20
`
`25
`
`FIGURE 1. Time to progression of patients who proceeded to early
`stem cell transplant and those who did not.
`
`sponse rates at month 4, which, in our experience, was
`when most patients decided whether to discontinue treat-
`ment to pursue SCT or to continue with Rev-Dex therapy.
`Baseline characteristics of the transplant vs no transplant
`group are summarized in Table 1. The overall response rate
`was 90% among the no transplant group and 100% among
`the transplant group. The details regarding depth of re-
`sponse at the 4-month time point are listed in Table 3.
`
`TOXICITY AND DEATHS
`Major toxicities seen in this trial were described in detail in
`our previous publication.18 Overall, 55% of patients experi-
`enced grade 3 or higher nonhematologic toxicity at some
`point during therapy, most commonly fatigue (21%), neu-
`tropenia (21%), anxiety (6%), pneumonitis (6%), muscle
`weakness (6%), and rash (6%). One patient developed a
`pulmonary embolism (grade 4 toxicity) but recovered with
`therapy; no other patient developed deep vein thrombosis
`or pulmonary embolism. Two patients died during the
`study, both from infection, possibly related to therapy. The
`4-month mortality rate was 5.9% (95% CI, 0.7%-20.0%).
`
`TIME TO PROGRESSION, PROGRESSION-FREE SURVIVAL,
`AND OVERALL SURVIVAL
`The median TTP was 32.4 months for the no transplant
`group; median TTP has not been reached for the transplant
`group. The 2-year TTP rates were 71% for the entire cohort,
`including 66% in the no transplant group and 83% in the
`transplant group (Figure 1). The 2-year PFS rates for the no
`transplant group and the transplant group were 59% and 83%,
`respectively (Figure 2). The median PFS was 29 months for
`the no transplant group and has not yet been reached for the
`transplant group. The 2-year OS rates for the no transplant vs
`transplant group were 90% and 92%, respectively; the corre-
`sponding 3-year rates were 85% and 92%, respectively (Fig-
`ure 3). The 3-year OS for the whole cohort was 88%.
`
`TABLE 2. Long-term Results of Lenalidomide-
`Dexamethasone Therapy*†
`
`Entire cohort
`(N=34)
`
`No transplant group
`(n=21)
`
`Objective response
`(CR or VGPR or PR)
`CR
`VGPR
`PR
`
`31 (91)
` 6 (18)
`13 (38)
`12 (35)
`
`18 (86)
` 5 (24)
` 9 (43)
` 4 (19)
`
`*CR = complete response; PR = partial response; VGPR = very good
`partial response.
`† Data are given as number (percentage).
`
`who did not achieve at least a PR to treatment, 2 had at least
`a 25% reduction in M protein levels, and 1 had stable
`disease. Responses were rapid; the median time to response
`was 1 month.
`As described previously, patients were allowed to pro-
`ceed to stem cell harvest after completing 4 cycles of
`therapy if they were willing to undergo and were deemed
`eligible for such therapy. As of December 2006, 15 of the
`34 patients (44%) had undergone a stem cell harvest, 13 of
`whom discontinued treatment to proceed with early autolo-
`gous SCT within 1 year of diagnosis (transplant group).
`Adequate stem cells (>3.0 × 106 CD34 cells/kg of body
`weight) were obtained in all patients who underwent autol-
`ogous SCT; the median CD34 cell count was 7.9 × 106/kg
`body weight over 2 to 7 collections. Stem cells were mobi-
`lized with 10 µg/kg of G-CSF in all but 2 patients who
`received a daily dose of 1500 mg/m2 of cyclophosphamide
`for 2 days in addition to G-CSF. Both patients initially
`responded to Rev-Dex; however, their levels of M protein
`and circulating monoclonal plasma cells later increased.
`Among the 21 patients who continued to receive Rev-
`Dex as primary therapy (the no transplant group), the depth
`of remission improved over time. Complete response was
`achieved by 5 patients (24%), VGPR by 9 patients (43%),
`and PR by 4 patients (19%) as their best response to treat-
`ment. The CR plus VGPR rate was 67%.
`To assess whether transplant was offered only to pa-
`tients with less-than-optimal responses, we examined re-
`
`TABLE 3. Responses to Lenalidomide-Dexamethasone Therapy
`at Time of Stem Cell Transplant Decision (Month 4)*†
`
`No transplant
`(n=21)
`
`Transplant
`(n=13)
`
`CR or VGPR or PR
`CR
`VGPR
`PR
`NR
`
`18 (86)
` 1 (5)
` 9 (43)
` 8 (38)
` 3 (14)
`
`13 (100)
` 1 (8)
` 4 (31)
` 8 (62)
` 0 (0)
`
`*CR = complete response; PR = partial response; NR = no response;
`VGPR = very good partial response.
`†Data are given as number (percentage).
`
`1182
`
`Mayo Clin Proc. • October 2007;82(10):1179-1184 • www.mayoclinicproceedings.com
`
`For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
`
`ALVOGEN, Exh. 1038, p. 0004
`
`

`

`LONG-TERM RESULTS OF REV-DEX THERAPY FOR NEWLY DIAGNOSED MYELOMA
`
`No transplant
`Transplant
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Overall survival (%)
`
`No transplant
`Transplant
`
`5
`
`10
`
`15
`Months
`
`20
`
`25
`
`0
`
`5
`
`10
`
`15
`
`25
`20
`Months
`
`30
`
`35 40
`
`45
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`Progression-free survival (%)
`
`FIGURE 2. Progression-free survival of patients who proceeded to early
`stem cell transplant and those who did not.
`
`FIGURE 3. Overall survival of patients who proceeded to early stem
`cell transplant and those who did not.
`
`DISCUSSION
`
`We previously reported a remarkably high response rate
`(91%) with oral Rev-Dex therapy in newly diagnosed my-
`eloma.18 The observed response rate compares favorably to
`those previously reported with Thal-Dex. With extended
`follow-up we now provide evidence of the depth and dura-
`bility of these responses. The CR plus VGPR rate for the
`entire cohort was 44% at 4 months but improved over time
`to 56% for the entire cohort and 67% for those who contin-
`ued to receive Rev-Dex as primary therapy.
`We also show that responses are durable and that the OS
`rate at 2 years is excellent. The TTP and PFS of patients
`who proceeded to transplant vs those who received Rev-
`Dex as primary therapy should not be compared because
`this was not a randomized trial. The no transplant group
`includes patients (n=2) who died early before a decision on
`SCT could be made. The study is also potentially biased by
`the choice of one approach over the other. The estimated
`median TTP of 32.4 months in the no transplant group is
`comparable to that reported in the Intergroupe Français Du
`Myélome single vs double transplant trial in which all
`patients were younger than 60 years (vs the median age of
`64 years in our trial).21
`With the advent of new drugs and new drug combina-
`tions, response rates that exceed 80% are being seen with
`increasing frequency in patients with newly diagnosed
`myeloma. As an induction regimen, bortezomib has
`shown response rates of approximately 40% as a single
`agent.22 Significantly higher response rates (approxi-
`mately 70%-90%) have been observed with bortezomib
`plus dexa-methasone23; bortezomib, thalidomide, dexam-
`ethasone24; and other bortezomib-based combinations.25
`In one study,23 the CR plus VGPR rate was approximately
`25% to 30% with bortezomib plus dexamethasone. Future
`
`studies are needed to compare Rev-Dex to bortezomib-
`based regimens.
`Treatment with Rev-Dex was well tolerated in this
`trial, in contrast to results reported elsewhere with thali-
`domide. Adverse effects such as constipation and neur-
`opathy were uncommon, and sedation was not seen; no
`patient developed grade 3 or higher neuropathy. Concerns
`regarding the toxicity of dexamethasone led ECOG to
`complete a large phase 3 trial that compared lenalidomide
`with standard high-dose pulse dexamethasone to
`lenalidomide with low-dose weekly dexamethasone. Pre-
`liminary results show that toxicity rates are significantly
`higher with Rev–standard-dose Dex compared to Rev–
`low-dose Dex. Early mortality rates (ie, first 4 months)
`were 5% and 0.5%, respectively.26 Despite the use of
`high-dose dexamethasone, the incidence of thromboem-
`bolism in this series was only 3%. We attribute this low
`rate to prophylaxis with aspirin and minimal use of eryth-
`ropoietins in these patients.
`
`CONCLUSION
`
`We showed that Rev-Dex is highly active in the treatment
`of newly diagnosed multiple myeloma and that responses
`were durable, with a low progression rate at 2 years. The
`development of new active agents for multiple myeloma
`has resulted in many such combination regimens. The high
`response rates observed with these regimens have raised
`questions about whether we should still be offering autolo-
`gous SCT to patients as initial therapy. High response rates
`are not the only factor determining the desirability of using
`SCT. All new regimens have unique toxicities, and quality-
`of-life measures should be included in all future random-
`ized trials. The challenge now is to build on this progress
`and find new, more active, and less toxic agents and combi-
`
`1183
`Mayo Clin Proc. • October 2007;82(10):1179-1184 • www.mayoclinicproceedings.com
`
`For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
`
`ALVOGEN, Exh. 1038, p. 0005
`
`

`

`LONG-TERM RESULTS OF REV-DEX THERAPY FOR NEWLY DIAGNOSED MYELOMA
`
`nations. Randomized trials need to be designed to critically
`assess which regimens should be used upfront and which
`should be reserved for later.
`
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`1184
`
`Mayo Clin Proc. • October 2007;82(10):1179-1184 • www.mayoclinicproceedings.com
`
`For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
`
`ALVOGEN, Exh. 1038, p. 0006
`
`