`
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`www.bloodjournal.orgFrom
`
`on July 29, 2016.
`
`For personal use only.
`
`CLINICAL TRIALS AND OBSERVATIONS
`
`Combination therapy with lenalidomide plus dexamethasone (Rev/Dex)
`for newly diagnosed myeloma
`S. Vincent Rajkumar, Suzanne R. Hayman, Martha Q. Lacy, Angela Dispenzieri, Susan M. Geyer, Brian Kabat, Steven R. Zeldenrust,
`Shaji Kumar, Philip R. Greipp, Rafael Fonseca, John A. Lust, Stephen J. Russell, Robert A. Kyle, Thomas E. Witzig, and Morie A. Gertz
`
`We report the results of a phase 2 trial using
`lenalidomide plus dexamethasone (Rev/
`Dex) as initial therapy for myeloma. Thirty-
`four patients were enrolled. Lenalidomide
`was given orally 25 mg daily on days 1 to 21
`of a 28-day cycle. Dexamethasone was given
`orally 40 mg daily on days 1 to 4, 9 to 12, and
`17 to 20 of each cycle. Objective response
`was defined as a decrease in serum mono-
`clonal protein level by 50% or greater and a
`decrease in urine M protein level by at least
`Introduction
`
`90% or to a level less than 200 mg/24 hours,
`confirmed by 2 consecutive determinations
`at least 4 weeks apart. Thirty-one of 34
`patients achieved an objective response,
`including 2 (6%) achieving complete re-
`sponse (CR) and 11 (32%) meeting criteria
`for both very good partial response and
`near complete response, resulting in an
`overall objective response rate of 91%. Of
`the 3 remaining patients not achieving an
`objective response, 2 had minor response
`
`(MR) and one had stable disease. Forty-
`seven percent of patients experienced grade
`III or higher nonhematologic toxicity, most
`commonly fatigue (15%), muscle weakness
`(6%), anxiety (6%), pneumonitis (6%), and
`rash (6%). Rev/Dex is a highly active regi-
`men with manageable side effects in the
`treatment of newly diagnosed myeloma.
`(Blood. 2005;106:4050-4053)
`
`© 2005 by The American Society of Hematology
`
`Multiple myeloma is a malignant plasma-cell proliferative disorder
`that accounts for over 11 000 deaths each year in the United
`States.1,2 For many years, melphalan and prednisone had remained
`the standard therapy for this disease.3 Response rates with this
`therapy are approximately 50%, and median survival is approximately 3
`years. Recently, autologous stem cell transplantation has been shown to
`be effective in the treatment of multiple myeloma in 2 randomized
`clinical trials.4,5 Patients eligible for stem-cell transplantation should
`avoid alkylator-based induction therapy to enable an adequate and safe
`stem-cell harvest early in the disease course.
`Vincristine, doxorubicin, and dexamethasone (VAD) was typi-
`cally used as pretransplantation induction therapy for patients who
`were considered candidates for stem-cell transplantation.2,6,7 How-
`ever, VAD had several disadvantages, including the need for an
`intravenous indwelling catheter, which predisposes patients to
`catheter-related sepsis and thrombosis; most of the activity of VAD
`was from the high-dose dexamethasone component.8 Recently the
`combination of thalidomide plus dexamethasone (Thal/Dex) has
`emerged as an alternative to VAD in newly diagnosed myeloma
`based on three phase 2 clinical trials and a case-control study.9-12
`Response rates with Thal/Dex range between 64% and 76%, which
`are comparable to or better than those obtained with VAD.12,13 In a
`recent randomized trial conducted by the Eastern Cooperative
`Oncology Group (ECOG), the response rate with Thal/Dex was
`
`significantly higher compared with dexamethasone alone, 58% versus
`42%, respectively (P ⫽ .02).14 However, grade III or greater nonhema-
`tologic toxicities were significantly higher with Thal/Dex compared
`with dexamethasone alone, 68% versus 43%, respectively.
`Lenalidomide (CC-5013) is an analog of thalidomide that has
`demonstrated significantly more potent preclinical activity com-
`pared with thalidomide.15,16 It has also shown significant activity in
`relapsed and refractory myeloma alone and in combination with
`dexamethasone, with fewer nonhematologic side effects compared
`with thalidomide.15,17,18 Responses were observed even in patients
`in whom thalidomide treatment had previously failed. Thus,
`lenalidomide (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 previously untreated, newly
`diagnosed multiple myeloma.
`
`Patients and methods
`
`Eligibility
`
`Informed consent was provided according to the Declaration of Helsinki.
`Patients were eligible to enter the study if they had previously untreated
`symptomatic multiple myeloma. Patients were required to have bone
`marrow plasma cells 10% or greater and measurable disease defined as
`
`From the Divisions of Hematology and Biostatistics, Mayo Clinic, Rochester,
`MN; and the Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ.
`
`Submitted July 15, 2005; accepted August 13, 2005. Prepublished online as
`Blood First Edition Paper, August 23, 2005; DOI 10.1182/blood-2005-07-2817.
`
`Supported in part by grants CA93842 and CA10080 from the National Cancer
`Institute; National Institutes of Health and the Department of Health and Human
`Services; and Celgene Corporation, NJ. S.V.R. has received grant support
`from Celgene for the conduct of clinical trials at Mayo Clinic.
`
`S.V.R., M.A.G., R.A.K., A.D., and P.R.G. were involved in conception and
`design of
`the study, provision of study patients, data analysis and
`interpretation, and manuscript review and approval. S.J.R., J.A.L., R.F., S.K.,
`
`M.Q.L., S.R.H., T.E.W., and S.R.Z. were involved in conception and design of
`the study, provision of study patients, and manuscript review and approval.
`S.M.G. was involved in data analysis, manuscript writing, review, and approval.
`B.K. was involved in data analysis and manuscript review and approval.
`
`An Inside Blood analysis of this article apears at the front of this issue.
`
`Reprints: S. Vincent Rajkumar, Division of Hematology, Mayo Clinic, 200 First
`Street SW, Rochester, MN 55905; e-mail: rajks@mayo.edu.
`
`The publication costs of this article were defrayed in part by page charge
`payment. Therefore, and solely to indicate this fact, this article is hereby
`marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
`
`© 2005 by The American Society of Hematology
`
`4050
`
`BLOOD, 15 DECEMBER 2005 䡠 VOLUME 106, NUMBER 13
`
`ALVOGEN, Exh. 1036, p. 0001
`
`
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`by guest
`
`
`
`www.bloodjournal.orgFrom
`
`on July 29, 2016.
`
`For personal use only.
`
`BLOOD, 15 DECEMBER 2005 䡠 VOLUME 106, NUMBER 13
`
`Rev/Dex FOR NEWLY DIAGNOSED MYELOMA
`
`4051
`
`serum monoclonal protein level greater than 10 g/L, urine monoclonal
`protein level greater than or equal to 200 mg/24 hours, or measurable soft
`tissue plasmacytoma that had not been radiated. Patients also needed to
`have hemoglobin level greater than 80 g/L, platelet count greater than
`100 ⫻ 109/L, absolute neutrophil count greater than 1.5 ⫻ 109/L, and
`creatinine level less than 221 M (2.5 mg/dL). No systemic therapy for
`myeloma, with the exception of bisphosphonates, was permitted. Prior
`corticosteroid use for the treatment of myeloma was not permitted; prior
`corticosteroid use for the treatment of nonmalignant disorders was permit-
`ted but concurrent use was restricted to the equivalent of prednisone 10 mg
`or less per day. Prior localized radiation therapy for solitary plasmacytoma
`was permitted provided at least 4 weeks had passed from the date of last
`radiation therapy to the date of registration. Patients with smoldering
`multiple myeloma or monoclonal gammopathy of undetermined signifi-
`cance were excluded. Also excluded were patients with uncontrolled
`infection, another active malignancy, deep vein thrombosis (DVT) that had
`not been therapeutically anticoagulated, and ECOG performance score of 3
`or 4. Pregnant or nursing women, as well as women of child-bearing
`potential who were unwilling to use a dual method of contraception, and
`men who were unwilling to use a condom were not eligible for the study.
`Women of child-bearing age were required to have a pregnancy test done
`every 4 weeks if their periods were regular, and every 2 weeks if their
`periods were irregular. Patients were required to be at least 18 years of age.
`The study was approved by the Mayo Clinic Institutional Review Board in
`accordance with federal regulations and the Declaration of Helsinki.
`
`Treatment schedule
`
`Lenalidomide was given orally at a dose of 25 mg daily on days 1 to 21 of a
`28-day cycle. Dexamethasone was given orally at a dose of 40 mg daily on
`days 1 to 4, 9 to 12, and 17 to 20 of each cycle. Patients also received an
`aspirin (80 mg or 325 mg per physician discretion) once daily as thrombosis
`prophylaxis. Each cycle was repeated every 4 weeks. Patients were allowed
`to go off treatment after 4 cycles of therapy to pursue stem-cell transplanta-
`tion, but treatment beyond 4 cycles was permitted at physician’s discretion.
`For patients continuing therapy beyond 4 months, the dose of dexametha-
`sone was reduced to 40 mg on days 1 to 4 of each cycle.
`Dose adjustments were permitted based on toxicity. Lenalidomide was
`to be permanently discontinued in the event of erythema multiforme/
`Stevens Johnson syndrome, desquamating/blistering rash of any grade, any
`rash of grade IV severity, grade IV neuropathy or hypersensitivity, and
`grade III or higher bradycardia or cardiac arrhythmia. Subjects experienc-
`ing other grade III or greater adverse events felt related to lenalidomide had
`the drug held until resolution of the adverse event and restarted at the next
`lower dose level. Except for isolated neutropenia, in which case the addition
`of granulocyte colony-stimulating factors (G-CSFs) were permitted instead
`of dose reduction, lenalidomide was progressively reduced for other related
`grade III or higher adverse events to dose levels of 15 mg, 10 mg, and 5 mg
`administered on days 1 to 21 of a 28-day cycle. When grade III or IV adverse
`events occurred prior to day 15 of a cycle and resolved to grade II or lower
`severity prior to 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 III or IV adverse events occurring on or after day 15 of a given cycle,
`lenalidomide was held for the remainder of the cycle and reduced by one dose
`level beginning with the next cycle. Once the dose of lenalidomide was reduced
`for toxicity, no dose re-escalation was permitted. Dose reductions were permitted
`for dexamethasone-related toxicity by lowering the dose of dexamethasone
`progressively to 40 mg daily for 4 days every 2 weeks, 40 mg daily for 4 days
`every 4 weeks, and 20 mg daily for 4 days every 4 weeks. Patients unable to
`tolerate the lowest doses of lenalidomide or dexamethasone needed to stop
`therapy with that agent permanently.
`
`Response and toxicity criteria
`
`The primary end point of this trial was response rate estimated based on the
`best response to therapy for each patient during the course of treatment. The
`response criteria used were standard European Group for Blood and Bone
`Marrow Transplant (ie, Blade´ criteria).19 As a modification, categories of
`very good partial response (VGPR) and near complete response (nCR) were
`
`also defined. An objective (partial) response was defined as at least 50%
`reduction in the level of the serum monoclonal (M) protein and a reduction
`in 24-hour urinary M protein level of at least 90% or to less than 200 mg. In
`addition, there must be no increase in the number or size of lytic bone
`lesions or any other evidence of progressive disease by other parameters. In
`addition to criteria listed for partial response, complete response (CR)
`required complete disappearance of the monoclonal protein in the serum
`and urine by immunofixation studies and 5% or less plasma cells on bone
`marrow examination. Subclassification as VGPR required in addition to
`criteria for partial response, at least 90% reduction in serum M protein level,
`24-hour urine M protein level 100 mg or less, and 5% or less plasma cells
`on bone marrow examination. Similarly, subclassification as nCR required
`all criteria for CR except that the monoclonal protein level in serum and
`urine was not present on electrophoresis but detectable on immunofixation
`alone. Patients achieving at least 25% reduction in serum M protein level and at
`least 50% to 89% reduction in urine M protein level were considered to have
`minor response (MR) but were not included in the calculation of the overall
`response rate. All response categories needed confirmation by 2 consecutive
`measurements at least 4 weeks apart, which is a modification from the Blade´
`criteria19 in which responses are confirmed at least 6 weeks apart.
`Disease progression required any one of the following criteria: (1)
`increase in serum M protein level 25% or higher above the lowest response
`level or a rise in level by more than 5 g/L; (2) increase in urine monoclonal
`protein level by 25% above the lowest remission value or increase in
`excretion by 200 mg/24 hours or greater; (3) increase in size of soft tissue
`plasmacytoma by more than 50% or appearance of a new plasmacytoma;
`(4) definite appearance of bone lesions or increase in the size of existing
`bone lesions by more than 50%; and (5) unexplained hypercalcemia greater
`than 2.875 mM (⬎ 11.5 g/dL). For patients in CR, relapse included
`reappearance of monoclonal protein level by immunofixation or protein
`electrophoresis of the serum or urine or any other sign of progression (ie,
`new plasmacytoma, lytic bone lesion, or hypercalcemia).
`The National Cancer Institute Common Toxicity Criteria for Adverse
`Events (CTCAE), 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 criteria, toxicity was defined as an adverse event considered to be
`possibly, probably, or definitely related to treatment.
`
`Statistical design and analysis
`
`The primary end point of this trial was the proportion of confirmed
`responses (includes patients achieving CR, VGPR, or PR) as defined earlier.
`All patients meeting the eligibility criteria who had signed a consent form
`and had begun treatment were evaluated for response. Thirty evaluable
`patients with previously untreated symptomatic multiple myeloma were to
`be accrued. A one-stage design with an interim analysis was used to
`evaluate the confirmed response rate in 30 evaluable patients with
`previously untreated symptomatic multiple myeloma. Specifically, a true
`response rate of 45% in this patient population would be considered
`promising, versus the null hypothesis that the true response rate was at most
`20%. Based on these assumptions, this treatment regimen was considered
`inactive if 9 or fewer confirmed responses were seen. If 10 or more
`confirmed responses would be considered sufficient evidence of promising
`activity then this treatment regimen may be recommended for further
`testing in subsequent studies. These decision criteria were based on a
`modification of a 2-stage Fleming design where accrual was not halted for
`the interim analysis. An interim analysis was done after the 13th patient was
`accrued, where if 2 or fewer responses were observed this would be
`considered early evidence that the treatment regimen was inactive and
`could terminate accrual. Using this design, we had 92% power at 0.06 level
`of significance to detect a response rate of at least 45% (versus the null
`hypothesis that the true response rate was at most 20%). In addition, we
`anticipated accruing additional patients to account for the possibility of
`ineligibility, cancellations, or major treatment violations. To include all
`evaluated patients in the confidence interval, an exact binomial confidence
`interval will be used for the response rate, assuming that the number of
`patients who respond to treatment is binomially distributed. The maximum
`grade for each type of adverse event along with perceived causality was
`recorded and reported for each patient.
`
`ALVOGEN, Exh. 1036, p. 0002
`
`
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`by guest
`
`
`
`www.bloodjournal.orgFrom
`
`on July 29, 2016.
`
`For personal use only.
`
`4052
`
`RAJKUMAR et al
`
`BLOOD, 15 DECEMBER 2005 䡠 VOLUME 106, NUMBER 13
`
`Results
`
`Overall, 34 patients (median age, 64 years; range; 32-78 years) were
`registered to the study from March 2004 through October 2004 and all
`were evaluable for response and toxicity. Patient characteristics at study
`entry for these patients are presented in Table 1. All patients, including 4
`with Durie-Salmon stage I myeloma, were symptomatic at study entry.
`
`Response to therapy
`
`Thirty-one (91%) of 34 patients (95% confidence interval, 79% to
`98%) achieved an objective response to therapy. Of the 31
`responders, 2 patients (6%) achieved a CR, 11 patients (32%)
`achieved a VGPR, and 18 patients achieved a PR as their best
`response to treatment (Table 2). All patients who met criteria for
`VGPR also met criteria for nCR. Of the 3 patients who did not
`achieve at least a partial response to treatment, 2 met criteria for
`MR and one had stable disease. Responses were rapid; the median
`time to response was one month.
`Patients were allowed to proceed to stem-cell harvest after
`completing 4 cycles of therapy if they were willing and deemed
`eligible for such therapy. As of May 2005, 15 (44%) of the 34
`patients have undergone a stem-cell harvest; 10 of these patients
`went off treatment to proceed with autologous stem cell transplan-
`tation and the remaining 5 have elected to stay on treatment and
`their stem cells have been cryopreserved for future use. Adequate
`stem cells (⬎ 3.0 ⫻ 106 CD34 cells/kg body weight) were obtained
`in all patients who underwent autologous stem cell transplantation
`(median CD34 cells 7.9 ⫻ 106/kg over 2 to 7 collections). Stem
`cells were mobilized with G-CSF 10 g/kg in all but 2 patients who
`received cyclophosphamide 1500 mg/m2 intravenously daily for 2
`days in addition to G-CSF.
`Besides the 10 patients who have gone off treatment for
`autologous stem cell transplantation, 2 patients ended treatment to
`seek alternative treatment and 1 patient died on treatment (details in
`“Toxicity and deaths”).
`
`Toxicity and deaths
`
`Side effects were manageable. Major toxicities seen in this trial are
`listed in Table 3 and represent the most severe toxicity associated
`
`Table 1. Characteristics of eligible patients
`
`Characteristic
`
`Sex, female
`Durie-Salmon stage
`I
`II
`III
`ISS stage
`I
`II
`III
`Immunoglobulin heavy chain type
`IgG
`IgA
`Light chain only, Bence Jones protein
`Anemia, hemoglobin level less than 110 g/L
`Lytic bone lesions
`Beta 2-microglobulin level greater than 2.7 mg/L
`Lactate dehydrogenase level 250 U/L or greater
`Bone marrow plasma-cell percentage 40% or greater
`
`All patients, n ⴝ 34
`
`No. of
`patients
`
`Percent of
`patients
`
`11
`
`4
`14
`16
`
`14
`16
`4
`
`16
`11
`7
`14
`19
`18
`5
`10
`
`32
`
`12
`41
`47
`
`41
`47
`12
`
`47
`32
`21
`41
`59
`53
`15
`31
`
`Table 2. Response to therapy
`
`Response category
`
`No. of
`patients,
`n ⴝ 34
`
`Percent
`patients
`responding
`
`Overall objective response, CR ⴙ VGPR/nCR ⴙ PR
`CR
`VGPR/nCR
`PR
`MR
`No response
`
`31
`2
`11
`18
`2
`1
`
`91
`6
`32
`53
`6
`3
`
`with the study treatment for each patient. Overall, 47% of patients
`experienced grade III or higher nonhematologic toxicity. The most
`common grade III or higher nonhematologic toxicities were fatigue
`(15%), muscle weakness (6%), anxiety (6%), pneumonitis (6%),
`and rash (6%). One patient died on study and this was attributed to
`infection unrelated to therapy; the patient had stopped all therapy
`for over a month before the fatal infection occurred. One patient
`developed a pulmonary embolism (grade IV toxicity) but recovered
`with therapy; no other patient developed DVT or pulmonary embolism.
`
`Discussion
`
`In order to overcome the nonhematologic toxicities of thalidomide
`including its teratogenicity, several active analogs of thalidomide
`have been developed. Lenalidomide has demonstrated significantly
`more potent and promising preclinical activity than thalidomide
`
`Table 3. Major hematologic and nonhematologic toxicities
`Grade 1-2,
`Grade 3-4,
`% of patients
`% of patients
`
`Toxicity
`
`Hematologic toxicity
`Anemia
`Neutropenia
`Leukopenia
`Lymphopenia
`Thrombocytopenia
`Nonhematologic toxicity
`Fatigue
`Muscle weakness
`Pneumonitis
`Skin rash
`Anxiety
`Agitation
`Cardiac arrhythmia
`Nausea
`Hyperglycemia
`Elevated AST level
`Infection
`Colonic perforation
`Increased liver enzymes
`Deep vein thrombosis/pulmonary embolism
`Neuropathy
`Constipation
`Depression
`Confusion
`Dizziness
`Dyspepsia
`Elevated alkaline phosphatase level
`Bilirubin level
`Diarrhea
`Stomatitis
`
`6
`32
`15
`15
`27
`
`41
`29
`3
`6
`15
`15
`3
`3
`3
`0
`0
`0
`0
`0
`21
`15
`15
`12
`9
`9
`6
`6
`6
`6
`
`6
`12
`9
`6
`0
`
`15
`6
`6
`6
`6
`3
`3
`3
`3
`3
`3
`3
`3
`3
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`IgG indicates immunoglobulin G; and ISS, International Staging System.
`
`AST indicates aspartate amino transferase.
`
`ALVOGEN, Exh. 1036, p. 0003
`
`
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`by guest
`
`
`
`www.bloodjournal.orgFrom
`
`on July 29, 2016.
`
`For personal use only.
`
`BLOOD, 15 DECEMBER 2005 䡠 VOLUME 106, NUMBER 13
`
`Rev/Dex FOR NEWLY DIAGNOSED MYELOMA
`
`4053
`
`and has entered clinical trials.15,16 Two phase 1 trials of lenalido-
`mide showed activity in heavily pretreated patients with relapsed
`refractory myeloma with myelosuppression as the major adverse
`event.15,17 A subsequent multicenter randomized phase 2 study in
`relapsed and refractory myeloma18 showed that 38% of patients
`responded with at least a 25% or greater reduction in paraprotein
`levels, establishing the activity of this drug. Approximately one
`third of the patients who did not respond to monotherapy developed
`responses when dexamethasone was added to the regimen. More
`recently, two large phase 3 trials have compared Rev/Dex to
`placebo plus dexamethasone in relapsed, refractory myeloma.
`Preliminary results from both trials show superior response rates
`and time to progression in favor of Rev/Dex.20
`In this trial, we show a high response rate with oral Rev/Dex
`therapy in newly diagnosed myeloma. Ninety-one percent of
`patients responded to therapy, with 2 additional patients achieving
`MR. Although response confirmation was defined as being 4 weeks
`apart rather than 6 weeks, this would not affect the observed
`response rate since only one disease progression has occurred so far
`(10 months after the last patient was enrolled). The observed
`response rate compares favorably with those previously reported
`with Thal/Dex. More importantly, the rate of serious adverse
`effects seen in this trial was similar to that observed with
`dexamethasone alone in a recent randomized trial conducted by
`ECOG. Unlike, thalidomide side effects such as constipation and
`neuropathy were uncommon and sedation was not seen; no patient
`developed grade III or higher neuropathy. The similarity of the adverse
`event rate to that observed with dexamethasone alone suggests that
`high-dose corticosteroid therapy contributes greatly to most of the
`nonhematologic adverse events noted on this trial, especially fatigue,
`muscle weakness, hyperglycemia, agitation, and anxiety.
`Lenalidomide has been noted to cause myelosuppression in
`earlier trials conducted in myelodysplastic syndrome and relapsed
`myeloma. However, myelosuppression was minimal in this trial,
`probably reflecting the better bone marrow reserve of patients with
`
`previously untreated disease. There was no adverse effect on
`stem-cell mobilization, indicating that this would be a useful
`pretransplantation conditioning regimen. The relatively low toxic-
`ity of this regimen lends itself as a major contender for primary
`therapy of myeloma, provided appropriate phase 3 trials can be
`conducted. Since the regimen is orally administered it is less
`cumbersome than complex intravenous regimens.
`DVT was a toxicity about which we were particularly concerned and
`therefore initiated aspirin prophylaxis routinely in this study for all
`patients, based on the efficacy of aspirin in preventing Thal/Dex-
`associated DVT.21 Although typically used to prevent arterial thrombo-
`embolism, aspirin has been found to be effective in prevention of venous
`thrombosis as well in certain settings such as the antiphospholipid
`antibody syndrome.22 The incidence of DVT was low in this trial (3%),
`similar to that observed in the dexamethasone-alone arm of a recent
`randomized trial that compared Thal/Dex to dexamethasone alone.14 On
`the other hand, two phase 3 trials in relapsed refractory myeloma using
`Rev/Dex conducted without routine aspirin (or other anticoagulant)
`prophylaxis noted an increased incidence of DVT (9%-15%).20 Re-
`cently, accrual to a large phase 3 ECOG trial using Rev/Dex in newly
`diagnosed myeloma patients has been temporarily suspended because of
`an increased risk of DVT in the absence of mandatory thromboprophy-
`laxis. Based on this, we recommend caution and routine prophylaxis
`with aspirin once daily for all patients treated with Rev/Dex.
`We conclude that Rev/Dex is highly active in newly diagnosed
`multiple myeloma, inducing objective responses in over 90% of
`treated patients and complete or near complete responses in 38%.
`Both cooperative group randomized trials currently ongoing in the
`United States are testing Rev/Dex as initial therapy for myeloma.
`The Southwest Oncology Group trial compares Rev/Dex with
`dexamethasone alone as primary therapy. The ECOG trial on the
`other hand compares Rev/Dex as administered on the current trial
`to Rev/low-dose dexamethasone, in an attempt to further reduce
`toxicity while preserving the same response rate.
`
`References
`
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`Medicine. 22nd ed. Philadelphia, PA: W. B. Saun-
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`2. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl
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`3. Myeloma Trialists’ Collaborative Group. Combina-
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`4. Attal M, Harousseau JL, Stoppa AM, et al. A pro-
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`7. Sirohi B, Powles R. Multiple myeloma. Lancet.
`2004;363:875-887.
`8. Alexanian R, Dimopoulos MA, Delasalle K, Barlo-
`gie B. Primary dexamethasone treatment of mul-
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`
`ALVOGEN, Exh. 1036, p. 0004
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`by guest
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`www.bloodjournal.orgFrom
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`on July 29, 2016.
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`2005 106: 4050-4053
`doi:10.1182/blood-2005-07-2817
` originally published online
`August 23, 2005
`
`Combination therapy with lenalidomide plus dexamethasone (Rev/Dex)
`for newly diagnosed myeloma
`
`S. Vincent Rajkumar, Suzanne R. Hayman, Martha Q. Lacy, Angela Dispenzieri, Susan M. Geyer,
`Brian Kabat, Steven R. Zeldenrust, Shaji Kumar, Philip R. Greipp, Rafael Fonseca, John A. Lust,
`Stephen J. Russell, Robert A. Kyle, Thomas E. Witzig and Morie A. Gertz
`
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