` 2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00
`www.nature.com/bmt
`
`Peripheral blood progenitor cells
`
`Dexamethasone, paclitaxel, etoposide, cyclophosphamide (d-TEC) and
`G-CSF for stem cell mobilisation in multiple myeloma
`
`S Bilgrami, RD Bona, RL Edwards, Z Li, B Naqvi, A Shaikh, F Furlong, J Fox, J Clive
`and PJ Tutschka
`
`Bone Marrow Transplant Program, University of Connecticut Health Center, Farmington, CT, USA
`
`Summary:
`
`Forty-one patients with multiple myeloma were treated
`with a novel stem cell mobilisation regimen. The pri-
`mary end points were adequate stem cell mobilising
`ability (⬎1% circulating CD34-positive cells) and collec-
`tion (⭓4 ⴛ 106 CD34-positive cells/kg), and safety. The
`secondary end point was activity against myeloma. The
`regimen (d-TEC) consisted of dexamethasone, paclitaxel
`200 mg/m2 i.v., etoposide 60 mg/kg i.v., cyclophospham-
`ide 3 g/m2 i.v., and G-CSF 5–10 g/kg/day i.v. A total
`of 84 cycles were administered to these 41 individuals.
`Patient characteristics included a median age of 53
`years, a median of five prior chemotherapy cycles, and
`a median interval of 10 months from diagnosis of mye-
`loma to first cycle of d-TEC. Seventy-five percent of the
`patients had stage II or III disease, 50% had received
`carmustine and/or melphalan previously, and 25% had
`received prior radiation therapy. Eighty-eight percent
`of patients mobilised adequately after the first cycle of
`d-TEC and 91% mobilized adequately after the second
`cycle. An adequate number of stem cells were collected
`in 32 patients. Of the remaining nine patients, three
`mobilised, but stem cells were not collected, two mobil-
`ised but stem cell collection was ⬍4 ⴛ 106 CD34-positive
`cells/kg, three did not mobilise, and one died of disease
`progression. Major toxicities included pancytopenia,
`alopecia, fever and stomatitis. One patient died from
`multi-organ failure and progressive disease. Fifty per-
`cent of evaluable patients demonstrated a partial
`response and 28.6% of patients had a minor response.
`This novel dose-intense regimen was safe, capable of
`stem cell mobilisation and collection, even in heavily
`pre-treated patients, and active against the underlying
`myeloma. Bone Marrow Transplantation (2001) 28, 137–
`143.
`Keywords:
`dexamethasone; paclitaxel; etoposide; cyclo-
`phosphamide; stem cell mobilisation; multiple myeloma
`
`Correspondence: Dr S Bilgrami, MC-1315, University of Connecticut
`Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA
`Received 27 November 2000; accepted 16 May 2001
`
`High-dose chemotherapy (HDC) followed by autologous
`haemopoietic stem cell
`transplantation has become an
`accepted modality of treatment for patients with multiple
`myeloma.1,2 A randomised study has demonstrated the
`superiority of HDC over conventional chemotherapy.3 The
`use of autologous peripheral blood stem cell transplantation
`(PBSCT) has potential advantages compared to autologous
`bone marrow transplantation including earlier engraftment
`and, possibly, reduced tumor cell contamination of the stem
`cell product. Numerous regimens have been utilized for the
`purpose of stem cell mobilisation for patients with multiple
`myeloma.1,4–38 Repeated courses of dose-intense chemo-
`therapy may also result in sufficient tumor cytoreduction to
`allow a decrease in plasma cell contamination in peripheral
`blood progenitor cell collections.15,39 Individuals who have
`been treated previously with stem cell toxic agents such as
`melphalan and carmustine may experience difficulty
`mobilising an adequate number of stem cells for subsequent
`transplantation. An ideal stem cell mobilising regimen
`should enhance the yield of peripheral blood stem cells and
`produce optimal tumour cytoreduction. We utilised a novel
`regimen consisting of dexamethasone, paclitaxel (Taxol),
`etoposide and cyclophosphamide (d-TEC) supported by
`granulocyte colony-stimulating factor (G-CSF). The pri-
`mary end points of this study were to determine the stem
`cell mobilising and collecting ability, and safety of this
`regimen. The secondary end point was to ascertain the
`response of the underlying multiple myeloma.
`
`Patients and methods
`
`Patients
`
`Patients with multiple myeloma were referred to the Uni-
`versity of Connecticut Health Center, Farmington, CT, for
`HDC/PBSCT. Informed consent was obtained prior to the
`administration of stem cell mobilisation chemotherapy, and
`collection of PBSC. Between May 1994 and July 2000, 41
`patients with multiple myeloma received a dose-intense
`chemotherapy regimen with the aim of collecting PBSC.
`The protocol was approved by the institutional review
`board of the University of Connecticut Health Center. Eligi-
`bility criteria included stage II or III disease as well as those
`individuals with stage I myeloma who required treatment
`
`ALVOGEN, Exh. 1030, p. 0001
`
`
`
`d-TEC for stem cell mobilisation in myeloma
`S Bilgrami etal
`
`138
`
`for the management of disease manifestations, an age ⬍70
`years, an ECOG performance status of 0, 1, 2 or 3, an
`absolute neutrophil count (ANC) ⬎1.5 ⫻ 109/l, a platelet
`count ⬎100 ⫻ 109/l, a creatinine clearance of ⬎50 ml/min,
`a left ventricular ejection fraction of ⬎50%, and a diffusion
`lung capacity of ⬎50% of the predicted value.
`
`Chemotherapy
`
`Patients received combination chemotherapy supported by
`granulocyte colony-stimulating factor (G-CSF) to facilitate
`PBSC mobilisation and harvesting. The regimen (d-TEC)
`is presented in Table 1. G-CSF was initiated at a dose of
`5–10 g/kg/day intravenously from hour 60 until an ANC
`⬎5 ⫻ 109/l was reached or until completion of PBSC col-
`lection. Patients were hospitalised for 72 h during the
`administration of chemotherapy. Cycles of chemotherapy
`were repeated at 4-week intervals.
`
`Supportive care
`
`Supportive measures included an intensive anti-emetic regi-
`men consisting of lorazepam 0.5–1.0 mg intravenously
`every 6 h with dexamethasone and ondansetron 0.15 mg/kg
`intravenously every 6 h. Diphenhydramine 50 mg intra-
`venously and ranitidine 50 mg intravenously were adminis-
`tered 30 min prior to the commencement of the paclitaxel
`infusion. Antibiotic prophylaxis and treatment, and trans-
`fusion criteria have been outlined previously.40 Each indi-
`vidual was seen in the outpatient clinic on alternate days
`from day 6 until recovery of the WBC count. Toxicity was
`graded in accordance with the World Health Organization
`(WHO) criteria.41
`
`Definitions
`
`Adequate mobilisation of peripheral blood stem cells
`(PBSC) was defined by a peripheral blood CD34-positive
`cell count of ⬎1% when the total white blood cell (WBC)
`count exceeded 1 ⫻ 109/l. Adequate PBSC harvesting was
`defined as the collection of ⭓4 ⫻ 106 CD34-positive
`cells/kg in the harvest product. Efficient PBSC harvesting
`was defined as the collection of ⭓3 ⫻ 106 CD34-positive
`
`cells/kg/leukapheresis, because it identified individuals in
`whom adequate collection was likely to be achieved after
`one or two leukaphereses.
`
`Peripheral blood stem cell collection
`
`The CD34-positive cell count was determined from a whole
`blood specimen prior to leukapheresis and from the leu-
`kapheresis product by a method described previously.42 The
`number of colony-forming units granulocyte–macrophage
`(CFU-GM) after 14 days of culture of the PBSC product
`was determined by modification of a previously described
`method.43 If the circulating CD34-positive cell count was
`greater than 1%, stem cell leukapheresis was conducted
`with a continuous flow cell separator (Cobe Spectra; Cobe
`CBT, Lakewood, CO, USA) processing 10–20 l of blood
`per day at flow rates of 50–80 ml/min. Stem cell leukapher-
`esis was attempted following both the first, as well as the
`second cycle of chemotherapy in the initial group of
`patients. If an adequate number of stem cells was harvested
`after the second cycle of d-TEC, they were utilised for the
`PBSCT. Patients who mobilised well (⬎5% CD34-positive
`cells in the circulation) following the first cycle of chemo-
`therapy usually mobilised adequately (⬎1%) after the
`second course. In subsequent patients, stem cell collection
`was deferred to the second cycle of chemotherapy if mobil-
`isation of CD34-positive cells exceeded 5% following the
`first cycle of d-TEC. The level of contamination of the leu-
`kapheresis products with malignant plasma cells was not
`evaluated in this study. Whenever possible, we attempted
`to re-infuse only those stem cells that had been collected
`after the second course of chemotherapy. To that end, stem
`cell collection was performed daily until a target of ⭓4.0
`⫻ 106/l CD34-positive cells/kg body weight was achieved,
`if possible.
`
`Response to chemotherapy
`
`Response was assessed by bone marrow aspirate and
`biopsy, serum immunofixation electrophoresis and quanti-
`fication of Bence-Jones protein in the urine over 24 h.
`Evaluation of disease status was conducted prior to the
`initiation of d-TEC and approximately 3 weeks following
`the completion of the last course of d-TEC. Response was
`defined using the common criteria of the EBMT, IBMTR
`and ABMTR.44
`
`Table 1
`
`Chemotherapy regimen
`
`Hour
`
`0–18
`
`24–25 and 30–31
`
`24, 27, 30, 33, 36, 39 and 42
`
`48–51
`
`60
`
`Bone Marrow Transplantation
`
`Therapy
`
`Statistical analysis
`
`Etoposide 60 mg/kg ideal body
`weight by continuous i.v. infusion
`Cyclophosphamide 1.5 g/m2 (actual
`body weight) in 250 ml of 5%
`dextrose i.v.
`Mesna 12 mg/kg actual body
`weight i.v.
`Paclitaxel 200 mg/m2 (actual body
`weight) by continuous i.v. infusion
`Granulocyte colony-stimulating
`factor 5–10 g/kg actual body
`weight i.v.
`
`Several variables were examined as potential determinants
`of adequate PBSC mobilisation (total collection of ⭓4 ⫻
`106 CD34-positive cells/kg vs ⬍4 ⫻ 106 CD34-positive
`cells/kg) and mobilisation per leukapheresis (⭓3 ⫻ 106
`CD34-positive cells/kg/leukapheresis vs ⬍3 ⫻ 106 CD34-
`positive cells/kg/leukapheresis). These included age ⬍53
`years vs ⭓53 years, male vs female sex, stage 1 vs stages
`2 and 3, IgG myeloma vs other subtypes, vs light
`chains, prior radiation therapy vs no prior radiation, prior
`use of interferon-␣ vs no prior interferon-␣, prior use of
`stem cell toxic agents such as melphalan or carmustine vs
`no previous stem cell toxic chemotherapy, one or no pre-
`
`ALVOGEN, Exh. 1030, p. 0002
`
`
`
`vious chemotherapy regimen vs ⭓2 prior regimens, ⬍5
`prior cycles of chemotherapy vs ⭓5 prior cycles, interval
`from diagnosis of myeloma to first cycle of d-TEC of ⬍10
`months vs ⭓10 months, use of d-TEC at initial remission
`vs use of d-TEC at relapse or second or greater remission,
`ECOG performance status of 0 and 1 vs 2 and 3, and inter-
`val from last cycle of standard chemotherapy to first cycle
`of d-TEC ⬍6 weeks vs ⭓6 weeks. The same variables were
`also examined as potential determinants of partial response
`vs less than a partial response. Contingency table (2)
`analyses were utilised to estimate the statistical significance
`of each discrete variable. Continuous variables were com-
`pared using the median test. Finally, the joint effect of a
`combination of variables as a set of ‘risk factors’ for not
`mobilising an adequate number of PBSC following d-TEC
`was determined using a logistic regression model.
`
`Results
`
`Patient characteristics
`
`Forty-one patients with multiple myeloma received a total
`of 84 cycles of d-TEC. Twenty-seven individuals were
`given two cycles of d-TEC, six received one cycle only
`and eight received three cycles. The third cycle of d-TEC
`was administered for further tumor cytoreduction rather
`than for the purpose of PBSC mobilisation. Patient charac-
`teristics are outlined in Table 2. Thirty-nine individuals had
`received a median of five cycles (range 2 to 48 cycles) of
`chemotherapy previously. Moreover, 21 patients had been
`administered a median of six cycles (range 3 to 22 cycles)
`of regimens containing stem cell toxic agents, such as mel-
`phalan or carmustine. Two patients did not receive any
`prior chemotherapy. One of these two patients had received
`radiation therapy for relief of symptoms. The other patient
`
`Table 2
`
`Patient characteristics
`
`Number of patients
`Median age in years (range)
`Cycles of d-TEC
`Median number of cycles of d-TEC/patient (range)
`Male:Female ratio
`Type of multiple myeloma
`
`Stage
`Prior radiation therapy
`Prior interferon-␣ therapy
`Median number of prior chemotherapy cycles
`Median number of prior chemotherapy regimens
`Prior stem cell toxic chemotherapy
`ECOG performance status
`Disease status at first d-TEC
`
`Interval from diagnosis of myeloma to first cycle of d-TEC
`Interval from last cycle of standard chemotherapy to first cycle of d-
`TEC
`
`d-TEC for stem cell mobilisation in myeloma
`S Bilgrami etal
`
`was given d-TEC as initial treatment of symptomatic myel-
`oma. Twenty-one patients were treated with d-TEC for
`refractory or relapsed disease.
`
`139
`
`Stem cell mobilisation and collection
`
`Thirty-six (88%) out of the 41 patients who received a first
`cycle of d-TEC mobilised an adequate number of PBSC
`(Table 3). The median peripheral blood CD34-positive cell
`count was 7.8% (range 0% to 69.1%). Stem cell leukapher-
`esis was conducted in 23 patients and yielded a median of
`
`Table 3
`
`Mobilisation and collection of peripheral blood stem cells
`
`Number of patients
`Number of patients who
`mobilised adequately (⬎1%
`CD34+ cells in the peripheral
`blood)
`Number of patients in whom
`collection was attempted
`Median number of
`leukapheresis/cycle of d-TEC
`(range)
`Median peripheral blood CD34+
`cell % (range)
`Median number of CD34+ cells
`collected ×106/kg (range)
`Median CFU-GM colony
`count/105 cells plated (range)
`
`d-TEC
`cycle 1
`
`d-TEC
`cycle 2
`
`41
`36
`
`23
`
`1
`(1–3)
`
`7.8
`(0–69.1)
`7.1
`(0.1–61.6)
`66
`(8-TNTC)
`
`35
`32
`
`33
`
`1
`(1–5)
`
`3.4
`(0–31.8)
`6.6
`(0.3–29.8)
`68.7
`(13.3-TNTC)
`
`d-TEC = dexamethasone, paclitaxel, etoposide and cyclophosphamide;
`CFU-GM = colony-forming units granulocyte–macrophage; TNTC = too
`numerous to count.
`
`41
`53 (39–65)
`84
`2 (1–3)
`23:18
`IgG (n = 20); IgG (n = 6); IgA (n = 2); IgA (n = 6); LCM (n =
`5); LCM (n = 1); non-secretory (n = 1)
`I (n = 9); II (n = 22); III (n = 10)
`11 patients
`6 patients
`5 (range 0–48)
`1 (range 0–5)
`21 patients
`0 (n = 10); 1 (n = 17); 2 (n = 9); 3 (n = 5)
`Initial treatment or remission (n = 20); relapsed or refractory disease (n
`= 21)
`Median 10 months (range 2–156 months)
`Median 6 weeks (range 0 weeks to 5 years)
`
`d-TEC = dexamethasone, paclitaxel, etoposide and cyclophosphamide; n = number; LCM = light chain myeloma.
`
`Bone Marrow Transplantation
`
`ALVOGEN, Exh. 1030, p. 0003
`
`
`
`140
`
`d-TEC for stem cell mobilisation in myeloma
`S Bilgrami etal
`
`7.1 ⫻ 106 CD34-positive cells/kg (range 0.1–61.6 ⫻ 106
`CD34-positive cells/kg) after a median of 1 (range 1–3)
`leukaphereses. The median CFU-GM colony count was 66
`colonies/105 cells plated (range, eight colonies to too many
`colonies to count/105 cells plated).
`Thirty-five individuals received a second cycle of d-TEC.
`Three of these 35 patients failed to mobilise an adequate
`number of PBSC. Patients who failed to mobilise
`adequately with the first cycle of d-TEC were also unsuc-
`cessful in mobilising PBSC with the second course. The
`median peripheral blood CD34-positive cell count was
`3.4% (range 0 to 31.8%). Stem cell leukapheresis was
`attempted in 33 patients including one individual with inad-
`equate mobilisation. A median of 6.6 ⫻ 106 CD34-positive
`cells/kg (range 0.3–29.8 ⫻ 106 CD34-positive cells/kg) was
`collected with a median of one leukapheresis (range 1–5
`leukaphereses). The median CFU-GM colony count was
`68.7 colonies/105 cells plated (range 13.3 colonies to too
`many colonies to count/105 cells plated).
`Stem cell leukapheresis was conducted after both first
`and second cycles of d-TEC in 21 patients, after the second
`cycle only in 12 patients, and following the first cycle only
`in three individuals. Two of these 36 patients underwent
`an unsuccessful attempt at PBSC harvesting even though
`they had failed to demonstrate adequate mobilisation of
`stem cells in the peripheral blood. Five patients did not
`undergo leukapheresis following d-TEC. One of these
`patients had failed to mobilise PBSC and an additional
`patient died of progressive myeloma following d-TEC. The
`three remaining individuals, all of whom mobilised an
`adequate number of PBSC after the first cycle of d-TEC,
`but did not undergo stem cell collection, developed side-
`effects which precluded a second cycle of d-TEC. Two of
`these three patients underwent successful PBSC harvesting
`utilising alternate regimens. Furthermore, 17 out of 20 eval-
`uable patients (85%) who had received prior melphalan or
`carmustine mobilised adequately with d-TEC.
`Thirty-two (78%) of 41 individuals underwent successful
`collection of an adequate number of PBSC. One of these
`patients was not transplanted because of chronic sinusitis
`secondary to aspergillosis. She continues to do well at the
`time of this report. The remaining 31 patients proceeded to
`HDC-PBSCT. Two other individuals (4.9%) in whom an
`adequate number of stem cells could not be collected (2.6
`⫻ 106 CD34-positive cells/kg and 3 ⫻ 106 CD34-positive
`cells/kg, respectively) were also transplanted. Therefore, 33
`patients underwent HDC-PBSCT utilising stem cells col-
`lected after d-TEC. The myelo-ablative regimen consisted
`of busulfan 16 mg/kg orally (day ⫺7 to⫺4 in 16 divided
`doses), etoposide 60 mg/kg i.v. (day ⫺3), cyclophospham-
`ide 90 mg/kg i.v. (day ⫺2 in two divided doses), and G-
`CSF 5 g/kg/day i.v. from day +1 until recovery of the
`neutrophil count. The median duration of neutropenia fol-
`lowing transplantation was 6 days (range 3–12 days). The
`median day of engraftment (ANC ⬎1 ⫻ 109/l) post trans-
`plantation was day +9 (range day +8 to day +13). Major
`toxicities included pancytopenia, fever, stomatitis and alo-
`pecia. Transplant-related mortality was limited to one
`patient who died at day +48 as a result of cytomegalovirus–
`interstitial pneumonitis. The product collected after the
`second cycle of d-TEC was utilized in 31 individuals,
`
`whereas the two remaining patients received PBSC that had
`been harvested after the first cycle. Neither of the two
`patients who received less than 4 ⫻ 106 CD34-positive
`cells/kg demonstrated any delay in engraftment. Two
`additional patients underwent successful PBSC harvesting
`utilising alternate regimens (cyclophosphamide and G-CSF,
`and cyclophosphamide, etoposide and G-CSF, respectively)
`followed by autologous PBSCT. Both patients had mobil-
`ised previously with an initial cycle of d-TEC, and were in
`the process of PBSC harvesting as part of the initial treat-
`ment of myeloma. Neither had received stem cell toxic
`agents previously. Two non-mobilisers underwent autolog-
`ous bone marrow transplantation. One additional patient
`died following d-TEC. Another individual who mobilised
`PBSC was not collected or transplanted, and one non-
`mobiliser was also not transplanted.
`None of the variables studied, including prior use of mel-
`phalan or carmustine, predicted failure to achieve the goal
`of adequate PBSC collection (⭓4 ⫻ 106 CD34-positive
`cells/kg). However, collection of ⭓3 ⫻ 106 CD34-positive
`cells/kg/leukapheresis was significantly associated with an
`age equal to or less than 53 years (P = 0.034), fewer than
`five prior cycles of chemotherapy (P = 0.005), and avoid-
`ance of melphalan/carmustine in prior chemotherapy regi-
`mens (P = 0.005). Successful collection of ⭓3 ⫻ 106
`CD34-positive cells/kg/leukapheresis was also analyzed
`using a logistic regression model. Candidate predictors
`included younger age, fewer prior cycles of chemotherapy,
`and avoidance of prior melphalan or carmustine. The final
`model included avoidance of prior treatment with mel-
`phalan or carmustine (P = 0.0095; odds ratio 0.1; and
`confidence interval 0.018–0.569).
`
`Response rates
`
`the time of
`No patient was in complete remission at
`initiation of d-TEC. However, 13 individuals could not be
`evaluated for response to d-TEC because their serum
`immunoglobulin levels were within normal limits following
`standard chemotherapy. The remaining 28 patients were
`evaluable for response to d-TEC. Upon completion of d-
`TEC chemotherapy,
`there were 14 partial
`responders
`(50%),
`eight minor
`responders
`(28.6%),
`four non-
`responders (14.2%), and two patients with progressive dis-
`ease (7.1%). A median 48.5% decline in serum paraprotein
`level was evident
`in evaluable patients following com-
`pletion of d-TEC. The serum and/or urine immunoglobin
`level was within normal limits upon completion of d-TEC
`in 12 of 28 evaluable patients. Among 15 evaluable patients
`with relapsed or refractory multiple myeloma, there were
`five partial responders (33%), six minor responders (40%),
`two non-responders (13%), and two individuals with pro-
`gressive disease (13%). None of the variables studied were
`predictive of a partial response. However, earlier treatment
`with d-TEC (P = 0.058) and fewer than five prior cycles
`of conventional chemotherapy (P = 0.053) demonstrated an
`increased probability of attaining a partial
`response
`although this trend did not achieve statistical significance
`with either of the two variables.
`
`Bone Marrow Transplantation
`
`ALVOGEN, Exh. 1030, p. 0004
`
`
`
`141
`
`Toxicity
`
`The World Health Organization (WHO) toxicity grading is
`outlined in Table 4. The median duration of neutropenia
`was 7 days (range 4–17 days). The maximum depth of neu-
`tropenia was an ANC of ⬍0.1 ⫻ 109/l in all patients. The
`ANC recovered at a median of 14 days (range 11–20 days)
`following the initiation of chemotherapy. There were 23
`(27%) readmissions for fever during neutropenia. However,
`only six patients developed bacteremia (three staphylo-
`coccus species; three viridans streptococcal species). Alo-
`pecia was universal. A median of one PRBC transfusion
`(range 0–5) was administered during each cycle of d-TEC.
`A median of one platelet product (range 0–6) was trans-
`fused during each cycle of d-TEC. Two individuals were
`unable to receive a second cycle of d-TEC because of sev-
`ere generalised skeletal pain at the time of recovery of
`blood counts following the first cycle. An additional patient
`died 27 days after the initiation of chemotherapy from
`sepsis and progressive disease.
`
`Discussion
`
`Numerous strategies have been devised to optimise PBSC
`mobilisation among patients with multiple myeloma. High-
`dose cyclophosphamide with growth factor support, or use
`of growth factors alone, are utilised most frequently.1,4–38
`On an average, three or more leukapheresis procedures are
`required with these regimens in order to attain the targeted
`stem cell yield. In this study, we combined cyclophospham-
`ide with paclitaxel and etoposide because all three agents
`are capable of PBSC mobilisation. G-CSF was adminis-
`tered on a daily basis following the completion of chemo-
`therapy until recovery of the WBC count and/or collection
`of PBSC. It is noteworthy that the targeted stem cell yield
`was attained with a median of one leukapheresis procedure
`in our patients which compares favorably with the results
`of most other regimens.
`Factors predicting a poor yield of PBSC include duration
`of prior treatment with alkylating agents such as melphalan,
`number of prior cycles of chemotherapy,
`interval from
`
`Table 4
`
`Major toxicities (n = 84 cycles)
`
`Clinical features
`
`Grade
`
`Neutrophils
`Hemoglobin
`Platelets
`Stomatitis
`Liver
`Lungs
`Heart
`Kidneys
`Peripheral neuropathy
`Rash
`Nausea/Emesis
`Diarrhea
`Skeletal pain
`
`0
`
`0
`9
`0
`36
`59
`62
`78
`82
`27
`74
`51
`66
`35
`
`1
`
`0
`26
`0
`29
`14
`11
`4
`2
`57
`9
`20
`13
`35
`
`2
`
`0
`33
`1
`14
`7
`8
`2
`0
`0
`1
`8
`4
`7
`
`3
`
`0
`16
`10
`4
`3
`2
`0
`0
`0
`0
`5
`1
`7
`
`4
`
`84
`0
`73
`1
`1
`1
`0
`0
`0
`0
`0
`0
`0
`
`d-TEC for stem cell mobilisation in myeloma
`S Bilgrami etal
`
`diagnosis to stem cell mobilising chemotherapy, prior radi-
`ation therapy,
`response to treatment before stem cell
`mobilising chemotherapy, extensive infiltration of the bone
`marrow with plasma cells, and lack of growth factor sup-
`port.8,10,14,18,45 Mobilisation may be improved in patients
`with multiple myeloma if a growth factor is added to high-
`dose cyclophosphamide.4,13,18 Moreover, both G-CSF and
`GM-CSF appear to be equivalent when added to cyclophos-
`phamide.19 It has also been suggested that a combination
`of cyclophosphamide, etoposide and G-CSF is superior to
`either cyclophosphamide plus growth factor or G-CSF
`alone in patients with multiple myeloma.10 We combined
`cyclophosphamide with etoposide and G-CSF and added
`paclitaxel because of its ability to mobilise PBSC in other
`malignancies.46 Despite heavy pretreatment, a long interval
`from diagnosis, and use of prior alkylator therapy in many
`of our patients, mobilisation was more than adequate in
`90% of cases. Even though the number of PBSC
`harvested/leukapheresis was reduced, statistical analysis
`failed to demonstrate a significant negative impact of prior
`therapy with melphalan or carmustine on subsequent collec-
`tion of an optimal number of stem cells.
`Cyclophosphamide, etoposide,47 and paclitaxel45 have
`limited single agent activity in multiple myeloma. Dexame-
`thasone, paclitaxel, etoposide and cyclophosphamide were
`combined primarily for PBSC mobilisation in the current
`study. It is noteworthy that only between one and three
`cycles of this combination yielded a partial response rate
`of 50% in evaluable patients utilizing the strict EBMT,
`IBMTR and ABMTR criteria for response. It must also be
`mentioned that evaluation of response to d-TEC excluded
`a favorable group of 13 individuals in whom standard
`chemotherapy had already resulted in normalisation of
`serum and urinary immunoglobulin levels. Furthermore, a
`partial response rate of 33% and a minor response rate of
`40% in relapsed or refractory patients was not significantly
`inferior to most standard salvage chemotherapy regimens.
`It is possible that further cycles of d-TEC may have resulted
`in a greater number of partial responders. It is also possible
`that longer follow-up after completion of d-TEC may have
`demonstrated an even greater decline of the paraprotein
`level. Therefore, it appears that d-TEC results in more cyto-
`reduction than is observed with any of its chemotherapeutic
`components used alone. Although not evaluated in the cur-
`rent study,
`this anti-tumor activity may be potentially
`advantageous because it is possible that in vivo cytoduction
`may decrease contamination of the PBSC product with
`malignant plasma cells especially following two or more
`cycles of the regimen. In fact, two other groups of investi-
`gators have reported reduced plasma cell contamination of
`the PBSC product by adding cyclophosphamide to G-CSF
`vs G-CSF alone,39 and following repeated cycles of high-
`dose chemotherapy.15
`An ideal regimen for PBSC mobilisation in individuals
`with multiple myeloma should not only be efficient (fewer
`leukaphereses to collect adequate stem cells) even in heav-
`ily pre-treated patients, but should also be capable of tumor
`cytoreduction. The regimen described in the current report,
`d-TEC, appears to fulfill
`these criteria. Furthermore,
`adverse reactions and cumulative toxicity is manageable,
`
`Bone Marrow Transplantation
`
`ALVOGEN, Exh. 1030, p. 0005
`
`
`
`d-TEC for stem cell mobilisation in myeloma
`S Bilgrami etal
`
`142
`
`and mortality is low even in patients with advanced and
`heavily pre-treated myeloma.
`
`References
`
`1 Fermand JP, Ravaud P, Chevret S et al. High-dose therapy and
`autologous peripheral blood stem transplantation in multiple
`myeloma: up-front or rescue treatment? Results of a multicen-
`trial. Blood 1998; 92:
`ter sequential randomized clinical
`3131–3136.
`2 Barlogie B, Jaganath S, Desikan KR et al. Total therapy with
`tandem transplants for newly diagnosed multiple myeloma.
`Blood 1999; 93: 55–65.
`3 Attal M, Harousseau JL, Stoppa AM et al. A prospective, ran-
`domized trial of autologous bone marrow transplantation and
`chemotherapy in multiple myeloma. New Engl J Med 1996;
`335: 91–97.
`4 Boiron J-M, Marit G, Faberes C et al. Collection of peripheral
`blood stem cells in multiple myeloma following single high-
`dose cyclophosphamide with and without recombinant human
`granulocyte–macrophage colony-stimulating factor
`(rhGM-
`CSF). Bone Marrow Transplant 1993; 12: 49–55.
`5 Tricot G, Jaganath S, Vesole D et al. Peripheral blood stem
`cell transplants for multiple myeloma: identification of favor-
`able variables for rapid engraftment in 225 patients. Blood
`1995; 85: 588–596.
`6 Demuynck H, Delforge M, Verhoef G et al. Comparative
`study of peripheral blood progenitor cell collection in patients
`with multiple myeloma after single-dose cyclophosphamide
`combined with rhGM-CSF or rhG-CSF. Br J Haematol 1995;
`90: 384–392.
`7 Kelsey SM, Hazel D, Murrell C, Newland AC. GM-CSF for
`peripheral blood stem cell harvest in myeloma (letter). Br J
`Haematol 1996; 92: 505.
`8 Prince HM, Imrie K, Sutherland DR et al. Peripheral blood
`progenitor cell collections in multiple myeloma: predictors
`and management of inadequate collections. Br J Haematol
`1996; 93: 142–145.
`9 Goldschmidt H, Hegenbart U, Haas R, Hunstein W. Mobiliz-
`ation of peripheral blood progenitor cells with high-dose
`cyclophosphamide (4 or 7 g/m2) and granulocyte colony-sti-
`mulating factor in patients with multiple myeloma. Bone Mar-
`row Transplant 1996; 17: 691–697.
`10 Demirer T, Buckner CD, Gooley T et al. Factors influencing
`collection of peripheral blood stem cells in patients with mul-
`tiple myeloma. Bone Marrow Transplant 1996; 17: 937–941.
`11 Martinez E, Sureda A, De Dalmases C et al. Mobilization of
`peripheral blood progenitor cells by cyclophosphamide and
`rhGM-CSF in multiple myeloma. Bone Marrow Transplant
`1996; 18: 1–7.
`12 Long GD, Chao NJ, Hu WW et al. High-dose etoposide-based
`myeloablative therapy followed by autologous blood progeni-
`tor cell rescue in the treatment of multiple myeloma. Cancer
`1996; 78: 2502–2509.
`13 Alegre A, Tomas JF, Martinez-Chamorro C et al. Comparison
`of peripheral blood progenitor cell mobilization in patients
`with multiple myeloma: high-dose cyclophosphamide plus
`GM-CSF vs G-CSF alone. Bone Marrow Transplant 1997; 20:
`211–217.
`14 Goldschmidt H, Hegenbart U, Wallmeier M et al. Factors
`influencing collection of peripheral blood progenitor cells fol-
`lowing high-dose cyclophosphamide and granulocyte colony-
`stimulating factor in patients with multiple myeloma. Br J
`Haematol 1997; 98: 736–744.
`15 Omede P, Tarella C, Palumbo A et al. Multiple myeloma:
`
`Bone Marrow Transplantation
`
`reduced plasma cell contamination in peripheral blood pro-
`genitor cell collections performed after repeated high-dose
`chemotherapy courses. Br J Haematol 1997; 99: 685–691.
`16 Schiller G, Vescio R, Freytes C et al. Autologous CD34-selec-
`ted blood progenitor cell transplants for advanced multiple
`myeloma. Bone Marrow Transplant 1998; 21: 141–145.
`17 Desikan KR, Barlogie B, Jaganath S et al. Comparable
`engraftment kinetics following peripheral-blood stem-cell
`infusion mobilized with granulocyte colony-stimulating factor
`with or without cyclophosphamide in multiple myeloma. J
`Clin Oncol 1998; 16: 1547–1553.
`18 Marit G, Thiessard F, Faberes C et al. Factors affecting both
`peripheral blood progenitor cell mobilization and hematopo-
`ietic recovery following autologous blood progenitor cell
`transplantation in multiple myeloma patients: a monocentric
`study. Leukemia 1998; 12: 1447–1456.
`19 Abonour R, Scott KM, Kunkel LA et al. Autologous trans-
`plantation of mobilized peripheral blood CD34+ cells by
`immunomagnetic procedures in patients with multiple myel-
`oma. Bone Marrow Transplant 1998; 22: 957–963.
`20 Gupta D, Bybee A, Cooke F et al. CD34+-selected peripheral
`blood progenitor cell transplantation in patients with multiple
`myeloma:
`tumour cell contamination and outcome. Br J
`Haematol 1999; 104: 166–177.
`21 Vescio R, Schiller G, Stewart AK et al. Multicenter phase III
`trial to evaluate CD34(+) selected versus unselected autolog-
`ous peripheral blood progenitor cell transplantation in multiple
`myeloma. Blood 1999; 93: 1858–1868.
`22 Facon T, Harousseau JL, Maloisel F et al. Stem cell factor
`in combination with filgrastim after chemotherapy improves
`peripheral blood progenitor cell yield and reduces apheresis
`requirements in multiple myeloma patients: a randomized,
`controlled trial. Blood 1999; 94: 1218–1225.
`23 Gandhi M, Jestice H, Scott M et al. A comparison of CD34+
`cell selected and unselected autologous peripheral blood stem
`cell transplantation for multiple myeloma: a case controlled
`analysis. Bone Marrow Transplant 1999; 24: 369–375.
`24 Abraham R, Chen C, Tsang R et al. Intensification of the stem
`cell transplant induction regimen results in increased treat-
`ment-related mortality without improved outcome in multiple
`myeloma. Bone Marrow Transplant 1999; 24: 1291–1297.
`25 Boccadoro M, Omede P, Dominietto A et al. Multiple myel-
`oma: the number of reinfused plasma cells does not influence
`outcome of patients treated with intensified chemotherapy and
`PBPC support. Bone Ma