British Journal oJHaematoIogy, 1992, 82, 555-559
`
`Modified adriamycin-vincristine-dexamethasone (m-VAD)
`in primary refractory and relapsed plasma cell myeloma:
`an NCI (Canada) pilot study
`
`GEORGE P. B R O W M A N , l ANDREW BELCH,’ JAMEY s K I L L I N G S , 3 KENNETH
`DANIEL BERGSAGEL,’
`DIANNE JOHN ST ON^ AND JOSEPH L. PATER,‘ for The National Cancer Institute of Canada Clinical Trials Group
`IHamiIton Regional Cancer Center, and McMaster University, Hamilton, Ontario, 2Cross Cancer Institute, and
`University of Alberta, Edmonton, Alberta, 3London Regional Cancer Center, and University of Western Ontario, London,
`Ontario, 4British Columbia Cancer Agency, Victoria Clinic, and University of British Columbia, Victoria, B.C.,
`SPrincess Margaret Hospital, Ontario Cancer Institute, and University of Toronto, Toronto, Ontario, and
`hNational Cancer Institute of Canada Clinical Trials Group, and Queen’s University, Kingston, Ontario
`
`Received 30 April 1992; accepted for publication 17 June 1 992
`
`Summary. The purpose of this single arm phase I1 study was
`to test a modified version of the three drug combination
`vincristine, adriamycin and dexamethasone (m-VAD), in
`which intravenous vincristine (0.4 mg/d) and adriamycin (9
`mg/m2 per day) infusions are administered for only 2 h on
`days 1-4 of each 28 d cycle, in patients with refractory
`multiple myeloma. In addition, only two 4 d courses of
`dexamethasone 40 mg/d was given during each cycle. The
`entry criteria for 44 patients included plasma cell myeloma
`and a measurable monoclonal peak, either refractory to
`initial treatment with melphalan and prednisone. or resistant
`to melphalan and prednisone after initially responding
`(resistant relapsed disease, 2 7 patients). Patients treated
`previously with chemotherapy other than melphalan and
`predisone were excluded. There were no complete responses.
`Of the 41 evaluable patients who completed at least one
`course of therapy 11 had a partial response (2 7%. 95% C.I.
`14-40%). The response rates were 19% for primary refrac-
`
`tory disease patients, and 32% for those with resistant
`relapsed disease. The median duration of response was 4
`months. The median survival for all 44 patients was 7 . 6
`months (5.5 months for primary refractory patients, and 10
`months for relapsed resistant disease patients). Episodes of
`documented bacterial infection occurred in 12 patients, and
`10 patients had minor viral infection. The dexamethasone
`dose was reduced in 12 patients. The median neutrophil
`nadir was 1.2 x 109/1, and median platelet nadir was
`147 x 109/l. Five deaths were judged as treatment related
`and occurred during marrow cytopenia. The results of this
`modified form of VAD are inferior to that reported previously
`for 4 d continuous infusions of vincristine and doxorubicin.
`This could be related to either patient selection factors, or to a
`reduction of the efficacy of the drug combination produced by
`either the shortened intravenous infusions and/or omission
`of one 4 d course of dexamethasone.
`
`The combination of vincristine, adriamycin and dexametha-
`sone (VAD) chemotherapy is one of the most promising
`second line regimens for multiple myeloma (Barlogie et al,
`1984). Using the strict response criteria of the Southwest
`Oncology Group, the response rate in 29 patients (14
`refractory, 15 relapsed) was 5 9 f 18% (95% confidence
`interval). Furthermore, at 15 months 60% of patients were
`
`Correspondence: Dr George P. Browman, Department of Clinical
`Epidemiology and Biostatistics, McMaster University, Room HSc
`2C10B. 1200 Main St. West, Hamilton, Ontario L8N 325, Canada.
`
`alive and 45% were still in their first remission. Subsequently.
`the VAD regimen has been tested as first line therapy
`(Alexanian et al, 1990: Samson et al, 1989: Attal et al. 1992).
`The National Cancer Institute of Canada (NCIC) Clinical
`Trials Group was also interested in determining whether VAD
`could be introduced for treatment of new patients, but we
`were concerned about the logistics and safety of 4 d
`continuous infusions in ambulatory patients. Therefore, we
`developed a modified version of the VAD protocol (m-VAD)
`which could be administered in the ambulatory setting. This
`report describes our experience with a phase I1 pilot study of
`555
`
`ALVOGEN, Exh. 1034, p. 0001
`
`

`

`George P. Browman et a1
`556
`m-VAD in patients with primary refractory and relapsed
`plasma cell myeloma.
`
`METHODS
`Study design. This was a single arm phase I1 trial designed to
`estimate the antitumour effect and toxicity of m-VAD in two
`cohorts of patients with primary melphalan-refractory or
`relapsed myeloma. The protocol was approved by the
`Institutional Review Boards of all participating centres. The
`primary outcome was tumour response defined as stabiliza-
`tion of blood counts and bone lesions without hypercalcae-
`mia. and accompanied by at least 50% reduction of the
`baseline pretreatment serum monoclonal protein level for
`two measurements at least 1 month apart, or, when a urine
`protein only was present, at least 90% reduction of the
`baseline level (Chronic Leukemia-Myeloma Task Force,
`1973).
`Sample size was calculated to exclude a response rate
`below 45%. Survival was calculated using a life table method.
`Patients. Eligible patients had to have a diagnosis of plasma
`cell myeloma confirmed by biopsy of an osteolytic or soft
`tissue lesion, or L 10% plasma cells in the bone marrow. and
`a monoclonal protein in serum or urine. For patients with a
`urine monoclonal protein only, 24 h excretion had to be at
`least 500 mg. All patients had to be either clinically refractory
`to initial treatment with melphalan and prednisone (MP)
`(primary refractory disease). or resistant to a subsequent
`course of MP after a n initial response (relapsed disease).
`Criteria for exclusion were any one of the following: stable
`or responding myeloma while on MP, previous treatment
`with chemotherapy other than melphalan and a steroid.
`solitary plasmacytoma only, nonsecretory myeloma, IgM
`paraprotein, age > 74 years, other malignancy except for
`basal cell carcinoma or cervical carcinoma in situ, active
`peptic ulcer disease, diabetes mellitus requiring insulin or oral
`hypoglycaemics, previous history of heart failure or on anti-
`failure medications, history of multiple sclerosis or other
`symptomatic peripheral neuropathy. serum bilirubin > twice
`normal, inability or unwillingness to give signed informed
`consent.
`Treatment. Patients received doxorubicin 9 mg/m2 and
`vincristine 0.4 mg intravenously mixed together in 2 50 ml
`normal saline as a 2 h infusion through a central intravenous
`catheter or peripheral vein on days 1-4 every 2 8 d.
`Dexamethasone was given orally at a dose of 40 mg with
`breakfast on days 1-4 and 1 5-1 8 of each 28 d cycle.
`Dose modifications and treatment delays for doxorubicin
`were based on granulocyte and platelet counts. stomatitis.
`and on serum bilirubin. Doxorubicin could be discontinued
`for clinical evidence of cardiac failure. marked EKG changes.
`a fall in cardiac ejection fraction below normal and bilirubin-
`> twice normal. Vincristine dose could be reduced by 50% for
`painful parasthesia or moderate constipation, and was
`temporarily discontinued for severe motor weakness. para-
`lytic ileus, or severe constipation.
`Patients were closely monitored for steroid-induced
`hyperglycaemia. myopathy. psychosis, symptoms of gastric
`irritation and hypertension, with dose adjustments if necess-
`
`I. Baseline characteristics of all eligible
`Table
`patients.
`
`No.
`
`%
`
`Age:
`< 60 years
`> 60 years
`Gender:
`males
`females
`ECOG performance status:
`0-2
`> 2
`Primary refractory myeloma
`Relapsed myeloma
`Haemoglobin (g/dl):
`< 1 0 > 10
`% bone marrow plasma cells:
`10-40
`> 40
`Baseline serum calcium:
`hypercalcaemic
`normal
`Bone disease:
`generalized osteoporosis
`1 - 3 lytic lesions
`> 3 lytic lesions
`
`14
`30
`
`26
`18
`
`31
`13
`17
`27
`
`21
`23
`
`15
`29
`
`16
`28
`
`1
`6
`37
`
`31.8
`68.2
`
`59.1
`40.9
`
`70.5
`29.5
`38.6
`61.4
`
`48
`52
`
`34.1
`65.9
`
`36.4
`63.6
`
`2 . 3
`13.6
`84.1
`
`ary. Dexamethasone could be tapered for severe symptoms of
`withdrawal. Scheduled treatments were delayed for episodes
`of active infection. All patients were to receive a histamine HL
`antagonist, oral antibacterial prophylaxis, allopurinol, and
`a n oral antifungal agent throughout the treatment period.
`Patients who responded were treated until maximum
`reduction of the monoclonal protein concentration and then
`for four additional cycles. Nonresponders with progressive
`disease were taken off treatment immediately, and those with
`stahle disease were continued for at least six cycles and then
`were treated at the discretion of the attending physician.
`
`RE!; ULTS
`Putient population
`Forty-five patients were registered from 14 centres between
`March 1 9 8 7 and October 1989. One patient had not been
`shown to be clinically resistant to MP and was declared
`ineligible, leaving 44 eligible patients.
`Seventeen patients were classified with primary refractory
`disease. and 2 7 had previously responded to MP and were
`clinically resistant at the time of trial entry. Criteria for
`clinical MP resistance included progressive rise of mono-
`clonal protein ( 3 5 patients), hypercalcaemia (1 6 patients),
`and progression of skeletal lesions ( 3 3 patients) or enlarge-
`ment of plasmacytomas (five patients) while on treatment. Of
`the 44 patients, 38 met more than one criterion for
`
`ALVOGEN, Exh. 1034, p. 0002
`
`

`

`Treatment of Resistant Myeloma 5 5 7
`
`Table 11. Treatment response in evaluable patients.
`
`Resistance type
`
`Responses
`
`Stable Nonresponse*
`
`Progressive Total
`
`Primary refractory
`Relapse
`Total
`
`3
`8
`11
`
`I
`5
`6
`
`1
`2
`3
`
`11
`10
`22
`
`16
`25
`41
`
`* Patients who completed at least one course of m-VAD and either discontinued
`therapy because of toxicity or died of toxicity before response status verified. Included in
`the primary analysis as nonresponders.
`
`progressive disease. Of the six patients who qualified with
`only one criterion, four had a progressive rise in the
`monoclonal protein and two had an increase in the number
`or size of plasmacytomas.
`Table I summarizes clinical and tumour related baseline
`characteristics for all 44 eligible patients. The median age
`was 62.1 years with 59% males. 13 patients (30%) had ECOG
`performance status > 2, and 66% had >40% plasma cells in
`the bone marrow at study entry. Hypercalcaemia was present
`in 36% of patients, 48% had a haemoglobin level < 10 g/dl,
`and 84% had extensive bone involvement.
`
`Treatment response and survival
`To be assessable for response patients had to complete at least
`one course of therapy. Patients who withdrew because of
`toxicity, or who died oftoxicity before then, are not assessable
`for response. Patients who completed at least one course of
`treatment and who died of toxicity subsequently, before
`response status could be determined, are included as nonres-
`ponders in the primary analysis. A secondary analysis was
`
`also performed in which these patients were excluded. All
`patients were included in the survival analysis.
`According to these criteria, 41 patients are assessable for
`the primary analysis of response. In two patients, treatment
`was discontinued before completion of the first cycle because
`of complications or side-effects, and one patient died on day
`17.
`Table I1 shows that of the 41 evaluable patients there were
`11 responders (27%, 95% C.I. 14-40%), with no complete
`responses. 2 1 patients had progression of disease while on
`therapy, and in six patients the disease remained stable.
`Among the 16 patients with primary refractory disease there
`were only three responders (19%), and among those with
`relapsed disease the response rate was 32% (8/25). When
`patients who discontinued therapy, or died after one cycle
`because of toxicity are excluded, the overall response rate in
`the remaining 38 patients is still only 29% (95% C.I. 13-
`43%).
`
`Table 111. Toxicity in m-VAD treated patients.
`
`Toxicity
`
`No. patients
`
`\
`
`
`
`I
`
`20
`
`0 4
`
`,
`
`,
`
`,
`
`,
`
`,
`
`,
`
`, ,
`
`Nausea
`Alopecia
`Febrile neutropenia
`Documented: bacterial infection
`gram positive bacteraemia
`gram negative bacteraemia
`pneumonia
`Stomatitis:
`soreness only
`ulcers, able to eat
`ulcers, unable to eat
`Neuropathy :
`mild
`severe
`Liver enzyme elevation
`Gastric irritation
`Myopathy
`Hypoglycaemia
`Depression
`
`3.0
`2
`
`,
`
`,
`
`,
`
`,
`
`,
`2.0
`7
`
`,
`1.0
`14
`
`0.0
`44
`
`Time (years)
`# At Riak
`Fig 1. Overall survival of 44 eligible patients.
`
`ALVOGEN, Exh. 1034, p. 0003
`
`

`

`558 George P. Browman et a1
`Table IV. Description of treatment related deaths.
`
`Resistance type
`Patient
`-~
`Refractory
`K 1
`Refractory
`K2
`M 3
`Relapse
`Refractory
`~7 I
`2
`Relapse
`
`Cause of death
`
`hh-year-old male developed fatal pncumonia during pancytopenia in cycle 3
`Si-year-old female died of sepsis and gastrointestinal bleeding during an episode of pancytopenia in cycle 2
`iO-year-old female died of sepsis during pansytopenia in cycle 1
`66-year-old male died of pneumonia during neutropenia in cycle 2
`69-year-old male died of sudden massive hiiemorrhage of tracheostomy site during thrombocytopenia after
`biopsy of a benign subglottic mass following cycle 1
`
`At the time of analysis there were 36 deaths of which 3 1
`were attributed to progressive myeloma only. For the 11
`patients who responded, the median duration of response
`was 4 months, and all patients relapsed from m-VAD therapy
`by 20 months. Median survival for all 4 4 patients was 7.6
`months (Fig 1 ). Median survival was 5.5 months for primary
`refractory patients and 1 0 months for relapsed patients. At 1
`year, only 30% of patients were alive.
`
`Toxicity
`A total of 206 courses of treatment were delivered to 44
`patients evaluable for toxicity. 34 patients received at least
`three courses of therapy. three patients received two courses.
`and seven patients received only one course.
`Table 111 summarizes the observed toxic events and their
`frequency. 10 patients had non life-threatening viral infec-
`tions (6 localized herpes simplex, 1 localized herpes zoster. 3
`upper respiratory tract infection). Bacterial infection was
`documented in 12 patients (8 pneumonia, 3 gram negative
`bacteraemia. 1 gram positive bacteraemia 1. No patient was
`diagnosed with systemic fungal infection. Severe stomatitis
`occurred in one patient, and severe neuropathy occurred in
`10 patients (4 constipation. 1 parasthesia. 3 motor weakness.
`1 bladder dysfunction. and 1 radial neuropathy). Transient
`mild elevation of liver enzymes occurred in seven patients.
`Dexamethasone dosage was reduced in 12 patients: rea-
`sons were gastric irritation (three patients). myopathy (three
`patients), and hyperglycaemia, depression. neutropenia. ster-
`oid withdrawal symptoms, suspected infection. and severe
`parasthesia in one patient each. Dexamethasone was discon-
`tinued in three patients for myopathy.
`Weekly neutrophil counts were recorded for 1 3 7 cycles of
`therapy, and platelets in 147 cycles. The median neutrophil
`nadir was I .2 x 1 Oy/l, and the nadir fell below 0 . 5 x 1OY/1 in
`17 cycles (12%). and below 1 . O x 10y/l in 50 cycles (36%).
`The median platelet nadir was 1 4 7 x 109/1, and the nadir fell
`below 50 x 10y/l in 1 3 of 1 4 i evaluable cycles (9%).
`There were four deaths judged as treatment related only.
`and one judged as due to both disease and treatment. Details
`for these five patients are described in Table IV.
`
`DISCUSSION
`
`In the original report of VAD chemotherapy for multiple
`myeloma, the response rate in patients with relapsed disease
`was higher (73%) than in patients with primary refractory
`
`myeloma (43%). Infection (four bacterial and four viral) was
`the most important complication (Barlogie et al, 1984).
`In the current study, the overall response rate in 41
`evaluable patients was only 2 7%. and in those with relapsed
`disease only 31% responded. Also, overall survival was
`poorer for m-VAD. compared with the original VAD patients
`(Barlogie et al. 1984).
`The disappointing performance of m-VAD compared with
`the published results for VAD could be attributed to two main
`factors: (i) patient selection, and (ii) treatment differences.
`Because we did not perform a randomized comparison, we
`cannot rule out that the population studied by us. and that
`reported by Barlogie et al(1984) differed systematically with
`respect to important prognostic factors that influenced either
`response or survival. The most important prognostic variable
`for both studies, and for other reports of second line myeloma
`therapy. seems to be the nature of the drug resistant disease
`(Alexanian et a!. 1986, 1990; Finnish Leukaemia Group,
`1990). Patients with primary refractory myeloma respond
`less frequently than those with relapse. On this criterion, our
`study population has a more favourable prognosis, with only
`39% of patients having primary refractory disease, compared
`with 48% in the study of Barlogie et a1 (1984). Also, the
`baseline haemoglobin was < 10 g/dl in 52% of patients
`treated by Barlogie et a2 (1984) compared with 48% of our
`parients. Our eligibility criteria restricted entry to patients
`who were exposed to MP only. while patients in the original
`VAD study were exposed previously to more drugs, including
`other alkylating agents and anthracylines (Barlogie et al,
`1984). According to these criteria, the patients reported in
`this study do not appear to have had an inherently worse
`prognosis than those in the original VAD report (Barlogie et
`nl. 1984).
`Thirty-six per cent of our patients were hypercalcaemic at
`the time of entry, 66% had >4O% plasma cells in the
`marrow, and 84% had >three lytic bone lesions. The original
`report of VAD therapy does not provide sufficient information
`on these baseline data to allow comparison (Barlogie et al,
`1984).
`Our patients were treated with a modified version of the
`VAD protocol (Barlogie et al, 1984). Although the drug doses
`were the same, instead of using continuous infusions of
`vincristine and adriamycin over each 4 d treatment period,
`we infused the drugs for 2 h on 4 consecutive days. This
`modification was based on a physician survey that indicated
`resfstance to accepting continuous 4 d infusions through
`
`ALVOGEN, Exh. 1034, p. 0004
`
`

`

`indwelling catheters. The rationale for the use of a 2 h
`adriamycin infusion was based on studies indicating that a 2
`h infusion produces a pharmacokinetic profile similar to a 2 4
`h infusion (Greene et al, 1983). Vincristine was administered
`also for 2 h for convenience, but based on a phase I1 study
`that vincristine alone as a 24 h infusion produced a very low
`response rate in drug resistant myeloma, we did not feel that
`this modification would jeopardize efficacy (Jackson et a],
`1985). However, it is possible that use of 2 h infusions
`interfered with potential synergism between the two drugs
`(Zeller et al, 1979). Despite the change in infusion duration,
`the median granulocyte and platelet nadirs achieved in our
`study (1.2 x 109/1 and 147 x lo9/] respectively) were similar
`to that reported for the longer duration infusions (1.7 x 1 09/1
`and 13 8 x 1 OY/l), suggesting that myelotoxicity was equiva-
`lent.
`We also altered the schedule of dexamethasone therapy.
`Dexamethasone was administered for 4 d starting on days 1
`and 15 of each cycle. The original VAD report recommended
`that three 4 d treatments be abandoned because of the high
`infection rates (Barlogie et al, 1984). Subsequently, the
`original VAD regimen was altered to reduce the dexametha-
`sone exposure (Alexanian et ul. 1990). Our schedule provides
`for consistent treatment on each cycle, and achieves the same
`recommended total dose after every two complete cycles of
`therapy.
`In summary, this phase I1 study of a modified version of
`VAD for drug resistant myeloma failed to reproduce the
`promising results of the original protocol. We were able to
`confirm the finding of other similar studies that patients with
`primary refractory myeloma respond less well and have a
`poorer prognosis than those with drug resistant relapsed
`disease. Due to the study design we are unable to determine
`whether these disappointing results reflect differences in the
`treatments employed or patient selection factors. Also, it is
`not possible to determine whether the response differences
`observed between this and other studies may reflect chance
`variation. On the basis of this study we cannot recommend
`m-VAD as a substitute for VAD chemotherapy in drug
`resistant myeloma.
`
`Treatment of Resistant Mgelorna 5 5 9
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`ALVOGEN, Exh. 1034, p. 0005
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`