Vol. 310 No. 21
`
`TREATMENT OF ADVANCED MULTIPLE MYELOMA-BARLOGIE ET AL.
`
`1353
`
`EFFECTIVE TREATMENT OF ADVANCED MULTIPLE MYELOMA REFRACTORY TO
`ALKYLA TING AGENTS
`
`BART BARLOGIE, M.D., LON SMITH, M.D., AND RAYMOND ALEXANIAN, M.D.
`
`Abstract Twenty-nine patients with advanced refractory
`multlple myeloma were treated with Intermittent high-dose
`dexamethasone In combination with four-day Infusions of
`vlncrlstlne and doxorubicin. Rapid and marked tumor·
`mass reduction (> 75 per cent) was noted in 14 of 20
`patients whose disease was resistant to alkylating agents
`
`and in 3 of 9 patients with additional resistance to doxoru·
`blcin - a result far superior to those in previous trials with
`similar patients. In responsive patients, remissions were
`of excellent quality, and survival was significantly longer
`than in unresponsive patients. (N Engl J Med 1984;
`310:1353·6.)
`
`T HE prognosis of patients with multiple myeloma
`
`that is refractory to combinations of alkylating
`agents and prednisone has been poor because few ef·
`fective salvage treatments are available. 1"3 In a recent
`study, a combination ofvincristine, doxorubicin, and
`pulsed prednisone induced substantial reductions in
`tumor mass in about half the patients with advanced
`refractory disease. 4 More frequent courses of predni(cid:173)
`sone alone were also effective in patients who had been
`resistant to previous drug combinations that had in·
`eluded monthly prednisone, suggesting a dose-de(cid:173)
`pendent antitumor effect from corticosteroids. These
`observations suggested that the results might be im·
`proved with even higher doses of corticosteroids com·
`bined with a continuous infusion ofvinca alkaloid and
`doxorubicin to affect more slowly proliferating plasma
`cells. This report summarizes our experience with
`high doses ofdexamethasone in conjunction with four·
`day infusions of vincristine and doxorubicin. Seventy
`per cent of patients with advanced myeloma that was
`refractory to alkylating agents had marked reductions
`in tumor mass -
`a result superior to any previously
`achieved in our patients with resistant myeloma.
`
`METHODS
`
`Between .January and October 1983, 29 patients with advanct·d
`refractory multiple myeloma were treated with a mmbination of
`vincristinc, doxorubicin (adriamycin), and dexamethasoiw (\'AD).
`Their clinical features wcrt' similar to thost• dcsnibt'd in pre\'ious
`large groups of patients with resistant myeloma. 1•·1 The median agt•
`was 61 years, and 72 per cent of the patients had an intermediate or
`high tumor-mass stage. Twel\'e patients had lgG myt•loma and 11
`had lgA myt•loma; 6 patients st•creh·d Hmn• .Jont•s prntt•in only.
`Patients with nonscaetory mydoma wt•rt· indigiblt· for tht• study
`because there was no mydoma-prott•in marker from which to C\'alu(cid:173)
`ate a response. Previously unresponsivt· patients with a low and
`stable tumor mass were ineligible because they were asymptomatit·
`and had a good prognosis.
`The V AD regimen consisted of four-day continuous infusions of
`vincristine (0.4 mg per day) and doxorubicin (9 mg per square
`meter of body-surface area per day), given through an indwelling
`cathett'r with use ofTravenol pumps; in addition, patients received
`dexamethasone in a dose of 40 mg each morning for four days,
`beginning on Days I, 9, and 17 of each cycle. Treatment was usually
`initiated and continued in the outpatient clinic unless complications
`developed. Twenty patients were resistant to alkylating agent(cid:173)
`prednisone combinations (VAD I), and the other nine patients
`were also resistant to prior doxorubicin combinations (e.g., month·
`
`From the Department of Hematology, University of Texas M. D. Anderson
`Hospital and Tumor Institute. Address reprint requests to Dr. Barlogie at M. D.
`Anderson Hospital and Tumor Institute, 6723 Bertner Ave .. Box SS, Houston.
`TX 77030.
`Supported by grants (CA 28771 and CA 16672) from the National Cancer
`Institute, National Institutes of Health.
`
`ly vincristine, cyclophosphamide, doxorubicin [adriamycin], and
`prednisone) (VAD II). In all patients, tumor resistance was present
`despite myelosuppressive doses of chemotherapy. No patient had
`been included in previous studies concerning the utility of therapy
`with vincristine, doxorubicin, and pulsed prednisone therapy. 4
`There were 14 patients who had never responded to a median of 13
`months of prior therapy (VAD I, seven patients; VAD II, seven
`patients). A second group of 15 patients had responded to prior
`treatment and had relapsed after a median duration of 36 months
`despite continued chemotherapy (VAD I, 13 patients; VAD II, 2
`patients). Thus, all patients had obvious resistance to a long course
`ofmyelosuppressive chemotherapy, and tumor progression was evi(cid:173)
`dent in most patients.
`All patients received prophylactic antacid treatment with cimeti·
`dine and antibiotic prophylaxis with trimethoprim-sulfamethox(cid:173)
`azole. Special attention was given to the early detection of infection;
`all patients were asked to record evening temperatures and to seek
`medical evaluation promptly if temperatures exceeded 38°C.
`All trials included weekly measurements of blood counts and
`monthly assessment of laboratory chemistry and electrophoretic
`data. Marrow aspirations were performed to assess the RNA con·
`tent of plasma cells by flow cytometry and serial changes in the
`degree of plasma-cell infiltration. 5 A response was defined as a re(cid:173)
`duction in tumor mass exceeding 75 per cent, with disappearance of
`Bence Jones protein t'Xcretion.'; Changes in tumor mass from the
`start oftreatmt'nt were calculated from changes in myt'loma-protein
`production; this assessment considt•red the serum mydoma-protein
`concentration, the change in lgG cataholic rate with falling lt•\•els,
`tht• estimated plasma volume, and tht' background of normal gam·
`ma globulin. 1:our patients died during tht• first two months of
`tlwrapy, and their tn·aunents were mnsidt•rt>d failures.
`VAD clwmotherapy was repeatt•d until a maximum reduction in
`myeloma protein had ot·curred. Responsi\'e patit'nts in whom serum
`myeloma prott•in had disappt•arcd or le\'els had stabilized n·ceiwd
`four additional courses ofVAD bt'fore u·1·atment was stopped. Sur(cid:173)
`\'ival was t•akulatt'd b\' life-table anal\'sis from the onst•t of \'AD
`tn·atmt'nt until dt>ath. ·
`.
`
`RESULTS
`
`Twenty-nine consecutive patients with resistant
`myeloma received the V AD regimen. One group of20
`patients who were resistant to melphalan-prednisone
`included 7 patients who had received doxorubicin at
`least six months earlier (V AD I). Reductions in tumor
`mass exceeding 75 per cent were observed in 14 pa·
`tients in this group (70 per cent) (Table I); this re(cid:173)
`sponse rate was significantly higher than the 23 per
`cent frequency of 75 per cent tumor reduction ob(cid:173)
`served in comparable previous patients treated with
`vincristine, doxorubicin (adriamycin), and pulsed
`prednisone (V AP) (P<0.05). 4 The tumor reduction
`occurred rapidly; the median tumor-halving time
`among responders ranged from 0.3 to 1.6 months (me(cid:173)
`a period similar to the l.l-month period
`dian, 0.9) -
`observed in responders to VAP. 4 Among the 23 pa·
`tients with a serum monoclonal component, disap-
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org by Keely Southwick on November 21, 2017. For personal use only. No other uses without permission.
`
` From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`ALVOGEN, Exh. 1032, p. 0001
`
`

`

`1354
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`May 24, 1984
`
`Table 1. Response to VAD Therapy According to Effects of Earlier
`Treatment.
`
`RESPONDING PATIENTS •
`
`PREVIOUSLY
`UNRESPONSIVE
`
`PREVIOUSLY
`RELAPSING
`
`TOTAL
`
`3 of 7
`
`JI of 13
`
`14 of 20 (70%)
`
`3 of 7
`
`0 of 2
`
`3 of 9 (33%)
`
`PATIENT GROUP
`
`Resistant to
`melphalan (V AD I)
`
`Resistant to melphalan
`and doxorubicin
`(VAD II)
`
`Total
`
`6 of 14
`
`JI of IS
`
`17 of 29 (59%)
`
`"'A rei.ponfie was defined as a >75 per cent reduction in tumor ma"s. Among lhc re!i.pondin~
`patient•, tumor halving occurred in a median of 0.9 month (range, 0.3 to 1.6).
`
`pearance of the abnormal globulin from the electro(cid:173)
`phoretic strip occurred in two patients, as compared
`with none of the patients treated with VAP. Among
`six patients with Bence Jones protein only, light-chain
`excretion disappeared in two, as compared with none
`of eight similar patients treated with VAP. 4 In the
`second group, containing nine patients who had been
`resistant to both melphalan and doxorubicin combi(cid:173)
`nations (V AD 11), only three patients responded
`(Table 1); such patients had not been eligible for the
`earlier V AP program. Among the patients who had
`initially responded to previous treatment and then re(cid:173)
`lapsed, 73 per cent responded to VAD, as compared
`with 43 per cent of those who had been unresponsive
`to prior therapy (P = 0.16). All six patients in this
`latter group were clearly resistant in that they had
`either progressive disease (three patients) or a stable
`tumor mass despite at least six months of prior ther(cid:173)
`apy (three patients). As in previous studies, a high
`RNA index (ratio of mean RNA content of marrow
`plasma cells vs. that of normal lymphocytes5) was as(cid:173)
`sociated with a high response rate. Thus, there was a
`progressive increase in response rate, from 0 per cent
`in patients with a low RNA index (<4) to 50 per cent
`in those with intermediate values (4 to 6) and 87 per
`cent in those with a high RNA index (>6) (P<0.01)
`(Fig. 1).
`
`Cllnlcal Courae
`All 17 responding patients also had marked clinical
`benefit, with reduced pain and improved perform(cid:173)
`ance. In 15 of the 29 patients, the pretreatment hemo(cid:173)
`globin concentration was <IO g per deciliter. In six of
`nine anemic responders the hemoglobin rose by at
`least 2.5 g per deciliter, to more than 11.5 g per decili(cid:173)
`ter during remission, with chronic renal failure ac(cid:173)
`counting for the exceptions. None of the six anemic
`nonresponders had any rise in hemoglobin level.
`Myeloma-protein reduction was accompanied by a
`similarly rapid and marked clearing of bone-marrow
`plasmacytosis, from a pretreatment median of 38 per
`cent to a median of 1 per cent within one month (Fig.
`2). The survival of responding patients was signifi(cid:173)
`cantly longer than that of patients in whom treatment
`failed (P = 0.002); the projected survival time for re(cid:173)
`sponders exceeds one year (Fig. 3). Although the me-
`
`dian survival time of all patients was short, the median
`relapse-free survival time has not been reached. There
`were two patients who had relapsed four and six
`months, respectively, after completion of VAD ther(cid:173)
`apy, who again had a prompt >75 per cent reduction
`in tumor mass upon reinitiation of V AD.
`VAD chemotherapy induced mild and reversible
`depressions of blood counts. During the first two
`courses, the median nadir of granulocytes was 1700
`per microliter (range, 250 to 4100), and that of plate(cid:173)
`lets was 138,000 per microliter (range, l l ,000 to
`233,000). As in previous studies with pulsed predni(cid:173)
`sone, infection represented the most important com(cid:173)
`plication. Eleven patients had episodes of fever, re(cid:173)
`quiring hospitalization in nine, and an infectious
`agent was identified in eight patients. There were four
`cases of pneumonia, two episodes of gram-positive
`bacteremia (probably related to the indwelling cath(cid:173)
`eter), and two cases of gram-negative sepsis. Four
`patients had documented viral infections, including
`herpetic esophagitis (two patients), herpes zoster in(cid:173)
`fection (one patient), and cytomegalovirus infection
`with hepatitis (one patient). The herpetic infections
`responded promptly to treatment with acyclovir and
`did not require interruption ofVAD therapy. Perhaps
`because of the regular use of cimetidine, gastrointesti(cid:173)
`nal side effects were minimal. A paralytic ileus devel(cid:173)
`oped in one patient but did not recur after omission of
`vincristine from the V AD regimen. Severe depression
`developed in another patient but was managed suc(cid:173)
`cessfully with antidepressants, so that dexamethasone
`treatment could be continued.
`
`DISCUSSION
`The V AD regimen was developed as a result of
`our previous findings that the addition of frequent
`
`Responaa
`
`No
`Responaa
`
`Responaa
`Rate
`
`14
`
`12
`
`10
`
`•
`•
`·>
`j 8
`i 6 UI
`I
`
`~
`
`4
`
`2
`
`0
`
`0
`
`B
`0
`8
`0
`
`000
`
`87%
`
`}
`
`50%
`
`O'lli
`
`0
`Figure 1. Relation between the RNA Index of Plasma Cells
`and the Response to VAD In 27 Patients.
`See text for definition of RNA Index.
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org by Keely Southwick on November 21, 2017. For personal use only. No other uses without permission.
`
` From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`ALVOGEN, Exh. 1032, p. 0002
`
`

`

`Vol. 310 No. 21
`
`TREATMENT OF ADVANCED l\WLTIPLE l\1YEL0l\1A- BARLOGIE ET AL.
`
`1355
`
`60
`
`(/)
`
`(/)
`
`•
`•
`~
`0
`~
`•
`.!!! 40 •
`a..
`•
`'E
`•
`•
`Cl>
`u ...
`Cl> a..
`•
`•
`
`20
`
`0
`
`0
`
`0
`
`0
`
`0
`0
`0
`
`0
`
`0
`
`•
`•
`
`•
`
`0
`
`0
`
`•
`•
`
`0
`
`Pre Rx
`
`1 Month
`
`3 Months
`
`Figure 2. Proportions of Bone-Marrow Plasma Cells Determined
`by Flow Cytometry before and after VAD Therapy in Responsive
`and Unresponsive Patients.
`
`sponses occurred in about 70 per cent of patients who
`were resistant to melphalan, as compared with about
`25 per cent of patients treated with YAP. The marked
`sensitivity of plasma cells was also demonstrated by
`the prompt and marked decrease in bone-marrow
`plasmacytosis, indicating that reductions in myeloma
`protein resulted from a true tumoricidal effect. Since
`all responses were evident after only one course, the
`toxicity could be minimized in patients who were un(cid:173)
`likely to benefit from this treatment, who should be
`offered other investigational therapies. In addition,
`unresponsive patients had a significantly lower RNA
`content in their plasma cells than did responsive pa(cid:173)
`tients. Confirming the important prognostic role of
`plasma cell RNA content in regard to induction of re(cid:173)
`mission, this assessment identified patients who were
`most likely to benefit from this treatment program. 5
`The superior results achieved with Y AD as com(cid:173)
`pared with YAP resulted from one or both of the two
`major alterations in the treatment regimen: dcxamcth(cid:173)
`asone was provided in a higher steroid dose, and a
`prolonged vincristine-doxorubicin dose regimen was
`given; this regimen may have been more effective
`against slowly cycling plasma cells. The important
`therapeutic role of dexamethasone was also support(cid:173)
`ed by the observed responses in 4- of 10 other melpha(cid:173)
`lan-resistant patients who were receiving this steroid
`alone (not included in the present series) and in a
`similar proportion of doxorubicin-resistant patients
`who were receiving YAD (YAD II). These observa-
`
`1 .0
`
`.8
`
`.6
`
`.4
`
`.2
`
`Reeponaa
`O Yea
`e No
`
`No. of P1tlen11
`Total
`Deed
`17
`2
`12
`8
`
`p
`
`0.002
`
`Survival
`<:> Rel1p11·Free
`• Overall
`
`No. of P11len11
`Total
`Fell
`29
`16
`29
`10
`
`prednisone pulses increased the response rate among
`patients with resistant myeloma. 4 Thus, a sixfold
`higher dose of steroid equivalent in the form of
`dexamethasone was combined with continuous infu(cid:173)
`sion of vincristine and doxorubicin. The rationale for
`the protracted administration of vincristine and dox(cid:173)
`orubicin was based on the long gen-
`eration time and low growth frac(cid:173)
`tion of plasma cells in most pa(cid:173)
`tients. 7 Indeed, a greater reduction
`of myeloma cells grown in tissue
`culture has been reported after pro(cid:173)
`longed as opposed to brief expo(cid:173)
`sures to vincristine.8 Since vincris(cid:173)
`tine has a serum-half life of less
`than 30 minutes after administra-
`tion as a bolus, a prolonged infusion
`seemed more appropriate. 9 In addi(cid:173)
`tion to exerting a possibly superior
`antitumor effect, a continuous infu(cid:173)
`sion of doxorubicin would also re(cid:173)
`duce the risk of cardiomyopathy as(cid:173)
`sociated with repeated injections as
`a bolus and would therefore permit
`a longer use of the drug in respond(cid:173)
`ing patients.
`In patients who were resistant
`to alkylating agent-corticosteroid
`combinations, V AD treatment in(cid:173)
`duced a higher frequency of sub-
`stantial tumor reduction in a more
`rapid manner than observed with
`any previous program, either for
`initial or salvage therapy. With a
`>75 per cent reduction of tumor
`mass as a criterion for response, re-
`
`0
`
`6
`
`12
`
`6
`
`12
`
`0
`Months
`Figure 3. Survival from Start of VAD Chemotherapy In Responsive and Unresponsive
`Patients (Left Panel) and Disease-Free Survival In Responsive Patients Compared
`with Overall Survival In the Patient Population (Right Panel).
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org by Keely Southwick on November 21, 2017. For personal use only. No other uses without permission.
`
` From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`ALVOGEN, Exh. 1032, p. 0003
`
`

`

`1356
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`May 24, 1984
`
`tions suggest that patients who are resistant to doxoru(cid:173)
`bicin are more likely to be resistant to corticosteroids.
`Such steroid therapy seems appropriate for patients
`with pancytopenia from extensive bone-marrow infil(cid:173)
`tration by plasma cells and for those receiving pallia(cid:173)
`tive radiotherapy when myelosuppressive chemo(cid:173)
`therapy must be delayed.
`The major toxic effect ofVAD was infection, which
`was attributed in part to the intensive steroid pro(cid:173)
`gram -
`a complication noted previously with pulsed
`prednisone therapy. Combined with frequent self(cid:173)
`monitoring for fever, longer periods without any ster(cid:173)
`oid therapy might allow earlier recognition of sepsis
`and recovery from immunosuppression. Less frequent
`infection has resulted from our current program,
`which omits the second and third dexamethasone
`pulses in every second course of VAD. Finally, pre(cid:173)
`viously untreated patients may benefit from alternat(cid:173)
`ing two therapeutic combinations that are unlikely to
`lead to cross-resistance - namely, VAD and melpha(cid:173)
`in an effort to reduce the emergence
`lan-prednisone -
`of drug-resistant tumor clones. 10 Such an approach
`has been successful with alternating combinations
`of mechlorethamine-vincristine-procarbazine-pred(cid:173)
`nisone and doxorubicin-bleomycin-vinblastine-da(cid:173)
`carbazine in the treatment of Hodgkin's disease. 11 It is
`also supported by our experience with three consecu(cid:173)
`tive patients receiving V AD who had further mye(cid:173)
`loma-protein reductions after a stable response was
`
`achieved with standard vincristine-cyclophospha(cid:173)
`mide-doxorubicin-prednisone induction treatment.
`
`We are indebted to Kay Delasalle and Leslie Smallwood for as(cid:173)
`sistance in the data analysis and to Mattie Scott-Thomas for assis(cid:173)
`tance in the preparation of this manuscript.
`
`REFERENCES
`
`I. Kyle RA, Pajak TF, Henderson ES, et al. Multiple myeloma resistant to
`melphalan: treatment with doxorubicin, cyclophosphamide, carmustinc
`(BCNU), and prednisone. Cancer Treat Rep 1982; 66:451-6.
`2. Bonnet J, Alexanian R, Salmon S, ct al. Vincristine, BCNU, doxorubicin,
`and prednisonc (VPAB) combination in the treatment of relapsing or resist(cid:173)
`ant mycloma: a Southwest Oncology Group study. Cancer Treat Rep 1982;
`66:1267-71.
`3. Alexanian R, Gutterman J, Levy H. Interferon treatment for multiple mye(cid:173)
`loma. Clio Haematol 1982; 11:211-20.
`4. Alexanian R, Yap BS, Bodey GP. Prednisonc pulse therapy for refractory
`myeloma. Blood 1983; 62:572-7.
`5. Barlogic B, Alexanian R, Gehan EA, Smallwood L, Smith T, Drewinko B.
`Marrow cytometry and prognosis in myeloma. J Clin Invest 1983; 72:853-
`61.
`6. McLaughlin P, Alexanian R. Myeloma protein kinetics following chemo(cid:173)
`therapy. Blood 1981; 60:851-9.
`7. Drewinko B, Alexanian R, Boyer H, Barlogie B, Rubinow SI. The growth
`I fraction of human myeloma cells. Blood 1981; 57:333-8.
`8. MacKenzie MR, Larchandini R, Peng R. Plasma cell sensitivity due to
`vincristine, in vitro evidence of increased efficacy of prolonged exposure.
`Presented at the 13th International Congress of Chemotherapy, Vienna,
`August 28-Septembcr 2, 1983.
`9. Jackson DV Jr, Sethi VS, Spurr CL, et al. Pharmacokinetics of vincristine
`infusion. Cancer Treat Rep 1981; 65:1043-8.
`10. Goldie JH, Coldman AJ. A mathematical model for relating the drug sensi(cid:173)
`tivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 1979;
`63:1727-33.
`11. Bonadonna G. Chemotherapy strategies to improve the control of Hodgkin's
`disease. Cancer Res 1982; 42:4309-20.
`
`Massachusetts Medical Society
`Registry on Continuing Medical Education
`To obtain information on continuing medical education courses in the New England area,
`write or call, indicating field(s) or specialty in which information is desired, to the Commit·
`tee on Medical Education, 1440 Main St., Waltham, MA 02254; telephone (617) 893-4610
`(Metropolitan Boston) or WATS 1-800-322-2303 (Massachusetts).
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org by Keely Southwick on November 21, 2017. For personal use only. No other uses without permission.
`
` From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`ALVOGEN, Exh. 1032, p. 0004
`
`