High-Risk Multiple Myeloma Treated With High-Dose Melphalan
`
`By Henk M. Lokhorst, Otger J.A.Th. Meuwissen, Leo F. Verdonck, and Adriaan W. Dekker
`
`Purpose: This study was undertaken to evaluate the
`efficacy and toxicity of high-dose melphalan (HDM) 140
`mg/m' in poor-risk multiple myeloma (MM).
`Patients and Methods: Thirteen patients were previ-
`ously untreated, and 13 had been pretreated with vincris-
`tine, Adriamycin (doxorubicin; Adria Laboratories, Colum-
`bus, OH), and dexamethasone (VAD) for refractory or
`relapsed MM.
`Results: All 11 fully assessed, untreated patients re-
`sponded, and six achieved a complete response. Remis-
`sions were of excellent quality, but response duration-a
`median of 16 months-was short. This was probably due
`to the high incidence of unfavorable prognostic signs, like
`a high beta2-microglobulin (B2M) and/or a high plasma
`index (LI). None of the nine pretreated
`labeling
`cell
`patients with a measurable M component had more than
`50% reduction of M component after HDM, indicating that
`intensive treatment has no effect on a residual tumor
`population. The relapse-free period after HDM in this
`
`T HE PROGNOSIS FOR patients with multiple my-
`eloma (MM) has hardly improved since the intro-
`duction of alkylating agents almost 30 years ago. Various
`treatment combinations with melphalan, prednisone, or
`cyclophosphamide, and one or more additional agents
`including anthracyclines have been used. However, me-
`dian survival of patients with MM is still about 30 to 36
`months after diagnosis.'' When unfavorable prognostic
`signs are present, such as a high beta,-microglobulin
`(B2M) or a high plasma-cell growth fraction, survival is
`reduced to between 8 and 18 months.3 5 The prognosis
`for patients who are primarily resistant or who have
`become refractory to first-line treatment is even worse.6
`Although the vincristine, Adriamycin (doxorubicin; Adria
`Laboratories, Columbus, OH), and dexamethasone
`(VAD) regimen produces responses in about 60% of
`these patients, response duration is short; most patients
`relapse within 1 year.7'8
`Two promising approaches have been introduced
`recently: the use of high-dose melphalan (HDM) and
`the introduction of several biologic response modifiers,
`of which interferon is the most well known.9 '10 We report
`our experience with HDM 140 mg/m2 in a group of
`treated and pretreated high-risk MM patients.
`
`PATIENTS AND METHODS
`
`From February 1985 until January 1990, previously untreated
`patients with multiple myeloma under age 65 years and with a high
`tumor mass (stage III according to the staging system reported by
`
`group of patients (median, 9 months) was not better than
`in a historical control group of patients treated with VAD
`alone. The major complications due to the prolonged
`myelosuppression were severe infections. After primary
`HDM, median time to recovery to greater than 0.5 x 169
`granulocytes was 30 days; in previously treated patients,
`the recovery period was even longer. There were three
`toxic deaths. Fulminant relapses with features of J-chain
`disease were frequently observed, indicating a dediffer-
`entiated tumor, probably induced or selected by the
`HDM.
`Conclusions: HDM is an effective treatment resulting
`in good remissions for untreated MM. However, other
`therapy strategies should be explored first, focusing on
`the reduction of toxicity and prolongation of the relapse-
`free period, before HDM can be recommended as first-
`line treatment for the younger MM patient.
`J Clin Oncol 10:47-51. © 1992 by American Society of
`Clinical Oncology.
`
`Durie and Salmon") and patients under age 65 years with a
`response to second-line therapy that consisted of VAD were
`entered onto a study with intravenous HDM 140 mg/m2. All
`patients had a creatinine clearance greater than 40 mL/min. No
`patient was excluded because of renal insufficiency in this period.
`All patients had routine evaluations before treatment, including
`physical examination, skeletal x-ray, bone marrow aspirate, bone
`marrow biopsy, and myeloma protein, serum B2M, lactate dehydro-
`genase (LDH), and albumin measurements. For immunofluores-
`cence staining of the plasma cells, mononuclear cells were sepa-
`rated from the bone marrow on Ficoll-hypaque. Slides were
`prepared with a cytocentrifuge. After fixation of the cells, they
`were stained with purified fluorescein isothiocynate (FITC) or
`tetramethylrhodamine isothyocyanate (TRITC)-conjugated H chain
`antibodies (a, -y, ý) and with L chain conjugates (K, X). The
`plasma-cell labeling index (LI) was performed with bromodeoxyu-
`ridine (BRDU) in a double fluorescence technique.1
`As shown in Table 1, 26 patients, median age 55 years, were
`treated. Most untreated patients had one or more unfavorable
`prognostic signs, eg, high B2M or a high LI. In eight patients B2M
`was more than 6 mg/L; in four patients, the LI was more than 3%.
`Serum albumin under 30 g/L was not present in any of the patients;
`the LDH level was over 500 U/L in only one patient. A complete
`response (CR) after VAD and HDM was determined as complete
`
`From the University Hospital Utrecht, Utrecht; and Sint Antonius
`Hospital, Nieuwegein, The Netherlands.
`Submitted March 4, 1991; accepted July 22, 1991.
`Address reprint requests to Henk M. Lokhorst, MD, University
`Hospital Utrecht, Department of Haematologie, G03.647, PO Box
`85500, 3508 GA Utrecht, The Netherlands.
`© 1992 by American Society of Clinical Oncology.
`0732-183X/92/1001-0009$3.00/0
`
`Journal of Clinical Oncology, Vol 10, No 1 (January), 1992: pp 47-51
`
`47
`
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`48
`
`LOKHORST ET AL
`
`Table 1. Characteristics of Patients With MM Treated With HDM
`
`RESULTS
`
`Median age, years (range)
`Sex (male/female)
`Immunoglobulin G
`Immunoglobulin A
`Immunoglobulin D
`BJP
`Stage IIIA
`B2M > 6 mg/L
`LI > 3%
`B2M and Ll > 3
`LDH > 500 U/L
`Albumin < 30 g/L
`Performance status (ECOG)
`0
`1
`2
`3
`4
`
`Previously
`Untreated
`(n= 13)
`
`58 (44-65)
`5/8
`10
`2
`0
`1
`13
`8
`4
`2
`1
`0
`
`0
`4
`5
`4
`0
`
`Previously
`Treated
`(n = 13)
`
`53 (32-60)
`7/6
`7
`2
`1
`3
`
`3
`8
`2
`0
`0
`
`Abbreviation: BJP, Bence Jones proteinuria.
`*Four patients were refractory to melphalan and prednisone; five
`relapsed during and four relapsed after melphalan and prednisone.
`Three patients had a CR, seven a PR, and three a minor response after
`VAD. Median number of VAD courses was five (range, 3 to 11 courses)
`and median time of follow-up before HDM was 20 months (range, 9 to
`31 months).
`
`disappearance of myeloma proteins, as determined by immunofix-
`ation of serum and/or concentrated (10 x) urine, and normaliza-
`tion of the bone marrow, including less than 5% plasma cells in a
`representative bone marrow biopsy and less than 5% plasma cells
`in a normocellular bone marrow aspirate. The plasma cells should
`be polyclonal after immunofluorescent staining. A partial response
`(PR) was identified as a more than 50% reduction of myeloma
`proteins and a minor response, between 25% and 50% reduction of
`M component.
`Response and survival curves after HDM were calculated using
`the method of Kaplan and Meier." Performance status was
`determined according to the criteria of the Eastern Cooperative
`Oncology Group (ECOG)14: 0, normal; 1, ambulant with symp-
`toms; 2, bedrest less than 50% of the day; 3, bedrest greater than
`50% of the day; 4, bedrest all day.
`Patients were treated in a single room. A central indwelling
`catheter was used for intravenous (IV) infusions and blood
`sampling. Melphalan 140 mg/m 2 was given as a slow bolus injection
`with a forced saline diuresis. Diphenhydramine hydrochloride 50
`mg IV, dexamethasone 10 mg, and metoclopramide 1 mg/kg IV
`were administered 1 hour before and 6 hours after HDM, provid-
`ing effective antiemesis. Selective decontamination of the alimen-
`tary tract was started the week before HDM and consisted of oral
`ciprofloxacin 500 mg twice daily and amphotericin B suspensions
`and tablets. In addition, amphotericin B was given IV every other
`day at a dose of 0.4 mg/kg body weight prophylactically when the
`neutrophil count was below 0.5 x 10 9/L. Final evaluation was
`dated June 1, 1991.
`
`Primary HDM
`All 11 assessable patients showed a response; six had
`a CR, five patients entered a PR. Two patients died
`during the aplastic period after HDM: one patient on
`day 28 due to interstitial pneumonia (no specific cause
`was found in broncheolar alveolar lavage and postmor-
`tem examination), and the other patient on day 21 due
`to overwhelming septicemia caused by enterococci. Post-
`mortem examination showed severe mucositis of the
`entire digestive
`tract. All other patients showed a
`remarkable improvement in their performance status
`and in other parameters such as pain grade and anemia.
`Normalization of hemoglobin occurred
`in all seven
`patients with anemia. Only three patients complained of
`residual minor nonspecific pain, and none of these
`patients required specific analgesia. Most patients were
`able to perform their normal daily activities. In three
`patients minor radiographic bone healing was observed,
`and in nine patients complete recovery of polyclonal
`humoral immunoglobulins occurred. The results of pri-
`mary treatment with HDM are listed in Table 2.
`Eight patients have relapsed: all five patients with a
`PR and three of the six patients with a CR. In three
`patients extramedullary relapse preceded bone marrow
`relapse. Median follow-up is 27 months (range, 17 to
`41+ months). Median response duration is 16 months
`(Fig 1). One patient died after 29 months due to
`fulminant disease. Median survival has not been reached
`yet (Fig 2). None of the relapsed patients was given a
`second dose of induction with HDM.
`
`Consolidation HDM
`Thirteen patients received HDM after a response to
`VAD chemotherapy. None of nine patients with a
`still-present M component after VAD had more than a
`50% reduction in the M component. In seven patients
`the M component was lower after treatment (median,
`28%; range, 8%
`to 44%), and in two patients the M
`component remained unchanged. One patient died
`suddenly, within 1 month after HDM, due to pulmonary
`hemorrhage. Postmortem examination showed a rup-
`ture of the pulmonary artery due to invasive aspergillo-
`sis. Eleven of the remaining 12 patients have relapsed
`after HDM, including the three patients in CR after
`VAD with no measurable M component and immuno-
`morphologically normal bone marrow. These three re-
`lapsed at 4, 4, and 30 months, respectively. In three
`patients extramedullary relapses preceded a fulminant
`bone marrow relapse. Median time to relapse was 9
`
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`HIGH-DOSE MELPHALAN FOR MULTIPLE MYELOMA
`
`49
`
`Patient
`No.
`
`B2M >
`6 mg/L
`
`U >
`3%
`
`Response
`
`Response
`(months)
`
`Survival
`(months)
`
`Performance
`Before HDM
`
`Status
`After HDM
`
`Bone
`Healing
`
`Recovery
`(humoral Ig)
`
`Table 2. HDM in Previously Untreated MM: Clinical Outcome
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`
`-
`
`+
`+
`+
`+
`+
`-
`+
`-
`+
`+
`
`-
`+
`-
`-
`-
`-
`-
`-
`
`+
`+
`+
`-
`
`CR
`PR
`CR
`CR
`CR
`PR
`CR
`PR
`CR
`PR
`PR
`ED
`ED
`
`28
`17
`31+
`30+
`17
`12
`24+
`9
`16
`12
`5
`NA
`NA
`
`41+
`34+
`31+
`30+
`29
`27+
`24+
`23+
`21+
`18+
`17+
`0
`0
`
`2
`2
`2
`2
`3
`1
`3
`3
`2
`3
`1
`2
`3
`
`0
`0
`0
`0
`1
`0
`0
`1
`0
`1
`1
`NA
`NA
`
`+
`
`+
`-
`
`-
`
`+
`
`NA
`NA
`
`+
`
`+
`+
`+
`
`+
`
`+
`
`NA
`NA
`
`days) and to greater than 30 x 10' platelets per liter, 31
`days (range, 25 to 35 days). In previously treated
`patients, bone marrow recovery was even slower: me-
`dian time to recovery to greater than 0.5 x 10' granulo-
`cytes per liter was 36 days (range, 31 to 55 days), and to
`greater than 30 x 10' platelets per liter, 40 days (range,
`31 to 70 days).
`As a result of the prolonged myelosuppression, com-
`plicating infections such as pneumonia (seven patients)
`and bacteremias (18 patients) were experienced. Most
`bacterial infections were due to gram-positive organisms
`(16; one fatal), of which about 50% were central
`line-related. In the first eight patients, five required
`treatment with IV amphotericin B because of suspected
`systemic fungal infection. Therefore, we modified our
`standard antiinfection prophylaxis, adding IV amphoter-
`
`inn
`
`a
`
`C
`
`L i
`
`n o
`
`o`
`
`Abbreviations: ED, early death; NA, nonassessable.
`
`months (Fig 1); median survival was 26 months (range,
`11 to 60+ months; Fig 2).
`Bone healing and/or restoration of humoral immune
`deficiency was not observed in this group of pretreated
`patients. The results of HDM consolidation treatment
`are shown in Table 3.
`
`Toxicity of HDM
`Most patients experienced nausea and vomiting
`(World Health Organization [WHO] grade 2) during the
`first days after HDM, but good control of these compli-
`cations was achieved with conventional antiemetics.
`Diarrhea (WHO grade 2) lasting for a few days and
`mucositis (WHO grade 2 to 3) lasting for 1 or 2 weeks
`started approximately 1 week after treatment. In one
`patient, mucositis grade 4 was observed. Complete but
`reversible alopecia occurred in all patients (Table 4).
`The major toxicity-related problem after HDM was
`prolonged myelosuppression. In previously untreated
`patients, median time to recovery to greater than 0.5 x
`109 granulocytes per liter was 30 days (range, 27 to 35
`
`S100
`
`A
`
`"50.
`
`11
`
`----
`12
`
`36
`24
`months
`
`-
`
`------------
`24
`36
`12
`
`48
`
`60
`months
`
`12
`
`24
`
`36
`
`48
`months
`
`60
`
`(A) Patients treated with primary HDM; probability of
`Fig 1.
`remaining in remission for patients in CR or PR. (B) Patients treated
`with consolidation HDM after a response to VAD chemotherapy.
`Probability of remaining in PR or CR from the start of HDM treatment.
`
`(---) Patients treated with primary HDM. Probability of
`Fig 2.
`survival from the start of treatment. (-) Patients treated with consoli-
`dation HDM after a response to VAD chemotherapy. Probability of
`survival from the start of HDM treatment.
`
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`50
`
`LOKHORST ET AL
`
`Table 3. HDM in Previously Treated Patients: Clinical Outcome
`
`Patient
`No.
`
`Follow-Up
`Pre-HDM
`(months)*
`
`Response
`to VAD
`
`Relapse-Free
`Post-HDM
`(months)
`
`Survival
`(months)
`
`M Component (g/L)
`
`Pre-HDM
`
`Post-HDM
`
`% Decrease in
`M Component
`Post-HDM
`
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`
`9
`12
`16
`24
`21
`31
`20
`9
`21
`12
`24
`26
`48
`
`PR
`CR
`MR
`PR
`MR
`MR
`PR
`PR
`CR
`CR
`PR
`PR
`PR
`
`60
`30
`6
`12
`3
`10
`11
`9
`4
`4
`5
`9
`ED
`
`60+
`48+
`39+
`35
`30
`28
`26+
`23+
`16+
`16
`12
`11
`0
`
`23
`0
`33
`21
`14
`25
`28
`26
`0
`0
`15
`20
`
`14
`0
`25
`15
`8
`23
`18
`26
`0
`0
`15
`16
`
`39
`NA
`24
`28
`43
`8
`35
`0
`NA
`NA
`0
`20
`NA
`
`Abbreviation: MR, mixed response.
`*Patients no. 14, 15, 21, and 22 were primary refractory to melphalan and prednisone. Patients no. 16, 17, 18, 19, and 23 relapsed during treatment.
`Patients no. 20, 24, 25, and 26 were on treatment when they relapsed.
`
`icin B 0.4 mg/kg body weight during the granulocytope-
`nic period. This was administered to all patients every
`other day. Thereafter, only one systemic fungal infection
`occurred in 18 patients. We observed three early deaths:
`one due to interstitial pneumonia, one due to severe
`mucositis with subsequent septicemia, and one due to
`invasive aspergillosis.
`
`DISCUSSION
`HDM is an effective therapy for previously untreated
`MM as far as response rate and improvement of perfor-
`mance are concerned: all 11 fully assessed patients in
`our study responded, with six achieving a CR. No failure
`was observed in this group. However, response duration
`was disappointing. In the study by McElwain and Powles,9
`response duration was about 18 months. Our group of
`patients was in a similar range, ie, 16 months. A high
`incidence of unfavorable signs may have influenced this
`outcome: most patients had a high B2M or a high LI, or
`both. Advantages of HDM in high-risk untreated MM
`are prolonged survival (median survival has not yet been
`reached in our group) and an improvement in the quality
`of life during the remission; all patients were able to
`perform normal activities again, and analgesics were not
`
`Table 4. Toxicity of HDM (N = 26)
`
`Nausea, vomiting
`Diarrhea
`Alopecia
`Infections
`
`WHO Grade
`
`1
`
`4
`14
`0
`0
`
`2
`
`16
`10
`0
`9
`
`3
`
`5
`1
`0
`15
`
`4
`
`1
`1
`26
`2
`
`needed. Radiographic signs of bone healing were ob-
`served in a minority (three of 11), but reversal of
`humoral immunodeficiency occurred in most patients
`(nine of 11). A disadvantage of HDM is the considerable
`toxicity. There were three early deaths (11%): two of 13
`patients treated with primary HDM and one of 13
`patients treated with consolidation HDM. Major infec-
`tive complications due to prolonged severe myelosuppres-
`sion were experienced. The median time to recovery to
`greater than 0.5 x 109 granulocytes per liter was 30 days
`after primary HDM. In previously treated patients, the
`recovery period was even longer (36 days). This confirms
`reports by others15,16 that HDM is difficult to manage,
`especially in pretreated patients.
`HDM does not seem to have a major effect on a
`residual plasma-cell population after previous chemo-
`therapy. In a recent study, only 50% of 34 VAD-
`responsive patients obtained significant cytoreduction
`after HDM plus total body irradiation (TBI) and autolo-
`gous bone marrow transplantation (ABMT).'7 We also
`found no significant reduction in tumor load, as re-
`flected by the M component, when HDM was given as
`consolidation treatment after VAD for refractory and
`relapsed myeloma. The relapse-free period (median, 11
`months) in this group of patients was no better than in a
`control group of patients treated with VAD alone.t
`A new phenomenon was fulminant relapse after
`HDM, observed in six patients. Six of the 17 relapses had
`transformed into so-called nonproducing myeloma with
`features of J chain disease."8 These patients had very
`high tumor-growth fractions. In six patients extramedul-
`lary relapses (including skin, pancreas, and breast)
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`HIGH-DOSE MELPHALAN FOR MULTIPLE MYELOMA
`
`preceded bone marrow relapses. This indicates a dedif-
`ferentiated tumor, probably induced or selected by the
`HDM, with high resistance to chemotherapy.
`Unfortunately, the remissions after HDM are short,
`and the development of new treatment strategies should
`be encouraged. It is debatable if the relapse-free period
`can be prolonged by the use of even higher doses of
`cytotoxic drugs, or the combination of HDM with TBI.
`In a 1989 study with 200 mg/m2 melphalan and bone
`marrow rescue, more CRs were achieved (± 50%), but
`the relapse-free periods were not prolonged.19 In a
`recent study by Jagannath et al,' 7 55 pretreated patients
`underwent ABMT after HDM or thiotepa with TBI, but
`the median relapse-free period was only 15 months.
`Patients with a high B2M level had a very short remis-
`sion period.
`As yet there is no effective treatment against the
`clonogenic myeloma cell. It appears to be unresponsive
`to allogeneic bone marrow transplantation 20 or to purg-
`ing with monoclonal antibodies.21 Plasma-cell purging
`
`51
`
`may be also insufficient, as the myeloma stem cell is
`probably not a mature plasma cell but a preplasma cell22
`or an immature B cell.23
`The bone marrow toxicity of HDM might be reduced
`by the combination of hematopoietic growth factors
`granulocyte (macrophage)-colony-stimulating
`factor
`(G[M]-CSF) and interleukin-3. This approach (HDM
`with GM-CSF) is under investigation in a randomized
`multicenter trial in Europe. Maintenance therapy with
`interferon alfa (as opposed to intensive follow-up treat-
`ment) after response to HDM may help to prolong
`remission time.
`In conclusion, HDM is the most effective induction
`treatment available, even for unfavorable multiple my-
`eloma. However, the toxicity is considerable, and remis-
`sions, though of excellent quality, are not sustained. It
`therefore remains questionable whether HDM should
`be recommended as first-line treatment for the younger
`MM patient. Based on our results, consolidation HDM
`could not be recommended.
`
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