`
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`
`
`
`NOVEMBER 2000
`
`VOL 14*NO 11A*NCCN PROCEEDINGS
`
`
`
`
`NCCN’
`Oncology Practice Guidelines
`Volume 7
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`We
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`=
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`¢
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`3
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`=>
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`zee
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`Cancer Center
`
`NCCNPractice Guidelines for
`Acute Myelogenous Leukemia
`Chronic Myelogenous
`Chaired by
`Leukemia
`Margaret R. O’Donnell, mp
`Chaired by MosheTalpaz, mp
`City of Hope
`The University of Texas
`National Medical Center
`M. D. Anderson Cancer Center
`Breast Cancer
`Colorectal Cancer
`Chaired by Robert W. Carlson, mp
`Chaired by Paul F. Engstrom, mp
`Stanford Hospital and Clinics
`Fox Chase Cancer Center
`Cancer Pain
`Head and Neck Cancers
`Chaired by Stuart A. Grossman, MD
`Panel chaired by
`Johns Hopkins Oncology Center
`Arlene A. Forastiere, mp
`:
`Johns Hopkins Oncology Center
`Cancer-Related Fatigue
`Conference presentation by
`
`Chaired by Victoria Mock, pNse, RN
`David Pfister, utp
`Johns Hopkins Oncology Center
`Memorial Sloan-Kettering
`
`
`Prostate Cancer
`
`Chaired by Laurence H. Baker, po
`
`+
`=
`o
`=
`University of Michigan
`Comprehensive Cancer Center
`B= ts §
`ae eS v- oO
`
`“Ee 8
`ze 57 5
`“Ee BEog
`Full table ofcontents on pages 17-18 and 21-23
`
`He— Cause
`
`TEE Agees
`ForONCOLOGYon theWeb,visit www.cancernetwork.com
`mE SSees
`
`
`
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`
`MAYERN. FISHMAN, MD, PhD
`Assistant Professor
`Interdisciplinary Oncology Program
`
`WILLIAM S. DALTON, MD, PhD
`Professor and Chairman
`H. Lee Moffitt Cancer Center
`& Research Institute
`University of South Florida
`Tampa, Florida
`
`ore than 13,500 cases of mul-
`tiple myeloma will have been
`diagnosed in the United States
`in 2000. Treatments are designed to pro-
`long the symptom-free interval, overal]
`survival, and quality of life. Despite the
`development of numeroustreatment reg-
`imens, median survival remains less
`than 4 years. For a few patients, howev-
`er, potentially curative therapy exists.
`Wewill first review issues of diag-
`nosis, estimation of prognosis, and mea-
`surement of response to therapy. The
`latter part of the article will address
`contemporary management options,
`with an emphasis on the ongoing clini-
`cal development of newer transplant
`approaches and drug applications.
`When discussing prognosis and
`treatment options with patients, the phy-
`sician should address the following ba-
`gic issues: (1) What distinguishes the
`diagnosis of myeloma from other mon-
`oclonal gammopathies? (2) When in
`the disease course is treatment neces-
`sary? (3) Which drugs should be used
`for treatment? (4) How should non-
`cytotoxic drugs,
`including interferon
`bisphosphonates, and growth factors be
`integrated? (5)
`Is high-dose therapy
`with stem-cell rescue or allogeneic bone
`marrow transplantation appropriate?
`Understanding these issues will be use-
`ful when planning a consolidated ap-
`proach for
`all phases of
`the
`disease—from initial
`treatment and
`maintenance to salvage therapy and
`palliation. We are hopeful that these
`guidelines will provide a starting point
`from which risks and benefits can be
`individualized.
`
`Considerations in
`the Management
`of Myeloma
`
`ABSTRACT
`
`
`
`Multiple myeloma remains an incurable cancer. Inrecentyears, progress
`in different drug classes has improved outcomes, but management has
`become more complicated. Areas such as prognostic classification, the
`increased use ofhigh-dose chemotherapy with autologous stem-cell rescue,
`and a widerarray ofancillary drugs must be integrated into recommenda-
`tionsfor a consolidated treatmentplan. Estimatingprognosis is dependent
`onbothclinicalfeatures and a growing list oflaboratory tests. Autologous
`transplantation has been applied to an increasingproportionofpatients, at
`different points in the disease process. Besides the age cut-off issue, there
`are still significant treatment choices to be made within the transplant
`technique. Newer drugs, most recently, thalidomide (Thalomid), may offer
`benéfits independent of conventional cytotoxic drugs orsteroids. Use of
`ancillary drugs, such as bisphosphonates, interferon, P-glycoprotein block-
`ers, antibiotics, and growth factors, are also discussed. Forthe future,
`inumunotherapy intheposttransplantsetting appearspromising. Ulfimate-
`ly, basic research must identify intracellulartargetsfor the development of
`specific new-generation drugs.
`
`Diagnosis
`
`A referral for diagnosis of myeloma
`may result from abnormalities on rou-
`tine tests or from a presentation with
`symptoms. Test abnormalities may oc-
`cur at any stage of disease, but a pre-
`sentation of symptoms is usually
`indicative of stage II] disease. The phy-
`sician must decide not only how totreat
`the patient, but also when.
`Laboratory results, such as those
`showing anemia, hyperproteinemia,re-
`nal failure, or hypercalcemia, may ex-
`plain the symptoms. Alternatively,
`infection, neurologic symptoms, abnor-
`
`mal bone imaging, or pathologie frac-
`ture, may lead more indirectly to the
`diagnosis. The need to improve symp-
`toms may obviate the decision regard-
`ing when to proceed with treatment.
`However, more commonly, the deci-
`sion will be based on the factors dis-
`cussed below.
`The initial parts of the diagnostic
`work-up algorithm from the 1998 Na-
`tional Comprehensive Cancer Net-
`work’s (NCCN)Guidelines are in Table
`1.[1] The major and minor diagnostic
`criteria of Durie and Salmonare repro-
`duced in Table 2.(2] Examination of a
`unilateral marrow aspirate and biopsy
`
`
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`in some cases, an
`While there is,
`apparent functional overlap ofthe ther-
`apeutic options (eg, alkylators, steroids
`for Waldenstrém’s macroglobulinemia),
`distinct treatments are usually recom-
`mended. For example, a radiation dose
`of 40 cGy to 55 cGy would be recom-
`mended for plasmacytoma, compared
`to < 30 cGyforpalliation of a symp-
`tomatic myeloma lesion.[i] The diag-
`nosis should be clearbefore proceeding
`to treatment.
`If the patient presents with MGUS
`or smoldering myeloma,a serial obser-
`vation will be necessary to rule out pro-
`gressive disease. Diagnostic criteria for
`MGUS,indolent myeloma,or smolder-
`ing myeloma (also described by Durie
`and Salmon) are in Table 3.[2] Solitary
`plasmacytomas are distinguishable by
`having noninvolved marrow findings
`away from the single site. Patients with
`solitary plasmacytomaof the bone will
`frequently convert to multiple myelo-
`ma and require long-term follow-up.
`Waldenstrém’s macroglobulinemia—an
`infrequentand indolent disorder—is dis-
`tinguished principally by the immuno-
`globulin M isotype paraprotein, a more
`lymphomatoid appearance of the ma-
`lignant plasma cells. and a clinical
`course similar to low-grade NHL.
`
`
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`Table 2
`
`Major and Minor Diagnostic
`Criteria
`
`(Multiple myeloma = 4 major + 1 minor,
`or 3 minor)
`
`Major
`
`Plasmacytoma ontissue biopsy
`*
`* Marrow plasmacytosis 304%
`* Monoclonal protein (one of):
`*
`IgG>3.5
`
`*
`
`IgA>2
`
`* Bence-Jones > 1 9/24 hours
`Minor
`
`* Marrow plasmocytosis 10% to 29%
`
`* Monoclonal protein, at less than above
`levels
`
`*
`
`Lytic bone iesions
`
`* Decrease of the uninvolved
`immunoglobulins
`
`.
`
`*
`
`IgM < 50 mo/dL
`
`IgA < 100 mg/dL
`
`IgG < 600 mg/dL
`°
`en
`IgA = immunoglobulin A; IgG = immunoglobulin G;
`IgM = immunaglobutin M.
`
`Celgene Ex. 2007, Page 3 iy
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`
`Theclinical staging system of Durie
`and Salmon, shown in Table 4,[2,3] is a
`usualstarting point for treatment deci-
`sions and prognostic stratification. In
`the 25 yearssinceits publication, addi-
`tional factors to predict prognosis have
`been identified in multiple studies.
`These additional factors reflect tumor
`bulk. growth rate, biology, drug re-
`sponse, and organ-system reserve. The
`most frequently identified factor ig the
`serum level of beta.-microglobulin
`(B2-M).|5] New prognostic factors may
`often turn out to be closely correlated
`with previously identified factors, es-
`pecially B2-M.A list of these prognos-
`lic factors, which are only partly
`evaluated for interdependence,
`is in
`Table 5. Clinical factors, such as Stage
`and length ofinitial plateau phase, [6]
`remain as important as newer molecu-
`lar factors.
`
`Prognostic Stratification
`Prognostic stratification serves two
`
`
`
`
`
`
`
`
`
`
`purposes: (1) For the individual physi-
`clan/patient relationship, the quantita-
`tion ofthe risk of rapid progression will
`give the patient a more precise estimate
`of prognosis and provide a useful basis
`for making treatment choices. (2) An-
`other purpose is to achieve more bal-
`ance in the stratification of randomized
`trials or in comparing treatments that
`are described in separate, nonrandom-
`ized studies. Analyses ofprognostic fac-
`tors that are continuous variables may
`be facilitated through the use of thresh-
`old values. However, while thresholds
`are useful for group comparisons,it may
`be intuitively unclear how to apply a
`threshold to an individual patient,
`The relative prognostic importance
`of pretreatment factors (especially B2-
`M) can be comparedto the importance
`of the assessment of treatment decj-
`sions. Studies[7-10] have consistently
`shownthat biologic disease factors ap-
`pear to be more importantin predicting
`survival than the treatment decisions
`
`NCCN PROCEEDINGS * NOVEMBER 2000 * ONCOLOGY
`
`73
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`jf
`
` Waldenstrim’s macroglobulinemia,
`
`
`
`
`
`is the cornerstone of pathologic confir-
`mation. Evaluation ofa paraprotein is a
`frequent starting point, but light chain
`disease, immunoglobulin D, and non-
`secretory myeloma diagnoses may be
`confirmed in the absence of a detect-
`able paraproteing. Non-Hodgkin’s lym-
`phoma (NHL), chronic lymphocytic
`leukemia, and nonmalignant plasma-cel]
`disorders may also have monoclonal
`paraproteins.[3,4} Smoldering or indo-
`lent myeloma, which may be managed
`initially with observation, should be con-
`sidered before proceeding to treatment.
`Similarly, the foliowing non-myeloma
`plasma-cell dyscragias may bear con-
`sideration: monoclonal gammopathy of
`unknown significance (MGUS), plas-
`macytoma (bone or soft
`tissue), and
`
`
`
`F
`Z
`.
`7
`
`
`
`!
`
`:
`a
`
`Seana
`
`Table 1
`
`NCCN 1998Initial Diagnostic
`Guidelines for Multiple
`Myeloma{[?]
`
`eeeBeweaans
`
`Diagnostic Work-Up
`H&P
`CBC
`Calcium, albumin
`Quantitative immunoglobulin
`SPEPand immunofixation
`UPEP and immunofixation
`Quaniitation of M protein
`Skeletal survey
`Unilateral bone marrow aspirate
`and biopsy
`
`Generally Useful
`
`B-2M
`*
`* Labeling index (PCLI)
`* C-reactive protein
`*
`LDH
`
`Useful Under Some Circumstances
`
`* MAI ior cord compression
`* MRi for suspicion of solitary bone
`plasmacytoma
`° CT to evaluate suspected
`metastases
`* Tissue biopsyto diagnose a solitary
`OSSeOUS OF exiraosseous plasma-
`cytoma
`* Cytogenetics In candidatesfor
`autologous stem-celt transplantation
`
`a B
`
`-2M = beta,-microglobutin: CBC = complete
`blood count; CT = computed tomography; H&P =
`history and physical; LDH = lactate dehydrogena-
`se; MRI = magnetic resonance imaging; NCCN =
`National Comprehensive Cancer Network; PCLI =
`plasma cell labeling index: SPEP = serum protein
`electrophoresis; UPEP = urinary protein electyo-
`phoresis,
`
`Prognostic Factors
`
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`nsoe
`
`
`
`
`
`Table 3
`
`Table 4
`
`Non-Myeloma Diagnostic
`Criteria
`
`*
`
`Indolent Myeloma
`
`Durie-Salmon Staging System
`
`* A=BUN <3 mg/dL;creatinine
`<2 mg/dL
`
`6 months in the observation or plateau
`phase of treatment.[]] The proposed tar-
`get for quantitative myeloma tumorre-
`duction has been honed because of dose
`intensification and new measurement
`techniques.
`The question of whether improving
`* B=BUN>83mg/dL;creatinine
`*
`3 or fewer lytic bone lesions
`the frequency of complete response or
`> 2 mg/dL
`partial response will necessarily improve
`overall survival and event-free survival
`must be addressed empirically. For con-
`ventional therapy, a complete response
`does not show an advantage overa par-
`tial response for overall survival, al-
`though plateau duration does influence
`overall survival. [6]
`A higher frequency of complete re-
`Sponse and partial response occurs in
`autologous transplants than with con-
`ventional therapy. In the analysis of pa-
`tients treated with up-front,
`tandem
`autologous transplant (see Arkansas
`Group’s Total Therapy discussed. later
`in this article), Barlogie et al found that
`achievement of a complete response,as
`opposed to a partial response, before
`the second transplant, resulted in an
`improved median survival (80+ vs 68
`months, P = .001).[14]
`With the advent of molecular tech-
`niques,
`the category of complete re-
`sponse (ie, histologically absent
`malignant marrow infiltrate and disap-
`pearance of paraprotein) has been re-
`fined. The molecular complete response
`is the subset of the clinical complete
`response, in which the malignant clone
`is not detected by sensitive polymerase
`chain reaction techniques. Based on the
`experience with other malignancies, a
`molecular complete response may be
`viewed as the rational prerequisite for
`potential cure.[15] Early analyses favor
`a better outcome(later relapses) forthe
`subset of patients with a molecular com-
`plete response.|16]
`Careful, empiric assessment of how
`these better complete responses imply
`or cause improvementof event-free sur-
`vival and overall survival is necessary
`in the context of previous experience
`with conventional therapy. Conclusive
`proof of cure amongpatients achieving
`
`
`
`
`
`
`
`
`SailaeShsstneoemee
`
`*
`
`*
`
`IgA paraprotein < 50 g/L
`
`IgG paraprotein < 70 g/L
`
`* No symptoms
`
`* No anemia < 10 g/L
`* Normal calcium
`
`* Normal creatinine
`
`Smoldering Myeloma
`
`¢
`
`Indolent myeloma criteria and
`10% te 30%
`
`* Marrow plasma cells
`e No bone lesions
`
`MGUS
`
`*
`
`*
`
`lgG paraprotein < 35 g/L
`
`IgA paraprotein < 20 g/L
`
`* Bence-Jones protein <1 g/24 hrs
`
`* <10% marrow plasma cells
`
`¢ No symptoms
`¢ No bene lesions
`
`
`IgA = immunoglobulin A; IgG = immunoglobulin G;
`MGUS = monoclonal gammopathy of unknown
`significance.
`
`being evaluated. Two polarized views
`may arise from implications of this hi-
`erarchy: (1) One view is that pair-match-
`ing or retrospective estimates do
`accurately gauge whether a new treat-
`ment causes an improvement of out-
`comes or whether the new treatment
`produces results that appear better mere-
`ly as a reflection of the selection of a
`patient cohort with better prognostic fea-
`tures.[10-12] (2) The other view is that
`only prospective randomization pro-
`vides a fair balance of known molecu-
`lar prognostic features, performance
`status, disease stage, lead time, comor-
`bidities, and available supportive
`care.[13] An unfortunate result of these
`views is that issues of selection bias
`and risk stratification may dominate
`comparative discussions of either retro-
`spective or randomized trials. This is
`
`Stage |
`
`*
`
`Low tumor mass (< 0.6 x 107/m?}
`
`All of
`
`* Hgb> 10 g/dl
`
`*
`
`IgG <5 g/dL; IgA <3 g/dL;
`Bence-Jones < 4 9/24 hours
`* Ca: Normal
`
`* Qor1 lytic bone lesion
`
`StageIl
`
`*
`
`Intermediate tumor mass
`(0.6 to 1.2 x 10"/m?) neither | nor Ill
`
`StageIll
`
`* High tumor mass (> 1.2 x 10%/m?)
`
`Any of
`
`* Hgb< 8.5
`
`*
`
`*
`
`IgG>7 g/dL
`
`IgA> 5 g/dL
`
`* Bence-Jones > 12 9/24 hours
`
`* Ga>12 mg/dL (adjusted for albumin)
`
`* Multiple lytic lesions
`
`
`BUN = blood urea nitrogen; Ca = calcium; Hgb =
`hemoglobin; Ig4 = immunoglobulin A; IgG = im-
`munoglobulin G.
`
`mentioned again below in relation to
`the phase II experience with autologous
`transplantation.
`
`Measuring Response
`The finding that the serum or urine
`paraprotein level is directly correlated
`with tumor burden allows for serial
`measurements and determination ofpro-
`gressive disease and treatment response.
`Progressive disease can be defined as a
`sustained > 25% rise of M protein, or
`the appearance of new bonelesions.[1 ]
`Table 6 provides a hierarchy of response
`categories.
`The recommended frequency for
`quantitation of immunoglobulin is ev-
`ery othercycle of therapy, or every 3 to
`
`Address all correspondence to:
`William S. Dalton, Phd, MD
`H. Lee Moffitt Cancer Center
`& Research Institute
`University of South Florida
`12909 Magnolia Drive
`Tampa, FL 33612
`
`74
`
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`Table 6
`
`Hierarchy of Responses?
`
`* Progressive disease (> 25%increase
`in M protein or new bony lesion}
`* Stable disease/plateau phase
`
`* Minimai response
`
`PR (PR, > 50% decrease in M protein)
`*
`* Very good PR (> 90%decreasein
`M protein)
`
`* CR (CR, undetectable paraprotein,
`low marrow plasma cell %)
`
`* CR (no clonal kappa/lambda
`population in marrow)
`
`* CR (no PCR-detectable clonal
`rearrangementin marrow)
`* Cure
`
`a A
`
`* % of reduction: GR, PR, vs SD or
`worse
`
`* Achievement of plateau
`
`* Duration of plateau{é]
`
`* Molecular CR vsclinical CA[16]
`tr
`B2-M = beta-2-micraglobulin; CR = complete re-
`sponse; CRP = C-reactive protein; IL-6 = interleu-
`kin-6; PCLI = plasmacell labeling index; P-gp =
`P-glycoprotein; PR = partial response; SD = sta-
`ble disease.
`
`
`
`flicting reports, a balanced conclu-
`sion(21,22] suggests that the effect of
`interferon therapy after a complete or
`partial response from conventional che-
`motherapyis, at best, a several-month
`improvementof event-free survival (but
`not overall survival) for a minority
`(< 15%) ofpatients. A 1998 meta-anal-
`ysis of 4,000 randomized patients, pre-
`sented in abstract form, concluded that
`the benefit is 7 months ofoverall sur-
`vival with P <.03.[23] Newly published
`studies with interferon randomization
`and various conventional treatments are
`similar to the earlier pattern—some-
`times with a significant event-free sur-
`vival
`advantage,
`but
`either
`a
`nonsignificant overall survival advan-
`tage[24] or no advantage.[25,26]
`A decision to use interferon for pos-
`tremission maintenanceshould be made
`
`recognizing that further study will be
`necessary to define which patient sub-
`sets may derive the most benefit.[22]
`Toxicity ofinterferon at the typical dose
`of 3 million units three times a week
`mayincludeflu-like symptoms, depres-
`sion, andfatigue. For most, the expense,
`toxicity, and inconvenience of the in-
`jections will accrue no survival benefit.
`
`Steroids
`Steroids have also been applied for
`the purpose of postconventional thera-
`py maintenance. In the Southwest On-
`cology Group (SWOG) Study 9028,
`myeloma patients who had achieved at
`least a partial response after VAD
`chemotherapy were randomized be-
`tween interferon or interferon/pred-
`nisone maintenance. The addition of
`prednisone to interferon resulted in a
`significant progression-free survival dif-
`ference (19 vs 9 months, P= 008), but
`a nonsignificant overall survival advan-
`tage (57 vs 46 months, P = .36).[27]
`
`Interferon After Transplant
`Anincreased frequency of very low
`tumorburden is associated with molec-
`
`75
`NCCN PROCEEDINGS » NOVEMBER 2000 - ONCOLOGY
`IPR2018-01714
`
`Conventional Cytotoxics
`Conventional chemotherapy can be
`divided into aikylator-based (usually
`oral) melphalan (Alkeran) and pred-
`nisone (MP), and non-alkylator-based
`(such as 96-hour continuous infusion)
`vincristine, doxorubicin (Adriamycin),
`and dexamethasone (VAD). The high
`therapeutic indexof steroids favors their
`inclusion in most regimens. Single-agent
`dexamethasone has activity without the
`side effects of cytotoxics.
`Numerous published series over the
`last decades have compared different
`conventional therapy arms with a vari-
`ety of alkylator, nitrosourea, steroid,
`vinea, and anthracycline combina-
`tions.[3,4] A 1992 meta-analysis
`BMTR = Autologous Blood and MarrowTransplant
`Registry; CR <complete response; EBMT =Euro-
`showed that MP appearsto be as good
`pean Blood and Marrow Transplant; IBMTR =Inter-
`Plasmablastic morphology
`*
`as other, more complex, toxic, and ex-
`national Bone MarrowTransplant Registries; PCR=
`polymerase chain reaction: PR=partial response.
`pensive regimens.[17] More recent anal-
`Response Features
`yses
`have
`reached
`a
`similar
`“The Annotation of the EBMT,IBMTR, and ABMTR
`conclusion.[18,19]
`response definitions, authored by Bladé etal, pro-
`vides a more detafled description, encompassing
`Therapy with VAD offers the fea-
`measurements otherthan just M protein.[72]
`tures of a more rapid response, without
`the useofalkylating agents, which may
`be toxic to stem cells. Even so, a series
`of 66 patients with stem cells collected
`at the point of salvage had only a 3%
`failure ofstem-cell collection.[20] Like
`VAD, high-dose cyclophosphamide
`(Cytoxan, Neosar)—which also mobi-
`lizes stem cells—is frequently used in
`the pretransplant context. For salvage
`treatment, a non—cross-resistant regi-
`men, such as etoposide, dexamethasone,
`ara-C, cisplatin (Platinol) (EDAP),
`VAD;or high-dose cyclophosphamide,
`may be used.[1,15]
`
`a molecular complete response(notjust
`prolonged event-free survival) may de-
`velop in the coming years.
`
`Treatment
`
`Table 5
`
`Prognostic Factors[2,3]
`Disease Features
`
`* Clinical stage (hemogtobin, para-
`Protein, calcium, renal function)(1,2]
`* B2-M[1]
`
`* CRP
`
`+
`
`PCLI[1]
`
`* Lactate dehydrogenase[1}
`
`* Presence of deletion 13 chromosome
`abnormality (for transplant)[47,71]
`* Microvessel density[55,56]
`*
`Peripheral blood monoclonai plasma
`cells > 4%
`
`
`
`*
`
`*
`
`P-gp expression
`
`Soluble iL-6 receptor
`
`* Serum (shed) CD56
`
`
`
`MaintenanceT:herapy
`
`Interferon After
`Conventional Therapy
`The use ofinterferon alfa-2b (Intron
`A) for the maintenance of remission
`has been studied in detail in multiple
`randomizedtrials overthe last 15 years.
`Some show noeffect, some show a
`modest event-free survival benefit with-
`out an overall survival benefit, and a
`few demonstrate an overall survival ben-
`efit. The overall conclusion from this
`data remains controversial.
`Synthesizing these independent, con-
`
`oeana)ee
`
`
`
`ete
`
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`SIE.arD7ABSEH
` Prenatte
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` ular complete response and an altered
`
`immunologic environment occurs fol-
`lowing high-dose chemotherapy with
`autologous stem-cell rescue. Conceptu-
`ally, this context may engender a more
`substantial clinical effect of interferon
`than in maintenance with conventional
`therapy.
`Phase II studies have shownthe fea-
`sibility of posttransplant interfer-
`on.[14, 15,28] A small phase III trial (42
`patients on each arm) showed improve-
`ment in event-free survival, but not
`survival benefit.[29] While the above-
`mentioned conclusion for interferon
`maintenance after standard chemother-
`apy remission presumes a similar effect
`no matter which conventional chemo-
`therapy is used, it is possible that the
`conclusions ofphase II interferon-after-
`transplant trials may beregimenspecific.
`
`Bisphosphonates
`
`Fracture Prevention
`including
`Bisphosphonate drugs,
`etidronate (Didronel), clodronate,
`alendronate (Fosamax), pamidronate
`(Aredia), and zoledronate (Zometa),
`bind tightly to the hydroxyapatite min-
`eral of bone, inhibiting osteoclast func-
`tion. This tips the balance of osteoclast
`activity from bone reabsorption to bone
`formation, with a net result of stronger
`bones. Additional mechanisms may in-
`clude induction of osteoclast apopto-
`sis(30] and possibly in vitro myeloma
`cell apoptosis.(31] Also, an immuno-
`logic effect of the bisphosphonates has
`been demonstrated:
`the induction of
`gamma—delta-resiricted anti-myeloma T
`cells by aminobisphosphonates[32] re-
`mains to be clinically developed.
`Conventionally, the bisphosphonates
`are ranked by their antihypercalcemic
`potency. Zoledronate is more potent
`than pamidronate, which is more potent
`than clodronate or etidronate.[33] As
`an understanding develops about how
`to focus on mechanisms of action other
`than antihypercalcemic effects,itis con-
`ceivable that a primarily “antimyelo-
`ma” member of the drug class will be
`identified. Randomized phase III data
`are available for the application ofetidr-
`onate,[34] clodronate,[35] and pami-
`dronate to the management of myel-
`oma.[36] For zoledronate, phase II
`trial data are not yet available.
`
`* Etidronate—In theearliest of these
`
`trials, myeloma patients received oral
`etidronate or placebo in conjunction
`with MP. Absence of a significant dif-
`ference in bone pain, episodes of hy-
`percalcemia, or development of
`pathologic fractures was observed.[34]
`In the clodronate trial, myeloma pa-
`tients received oral clodronate or place-
`bo in conjunction with MP. The data
`showed that clodronate treatment re-
`sulted in a significantly decreased rate
`of progression ofosteolytic lesions (12%
`vs 24%, P = .026), a nonsignificantly
`decreased rate of vertebral fractures
`(30% vs 40%, P not significant), and
`significantly better pain scores.[35]
`
`*® Pamidronate—In the pamidronate
`phase II trial, originally published by
`Berenson et al in 1996 and updated in
`1998, patients receivinga variety ofcon-
`ventional chemotherapy regimens were
`randomized between monthly intrave-
`nous (IV) pamidronate vs placebo for
`21 cycles.[36] Considering the end point
`of “skeletal events,” the pamidronate-
`treated group showeda statistically sig-
`nificant advantage over the placebo
`group (eg, 38% at 21 cycles vs 51%, P=
`.015). There was no difference in the
`rates of hypercalcemia, chemotherapy
`response rates, and overall survival. A
`subset analysis, however, showed a me-
`dian survival benefit for patients receiv-
`ing pamidronate, whenrestricted to those
`patients who were receiving second-line
`chemotherapy (21 vs 14 months, P =
`.041, after adjustment).[36]
`
`« Clodronate—The initiation of bis-
`phosphonate treatment may occurat the
`onset of any bonelesion or osteopenia,
`or othertreatment requiring chemother-
`apy; phase Ill data support its use.[37]
`The duration of treatment analyzed in
`the clodronate trial was daily for 24
`months;
`in the pamidronate study,
`it
`was up to 21 monthly IV cycles.
`Considering the good safety profile
`of the biphosphonates, an open-ended,
`individually tailored treatment duration
`can be recommended. The American
`Society of Clinical Oncology’s (ASCO)
`1998 Guidelines on the Role of Bisphos-
`phonates in Breast Cancer have two
`points that may be applied: (1) once
`initiated, bisphosphonates may be con-
`tinued until there is evidence of a clini-
`cally assessed “substantial decline,”(2)
`their benefits consist of reduced skele-
`tal events and improved extent of pain,
`
`butnotlife prolongation.[38]
`Interval monitoring for skeletal pro-
`gression, with bone survey, is recom-
`mended at yearly intervals or for
`symptoms.[1] Patients on the pami-
`dronate treatment arm of the above-
`mentionedtrial still had a 31% incidence
`of “any pathologic fracture” at 21
`months.(36] Similarly, interval moni-
`toring of calcium, renal function, and
`anemia may anticipate symptomatic
`presentation.
`
`Hypercalcemia
`Hydration, prednisone, and (posthy-
`dration) furosemide (Lasix) diuresis
`may be the initial treatment for hyper-
`calcemia. Bisphosphonate therapy—eg,
`90 mg IV pamidronate—will be fre-
`quently effective, and should be usedif
`hypercalcemia has not resolved with
`less conservative measures.[39]
`
`Other Supportive Care
`
`Growth Factors
`Anemia, whether disease-related or
`treatment-related, is frequent in myelo-
`ma. Use of exogenous erythropoietin
`(Epogen, Procrit) therapy may improve
`both the hemoglobin level and sense of
`well-being.(39] Schedules,
`including
`erythropoietin 150 U/kg three times a
`week, 10,000 units three times a week,
`and 40,000 units once a week, have
`been advocated. The likelihood of re-
`sponse is influenced by the absence of
`other causes of anemia (vitamin By,
`folate, or iron deficiency), as well as
`the pretreatment (endogenous) erythro-
`poietin level. Increments of 2 g/dL of
`hemoglobin may be seen in 60% to
`80% of myeloma patients. [40]
`
`
`
`Neutropenia
`Neutropenia may be related to marrow
`damage from chemotherapy, delayed
`recovery from high-dose therapy with
`stem-cell rescue, or disease progression.
`For chemotherapy-related neutropenia,
`the ASCO guidelines, developed main-
`ly for solid tumors, may be applied. [41]
`The prophylactic use of granulocyte
`colony-stimulating factor (G-CSF: Ne-
`upogen) or granulocyte-macrophage
`colony-stimulating factor (GM-CSF;
`sargramostim, Leukine) should be lim-
`ited to those patients who have had hos-
`pitalization for neutropenia-related
`infection, but not for uncomplicated fe-
`brile (or afebrile) neutropenia. For neu-
`
`76
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`SN ,
`tropenia related to disease progression,
`status = 0, 1, 2; chemotherapy-respon-
`treatment of the myeloma should be the
`sive disease) was 60 months—much
`priority. Growth factors may also be
`better than the overall median of 29
`used as part of a stem-cell mobilization
`months.[9] Similarly, Oivanen’s analy-
`regimen.
`sis of conventionally treated myeloma
`patients in Finnishtrials shows a subset
`(those with the longest initial plateau
`response) of patients with a median sur-
`vival of 81 months compared to 44
`monthsforthe entire group.[6]
`The magnitude ofsurvival differenc-
`es shows that it may be unclear what
`standard results of single-arm, phaseII
`trials of high-dose chemotherapy in
`patients with myeloma should be com-
`pared against. Some of the analyses
`described below use a pair-matching
`system to estimate what the prognosis
`of the high-dose chemotherapy group
`would have beenif treated convention-
`ally. Phase JI data are described
`separately.
`An alternative perspective regard-
`ing the overall effect of high-dose che-
`motherapy is found in the analysis by
`the Nordic Myeloma Study Group. This
`report analyzed outcomes of (nonran-
`domized) trial-registered myeloma
`cases, which accounted for about three-
`quarters of the predicted total number
`of cases in Denmark, Norway, and Swe-
`den. Their population-based analysis
`showsthatthe introduction of the trans-
`plant technique is associated with a sur-
`vival advantage, whether the apparently
`iransplant-eligible patients (relative risk.
`[RR] = 1.62; 95% confidence interval
`(CI] = 1.22-2.15; P = .001) or the entire
`trial-registered population (RR = 1.46;
`95% CI = 1.14-1.86; P = .002) were
`considered.[44] This analysis did not
`consider early vs late transplant;
`the
`214 transplants were all within 1 year
`of the start of VAD therapy.
`
`Table 7
`
`Transplant Regimen Choices
`
`Type of Graft
`
`*
`
`Peripheral blood vs bone marrow
`
`* Autologous vs allogeneic
`
`+ Unmanipulated or purged
`
`Time of Autologous Graft Collection
`
`* At diagnosis, after cytoreduction
`
`* At-best response
`
`* At salvage
`
`Time of High-Dose Therapy
`
`°
`
`*
`
`Early, as consolidation
`
`Salvageafter relapse from
`conventional treatment
`
`Cytoreductive Regimens Prior to
`High-Dose Chemotherapy
`* VAD
`
`* VAMP
`
`* VAD + EDAP
`
`Preparative Regimens
`
`*
`
`+/- high-dose cyclophosphamide
`
`* Melphaian 100 mg/m? x 2 to 3
`autografts
`
`* Melphalan 140 + TB!
`
`* Melphalan 160 + TBI + etoposide
`60 mg/kg (more toxic)
`
`¢ Mealphalan 200
`
`* Melphalan 220
`Maintenance
`
`«
`
`+/- interferon
`
`A E
`
`DAP= etoposide, dexamethasone, ara-C, cis-
`platin (Platinol); TBI = total-bodyirradiation; VAD
`= vincristine (Oncovin, Vincasar), doxorubicin
`(Adriamycin), dexamethasone; VAMP = vincris-
`tine, Adriamycin, and methylprednisolone,
`
`assessable patients. On an intent-to-treat
`basis, the median survival from time of
`transplant was 19 months.
`Oneofthe earlier up-front treatment
`series was reported by Cunningham et
`al.[45] High-dose chemotherapy treat-
`ment for the 63 previously untreated
`patients
`administered a dose of mel-
`phalan of 140 mg/m?(MEL140). A total
`of 20 patients had complete responses,
`with a median response duration of 18
`
`Infection
`Antibiotic prophylaxis, with cotri-
`maxozole (trimethoprim/sulfamethox-
`azole; Bactrim, Septra, Sulfatrim) or
`penicillin, in the first months of chemo-
`therapy (or in the context of stem-cell
`transplant) may be useful. Immuniza-
`tion for prevention of pneumococcal or
`influenza infection is also recommend-
`ed—notwithstanding a likely subopti-
`mal antibody response.[39]
`
`Renal Failure
`Anelevated creatinine level in my-
`eloma may be a consequence of hyper-
`calcemia, disease-related kidney
`complications (in which light chains of
`the paraprotein accumulate in the col-
`lecting tubules), amyloid deposition
`(with more prominent albuminuria), or
`other intercurrent renal disease. Owing
`to its rapid response, VAD is a regimen
`that may be useful for resolution of
`renal failure.(39] The successful appli-
`cation of high-dose chemotherapy in
`patients with renal failure has been
`reported. [42]
`
`High-Dose Chemotherapy
`
`Since the first phase II series was
`reported in 1983,[43] a variety of regi-
`mens, predominantly based on high-
`dose melphalan, usually 140 mg/m?
`(MEL140), have been published. Some
`feasible transplant choices are summa-
`rized in Table 7. Patients treated on
`these protocols represent a relatively
`large phase II experience.
`To fairly assess the benefit of high-
`dose chemotherapy,it is useful to quan-
`titate the heter