Chemotherapy of multiple myeloma

9 Chemotherapy of multiple myeloma B R I A N G. M. D U R I E

Multiple myeloma is the primary malignancy of the plasma cell. The disease is characterized by proliferation of plasma cells, predominantly within the axial skeleton, with bone destruction and associated suppression of normal haemopoiesis, primarily erythropoiesis, within the marrow. Typical features of the disease are bone pain associated with the bone invasion, hypercalcaemia and renal insufficiency, plus susceptibility to infections because of the suppression of normal immunoglobulin synthesis. In considering the approach to chemotherapy, one must assess both the cytoreduction of the myeloma as well as the ancillary therapies necessary to manage the potential complications of the disease. Before proceeding to initiate chemotherapy one must also be sure of the diagnosis and exclude early forms of the disease or precursor states such as monoclonal gammopathy of undetermined significance (MGUS), which do not require treatment (Durie and Salmon, 1975; Durie, 1986; Greipp, 1989). 9The last decade has been rather disappointing as far as the chemotherapy for multiple myeloma is concerned in that no definitively curative approach has been identified. Nonetheless, it has been a decade of considerable promise, because a number of new chemotherapeutic approaches have evolved and a much better understanding of the basic biology of the disease has been acquired (Barlogie et al, 1989a). It thus seems likely that within the next decade there can be truly important advances in the management of patients with myeloma, with a realistic hope that at least a subset of patients may indeed have more prolonged survival or may even be cured of this dangerous disease.

DIAGNOSIS OF MULTIPLE MYELOMA The most crucial first step in management is to be sure of the diagnosis. Table 1 summarizes the features necessary to make a diagnosis of active symptomatic disease. It is most important to exclude MGUS or related conditions which require no initial therapy. Having established a diagnosis, the next step is to be sure that enough data is gathered to make an informed decision about patient prognosis as a basis for treatment selection. Since' multiple myeloma is not really a single disease, but a collection of diseases Baillibre's Clinical ttaematolog)~ Vol. 4, No: 1, January 1991 ISBN 077020-1531-8

181 Copyright 9 1991,by Bailli~rcTindall All rights of reproduction in any form reserved

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B . G . M . DURIE Table 1. Criteria for myeloma. Presence of monoclonal protein Increased myeloma cells in marrow and/or other tissue sites* Associated features:t Bone lesions Anaemia Renal insufficiency Hypercalcaemia End organ/tissue dysfunction LI%>1%$ * See Greipp et al (1988) for discussion of myeloma cell percentages and more detailed criteria. t Normally presence of one or more necessary to make diagnosis. :~ LI% =labelling index of bone marrow plasma cells using thymidine and/or BU-1 techniques; see Greipp (1989) for discussion. Table 2. Prognostic factors.

Survival duration Clinical staging* LI% Serum albumin Age Plasma cell morphology/phenotype Serum LDH Cytogenetics H-ras expression K/N-ras mutations DNA/RNA content Serum IL6 Serum IL2 Response to therapy P-glycoprotein (multidrug resistance expression) DNA/RNA Otherst * See Dude and Salmon (1975), Dude (1986), Dude and Bataille (1989) and Dude et al (1990a). Includes extent of bone lesions, haemoglobin, serum/urine M component, serum calcium and serum creatinine. t See Deuchars and Ling (1989) for discussion.

with a very variable prognosis, it is especially important to gather as much information as possible which may be helpful in assessing risk. Table 2 lists the major prognostic factors which are important both to predict survival duration and to make some attempt at evaluating the likelihood of response to the various forms of therapy available (Bataille et al, 1986; Greipp et al, 1988; Durie et al, 1990a). Serum 132-microglobulin is the most important single prognostic factor for reliable prediction of survival duration (Bataille et al, 1986; Greipp et al, 1988; Durie et al, 1990a). Additional parameters which can add to the accuracy of prediction include the labelling index of bone marrow plasma

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cells (Greipp et al, 1988), the serum albumin (Bataille et al, 1986), the age of the patient (Durie et al, 1990a) and a whole range of other parameters (as detailed in Table 2). These factors have a variable impact, depending upon the exact population under evaluation. From recent biological studies, a number of new parameters have emerged as potentially important in assessing pretreatment status. These include the serum lactate dehydrogenase (LDH) (Barlogie et al, 1989b), abnormal cytogenetics (DeWald et al, 1985; Gould et al, 1988; Durie et al, 1990b) and DNA/RNA content plus the molecular findings of the malignant cell, including the H-ras expression and the presence or absence of mutations of K- and N-ras (Neri et al, 1989). In addition, it appears that the ability of the myeloma cells to synthesize and secrete a variety of cytokines is crucially important. A predilection for bone disease is associated with the production of interleukin-li3 (ILl[3) and/or tumour necrosis factor (TNF) oLor ~ (Garrett et al, 1987; Carter et al, 1990). It also seems likely that the suppression of erythropoiesis (with associated anaemia) is correlated with the synthesis and secretion of ILl[3 and possibly other cytokines. New tools have become available to assess the intrinsic drug sensitivity to chemotherapeutic agents. The most information has accumulated concern"ing the presence or absence of increased expression of p-glycoprotein, which correlates with the presence of multidrug resistance (Dalton et al, 1986, 1987, 1989, Deuchars and Ling, 1989). This represents resistance to a variety of biological substances, including anthracyclines and vincristine. Increased .production of the p-glycoprotein also correlates with clinical drug resistance. Assessment of resistance to alkylating agents is at a much earlier stage. Resistance to alkylating agents such as melphalan can be detected by in vitro colony assay systems and is correlated with unusually high thymidine incorporation levels. What the principal correlates or mechanisms associated with this are remains to be determined. Parameters under review include intracellular drug levels, DNA interstrand cross linkage and repair, glutathione and glutathione synthetase (GSH) levels, non-protein thiol levels, topoisomerase II levels and a variety of related enzyme systems. Obviously the careful assessment of intrinsic resistance is potentially helpful in pretreatment evaluation, particularly as new approaches become available to circumvent resistance, for example, using bimethyl sulphoxide (BSO) as a chemo-enhancer of melphalan. Of further importance, drug resistance patterns are associated with a variety of phenotypic aberrations (Durie and Grogan, 1985a; Durie et al, 1985), including expression of aberrant antigens, such as CALLA (common acute lymphocytic leukaemia afltigen), and myeloid, erythroid and megakaryocyte antigens, plus T lymphocyte and NK lymphocyte markers. The basic biological significance of these associated aberrations remains to be determined. CURRENT THERAPEUTIC APPROACHES IN MYELOMA In contrast to other haematological malignancies such as non-Hodgkin's lymphoma, selection of treatment for multiple myeloma cannot yet be based

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upon the clinical stage of the disease and the histology or other basic pathological parameters. This is because, until very recently, true pathological complete remissions (CRs) were not possible for any subset of patients. Treatments other than single alkylating agent regimens therefore have to be selected either on a patient-by-patient basis or as part of ongoing clinical trials. Clearly it is possible to select patients suitable for particular ~:egimens based upon pretreatment prognostic factors, including the very crucial one of the age of the patient (Durie and Bataille, 1989). The chemotherapeutic management of multiple myeloma is now at a very important transitional stage, when new and promising approaches can be introduced, but need to be compared in a stratified and randomized fashion with more traditional approaches, so that the full benefit can be assessed in large study populations. Since myeloma is truly a very heterogeneous disease, this is particularly important. Over-interpretation of small pilot studies must be avoided. Simple approaches to treatment The single alkylating agent melphalan plus prednisone unfortunately remains the gold standard for management of patients with myeloma (Bergsagel, 1989). A pulse schedule utilizing 1 mg/kg of melphalan and 8mg/kg of prednisone over 4 days, repeated every 4-6 weeks depending upon blood counts, is recommended. It is important to remember that melphalan absorption and metabolism are quite variable. Sequential dose escalation must be employed, to produce at least some myelosuppression, to ensure optimal efficacy and exclude false melphalan resistance. Continuous low dose (daily) melphalan is not routinely recommended because of the cumulative myelosuppression and increased leukaemogenic potential. However, occasional patients may respond on a continuous schedule when pulse doses have failed. Melphalan is the obvious choice for all elderly patients and patients not being considered for more experimental approaches, such as younger patients in whom bone marrow transplantation is an option. Strangely, despite extensive testing with melphalan and prednisone, the optimal duration of treatment remains unclear. From a randomized Canadian study, indefinite maintenance adds little to the duration of time spent in remission, but has the additional risk of increased leukaemogenic potential (Belch et al, 1988). Arbitary guidelines commonly used include induction therapy for 12-18 months and/or treatment for 6 months beyond the time that disease stabilization (plateau) occurs. Guidelines have to be flexible because of the variable pattern of response to induction, with some patients continuing to show ongoing response even after 1 year of therapy. If after 1 year or 18 months a patient is completely stable and doing well clinically, consideration can be given to stopping therapy or reviewing the pros and cons of maintenance as discussed below. All patients stopping therapy must be closely monitored for the possibility of early relapse. A complete battery of tests is necessary as a baseline, including a skeletal survey and bone marrow evaluation. It must be remembered that serum monoclonal protein levels may be insensitive for the

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detection of early relapse. In fact, at least 10-15% of patients relapse with what is called 'Bence-Jones' escape, in which the serum monoclonal protein levels may drop rather than increase at the time of development of relapse (Garewal et al, 1984). In addition, relapse may develop in an extramedullary site rather like lymphoma (rather than in bone like traditional myeloma). The treating physician must therefore be extremely vigilant in assessing the potential for all types of relapse or escape in an individual patient. It is dangerousto rely on single parameters without overall clinical and laboratory review. The serum 132-microglobulin is quite helpful, as is the bone marrow (or peripheral blood lymphocyte) labelling index, both of which increase significantly at (or before) the time of clinical relapse in the majority of patients.

Combination chemotherapeutic approaches A huge number of clinical trials have been conducted in countries around the world in an effort to identify a combination chemotherapeutic regimen with efficacy clearly superior to melphalan plus prednisone. No data have emerged sufficient to convince everyone that a combination approach is absolutely superior. Nonetheless, it is important to note that the two largest studies conducted, which incorporate combinations of alkylating agents plus the anthracycline adriamycin (doxorubicin USP), both show a significant survival benefit over single alkylating agent regimens. These two studies, the Southwest Oncology Group VMCP-VBAP study (Durie, 1988) and the Medical Research Council ABCM study (MacLennan et al, 1988), both show a survival benefit of 6-12 months overall for the combination approach. Since these regimens are both quite well tolerated, they can certainly be utilized in an effort to achieve the 20-30% increase in survival duration possible. It should be noted that in virtually no instance has a combination regimen shown survival inferior to melphalan plus prednisone and that virtually all studies show at least a marginal benefit or in the two studies highlighted, a statistically significant benefit for the combination approach. Part of the problem is certainly that patients entered into myeloma studies are very heterogeneous, including subsets which may be more or less likely to benefit from combination chemotherapy. The fact that the predictors of response are as yet not well identified compounds the difficulty in assessing clinical benefit. Recent critical analyses of response and survival duration further complicate recommendations (Palmer et al, 1987). These analyses and observations indicate that the magnitude of regression, as for example assessed by monoclonal (M) component reduction, does not correlate in a quantitative way with the anticipated response or survival duration. Thus 75% regression is not necessarily intrinsically better than 50% or even 25% regression. This is clearly because all of the responses achieved with conventional therapy are partial responses, and the intrinsic biology of the disease, and the kinetics and drug sensitivity in individual patients are the major determinants of survival outcome. In poorer prognosis patients with a rapid initial

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response o f greater than 75% but also a high labelling index and rapid myeloma regrowth, interpretation is especially complex. The most crucial conclusion is that the initial regression percentage cannot be used as a parameter to indicate the relative efficacy or non-efficacy of a particular induction approach unless pathological CR has occurred. Unfortunately this is highlighted by recent observations with high-dose melphalan, as discussed below. Very high initial cell kill rates are not associated with enhanced o(,erall survival. As discussed further below, true pathological CRs must be the accepted end-point. Perhaps only with CR as an end-point can more rational therapeutic advances become possible.

The VAD regbnen attd variants: the current role ht patient management Success with the V A D regimen (vincristine, adriamycin and dexamethasone) as a relapse approach has encouraged the wider application of vincristine/ adriamycin infusion combined with high-dose glucocorticoids (and potentially other agents) as primary therapy for multiple myeloma (Samson et al, 1989). Initial approaches have been quite encouraging in small pilot studies, with the initial response and survival comparing very favourably even with high-dose melphalan regimens, as illustrated in Table 3. Although the V A D regimen must be used with care, especially in elderly patients, because of infectious complications, it has a number of advantages, e.g. the high likelihood of response in patients with initial high tumour burden and aggressive disease patterns. A n o t h e r advantage is the ability to use full doses even in the presence of renal failure, since the drugs are metabolized primarily through the liver rather than the kidneys. In addition there is minimal risk of sustained injury to the normal haemopoietic stem cells, which is important if autologous bone marrow transplantation is a future treatment consideration. Table 3. Comparative results* with chemotherapeutic regimens. Regimen

Overall response

Complete response

Median survival duration(months)

MPt VMCP/VBAP ABCM VAD M2 + a-interferon HDM VAMPtHDM

60% 53%w -60%w 84% 80% 79% 74%

0-45% < 10% <10% 28%82 26% 27% 50%

24 48 ~32w 44 > 40 48 ~ 60

MP=melphalan and prednisone; VAD=vincristine, adriamycin and dexamethasone; HDM=high-dose melphalan; VAMP=vincristine, adriamycin and methylprednisone. * Data from Durie (1988), MacLennan et al (1988), Bergsagel ('1989), McElwain et al (1989), Samson et al (1989) and Oken et al (1990). t Results are similar for several SWOG and MRC studies (e.g. M7). r Percentage accomplishing ->75% regression. wApproximation from published and presented data. 82Based upon M component, but not marrow in every instance.

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For all these reasons VAD-based regimens are attractive and are now being widely used as part of experimental programmes to improve response and survival and as a basis potentially to accomplish long-term CRs in a subset of patients. A number of variations on the VAD regimen have already been utilized, including substitution of methylprednisone (VAMP) (McElwain et al, 1989) for dexamethasone and the use of alternate day prednisone in between the infusion cycles of VAD rather than repeated dexamethasone pulses. The substitution of mitoxantrone for adriamycin in an effort to reduce potential cardiotoxicity and the use of repeated boluses of vincristine to avoid the infusion of this agent over the 4 days have also been evaluated by some investigators. Additional drugs have been given along with VAD or variants, including cyclophosphamide, giving regimens such as CVAD or CVAMP, which in pilot studies appear to have slightly increased clinical efficacy. The true benefits of these variant regimens remain to be determined. However, it is clear that lasting CRs are uncommon and cure with these regimens alone is unlikely and/or rare. METHODS TO IMPROVE CELL KILL OR OVERCOME DRUG RESISTANCE Several recent observations have suggested the possibility that the traditional effect of chemotherapy can be enhanced by a variety of modifiers. The two major types already tested clinically are the interferons (Mandelli et al, 1990) (initially a-interferon), which appear capable of enhancing cell kill with a Variety of chemotherapeutic agents, and agents directed at the blockade of the p-glycoprotein system, which are capable of enhancing cell kill with biological agents such as anthracyclines and vincristine. In a pilot study reported by Oken et al (1990), a dramatic enhancement of cell kill was accomplished by the administration of a-interferon along with a variant of the M2 protocol as first-line therapy for 58 patients with multiple myeloma. The major new observation was that an unexpected number of patients (26%) achieved pathological CR. This CR was documented both by disappearance of myeloma protein from the serum and/or the urine, as well as pathological clearing of myeloma cells from the marrow. Since the group had considerable experience with the M2 protocol alone, even in a nonrandomized evaluation this was clearly a new observation of CRs. This has led to a more detailed randomized study, which is currently on-going, to assess the potential benefit of this approach. The observation has triggered the development of a large number of studies, e.g. utilizing the VAD regimen plus o~ interferon to see if greater cell kill can be accomplished with this combination. Other biological agents are being considered in a conceptually similar fashion. For example, granulocyte macrophage colony-stimulating factor (GM-CSF) and IL6 are being evaluated along with intensive chemotherapy to see if growth stimulation can improve the cell kill with subsequent high-dose therapy. Some investigators have noted encouraging results with these types of approaches in vitro and are considering clinical trials.

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Table 4. Approaches to reverse drug resistance in myeloma. Mechanism/target

Examples of inhibitor

General classes of chemosensitizer

(1) Multidrug resistance P-glycoprotein [P-170: mdr 1 / 3 ]

--Verapamil or nifedipine --Quinidine ---Cyclosporin

Calcium channel blockers;

(2) Topoisomerase II Multidrug resistance

--Novobiocin --Acridines* (e.g. m-AMSA) --VP-16* --Adriamycin* --Mitoxantrone*

--Inhibit topoisomerase II

--BSO (D,L-buthione --SR-sulphoximine)

--Modulate alkylating agent (e.g. melphalan).

(3) Glutathione (nonprotein sulphydryls)

Calmodulin inhibitors; Synthetic isoprenoids; Bisbenzylisoquinoline alkaloids; Tamoxifen and other tiparanol analogues; Cyclosporins

--Form stable complexes: DNA; topoisomerase II; and drug

* These are topoisomerase II inhibitors which are also chemotherapeutic agents.

A large number of clinical studies have now evaluated the incidence of enhanced p-glycoprotein expression associated with multidrug resistance. Some of the currently available data is summarized in Table 4. An early experience was reported with the combination of VAD plus verapamil in which a patient with advanced multiple myeloma had a dramatic and sustained response when verapamil was added to the regimen (Durie and Dalton, 1988). This unexpected and dramatic clinical improvement led to a larger study. Unfortunately only five out of 22 patients showed improvement with the addition of verapamil to the VAD regimen (Dalton et al, 1989). Nonetheless, this was sufficient to stimulate the development of a variety of other studies, particularly looking at other agents which might more effectively and safely block the p-glycoprotein system. Candidate agents for this type of approach are also listed in Table 4. More detailed studies have indicated that the system is obviously quite complex and that other enzymes and proteins are involved in the drug resistance, including topoisomerase II and GSH, which may be important targets for ancillary blockade to achieve better cell kill efficacy. Nonetheless, this whole area 6f research is quite promising. Hopefully sufficient cell kill of the drug-resistant clone(s) can be accomplished to contribute to the efficacy of other approaches. HIGH-DOSE CHEMOTHERAPY WITH OR WITHOUT TRANSPLANTATION OR CYTOKINE SUPPORT

A very large number of groups have now evaluated the role of high-dose alkylating agent and other high-dose schedules in multiple myeloma (Anderson et al, 1989; Buckner et al, 1989; Gahrton et al, 1989; Tura et al, 1989). In essence, the observations can be summarized as follows:

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.

Very high initial cell kill can be accomplished with high-dose alkylating agent based regimens alone or in combination. CR occurs in 25-50% of patients. . Because of a lack of adequate prognostic factor analyses and randomized studies, it is impossible to evaluate at this time the true impact of these responses upon ultimate patient survival. This is particularly true because late relapses have occurred, and thus the pattern of relapse is not the same as occurs with more conventional chemotherapy. One cannot predict a traditional type of survival plateau after the initial period of stable disease. Much longer follow-up plus careful comparative studies are essential to assess the survival benefit. . In an effort to capitalize upon the apparent true CRs achieved, further investigations and additional post-induction/transplant therapy are required. Current questions are (a) do residual drug-resistant clones remain (temporarily in a non-proliferative state) or (b) is true CR achieved but/or superseded by reinduction of active myeloma secondarily (e.g. by retrovirus or secondary idiotype specific antigen trigger or other mechanisms). If there is residual disease, maintenance therapy (e.g. with a-interferon, ~-interferon, IL2 or some other agent) could delay secondary proliferation of drug-resistant clones. Conversely, further reinduction can be considered if the sensitivity/resistance pattern of the minimal residual disease can be characterized. If there is secondary reinduction, alternate approaches must be employed (e.g. therapy for retrovirus). THE ROLE OF BIOLOGICAL APPROACHES TO TREATMENT With the advent of recombinant technology, a large number of biological agents are now available for in vitro and clinical testing. Table 5 lists the Table 5. Biological agents and myeloma therapy. Agent

Therapy

a-Interferon

Maintenance post-induction or transplant Combined with chemotherapy to enhance cell kill with induction

IL2 (+ lymphokine activated killer cells, LAK)

Maintenance ? Use in early disease

Erythropoietin

For persistent anaemia, especially if endogenous erythropoietin not high

Anti-IL6 (and anti-IL6 receptor)

For plasma cell leukaemia or patients with in vitro sensitivity and ? other groups

"/-Interferon Anti-ILll3 ) Anti-TNFa/13 } For potential further evaluation Anti-prostaglandins | Anti-oestrogens (e.g. tamoxifen)}

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agents which have potential in multiple myeloma, a-Interferon (Mandelli et al, 1990) is the one agent most extensively tested and the one which has found initial promise as a maintenance agent after successful therapy. In a randomized Italian study (Mandelli et al, 1990) there was both prolongation of response duration and survival in patients who had accomplished initial response to induction chemotherapy. A large number of randomized studies are in progress to more fully evaluate the validity of this initial experience. Another promising agent recently tested is recombinant erythropoietin, which improved the anaemia in patients with myeloma who had a persistent anaemia following initial therapy (Ludwig et al, 1990). The patients most likely to benefit were those who did not have endogenous elevation of erythropoietin levels. The fact that correction of anaemia can occur suggests that the inhibition of erythropoiesis is susceptible to modification or modulation and that perhaps other biological agents can be combined with erythropoietin to more satisfactorily correct the anaemia. Since the basis for the anaemia appears to be increased levels of ILl and/or TNFet in the microenvironment of the marrow, direct inhibitors of these substances could enhance the efficacy of erythropoietin. A particularly exciting area of biological therapy is the use of anti-IL6 as a therapeutic modality (Kishimoto, 1989; Klein et al, 1989; Noriko et al, 1990). Based on the observation that IL6 is a very important growth factor for active myeloma, the group in Montpellier in France have treated two patients with plasma cell leukaemia using repeated intravenous injections of recombinant anti-IL6. Dramatic cell kill and clinical benefit have been noted in these two patients, although in the first instance this was only of a transient nature. Responses are sufficient to proceed to larger clinical testing, which is now planned in France as well as in the UK and the USA. These examples of clinical efficacy with biological agents give hope that these and other such agents alone and/or in combination can be used as meaningful treatment modalities and have a true impact on long-term survival in myeloma.

MANAGEMENT OF REFRACTORY MYELOMA The management of refractory myeloma has recently been extensively reviewed. The following is a summary of the most important details to keep in mind in evaluating therapy for this difficult treatment group. Table 6 and Figure 1 summarize the overall approach and recommendations for management. As a basis for treatment selection one must distinguish between patients who are primarily resistant and those who relapse after initial response. Primarily resistant patients comprise those who either progress on initial therapy (usually defined as greater than or equal to 25% increase in M component or increase in size and number of lytic lesions) or those who remain stable or fail to achieve a response and then progress on therapy, despite having an initial decrease in M component. Although disease progression is clearly more unfavourable than simply failure to respond,

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CHEMOTHERAPY OF MULTIPLE MYELOMA Table 6. Management of refractory myeloma. Category of patient

Recommended approach

Resistant (progressive disease or non-responder)

Glucocorticoids e.g. pulse dexamethasone or methylprednisone; daily or every other day prednisone VAD or variant schedule

Early relapse (<6 months) Late relapse (>_6 months)

Reinduction, e.g. melphalan and prednisone, VMCP/ VBAP or ABCM VAD if above fails

Refractory disease

a-Interferon EDAP Sequential hemibody irradiation Peptichemio (if available) Anti-IL6 Other (see text)

(a) I

Progression on initial therapy I

I Resistant Stable or failure to achieve initial response

I

I

On therapy

I

Off therapy

I

I Relapsing

(b) [ Resistantpatients ] I Gluc~176176 I

//I therapy

lelapsing patients I ~ 6 months

> 6 months

If fail

1

I Investi~tion therapy

VAD regimen I

t

Resume

initial

regimen t

If not feasible _1' I

If fail I

c~Interferon or I rl, Sequential hemibody irradiation I

Figure I. Refractory myeloma. (a) Disease categories. (b) Schema for approach to treatment.

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most investigators have grouped these populations together, classifying them as 'previously unresponsive patients'. Patients who have responded and then relapsed also need to be carefully classified. Response either during continued alkylating agent therapy or within 6 months of stopping therapy is more unfavourable than response followed by a remission period of greater than 6 months followed by relapse at that point. Recommendations are correspondingly different for these two subcategories. Figure 1 summarizes the classification of these different categories of refractory and relapsing patients. The following are general recommendations for management: 1.

For truly resistant patients the administration of high doses or pulse glucocorticoids is the best standard approach to treatment in that approximately 40% of patients can be anticipated to have a clinically useful response to such treatment. It is clear that glucocorticoids have not been used to their full potential in the management of myeloma, despite the fact that their efficacy has been known for many years. With appropriate dose modification, pulsed or every-other-day steroids can be continued for long periods of time. Current studies are evaluating the optimal dose schedule and combinations such as glucocorticoids plus a-interferon and/or a variety of other biological or chemotherapeutic agents. Initial results have been quite promising with the combination of dexamethasone plus s-interferon, with higher response rates being observed both in previously untreated patients and in patients with relapsing or refractory disease. 2. For patients who relapse, either during therapy or within 6 months of stopping the initial treatment, the VAD .therapy is clearly the most effective salvage regimen, resulting in an approximately 75% response rate overall. The use of the VAD regimen has been discussed earlier, including the importance of management of toxicities or potential toxicities and the possibility of utilizing new variant regimens, with substitution for dexamethasone and/or adriamycin. 3. For patients who relapse more than 6 months after stopping therapy, i.e. m unmaintained remission, reinitiation of the initial induction therapy provides an excellent alternative and leads to recontrol of the disease in at least 60-70% of patients. This is true for both simpl~ alkylating agent therapy as well as more complex combinations, such as the VMACP-VBAP and ABCM regimens. Obviously with the anthracycline regimens the dosage of adriamycin becomes limiting because of the potential cardiotoxicity. If progression is observed following the reinduction approach then VAD chemotherapy can be administered as an additional salvage. 4. Patients who have failed with all of these second- and third-line approaches are clearly eligible for a variety of experimental approaches. The effectiveness of single agents or combinations, including c~interferon, alone or combined with dexamethasone, is noted above. The EDAP regimen (Alexanian et al, 1989), which incorporates VP 16 (etoposide), dexamethasone, cytosine arabinoside (cytarabine BP,

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USP) and cisplatinum is a useful relapse regimen which in the initial pilot study d e m o n s t r a t e d a response rate of approximately 40%. U n f o r t u n a t e l y the response duration is quite short (3--6 months). H o w e v e r , it is worth considering in patients with advanced refractory disease. O t h e r approaches include the use of tamoxifen, as it has b e e n recently n o t e d that m y e l o m a cells have o e s t r o g e n receptors and b o t h in vitro and in vivo responses can be noted with tamoxifen in the same dose and schedule as utilized for the m a n a g e m e n t of breast carcinoma (e.g. 10 mg twice daily). M o r e experimental a p p r o a c h e s include the use of high-dose c h e m o t h e r a p y with b o n e m a r r o w transplantation and peripheral stem cell rescue or cytokine support. N e w e r biological a p p r o a c h e s include the use o f anti-IL6 and/or antibodies to a variety of cytokines k n o w n to be involved in the proliferation of m y e l o m a and/or associated osteoclasts or m a c r o p h a g e s . CONCLUSIONS F r o m the material s u m m a r i z e d in this c h a p t e r it can be seen that, as stated at the outset, a c h i e v e m e n t s to date in terms of survival duration have been modest. H o w e v e r , the better u n d e r s t a n d i n g of the basic biology and mechanisms o f drug resistance show true promise for m o r e meaningful advances in the not too distant future.

REFERENCES Alexanian R, Barlogie B & Ventura G (1989) "Chemotherapy for resistant and relapsing multiple myeloma. EuropeanJourna! of Haematology 43: 140-144. Anderson KC, Barut BA, Ritz J, Freedman AS & Nadler LM (1989) Autologous bone marrow transplantation therapy for multiple myeloma. European Journal of Haematology 43: 157-163. Barlogie B, Epstein J, Selvanayagam P & AIexanian R (1989a) Plasma cell myeloma--new biological insights and advances in therapy. New EnglandJournal of Medicine73: 865-879. Barlogie B, Smallwood L, Smith T & Alexanian R (1989b) High serum levels of lactic dehydrogenase identify a high grade lymphoma-like myeloma. Annals of Internal Medicine I10: 521. Bataille R, Durie BGM, Grenier J & Sany J (1986) Prognostic factors and staging in multiple myeloma: a reappraisal. Journal of Clinical Oncology 4: 80. Belch A, Shelley W, Bergsagel DE et al (1988) A randomized trial of maintenance versus no maintenance melphalan and prednisone in responding multiple myeloma patients. British Journal of Cancer57: 94-99. Bergsagel DE (1989) Melphalan-prednisone versus drug combinations for plasma cell myeloma. EuropeanJournal of Haematology 43:117-123. Buekner CD, Fefer A, Bensinger WI et al (1989) Marrow malignant transplantation for malignant plasma cell disorders: summary of the Seattle experience. EuropeanJournal of Haematology 43: 186-190. Carter A, Merchav S, Silvian-Draxler I & Tatarsky I (1990) The role in intefleukin-I and tumour necrosis factor-alpha in human multiple myeloma. British Journalof Haematology 74: 242. Dalton W, Durie BGM, Alberts DS, Gerlach JH & Cress AH (1986) Characterization of a new drug-resistant human myeloma cell line that expresses p-glycoprotein. CancerResearch 46: 5125.

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Dalton WS, Durie GBM, Salmon SE, Grogan TM, Scheper RJ & Meltzer PS (1987) Multidrug resistance in multiple myeloma. Detection of p-glycoprotein in clinical specimens and reversal of resistance with verapamil. Blood 70: 834A. Dalton WS, Grogan TM, Rybski JA et al (1989) Immunohistochemical detection and quantitationof p-glycoprotein ifi multiple drug resistant human myeloma cells: association with level of drug resistance and drug accumulation. Blood 73: 747. Deuchars KL & Ling V (1989) P-glycoprotein and multidrug resistance in cancer chemotherapy. Seminars in Oncology 16: 156. DeWald GW, Kyle RA, Hicks GA & Greipp PR (1985) The clinicalsignificanceof cytogenetic studies in I00 patients with multiple myeloma, plasma cell leukemia or amyloidosis. Blood 66: 380. Dude BGM (1986) Staging and kinetics of multiple myeloma. Seminars in Oncology 13: 300-309. Dude BGM (1988) Chemotherapy of myeloma: SWOG studies. Hematological Oncology 6: 141-144. Durie BGM & Bataille R (1989) Therapeutic implications of myeloma staging. European Journal of Haematology 43:111-116. Durie BGM & Dalton WS (1988) Reversal of drug-resistance in multiple myeloma with verapamil. British Journal of Haematology 68: 203-206. Durie BGM & Grogan TM (1985) The CALLA-positive myeloma: an aggressive subtype with poor survival. Blood 66: 229. Durie BGM & Salmon SE (1975) A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment and survival. Cancer 36: 842-854. Dude BGM, Vela E, Baum Vet al (1985) Establishment of two new myeloma cell lines from bilateral pleural effusions. Evidence for sequential in vivo clonal change. Blood 66: 548. Dude BGM, Stock-NovackD, Salmon SE et al (1990a) Prognostic value ofpretreatment serum B2 microglobulin in myeloma: a Southwest Oncology Group study. Blood 75: 823-830. Dude B, Vela EE & Baum V (1990b) Cytogenetie abnormalities in multiple myeloma. Proceedings of Mechanisms in B cell Neoplasia. In press. Gahrton G, Tura S, Belanger M e t al (1989) Allogeneic bone marrow transplantation in patients with multiple myeloma. European Jo,trnal of Haematology 43: 182-185. Garewal H, Dude BGM, Kyle RA et al (1984) Serum 132mieroglobulin in the initial staging and subsequent monitoring of monoclonal plasma cell disorders. Journal of Clinical Oncology 2: 52. Garrett LR, Dude BGM, Edwin GE et al (1987) Production of the bone resorbing cytokine lymphotoxin by cultured human myeloma cells. New England Journal of Medicine 317: 526. Gould J, Alexanian R, Goodacre A, Pathak S, Hecht B & Barlogie B (1988) Plasma cell karyotype in multiple myeloma. Blood 71: 453-458. Greipp PR (1989) Monoclonal gammopathies: new approaches to clinical problems in diagnosis and prognosis. Blood Reviews 3: 222-236. Greipp PR, Katzmann JA, O'Fallon WM & Kyle RA (1988) Value of 132-microglobulinlevel and plasma cell labeling indices as prognostic factors in patients with newly diagnosed myeloma. Blood 72: 219-223. Grogan TM, Dude BGM, Spier CM, Richter L & Vela E (1989) Myelomonocytic antigen positive myeloma. Blood 73: 763. Kishimoto T (1989) The biology of interleukin-6. Blood 74: 1-10. Klein B, Zhang KG, Jourdan M & Bataille R (1989) GM-CSF synergizes with IL-6 in supporting the proliferation of human myeloma cells. Blood 74: 201a. Ludwig H, Fritz E, Kotzmann H, Hocker P, Gisslinger H & Barnas U (1990) Erythropoietin treatment of anemia associated with multiple myeloma. New England Journal of Medicine 322: 1693-1699. MacLennan ICM, Kelly K, Corckson RA, Cooper Ett, Cuzick J & Chapman C (1988) Results of the MRC myelomatosis trials for patients entered since 1980. Hematological Oncology 6: 145-158. Mandelli F, Awisati G, Amadori S et al (1990) Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy. New England Journal of Medicine 322: 1428--1434.

CHEMOTHERAPY OF MULTIPLE MYELOMA

195

McElwain TJ, Selby PJ, Gore ME et al (1989) High-dose chemotherapy and autologous bone marrow transplantation for myeloma. European Journal of Haematology 43: 152-156. Neri A, Murphy JP, Cro Let al (1989) RAS oncogene mutations in multiple myeloma. Journal of Experimental Medich~e 170: 1715. Noriko T, Karasuyama H & Tada T (1990) Growth autonomy and tumorigenicity of interleukin 6-dependent B cells transfected with interleukin 6 cDNA. Journal of Experimental Medicine 171: 389-400. Oken MM, Kyle RA, Greip PR, Kay NE, Tsiatis A & O'Connell MJ (1990) Chemotherapy plus intorferon in the treatment of multiple myeloma. Proceedingsof the American Society for Clinical Oncology 9: 228. Palmer M, Belch A, Brox E, Pollack E & Koch M (1987) Are the current criteria for response useful in the management of multiple myeloma? Journal of Clinical Oncology 5: 12721377. Samson D, Newland A, Kearney Jet al (1989) Infusion of vincristine and doxorubicin with oral dexamethasone as first-line therapy for multiple myeloma. Lancet if: 882-885. Tufa S, Cavo M, Gobbi M e t al (1989) High-dose chemoradiotherapy and allogeneic bone marrow transplantation in multiple myeloma. European Journal of Haematology 43: 191-195. Van Camp B, Durie BGM, Spier C et al (1990) Plasma cells in multiple myeloma express a natural killer cell-associated antigen: CD56 (NKH-1; Leu-19). Blood 76: 377-382.