REVIEW ARTICLE

Drugs 44 (2): 170-181, 1992 0012-6667/92/0008-0170/$06.00/0 © Adis International Limited. All rights reserved. DRUl173

Multiple Myeloma

New Treatment Options

Lionello Camba and Brian G.M. Durie Department of Haematology, Charing Cross and Westminster Medical School, Charing Cross Hospital, London, England

Contents 170 171 171 171 171 173 174 175 175 176 176 177 177 178 178 178 178 179 179

Summary

Summary I. Conventional Dose Chemotherapy 1.1 Melphalan and Prednisone or Prednisolone 1.2 Combination Chemotherapy 1.2.1 Untreated Patients 1.2.2 Relapsed and Refractory Myeloma 2. High Dose Chemotherapy2.1 High Dose Melphalan 2.2 Autologous Bone Marrow and Peripheral Blood ,Stem Cell Transplantations 2.3 Allogeneic Bone Marrow Transplantation 3. Interferon-a 4. New Therapeutic Approaches 4.1 Modulation of Drug Resistance 4.2 Cytokines arid Growth Factors 4.2: I Interleukin-2 4.2.2 Interleukin-6 4.2.3 Epoetin 4.3 Bisphosphonates 5. Conclusions and Future Prospects

Before proceeding to treatment selection for multi'pl~ lll(eloma, it is important to exclude monoclonal gammopathy of unknown significance or la~~ ; sin'\i1ar smouldering or indolent type of myeloma not requiring immediate chemotherapy. I~' , Hatients with active myeloma, pretreatment prognostic classification is important for approp&a~ell", ba"lancing of the risks and benefits of 111 "k ' , p~rticular treatmentopt~ons. For example, co~venti~n~I'I~~~Tolherapy s,",ph as melphalan/pr~dmsone may be appropnate for an elderly patient wltH" l\etlv~ stageIII lllyeloma, whereas high dose chemotherapy with or without bone marrow tra~i~~/~n~tii>n or cytokine support may be . . considere.d for the ~atient under age.45 with eve~ earitf~f ~ta~~ ~i~ease. I, . A va~ety of OPtlO~S are no~ avaIlable for patients Ir~t~ rf!\l~smg or resistant dls~ase, particularly usmg agents With potential for reversal of multl~~g ll'~s~st~nce. , iI:~e ,use of mterferon-a as. m.aintenanc~ following init~al respon~e to chem~thJI'~~"l~,.~ ,I,',Fii" i"m~, o, I., 1a,nt! f,. ~" rrroiongation of re~l11SslO.n, duration and p~tentlally surv~~al. A .vanetYIIR, :~~~p~rt,ye m~~sur~s ~re also helpful mcludmg the use of epoetm (erythropoeltm) to ImprovmhiYfrlif Wry lInaelJV~ aqd blSphosphonates

I,

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171

for the inhibition of ongoing bone resorption. With the availability of various treatment options, it has become important for patients to be evaluated by a specialist in the field.

Multiple myeloma (MM) represents the abnormal proliferation and accumulation of malignant plasma cells which are typically located in the bone marrow. The usual clinical features result from a combination of factors including the actual myeloma cell mass or tumour burden, the systemic effects of the monoclonal paraprotein and other paraneoplastic components such as cytokines (e.g. interleukin-6) and fh-microglobulin, as well as the intrinsic kinetic properties of the malignant clone (Durie et al. 1986; Durie & Salmon 1975). f32Microglobulin is the light chain of the HLA antigen which is expressed on the surface of cells.generally, but is over-produced in activated B cells and plasma cells such as myeloma cells. The monoclonal protein produced by myeloma cells is idiotype specific and reflects the exact specificity of the malignant clone. Based upon .these factors, criteria for disease classification and clinical staging are now well established (Durie 1989) [tables I and II], and have proven useful with regard to the timing and selection of treatment for individual patients (Durie & Bataille 1989). Benign forms of MM, such as monoclonal gammopathy of unknown significance (MGUS), benign MM and 'smouldering' MM, clearly do not need treatment until there is definite evidence of disease progression.

1. Conventional Dose Chemotherapy 1.1 Melphalan and Prednisone or Prednisolone Melphalan with or without prednisone or prednisolone (MP) has been the mainstay of the treatment of MM for over 30 years (Bergsagel 1989). Pulses of melphalan 6 to 9 mg/m 2 for 4 to 7 days and repeated every 4 to 6 weeks are usuaL Because intestinal absorption is variable, midcycle peripheral blood cytopenia should be evaluated to ensure optimal therapeutic effects. Prednisolone (40

to 60 mg/day) or prednisone (60 to 100 mg/day) is given during melphalan administration. Treatment is continued for 12 to 18 months until the paraprotein disappears or a plateau phase develops and remains stable for at least 6 months. MP produces objective responses in 40 to 60% of patients, although complete remission (CR) is rare (0 to 6%): Median survival is between 20 and 30 months, which contrasts with the 6 to 10 months for untreated patients (BergsageI et al. 1962; Sporn & Mcintyre 1986). MP is clearly the treatment of choice for elderly or sick patients for whom more aggressive therapy is not indicated (Bergsagel 1988). Furthermore, it should be borne in mind that lack of an initial rapid and/or dramatic response is not necessarily associated with shorter survival (Durie 1991a). Indeed, in a recent study of patients with stage III myeloma, an early response (within 3 months) was associated with a much lower survival (Marmont et al. 1991). Similarly, in the Fifth Medical Research Council myeloma trial, long term survival did not correlate directly with degree of response to melphalan alone or plus doxorubicin (adriamycin), carmustine and cyclophosphamide (MacLennan et al. 1988) [see table III]. Thus, slow responders and even patients with stable disease, without true partial or complete remission, can achieve prolonged survival. Patients with progressive disease should be treated with the therapeut~c options described below. Relapsed patients may be restarted on MP unless relapse occurs within 6 months of discontinuing MP (Buzaid & Durie 1988). 1.2 Combination Chemotherapy

1.2.1 .untreated Patients The list of combination chemotherapy regimens for newly diagnosed or resistant MM is very long indeed. The reader can refer to some recent re-

172

Table I. Diagnostic criteria 1. Multiple myeloma Major criteria I. Plasmacytoma on tissue biopsy II. Bone marrow plasmacytosis with> 30% plasma cells III. Monoclonal globulin spike on serum electrophoresis exceeding 35 gIL for IgG peaks or 20 gIL for IgA peaks, ~ 1.0 g/24h of.K or A light chain excretion on urine electrophoresis in the absence of amylOidosis Minor criteria a) Bone marrow plasmacytosis with 10 to 30% plasma cells b) Monoclonal globulin spike ,present, but less than the levels defined above c) Lytic bone lesions d) Normal IgM < 500 mglL, IgA < 1 gIL, or IgG < 6 gIL Diagnosis is confirmed when any of the following features are documented in symptomatic patients with clearly progressive disease: (The diagnosis of myeloma requires a minimum of 1 major + 1 minor criterion, or 3 minor criteria that must include a + b) 1. I + b, I + c, I + d (I + a not sufficient) 2. II + b, II + c, II + d 3. III + a, III + c, III + d 4. a + b + c, a + b + d 2. Monoclonal gammopathy of undetermined significance (MGUS), indolent myeloma and smouldering myeloma (stage I or IIA) I. MGUS Monoclonal gammopathy M component levels IgG ~ 35 gIL IgA ~ 20 gIL Bence Jones protein ~ 1.0 g/24h Bone marrow plasma cells < 10% No bone lesions No symptoms II. Indolent myeloma. Criteria as for myeloma (above) with the following limitations: Absent or only limited bone lesions (~ 3 lytic lesions); no compression fractures M component levels IgG < 70 gIL IgA < 50 gIL No symptoms or associated disease features Karnofsky performance status > 70% Haemoglobin > 100 gIL Serum calcium: normal Serum creatinine < 175 I'moilL « 2.0 mg/dl) No infections III. Smouldering myeloma. Criteria as for indolent myeloma with additional constraints: There must be no demonstrable bone lesions Bone marrow plasma cells 10-30%

Drugs 44 (2) 1992

views (Durie 1991 b; Sporn & MacIntyre 1986) and to table III. Before VAD (vincristine + doxorubicin + dexamethasone)-based regimens were introduced for the treatment of MM, most chemotherapy protocols for previously untreated patients contained melphalan and/or cyclophosphamide, prednisone or prednisolone, with one or more of lomustine (CCNU), carmustine (BCNU) or doxorubicin. A few randomised trials of combination chemotherapy versus MP have shown improved response rates, and longer response duration and median survival in patients receiving combined therapy. In particular, certain drug combinations such as the M2 protocol (Case et al. 1977; table III), VMCP/ VBAP (Durie et al. 1986), and ABCM (MacLennan et al. 1988) have proven superior. Nonetheless, patients continue to relapse and longer term survival has not been greatly affected by the use of combination regimens. At best, overall survival is improved by 6 to 9 months and the probability of survival beyond 5 years increased by only 10 to 15% at most. Furthermore, three recent randomised trials comparing VMCP/VBAPwith MP failed to show even this degree of benefit with respect to response rate, response duration and long term survival in newly diagnosed patients (Boccadorbet al. 1991; Hjorth et al. 1990; 0sterberg et al. 1989). Samson et al. (1989) were the first to publish results with the VAD protocol in a series of untreated patients. The response rate was higher than in previous combination chemotherapy trials: 84% of patients responded, including 28% with CR. These results compare favourably with high dose melphalan (HDM) which is associated with much higher morbidity and early mortality (Selby et al. 1987). The VAD regimen typically, although not always, produces a very rapid tumour mass reduction (as calculated by the time of paraprotein disappearance), with less bone marrow: toxicity than HDM and very little, if any, nephrotoxicity. It is therefore an ideal schedule when rapid disease control is necessary and in the presence of renal impairment. In a more recent report, however, Alexanian et al. (1990) compared VAD-based regimens with his-

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173

Table II. Myeloma staging system Criteria

Measured myeloma cell mass (cells x 1012/m2)

Stage I: All of the following : • Haemoglobin value > 100 gIL • Serum calcium value normal or < 3 I'moi/L « 12 mgldl) • Bone x-ray, normal bone structure (scale 0) or solitary bone plasmocytoma . only • Low M component production rates: IgG value < 50 gIL IgA value < 30 gIL • Urine light chain M component on elecrophoresis < 4 g/24h

< 0.6 (low)

Stage II: fitting neither stage I nor stage III

0.6-1.20 (intermediate)

Stage III: one or more of the following: . Haemoglobin value .< 85 gIL Serum calcium value> 3 I'moi/L Advanced lytic bone lesions (scale 3) High M component production rates: IgG value > 70 gIL IgA value> 50 gIL • Urine light chain on electrophoresis • • • •

>

> 1.20 (high)

12 g/24h

• Subclassification (A or B) A =relatively normal renal function (serum creatinine < 175 I'mol/L) B =abnormal renal function (serum creatinine ~ 175 I'mol/L) Examples: Stage IA = low cell mass with normal renal function Stage IIiB = high cell mass with abnormal remil function

torical controls previously treated with MP and/or the VCAP combination (vincristine + cyclophosphamide + doxorubicin + prednisone). They failed to demonstrate a long term survival advantage for VAD compared to MP or conventionalcombinations. Although such discrepancies may reflect different patient selection and/or different definitions for clinical response, the more fundamental problem is that conventional therapy does not eradicate

myeloma and relapse inevitably supervenes. Unfortunately this is true for both the VAD protocol and the HDM-based regimens used without interferon-a (IFNa) maintenance.

1.2.2 Relapsed and Refractory Myeloma With the VAD regimen, 43% of first-line refractory patients (i.e. refractory .to MP, VMCP/ VBAP, etc.) and 73% of relapsed (but still responsive patients), can attain an objective response (Barlogie et al. 1984). This has therefore become the regimen of choice for refractory and relapsing patients. However, with the EDAP (etoposide + dexamethasone + cytarabine + cisp1atin) and TDC (teniposide + dexamethasone + cyclophosphamide) regimens (table III) objective responses can also be obtained in about 40% of refractory and relapsed patients. Similar results can be achieved using high dose steroid monotherapy [e.g. dexamethasone 40mg (or 20 mg/m2) daily for 4 days,and repeated every 2 to 3 weeks acording to tolerability and response] in both resistant and relapsing myeloma (Buzaid & Durie 1988). This approach is particularly suitable for patients with poor marrow reserves due to extensive prior chemo- or radiotherapy. Finally, systemic hemibody irradiation may, in carefully selected cases, represent a satisfactory alternative to chemotherapy (Singer et al. 1989). It can provicie effective pain relief and is particularly suitable for older patients (unsuitable for chemotherapy), who have generalised bone pain. It should be avoided in patients with early stage disease because of the damage produced to the normal bone marrow reserves. Thus, with these second-line approaches, partial remissions (PRs) [> 50% reduction in paraprotein] can [be obtained in 60 to 70% of patients who relapsb more than 6 months after completion of firstline treatment!; and in about 40% of patients refractory to first-line therapy or relapsing within 6 months of in~tiating it (BuzaiQ & Durie 1988). However, CR~ (complete disappearance of paraprotein or · mo.noclonal protein in serum and/or urine, plus elimination of myeloma cells from bone

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Table III. Some combination chemotherapy regimens for myeloma treatment Protocol

Drugs

Schedules

Interval (weeks)

Reference

ABCM

Doxorubicin Carmustine Cyclophosphamide Melphalan Cyclophosphamide Carmustine Prednisone Vincristine Doxorubicin Dexamethasone (Methylprednisolone) Vincristine Carmustine Doxorubicin Prednisone Vincristine Cyclophosphamide Doxorubicin Prednisone Vincristine Carmustine Melphalan Cyclophosphamide Prednisone Vincristine Melphalan Cyclophosphamide Prednisone Etoposide Dexamethasone Cytarabine Cisplatin Teniposide Dexamethasone Cyclophosphamide

30 mg/m 2 IV day 1 30 mg/m 2 IV day 1 100 mg/m 2 PO days 21-24 6 mg/m 2 PO days 21-24 400 mg/m 2 IV day 1 75 mg/m 2 IV day 1 80 mg/m 2 PO days 1-7 0.4mg IV days 1-4 9 mg/m 2 IV days 1-4 40mg PO days 1-4a 1.5g IV/PO days 1-5 1mg IV day 1 25 mg/m 2 IV days 1-4 30 mg/m 2. IV day 1 60 mg/m 2 days 1-4 1mg IV day 1 100 mg/m 2 PO days 1-4 30 mg/m 2 IV day 1 60 mg/m 2 PO days 1-4 1-2 mg IV day 1 0.5 mg/kg day 1 1 mg/kg PO days 4-7 10 mg/kg IV day 1 0.5-1 mg/kg days 1-15 1mg IV day 1 5 mg/m 2 PO days 1-4 100 mg/m 2 days 1-4 60 mg/m 2 PO days 1-4 100-200 mg/m 2 IV days 1-4 40mg IV/PO days 1-5 1000 mg/m 2 IV day 5 20 mg/m 2 IV days 1-4 30 mg/m 2 IV days 1-2 40mg IV days 1-7 200 mg/m 2 IV days 1-7

6

Maclennan et al. (1988)

3

Cohen et al. (1979)

4

Samson et al. (1989)

3

Bonnet et al. (1982)

3

Alexanian et al. (1977)

5

Case et al. (1977)

3

Alexanian et al. (1981)

4

Barlogie et al. (1989)

4

Leoni et al. (1991)

CBP

VAD (VAMP)

VBAP

VCAP

M-2

VMCP

EDAP

TOC

a Plus days 9-12, 17-21 , odd cycles only. Abbreviations: PO orally; IV intravenously.

=

=

marrow, and absence of symptoms) are rare and median survival remains short in most instances.

2. High Dose Chemotherapy With conventional therapy, long term cure is an exceptional event (van Hoeven et al. 1990). Even

when CR is achieved with VAD-based regimens, patients continue to relapse and salvage chemotherapy produces only PRs. In an attempt to obtaindisease eradication, new protocols incorporating high dose chemotherapy with or without bone marrow transplantation and/or growth factor support have been used.

Treatment of Multiple Myeloma

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2.1 High Dose Melphalan

antigens (Anderson et al. 1991; Gobbi et al. 1991; Reece et al. 1989). However, neither response rate or long term survival are improved, and the role of purging remains uncertain. It should be kept in mind that relapse may result from stem cells located not in the bone marrow, but in other peripheraUymphoid tissue(s), and thus not eradicated by the preparative regimen and/or bone marrow purging. Peripheral blood stem cells collected after a brief bone marrow aplasia induced by high dose cyclophosphamide or other chemotherapy combination have also been used instead of, or together with, autologous . bone marrow transplantation. Response rates of up to 60% have been obtained, the highest proportion ofCRs occurring among patients with drug-sensitive disease or low tumour mass. The relapse rate remains high especially in patients with unfavourable prognostic features (progressive disease, stages II and III) [Anderson et al. 1991 ; Fermand et al. 1989; Marit et al. 1991]. Currently, peripheral blood stem cell harvesting is lengthy and inconvenient Five to 10 collections are necessary to obtain an . adequate number of granulocyte-monocyte colony forming units (Gianni et al. (989). Administration of granulocyte-macrophage colony-stimulating factor (sargramostim; GM-CSF) before peripheral blood stem cell collection may reduce the number of leukaphereses required and accelerate bone marrow reconstitution (Pileri et al. 1990). However, more studies are necessary concerning the role of GM-CSF in MM since it is known that (under certain in vitro conditions) GM-CSF can stimulate MM stem cells (Zhang et al. 1990) which are also known to be sometimes present in the peripheral blood of MM patients treated with high dose chemotherapy (Maitland et al. 1991). More recent studies have indicated that granulocyte colony-stimulating factor (G-CSF) can stimulate myeloma growth both in vitro and in vivo (Klein & Bataille 1991). More detailed studies on MM stem cells are necessary before more general use of peripheral blood stem cell transplantation with growth factor support can be considered. Obviously, if perfected, reconstitution of marrow with in vitro expansion of even a small aliquot of pur-

With melphalan given at doses of 80 to 140 mg/ m 2, 27% of previously untreated or responding patients and 13% of refractory patients may obtain CR (Selby et al. 1987). However, neither response rate or median survival (19 months) are different from those achieved with the VAD regimen, which is much less toxic. Essentially, all patients subsequently relapse after an initial excellent response. 2.2 Autologous Bone Marrow and Peripheral Blood Stem Cell Transplantations When high dose melphalan or other bone marrow ablative conditioning therapy is followed by autologous bone marrow transplantation, higher response rates can be achieved in both responsive and refractory myeloma. Using this approach, Jagannath et al. (1990) reported CR in 36% of patients with good prognostic features, in 20% of patients in relapse, and in 29% of patients with progressive disease. However, the relapse rate was high, especially in patients who received their transplant when in advanced DurieSalmon stage (stage IlIA or B), in heavily treated patients, and in patients with progressive disease. Harousseau et al. (1991) in a more recent study confirmed these results. They reported a 5-year survival of 44% and a median remission duration of 24 months after autologous bone marrow transplantation. Unfortunately, the survival curve showed no plateau, with relapses ·occurring up to 45 months post-transplant. A more durable remission and perhaps longer survival can be achieved if autologous bone marrow transplantation is followed by maintenance with IFNa (Attal et al. 1991, 1992; Cunningham et al.1991) [see section 3]. Although high dose chemotherapy is not curative in itself, the presence of clonogenic myeloma cells in the autografted marrow has also been implicated in the high ·relapse rate after autologous bone marrow transplantation. Removal of such cells has been attempted by purging the marrow with a variety of techniques, including monoclonal antibodies against plasma cells and early B cell surface

Drugs 44 (2) 1992

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ified normal haematopoietic stem cells is ultimately an ideal approach. 2.3 Allogeneic Bone Marrow Transplantation To date about 150 patients with MM have received allogeneic bone marrow transplantation. Both the European experience (Gahrton et al. 1991) and the Seattle experience (Bensinger et al. 1991) have demonstrated that allogeneic bone marrow transplantation is feasible in MM and that disease control can be achieved. The survival curve plateaus after 1 year, and the disease-free survival is 40% at 3 years. Longer survival is described in patients with low tumour burden (stage I), in patients who have received minimal prior treatment, and in those with grade I graft-versus-host disease (GVHD). Unfortunately, allogeneic bone marrow transplantation is associated with a higher rate of transplant-related deaths (30 to 40%) than autologous marrow transplantation. This is due both to GVHD and to risk factors including patient age, coexistent hypogamma globulinaemia, and organ dysfunction such as renal insufficiency. In summary, autologous bone marrow transplantation and administration of peripheral blood stem cells are safer procedures than allogeneic marrow transplantation, and can be performed in patients up to the age of 65 years, but long term survival is unusual in the absence of IFNa maintenance (see section 3). Long term disease control may occur mor~ frequently with allogeneic bone marrow transplantation, and may also be improved with post allograft IFNa. However, allogeneic transplantation is only possible in patients with a matched donor (30%) and is safe only in patients younger than 50 years. Since only 5 to 10% of MM patients are under this age, only 2 to 3% of patients overall are eligible for allogeneic bone marrow transplantation. But even then, the procedure is .currently associated with an unacceptably high level of graft-related deaths. It remains to be seen whether or not different preparative regimens or better methods to combat GVHD can improve matters.

3. Interferon-a The direct antitumour activity ofIFNa on myeloma cells has been previously demonstrated using in vitro clonogenic assays (Salmon et al. 1983)~ Clinical experience has confirmed this anti tumour effect in MM patients. Early studies with human purified and lymphoblhstoid IFNa showed art objective response rate of 15 to 30%, with rare CRs (Ohno 1987). More recently, Costanzi et al. (1985) treated 49 patients with resistant disease with IFNa-2b. 11 % of refractory patients and 26% of relapsed patients achieved an objective response, including one CR. Quesada et al. (1986) using human recombinant IFNa as a single agent, observed an objective response in 50% of previously untreated patients and in 15% of refractory patients. Clinical response was associated with a complete or partial restoration of immunoglobulin levels. In contrast, R'0djer et al. (1990) described only 2 PRs and 3 minor responses in 14 patients with refractory disease. IFNa has also been used in combination with chemotherapy in previously untreated patients. In a randomised trial, Preis et al. (1989) treated 29 patients with VMPC only and 23 patients with VMPC plus IFNa-2c. A clinical response was observed in 57% of patients in the IFN group and in 41% of the VMPC only group. The median survival was not significantly different at 22 and 21 months, respectively. Similarly, in a randomised trial Mellstetdt et al. (1991) treated 133 patients with MP plus natural IFNa and 134 patients with MP alone. All patients had previously untreated stage II or III disease. The overall response rate was 65% for the IFN group and 45% for the MP group. Response rate, re" sponse duration and median survivl,ll were significantly longer in the IFN group than i,n the MP only group for stage II patients (74 vs 45%; 40 YS 22 months; and 43 vs 24 months, respectively). However, the long term survival curves did not differ between the 2 groups. Oken et al. (1989) described a CR rate of 32% in patients treated with the M2 protocol plus IFNa. Prior experience with this reg-

177

Treatment of Multiple Myeloma

imen without IFN had given a maximum CR rate of 5 to 10% (Case et al. 1977). In a randomised trial Mandelli et al. (1990) allocated WI patients who responded to conventional therapy to either observation only (n = 51), or maintenance with IFNa-2b (n = 50). There was a significantly longer survival in the IFN group than in the control group (51 vs 39 months) and a longer disease-free survi,val (26 vs 14 months). In an update of these results (Mandelli 1991) after a median follow-up period .of 42 months (range 29 to 65), the relapse rate was 54% for the IFN group and 84% for the observation group. Furthermore, of the 24 patients still in CR, 18 (75%) were from the IFN group and 6 (25%) from the observation group. However, despite the significantly prolonged median response and survival, the long term survival did not differ significantly between groups; of the 46 patients who died, 22 received IFN and 24 did not. There are lingering, tantalising questions as to why there is only short term survival benefit despite prolonged remission duration. Is there a poor risk subgroup with improved remission and survival? Samson et al. (1991) presented some preliminary results of a randomised trial in which IFNa was added to the VAD regimen either during induction and maintenance or during maintenance only. Although it is tooeariy to draw any conclusion, initial results do not indicate any advantage in using IFN during induction along with VAD. From these studies it would appear that an initial substantial decrea~e in tumour mass may be necessary in order to exploit the antineoplastic effects ofIFN to the full (Bergsagel et al. 1990). Its use in combination with regimens that can cause rapid response and reduction of the tumour burden, such as the VAD regimen and high dose chemotherapy with bone marrow transplantation, is still being evaluated. Recently, 20 patients who responded to conventional first-line therapy received autologous bone marrow transplantation followed by maintenance with IFNa after bone marrow recovery (Attal et al. 1991). Ten patients (50%) achieved CR and 10 PR following autologous bone marrow transplantation. After a median

follow-up of20 months, 2 of the partial responders relapsed, while none of those in CR have relapsed thus far.

4. New Therapeutic Approaches 4.1 Modulation of Drug Resistance It has been known for many years that natural cytotoxic agents such as vincristine and doxorubicin increase multi-drug-resistance (MDR) both in vitro and in vivo (Ford & Hait 1990). MDR is mediated by a 170kD membrane glycoprotein (P-gp) encoded by the mdr-I locus. Among patients receiving VAD the proportion of P-gp-positive cells is much higher in resistant than in responding patients (Epstein 1989). Furthermore, both P-gp and its RNA are expressed in less than 5% of untreated patients and in up to 75% of patients who become refractory to chemotherapy (Dalton et al. 1991). This indicates that there is a selection process toward increased expression of mdr-I as treatment progresses. The mechanism(s) whereby this occurs remain(s) to be clarified. Both expansion of pre-existing resistant clones as well as creation or acquisition of new resistant clones may occur. In vitro clonogenic assays have demonstrated that MDR can be overcome (at least temporarily) by the action of certain compounds, e.g. calcium channel blockers (verapamiI, nifedipine), estrogen antagonists (tamoxifen, toremifene) and peptides (cyclosporins) [Ford & Hait 1990]. Furthermore, Durie and Dalton (1988) described a patient who had become resistant to. MP, VMCP/VBAP, and VAD. When VAD was repeated in association with verapamil there was a dramatic improvement both clinically and biochemically. The patient became mobile again, the paraprotein .level decreased from 65 to 31 giL and the Ih-microglobulin level from 8.1 to 2.1 mg/L, with subsequent remission lasting for over 2 years. In 21 further VAD-resistant patients treated · by Dalton et al. (1991), 5 (27%) achieved a PR when verapamil was added by continuous intravenous infusion. However, the duration of the responses

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was short, and toxicity, mainly cardiac, was significant. Clearly, more pharmacological and clinical experimentation is necessary before any of the chemosensitising drugs, such as verapamil, quinine or cyclosporin or their analogues, can be recommended to achieve reversal of drug resistance. Many trials are currently ongoing, including, for instance, an EORTC trial using VAD plus cyclosporin. A considerable amount of new data will soon be available for evaluation. 4.2 Cytokines and Growth Factors 4.2.1 Interleukin-2 (IL-2) Cimino et al. (1990) showed that high levels of IL-2 are associated with longer survival in MM. These authors postulated that IL-2 mediates suppression of the MM clone ·via the effects of tumour necrosis factor (TNF) and interferon), (IFN)') released by IL-2 stimulation. Gottlieb et al. (1990), on the basis of previous experiments showing myeloma cell kill by IL-2-stimulated autologous peripheral blood mononuclear cells (PBMs), treated 4 patients with IL-2 infusion following marrow transplantation, with apparent prolongation of remission. Clonogenic assays using PBMs taken after IL-2 administration did not show an increased cytotoxic effect against pretreatment bone marrow plasma cells. However, patients' sera contained raised levels of TNF and IFN)' which could mediate MM cell suppression. 4.2.21nterleukin-6 (IL-6) The role ofIL-6 as a myeloma cell growth factor has been recognised (Durie 1991 c). Furthermore, increased levels of IL-6 have been found in a number of patients at diagnosis or relapse (Giles et al. 1991). Based on their extensive similar data, Klein et al. (1991) treated 3 patients with plasma cell leukaemia and 1 with Severe MM with daily IV administration of anti-IL-6 monoclonal antibodies. Anti-IL-6 effectively produced a biological response in vivo and in vitro, as demonstrated by a reduction of bone marrow plasma cells in S phase, a decrease of C-reactive protein to normal levels,

and thrombocytopenia. Unfortunately, immunity to anti-IL-6 occurred in 2 patients and was followed by a dramatic relapse. 4.2.3 Epoetin The cause of anaemia in MM is multifactorial and may be due to bone marrow infiltration, renal failure, anaemia of chronic disease, as well as increased plasma volume due to the presence of paraprotein. The anaemia usually resolves if there is a good response to treatment. However, a proportion of patients with stable disease remain anaemic and have, or develop, end-stage renal failure. Ludwig et al. (1990) gave recombinant human

High dose chemotherapy'

Conventional chemotherapy b

Monotherapy or alternative treatments •

a After a PR orCR is obtained (e.g. with VAD or similar regimen), high dose chemotherapy with melphalan or a similar regimen followed by autologous or allogeneic bone marrow transplanta tion or peripheral blood stem cell transplantation can be utilised. b For example using VAD orthe M2 protocol, with or without IFNa during induction. c For example in elderly patients, utilising MP, steroids alone or IFNa alone. d For example with IFNa alone or combined with steroids and/or IL-2.

Fig. 1. Overall approach to myeloma induction treatment. = complete response; PR = partial response; VAD = vincristine + doxorubicin + dexamethasone; M2 = vincristine + carmustine + melphalan + cyclophosphamide + prednisone; IFNa = interferon-a; MP = melphalan + prednisone/prednisolone; IL-2 = ihterleukin-2.

Abbreviations: CR

Treatment of Multiple Myeloma

epoetin to 13 anaemic patients with MM. II (85%) responded with a median increase in haemoglobin level of 2 gIL and improved quality of life. This encouraging result has prompted further evaluation and use of epoetin in myeloma. Iron stores need to be checked before embarking on treatment with recombinant human epoetin, since iron deficiency may result in lack of response. 4.3 Bisphosphonates These pyrophosphate analogues inhibit calcium release from the bone by binding to hydroxyapatite crystals and preventing bone resorption through the inhibition of the osteoclast activity by an unknown mechanism (Fleisch 1989,1991). Early studies have shown their ability to reduce serum calcium levels in patients with malignancies, and to improve bone pain in patients with MM and with metastatic disease. In a randomised study investigating the long term use of clodronic acid (clodrotlate) in MM, Delmas et aL (1982) reported a significant improvement in bone pain and reduced progression of lytic lesions in the treatment group compared with the placebo group. Similar effects, including normalisation of serum calcium, were observed using monthly pulses of parenteral clodronic acid (Merlini et al. 1990). Clodronic acid and other bisphosphonates may therefore prove useful for the long term treatment of the osteolytic lesions in MM, and for the prevention and treatment of hypercalcaemia and bone pain in MM and other malignancies.

5. Conclusions and Future Prospects A general approach to the treatment of multiple myeloma is given in figure l. Current approaches to treatment of MM are not curative, representing methods to achieve maximum disease control with available agents. To do better, we need a clearer u~derstanding of the origin of the malignant plasma cell and what sustains its survival arid proliferation. At present we do not even know if the re-

179

cruitment of myeloma cells from the stem cell compartment is a one-off event, an ongoing process or an intermittent recruitment, depending upon. the disease phase, Since high dose chemotherapy (e.g with melphalan), with or without bone marrow graft or growth factor support, can produce at least temporary clinical CR, we must better understand the mechanism required to more effectively eradicate the true stem cellsandlor modulate their growth, or the transition from stem ~lls into myeloma cells. Since myeloma cell recruitment is probably intermittent or at least partly time dependent, the modulation or inhibition ofre-recruitment of stem cells following initial cytoreductive therapy may prove to be the most crucial step in achieving long term disease control. The beneficial effect of IFNa as maintenance therapy is an encouraging step forward. It seems likely that any successful new approaches must address novel mechanisms, such as apoptosis reversal or specific types of drug resistance. Ultimately, prevention will be the most effective tactic. As yet, we know little about the exact causes of myeloma, However, associations with environmental exposures (e.g. radiation, chemicals) make prevention a reasonable long term goal.

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Correspondence and reprints: Prof. B.G.M. Durie, Department of Haematology, Charing Cross Hospital, Full\am Place Road, London W6 8RF, England.