Guidelines on the Diagnosis and Management of Multiple Myeloma

5. Initial Chemotherapy and Transplantation

Currently available options include:

• single agent melphalan or cyclophosphamide (with or without prednisolone), or combination chemotherapy regimens (containing alkylating agents) given with the aim of achieving a stable response or "plateau"

OR

• VAD and similar regimens (which include high-dose dexamethasone but do not contain alkylating agents); these are normally followed by high dose chemotherapy with stem cell rescue

The choice of initial therapy will depend on factors such as age, performance status, and whether it is planned to proceed to stem cell collection and high-dose therapy (HDT). Wherever possible patients should be treated in appropriate clinical trials.

Melphalan with or without Prednisolone

Melphalan produces an objective response or partial remission (PR), defined as a greater than 50% reduction in paraprotein levels, in approximately 50% patients when administered at a dose of 6-8 mg/m²/day with prednisolone 40-60 mg/day for 4-7 days at 4-6 week intervals (Alexanian et al, 1969; Mellstedt et al, 1977). Response is gradual and maximum response may take several months. Complete remissions are rare. Most patients reach a stable plateau phase, defined as paraprotein level stable for at least 3 months and transfusion independent with minimal symptoms. Plateau phase usually lasts 18 - 24 months before relapse. The median duration of survival is between 2 and 4 years from diagnosis in most series (Bergsagel, 1995). Continuing chemotherapy after attainment of plateau phase does not prolong remission (Belch et al, 1988).

The addition of prednisolone increased the response rate in an early randomised study (Alexanian et al, 1969), and it has been widely used in combination with melphalan. However the results of comparative trials of melphalan (M) versus melphalan / prednisolone (MP) are contradictory. In 2 MRC trials there was no benefit from the addition of standard doses of corticosteroids to oral melphalan or to the ABCM combination chemotherapy regimen (MRC, 1980; Olojohungbe et al, 1996).

Doses of melphalan in different protocols have varied between 7-12 mg/m²/day, when given for 4 days every 3-4 weeks (Myeloma Trialists Collaborative Group, 1998). Meta-analysis of trials comparing MP with combination chemotherapy concluded there was no evidence for a difference in outcome depending on melphalan dose intensity in patients receiving MP (Myeloma Trialists Collaborative Group, 1998). Absorption of oral melphalan is variable and it has been suggested that the dose be increased until there is evidence of myelosuppression (Bergsagel, 1995). However there is no evidence that this produces benefit in practice and in one trial haematological toxicity was similar in responders and non-responders (Fernberg et al, 1990).

Melphalan and MP are generally well tolerated and alopecia is rare. Mild degrees of nausea do occur. Response is gradual, which may be a disadvantage for patients with aggressive disease. A meta-analysis of published trials shows no convincing survival benefit for combination chemotherapy as compared with oral melphalan and prednisolone (Myeloma Trialists Collaborative Group, 1998).

Melphalan should be avoided in patients in whom it is planned to proceed to HDT. Toxicity to normal marrow stem cells may be cumulative and may compromise their subsequent harvest (Tricot et al, 1995(a); Demirer at al, 1996; Clark and Brammer, 1998).

Recommendations:

Cyclophosphamide with or without prednisolone

Randomised trials have shown that cyclophosphamide (C) produces results similar to those of melphalan in terms of response rate and survival (MRC, 1971; MRC, 1980). The C-weekly regimen combines weekly i-v or oral cyclophosphamide with alternate-day prednisolone for the first 6-8 weeks (Brandes and Israels, 1987). C-weekly is less myelotoxic than MP and was used in the Vth MRC trial for patients with cytopenia (MacLennan et al, 1992). There have been no randomised trials comparing C-weekly with MP; cross-trial analysis of C-weekly with melphalan in the MRC Myeloma IV and V trials suggested similar efficacy (MacLennan et al, 1992 ). There are also no data from randomised controlled trials on the effect of adding prednisolone to cyclophosphamide.

Recommendations:

Alkylator-based Combination Chemotherapy Regimens

Various combination regimens have been used in at attempt to improve the outcome obtained with simple alkylating agents. These regimens generally include cyclophosphamide and melphalan with 2 or more of the following drugs: vincristine (V), adriamycin (A), prednisolone (P) and BCNU (B).

Such combinations require intravenous delivery and more frequent hospital attendance. They are also more toxic (e.g. more myelo-suppression, vomiting, alopecia, cardiotoxicity, infection). As with melphalan alone, complex regimens which include melphalan or nitrosoureas may prejudice subsequent stem cell harvesting (Tricot et al, 1995(a); Demirer et al, 1996; Clark and Brammer 1998).

Over 20 randomised trials have been carried out comparing such regimens with melphalan or MP (see Myeloma Trialists' Collaborative Group, 1998). While many of the studies found an increased response rate as compared to MP, and a CR rate up to 10%, only 2 studies have shown a significant survival benefit. The first of these was an early SWOG study comparing VMCP/VBAP with MP (Salmon et al, 1983), a benefit not confirmed in other studies (Osterborg et al, 1989(a); Boccadoro et al, 1991). The other was the MRC Myeloma V trial, which showed a significant survival benefit for ABCM as compared to melphalan alone: median survival 32 v 24 months, p<0.0001 (MacLennan et al, 1992).

A meta-analysis of 6633 patients in 27 randomised trials comparing combination chemotherapy with MP (Myeloma Trialists' Collaborative Group, 1998) concluded that there was no survival benefit for combination chemotherapy either for patients overall or in any prognostic sub-group (Level Ia). Although this analysis did not include the MRC Myeloma V study, because this used melphalan alone rather than MP, it is unlikely that the efficacy of ABCM regimen differs significantly from that of regimens such as VMCP/VBAP (Kelly et al, 1998).

Recommendations:

VAD and related Regimens

VAD: This comprises vincristine and doxorubicin (Adriamycin^TM) given by continuous 4 day infusion together with high-dose dexamethasone (Barlogie et al, 1984). In newly diagnosed patients VAD is associated with a high response rate of 60-80% and an appreciable CR rate of between 10 and 25% (Samson et al, 1989; Alexanian et al, 1990; Abrahamson et al, 1996). Response is rapid with 90% of maximum response reached after 2 courses of treatment.

VAD does not damage stem cells making it, or a similar regimen, the treatment of choice for patients proceeding to stem cell harvest and HDT. VAD is also suitable for patients with severe renal failure as no dosage modification is required and toxicity is not increased in these patients (Aitchison et al, 1990). The disadvantages are the requirement for a central line for administration and the high incidence of steroid-related side effects. Remissions are not durable and there is no long-term survival advantage of VAD over MP or combination chemotherapy.

VAMP and C-VAMP: In these regimens high-dose dexamethasone is replaced by intravenous methyl prednisolone with a view to reducing steroid-related toxicity. C-VAMP includes weekly i-v cyclophosphamide between courses of VAMP. There have been no randomised trials comparing VAMP, C-VAMP and VAD. Overall response and CR rates appear similar (Gore et al, 1989; Raje et al, 1997). In a non-randomised study comparing VAMP and C-VAMP, C-VAMP was associated with a higher CR rate than VAMP (24% vs 8%) (Raje et al, 1997) while the CR rate with VAD has varied from 7% to 28% in different non-randomised series (Samson et al, 1989; Abrahamson et al, 1997).

Oral Idarubicin with Dexamethasone: The introduction of oral idarubicin led to the development of a regimen in which idarubicin (Zavedos^TM) is given daily for 4 days together with high-dose dexamethasone (Z-Dex). In a phase I/II study (Cook et al, 1996) 80% of newly diagnosed patients responded with a CR rate of 7%. Responses appeared to be as rapid as those observed with VAD. Stem cell harvesting was not affected by this regimen (Cook et al, 1997). There are no data on long-term outcome.

On the basis of current evidence it is not possible to make a firm recommendation for the use of Z-Dex, however the regimen appears to offer a suitable alternative to VAD as initial therapy prior to stem cell harvest and HDT. It avoids the need for a central line with associated risk of complications. A randomised trial comparing VAD and Z-Dex as induction therapy is in progress. Caution is required in patients with renal impairment.

Recommendations:

High Dose Dexamethasone (HDD)

Historical comparison of the results in treating refractory patients with dexamethasone alone or with VAD suggested that dexamethasone alone is responsible for much of the efficacy of VAD (Alexanian, Barlogie and Dixon, 1986). In a non-randomised trial, HDD alone was found to induce responses in 43% of newly diagnosed patients (Alexanian et al, 1992). Responses were rapid and the incidence of serious side effects was only 4% compared with 27% in patients receiving VAD. Responding patients were then given interferon maintenance. Follow-up was not sufficient for accurate assessment of response duration or survival although survival appeared similar to that achieved with VAD.

The advantages of HDD alone for initial therapy include simplicity, absence of myelotoxicity, suitability for use in renal failure and rapidity of response. A schedule of dexamethasone 40 mg daily for 4 days every 2 weeks until response occurs then reducing to 4 weekly is widely used.

Recommendations:

No recommendation can be made on current evidence as to specific subsequent therapy after initial dexamethasone.

High dose Therapy (HDT) with Autologous Stem Cell Transplant (ASCT)

The past decade has seen increasing use of HDT in an attempt to improve disease control and prolong survival. HDT usually comprises high-dose melphalan with or without other cytotoxic drugs or total body irradiation (TBI), and requires stem cell support with peripheral blood progenitor cells or bone marrow. It is normally given after establishing initial responsiveness to VAD based chemotherapy regimens. Peripheral blood stem cells (PBSC) are usually harvested after mobilisation with a combination of chemotherapy and growth factors.

Several phase II studies have demonstrated that HDT with ASCT is effective at differing stages of the disease (Lokhorst et al, 1999; San Miguel et al, 1999). As first line therapy it is associated with complete remission rates varying between 24-75% and a median survival of 4-5 years. The procedure is not curative since >90% of patients ultimately relapse. Procedure-related mortality is generally <5%.

Only one prospective randomised trial comparing standard therapy with a high dose approach as first line therapy for newly diagnosed stage II/III myeloma patients has so far been reported (Attal et al, 1996). Two hundred patients <60 years old were randomised between HDT with autologous bone marrow rescue and standard chemotherapy. At 5 years the event free survival (28% v 10%) and overall survival (52 v 12%; p=0.03) were significantly better for patients undergoing high dose therapy analysed on an intention-to-treat basis. However, of the 100 patients randomised to the high dose arm only 74 patients underwent this treatment. A randomised study comparing transplant in first remission with chemotherapy followed by transplant at relapse has shown no significant survival difference but an advantage in duration of first remission and quality of life for early autograft (Fermand et al, 1998).

A systematic review has concluded that the combined data favoured HDT as offering a potential survival gain but emphasised the need to continue entry into clinical trials (Johnson et al, 1998). A historical case control study of patients undergoing high-dose and standard-dose chemotherapy from the Nordic Myeloma Study group has also shown a survival advantage for HDT. Median survival was 44 months in the standard-dose group but was not yet reached in the HDT group; p=0.001 (Lenhoff et al, 2000).

The majority of centres use intravenous high dose melphalan (HDM) alone at a dose of 200mg/m². Some centres also give total body irradiation (TBI). However, available data indicate greater toxicity with TBI and no survival benefit (Lokhorst et al, 1999). Purging harvested stem cells with monoclonal antibodies and/or CD34⁺ stem cell selection does reduce marrow contamination with tumour cells. However, these approaches are expensive and there is currently no evidence to suggest that they reduce the risk of relapse (Morineau et al, 2000; Stewart et al, 2001), while the risk of infection post-transplant may be increased (Goldschmidt et al, 2000). There is also no clear evidence that planned tandem autografting confers any benefit. Interim analysis of the French Intergroupe Francophone du Myelome (IFM) 94 study comparing one with two procedures has suggested a benefit in certain subgroups of patients but no survival difference overall (Attal et al, 2000), while preliminary data from similar studies in Italy and the Netherlands indicate no survival benefit for two procedures (Tosi et al, 1999; unpublished observations). Currently there is no evidence to support the use of tandem or double transplants outside of a clinical trial. The use of HDT in patients with renal impairment is discussed elsewhere.

A cost-utility analysis comparing HDT with conventional chemotherapy in a non-randomised population-based study has been carried out by the Nordic Myeloma Study Group (Gulbrandsen et al, 2001). The intensive treatment yielded a significant increase in median survival time from 44 to 62 months, with a gain of 1.2 quality-adjusted life years (QALY). The cost per QALY gained was estimated at $27, 000. A similar study in the UK showed that HDT provided a marginal benefit of 0.7 life years with an incremental cost per life-year gained of approximately £15, 000 (Sampson et al, 2001).

Recommendations:

Allogeneic Transplantation

The role of allogeneic SCT in multiple myeloma is controversial because of high transplant related mortality (TRM) and significant relapse rates after transplantation. TRM is higher in male patients and in those transplanted late in the course of the disease (Gahrton et al, 1996).

An EBMT case control study showed that the overall survival of patients receiving an allogeneic SCT was significantly shorter than that of patients undergoing autologous SCT (Bjorkstrand et al, 1996). However more recent EBMT data show a reduction in TRM; early TRM has fallen from 38% before 1994 to 21% since (Gahrton et al, 2001). This improvement probably reflects better patient selection and earlier SCT.

Patients transplanted in first response have a 60% chance of entering CR and one-third of these patients are in persistent molecular remission with a very low risk of relapse (Corradini et al, 1999). The potential benefit of this outcome may justify the risks of allogeneic SCT in younger patients, particularly women. Patients relapsing after an allogeneic SCT have been shown to respond to donor lymphocyte infusions (DLI), while patients with persistent disease may achieve a complete remission following DLI (Lokhorst et al, 2000; MacKinnon, 2000; Salama et al, 2000; Kroger et al, 2001).

Matched unrelated SCTs (MUD) have an even higher TRM than matched sibling SCTs and cannot be recommended. They may be considered in exceptional cases and must only carried out in accredited MUD transplant centres.

Recently 'low intensity' or 'mini' allograft approaches have been developed which are associated with lower toxicity and TRM (Craddock et al, 2000; Kottaridis et al, 2000; Badros et al, 2001; McSweeney et al, 2001). Such an approach may increase the numbers of patients who are suitable for an allogeneic SCT. As yet such procedures are experimental and should only be carried out in studies in accredited transplant centres.

Recommendations: