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BMJ Clin Evid. 2006; 2006: 2403.
Published online 2006 April 1.
PMCID: PMC2907638

Myeloma (multiple)

Abstract

Introduction

Multiple myeloma is the most common primary cancer of the bones in adults, representing about 1% of all cancers diagnosed in the US in 2004, and 14% of all haematological malignancies. In the UK, multiple myeloma accounts for 1% of all new cases of cancer diagnosed each year.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatment in people with asymptomatic early stage multiple myeloma (stage I)? What are the effects of first-line treatments in people with advanced stage multiple myeloma (stages II and III)? What are the effect of salvage treatments, or supportive therapy, in people with advanced stage multiple myeloma (stages II and III)? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2004 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 71 systematic reviews, RCTs, or observational studies that met our inclusion criteria.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: allogenic transplant (non-myeloablative), autologous stem cell transplant (early or late transplantation, double or single, purging of), bisphosphonates, bone marrow stem cells, bortezomib, chemotherapy (combination, conventional dose, intermediate dose plus stem cell rescue, high-dose plus stem cell rescue), combination chemotherapy plus corticosteroids, deferred treatment (in stage I disease), early chemotherapy plus corticosteroids (in stage I disease), epoetin alpha, first-line treatments, infection prophylaxis, interferon, maintenance therapy (in advanced multiple myeloma), melphalan (normal dose, high dose before autologous stem cell transplantation, plus total body irradiation), optimum priming regimen, peripheral blood stem cells, plasmapheresis, salvage therapy regimens, single-agent chemotherapy (adding prednisolone), single-agent chemotherapy (bendamustine, melphalan, cyclophosphamide, lomustine, carmustine) with or without corticosteroid (prednisolone, dexamethasone), syngeneic transplantation, and thalidomide (and derivatives).

Key Points

Multiple myeloma is a neoplastic proliferation of plasma cells, mainly within the bone marrow, causing anaemia, renal dysfunction, infections and bone lesions. Monoclonal protein is found in serum and/or urine in 97% of people.

Early chemotherapy plus corticosteroids have not been shown to improve survival in people with asymptomatic, early stage multiple myeloma.

In people with advanced multiple myeloma, combination chemotherapy or single agent chemotherapy plus prednisolone improves survival more effectively than single agent chemotherapy alone, and adding corticosteroids to combination chemotherapy is more effective still

Adding interferon to chemotherapy increases response rates and progression free, but not overall, survival, but increases toxicity.

In people with advanced disease, bisphosphonates reduce skeletal fractures and pain, epoetin alpha may improve anaemia, prophylactic treatment with antibiotics and immunoglobulin may reduce infections, and plasmapheresis may improve renal function when added to forced diuresis plus chemotherapy.

  • However, we don't know whether any of these treatments improve survival, and they may increase adverse effects.

About this condition

Definition

Multiple myeloma is characterised by neoplastic proliferation of plasma cells, mainly contained within the bone marrow. It is a debilitating malignancy that is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukaemia. Multiple myeloma can present outside the bone marrow as solitary plasmacytoma or extramedullary plasmacytoma, however, this chapter does not currently deal with these forms. The most common symptoms of multiple myeloma are those relating to anaemia, renal dysfunction, infections, or bone lesions. Multiple myeloma is most common in people over the age of 40 years. A diagnosis of symptomatic myeloma requires the presence of monoclonal protein (M-protein) in serum, urine, or both; bone marrow clonal plasma cells (> 10%) or plasmacytoma; and related organ or tissue impairment (ROTI) (see table 1 ). Ninety seven per cent of people with multiple myeloma have a presence of M-protein in serum, urine, or both. A diagnosis of asymptomatic myeloma (also known as smouldering myeloma) requires the presence of M-protein in serum of 30 g/L or more, bone marrow clonal plasma cells of 10% or more, or both; and no ROTI or symptoms. The most common differential diagnoses of symptomatic multiple myeloma are MGUS and asymptomatic (smouldering) multiple myeloma (see table 2 ). Other less common differential diagnoses include non-secretory myeloma, solitary and extramedullary plasmacytoma, plasma cell leukaemia, primary systemic amyloidosis, and Waldenstorm's macroglobulinaemia and other non-Hodgkin's lymphoma. Durie and Salmon proposed the initial clinical staging system for multiple myeloma in 1975. People with Durie Salmon stage I disease are usually asymptomatic (see table 3 ). In addition to the World Health Organization classification, a new international staging system for multiple myeloma was recently proposed, based on clinical and laboratory data from 10 750 people with previously untreated symptomatic myeloma (see table 4 ).

Table 1
Signs of multiple myeloma related organ or tissue impairment (ROTI)
Table 2
Differential diagnoses
Table 3
Durie Salmon staging system
Table 4
New international staging system

Incidence/ Prevalence

Multiple myeloma is the most common primary cancer of the bones in adults, representing about 1% of all cancers diagnosed in the US in 2004 and 14% of all haematological malignancies.The annual incidence of multiple myeloma in the US is three or four cases per 100 000 population and prevalence is 43 cases per 100 000. In the UK, multiple myeloma accounts for 1% of all new cases of cancer diagnosed each year. In 2001, the incidence of multiple myeloma in the UK was 6.1 cases per 100 000 population.

Aetiology/ Risk factors

The exact aetiology of multiple myeloma remains unclear. Genetic and environmental factors have been associated with the occurrence of multiple myeloma. However, evidence linking the genetic or environmental factors has not been substantiated.

Prognosis

Currently, no cure is available for multiple myeloma. The recently proposed new international staging system for multiple myeloma found median survival to be 29-62 months, based on clinical and laboratory data from 10 750 people with previously untreated symptomatic myeloma (see table 4 ).

Aims of intervention

To extend survival, induce and maintain remission, to prevent or delay disease progression and reduce symptoms, with minimal adverse effects.

Outcomes

Survival, progression free survival, response rate, adverse events of treatment.

Methods

BMJ Clinical Evidence search and appraisal November 2004. The contributors also carried out their own search, with the following search strategy and selection criteria. Contributors searched the following electronic databases to identify RCTs in myeloma: Medline, Embase, Cancerlit, Lilacs, and the Cochrane Controlled Trials Register. Various combinations of search terms were used depending on the requirements of the database being searched. These terms included: "myeloma", "multiple myeloma", "plasmacytoma", "plasm?cytom*", "myeloma", "myelom*", "multiple myeloma", "plasmacytom*", "plasmocytom*", (myeloma OR mieloma), and (multiplo OR multiple)). All randomised trials which solely enrolled people with myeloma were included, but those which included people with other tumour types were excluded. Relevant references in each article were scanned and the contributors also did hand searches of abstracts from the annual meetings of the American Society of Hematology (1993-2002), American Society for Clinical Oncology (1993-20027) , and European Haematology Association (1993-2001). In addition, the contributors compared their list with a list of RCTs maintained by the Oxford Clinical Trial Service Unit. Experts in the field were approached for unpublished data in this subject area. No search limits were applied on the basis of language. For the question on first line treatment, as well as including RCTs solely in people receiving first line treatment, we have included RCTs where most people were receiving first line treatment. We have defined advanced stage multiple myeloma as Durie Salmon stages II and III disease. However, we have included studies where the population was not described using the Durie Salmon staging system if it was clear that most of the population would have equivalently advanced disease stage.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Ambuj Kumar, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, USA.

Benjamin Djulbegovic, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, USA.

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2006; 2006: 2403.
Published online 2006 April 1.

Early chemotherapy

Summary

One systematic review of three small RCTs found that early chemotherapy plus corticosteroids in people with early stage multiple myeloma reduced disease progression compared with deferred treatment. However, it found no significant difference between early and deferred treatment in response rate or survival. The RCTs included in the review are likely to have been underpowered to detect clinically important differences in survival.

Benefits

We identified one systematic review (search date 2002, 3 RCTs, 262 people with stage I disease) that compared early versus deferred treatment for early stage multiple myeloma. Early treatment in all RCTs consisted of melphalan plus prednisolone. The review found that early treatment significantly reduced myeloma progression compared with deferred treatment (2 RCTs, 212 people; AR: 9/106 [8.5%] with early treatment v 46/106 [43.4%] with deferred treatment; OR 0.16, 95% CI 0.09 to 0.29) and reduced likelihood of vertebral compressions (0/97 [0%] with early treatment v 4/91 [4.4%] with deferred treatment; OR 0.18, 95% CI 0.02 to 1.59). However, there was no significant difference between early and deferred treatment in survival or response rate (mortality: 262 people, 3 RCTs; AR: 64/131 [48.9%] with early treatment v 59/131 [45.0%] with deferred treatment; OR 1.11, 95% CI 0.67 to 1.84; response: 2 RCTs, 212 people; AR: 43/100 [43.0%] with early treatment v 31/56 [55.4%] with deferred treatment; OR 0.63, 95% CI 0.33 to 1.23).

Harms

The review found that early treatment with melphalan plus prednisolone was associated with a non-significant increase in acute leukaemia compared with deferred treatment (AR: 4/131 [3.1%] with early treatment v 1/131 [0.8%] with deferred treatment; OR 3.20, 95% CI 0.55 to 18.73). The wide confidence interval suggests that the analysis may have lacked power to detect a difference between groups.

Comment

Current consensus is that treatment should be delayed until disease progression. To achieve a difference of 10% reduction in mortality between the two regimens, 800 people would have to be enrolled in the study. However, this meta-analysis with 262 people had power of only 51%, which means that the chance that findings are false negatives is 49%.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

High dose melphalan conditioning regimen before autologous stem cell transplantation versus melphalen plus total body irradiation

Summary

One RCT found limited evidence that high dose melphalan alone (200 mg/m 2 ) increased overall survival, but not event free survival compared with high dose melphalan (140 mg/m 2 ) plus total body irradiation (8 Gy). Melphalan plus total body irradiation increased severe mucositis and the duration of neutropenia compared with melphalan alone. There was also a trend towards increased treatment related mortality with melphalan plus total body irradiation.

Benefits

We found one RCT, which compared high dose melphalan alone 200 mg/m2 versus high dose melphalan 140 mg/m2 plus total body irradiation 8 Gy as conditioning regimens for peripheral blood stem cell transplantation. All participants received three cycles of vincristine plus adriamycin plus dexamethasone before randomisation. The RCT (298 people aged 60–65 years, about 94% with stage II or III disease) found no significant difference between groups in overall response (complete or very good partial response: 60/140 [43%] with melphalan alone v 78/142 [55%] with melphalan plus irradiation; P = 0.06) or duration of event free survival (median: 20.5 months with melphalan alone v 21.0 months with melphalan plus irradiation; P = 0.6). However, overall survival at 45 months was increased with melphalan alone compared with melphalan plus total body irradiation (65.8% with melphalan alone v 45.5% with melphalan plus irradiation; P = 0.05).

Harms

Treatment related mortality was higher in the melphalan plus total body irradiation group, although this increase did not reach significance (0/142 [0%] with melphalan alone v 5/140 [3.6%] with melphalan plus irradiation; P = 0.07). Melphalan plus total body irradiation also increased the duration of neutropenia (median: 8 days with melphalan alone v 10 days with melphalan plus irradiation; P < 0.001) and the incidence of severe (grade 3 or 4) mucositis (AR: 42/142 [30%] with melphalan alone v 71/140 [51%] with melphalan plus irradiation; P < 0.001) compared with melphalan alone.

Comment

The RCT reported that the difference in survival seen may have been owing to a difference in the salvage regimens used once participants had relapsed. More participants in the melphalan alone group (about 50%) received a second round of intensive treatment than in the melphalan plus total body irradiation group (about 25%).

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Different priming regimens versus each other

Summary

One RCT found that stem cell factor plus filgrastim plus cyclophosphamide enhanced yield of CD34+ after a single leukapheresis compared with filgrastim plus cyclophosphamide. It also found that stem cell factor plus filgrastim plus cyclophosphamide increased treatment related adverse events. One RCT found that filgrastim alone reduced the time taken to collect peripheral blood progenitor cells compared with filgrastim plus cyclophosphamide, and filgrastim plus cyclophosphamide increased admission to hospital, fever, and pneumonia/sepsis compared with filgrastim alone.

Benefits

We found no systematic review, but we found two RCTs. The first RCT (102 people with newly diagnosed multiple myeloma, or chemosensitive myeloma in relapse; see comment below) found that stem cell factor (SCF) plus filgrastim plus cyclophosphamide significantly increased the proportion of people reaching the target yield of 5 x 106 CD34+ cells/kg after a single leukapheresis compared with filgrastim plus cyclophosphamide (AR: 36/55 [65%] with SCF plus filgrastim plus cyclophosphamide v 19/47 [40%] with filgrastim plus cyclophosphamide; OR 2.79, 95% CI 1.25 to 6.25). The second RCT (44 people with multiple myeloma; see comment below) found that filgrastim alone significantly reduced the duration of mobilisation phase required to collect peripheral blood progenitor cells compared with filgrastim plus cyclophosphamide (median duration: 22 days with filgrastim plus cyclophosphamide v 8 days with filgrastim alone; P = 0.0001).

Harms

The first RCT found a higher incidence of treatment related adverse events with SCF plus filgrastim plus cyclophosphamide than with filgrastim plus cyclophosphamide (80% with SCF plus filgrastim plus cyclophosphamide v 17% with filgrastim plus cyclophosphamide; significance not reported). The second RCT found that filgrastim plus cyclophosphamide significantly increased admissions to hospital (100% with filgrastim plus cyclophosphamide v 32% with filgrastim alone; P = 0.0001), fever (32% with filgrastim plus cyclophosphamide v 5% with filgrastim alone; P = 0.02), and pneumonia/sepsis (18% with filgrastim plus cyclophosphamide v 0% with filgrastim alone; P = 0.04) compared with filgrastim alone.

Comment

Both studies were RCTs but they did not have adequate allocation concealment. The second RCT had a small sample size, and neither RCT reported power analysis. The first RCT included people who had already received radiotherapy (22% with SCF plus filgrastrim plus cyclophosphamide v 28% with filgrastrim plus cyclophosphamide), or had stage I disease (2% with SCF plus filgrastrim plus cyclophosphamide v 6% with filgrastrim plus cyclophosphamide). The second RCT included people with refractory disease (14% with filgrastim alone v 32% with filgrastim plus cyclophosphamide. We found a third RCT, but it was too small to meet Clinical Evidence inclusion criteria.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Double versus single autologous transplant

Summary

One RCT found that in people who have received high dose chemotherapy, double autologous stem cell transplant increased event free and overall survival at 7 years compared with single autologous stem cell transplant.

Benefits

We found no systematic review, but found one RCT, which compared high dose chemotherapy plus double autologous stem cell transplant versus high dose chemotherapy plus single autologous stem cell transplant. The source of stem cells used (bone marrow or peripheral blood) was also determined by randomisation (see benefits of source of autologous stem cells: bone marrow versus peripheral blood stem cell). The RCT found no significant difference between single and double transplant in response (403 people aged < 60 years, 92% with stage II or III disease; AR for complete or very good partial response: 50% with double transplant v 42% with single transplant; P = 0.10). However, double transplant significantly increased event free survival (20% with double transplant v 10% with single transplant; P = 0.03) and overall survival (42% with double transplant v 21% with single transplant; P = 0.01) at 7 years compared with single transplant.

Harms

There was no significant difference between single and double transplant groups in treatment related mortality (12/200 [6%] with double transplant v 8/199 [4%] with single transplant; P = 0.40).

Comment

The RCT was of good methodological quality. In this RCT, the single transplant arm received melphalan 140 mg/m2 once before transplantation, in comparison with the double transplant arm, which received melphalan 140 mg/m2 twice overall (before each transplantation). However, one RCT (see benefits of conditioning regimen before autologous stem cell transplantation) found that melphalan 200 mg/m2 increased overall survival compared with melphalan 140 mg/m2 and total body irradiation (8 Gy), so further trials using melphalan 200 mg/m2 are needed to resolve the question of double compared with single transplant. We found three additional RCTs reported in abstract form only. Two of these RCTs found significant improvement in event free survival with double transplant, while one RCT found no significant difference between single and double transplant in response, event free survival, or overall survival in people aged under 56 years with symptomatic multiple myeloma. As these RCTs were published in abstract form only we could not fully assess study quality.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Timing of autologous stem cell transplant

Summary

One RCT found that early autologous stem cell transplantation increased event free survival compared with late autologous stem cell transplantation. It found no significant difference in overall survival.

Benefits

We found no systematic review, but found one RCT (202 people) comparing early versus late autologous stem cell transplant (peripheral blood). It found no significant difference in overall survival between early and late transplant (median: 64.4 months with early transplant v 64.0 months with late transplant; RR 1.02, 95% CI 0.67 to 1.57). It found that early transplantation increased event free survival compared with late transplantation (median: 39 months with early transplantation v 13 months with late transplantation; significance not reported).

Harms

The RCT found that treatment related mortality was similar for early and late transplantation (10% with early transplant v 14% with late transplant; significance not reported).

Comment

The RCT used adequate methods of allocation concealment, but did not perform a power analysis. The data was analysed using intention to treat, and withdrawals were described. Prolonged administration of melphalan is toxic to stem cell procurement. Therefore, long term low dose melphalan is not recommended in people considered for stem cell transplantation.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Syngeneic versus autologous stem cell transplant

Summary

We found no systematic review, RCTs, or prospective cohort studies. Two retrospective comparative case matched analyses found that syngeneic transplantation in multiple myeloma increased survival compared with autologous transplant if a twin donor was available.

Benefits

We found no systematic review or RCTs. We found one retrospective comparative case series (see comment below). The case series indirectly compared three interventions: syngeneic (twin) donor transplant (25 people, about 76% stages II and III), autologous stem cell transplant (125 people, about 83% stages II and III), and allogeneic transplant (125 people, about 85% stages II and III). Each syngeneic transplant recipient (bone marrow, 96%; peripheral blood, 4%) was matched to five autologous or allogeneic transplant recipients (source of stem cells not reported) based on previous lines of treatment, response status at transplant, and date of transplant. The case series found that progression free survival was significantly longer with twin transplant than with autologous transplant or with allogeneic transplant (median: 72 months with twin transplant v 25 months with autologous transplant v 9 months with allogeneic transplant; twin v autologous, P = 0.009; twin v allogeneic, P value reported as significant). Overall survival was longest with twin transplant (median overall survival: 73 months with twin transplant v 44 months with autologous transplant v 16 months with allogeneic transplant; twin v autologous, P = 0.10; twin v allogeneic, P = 0.008).

Harms

In the case series, 8% of twin transplant recipients and about 40% of allogeneic transplant recipients died from treatment related toxicity (no further data reported). The incidence of treatment related mortality in the autologous transplant group was not reported.

Comment

While the case serues did attempt to match groups for known prognostic indicators, it is likely that the groups were not balanced for other confounding factors. There were more male participants in the autologous transplant group (75%) than in the syngeneic (twin) transplant or allogeneic transplant groups (48% in both groups; P value not reported).

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Autologous stem cell transplant versus allogeneic transplant

Summary

We found no systematic review, RCTs, or prospective cohort studies. Two retrospective comparative case matched analyses found that autologous stem cell transplantation increased survival compared with allogeneic bone marrow transplant. Treatment related toxicity was higher with allogeneic bone marrow transplant than with autologous stem cell transplantation. These are best available data to date.

Benefits

We found no systematic reviews or RCT. We found two retrospective comparative case series (see comment below). The first case series indirectly compared three interventions: syngeneic (twin) donor transplant (25 people, about 76% stages II and III), autologous stem cell transplant (125 people, about 83% stages II and III), and allogeneic transplant (125 people, about 85% stages II and III). Each syngeneic transplant recipient (bone marrow, 96%; peripheral blood, 4%) was matched to five autologous or allogeneic transplant recipients (source of stem cells not reported) based on previous lines of treatment, response status at transplant, and date of transplant. The case series found that progression free survival was longer with autologous transplant than with allogeneic transplant (median: 25 months with autologous transplant v 9 months with allogeneic transplant). Overall survival was longer with autologous transplant than with allogeneic transplant (median overall survival: 44 months with autologous transplant, 16 months with allogeneic transplant). The case series did not provide statistical comparisons of autologous and allogeneic transplant. The second case series compared allogeneic donor bone marrow transplant (189 people, median age 43 years, 85% stages II and III) versus autologous stem cell transplant (peripheral blood, 50%; bone marrow, 50%). Each allogeneic transplant recipient was matched to a concurrent autologous transplant recipient according to gender and previous lines of treatment. The study found that autologous transplant increased overall survival compared with allogeneic transplant (189 people, median age 49 years, 87% stage II and III: 34 months with autologous transplant v 18 months with allogeneic transplant; P = 0.001).

Harms

In the first study, 8% of twin transplant recipients and about 40% of allogeneic transplant recipients died from treatment related toxicity (no further data reported). The incidence of treatment related mortality in the autologous transplant group was not reported. In the second study, allogeneic bone marrow transplant was associated with a significantly higher treatment related mortality than autologous stem cell transplant (41% with allogeneic transplant v 13% with autologous transplant; P = 0.0001).

Comment

While the case series did attempt to match groups for known prognostic indicators, it is likely that the groups were not balanced for other confounding factors. In the first case series, there were more male participants in the autologous transplant group (75%) than in the twin transplant or allogeneic transplant groups (48% in both groups; P value not reported). In the second series, there were significant differences between groups in median age of participants (43 years with allogeneic transplant v 49 years with autologous transplant; P = 0.0001). Both studies included people who had received previous treatment (i.e. the transplant was not a first line treatment). About 68% of participants in the first study had one or no prior treatments, while all participants in the second study had at least one prior treatment. Matched concurrent controls would be subject to selection bias, as the groups may not be well matched according to important prognostic factors. However, selection bias would be expected to favour allogeneic transplant which was found to be inferior in these studies.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Peripheral blood stem cells (versus bone marrow stem cells)

Summary

One RCT found no significant difference between autologous peripheral blood stem cells and bone marrow transplant in response, event free survival, or overall survival. However, it found that peripheral blood stem cell transplant reduced the duration of neutropenia and thrombocytopenia compared with bone marrow transplant.

Benefits

We found one RCT, which randomised 344 participants with good performance status and normal respiratory function after initial high dose chemotherapy to either bone marrow or peripheral blood stem cell (PBSC) autologous transplant. Participants had previously been randomised to either single or double transplant (see benefits of double versus single autologous transplant). The RCT found no significant difference between bone marrow and PBSC in response (no further data reported), event free survival at 6 years (21% with bone marrow v 26% with PBSC; P reported as not significant), or overall survival at 6 years (37% with bone marrow v 50% with PBSC; P = 0.07).

Harms

The RCT found that PBSC reduced the mean duration of neutropenia (12 days with bone marrow v 10 days with PBSC; P = 0.001) and thrombocytopenia (21 days with bone marrow v 12 days with PBSC; P = 0.001) compared with bone marrow.

Comment

Although the sample size was relatively large, it was not clear whether a power analysis was undertaken for this comparison.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Non-myeloablative allogeneic stem cell transplant (reduced intensity conditioning, mini-transplant)

Summary

One non-randomised study with historical control found no significant difference in overall survival between non-myeloablative transplant and conventional allogeneic bone marrow transplant, but low treatment related mortality with mini-transplants. These are best available data to date.

Benefits

We found one systematic review (search date 2002), which found no RCTs, but found one comparative case series with a historical control group. The study compared non-myeloablative allogeneic stem cell (peripheral blood) transplant (31 people not eligible for conventional allogeneic bone marrow transplant, 97% with previous autologous transplant) versus conventional allogeneic bone marrow transplant (93 people). It found that overall survival at 1 year was greater with non-myeloablative transplant group than with conventional allogeneic transplant, but this difference did not reach significance (71% with non-myeloablative transplant v 45% with conventional allogeneic transplant; P = 0.09).

Harms

The study found that transplant related mortality was significantly greater with conventional allogeneic transplant than with non-myeloablative transplant (3/31 [10%] with non-myeloablative transplant v 27/93 [29%] with conventional allogeneic transplant; P = 0.03).

Comment

The study was non-randomised, therefore the groups are more likely to have been unbalanced with regards to prognostic and confounding factors, and results should be interpreted with caution. Compared with the conventional allogeneic transplant group, the non-myeloablative transplant group was found to have a significantly greater median age (56 years with non-myeloablative transplant group v 46 years with conventional allogeneic transplant group; P < 0.0001), more people with chromosomal abnormalities (97% with non-myeloablative transplant group v 62% with conventional allogeneic transplant group; P = 0.0003), and fewer people with less than two previous autologous transplants (45% with non-myeloablative transplant group v 78% with conventional allogeneic transplant group; P = 0.001). The study did not report on how it selected its historical control group, and this selection process may have been subject to bias. Use of a non-contemporaneous control group introduces greater risk of confounding. However, selection bias would be expected to favour conventional allogeneic transplant, which was associated with increased transplant related mortality despite the fact that were more younger participants in this treatment group. We found one case series (registry data from European Group for Blood and Marrow Transplantation [EBMT]), which reported that non-myeloablative allogeneic transplant is feasible but may not benefit many people with multiple myeloma.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Purging of autologous stem cells

Summary

One RCT found that purging autologous stem cells reduced myeloma cell contamination in peripheral blood cell collection. However, it found no significant difference in survival between selected and unselected cell autograft.

Benefits

We found no systematic review, but we found one RCT (190 people) comparing selected autograft of CD34 enriched versus unselected peripheral blood progenitor cells. It found that CD34 selection increased the proportion of people receiving an autograft with no detectable tumour cells compared with unselected autograft (54% with selected v 21% with unselected; P = 0.036). However, the RCT found no significant difference in overall survival at 37 months (36% with selected v 35% with unselected; P = 0.784) and disease free survival (median: 100 weeks with selected v 104 weeks with unselected; P = 0.82).

Harms

The RCT found no significant difference in neutrophil or platelet engraftment, and infection rates at 1 year between selected and unselected autografts (data not reported).

Comment

The trial was randomised, but it is not clear if the allocation concealment was adequate. The RCT included people with stable or responsive disease after a minimum of three cycles of standard dose chemotherapy.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

High dose chemotherapy plus stem cell rescue versus conventional dose chemotherapy

Summary

Two RCTs, which randomised participants at diagnosis, found that high dose chemotherapy plus stem cell rescue increased progression free survival and overall survival compared with conventional dose chemotherapy. One RCT, which randomised participants only if they responded to initial chemotherapy, found that high dose chemotherapy plus stem cell rescue increased complete remission rate compared with conventional dose chemotherapy. It found no significant difference in progression free survival and similar overall survival between groups. Two further RCTs were published in abstract form only, so we could not assess study quality fully.

Benefits

We found one systematic review, and two subsequent RCTs that compared high dose chemotherapy plus stem cell rescue versus conventional chemotherapy. The participants were randomised at diagnosis or after initial chemotherapy (see comments below). The systematic review (search date 2000) identified one fully published RCT (see comments below). The RCT (200 people aged < 65 years old and with stage II or III multiple myeloma) found that high dose chemotherapy plus autologous bone marrow transplantation significantly increased overall response (complete or partial overall response: 81% with high dose chemotherapy v 57% with conventional chemotherapy; P = 0.001), 5 year event free survival (28% with high dose chemotherapy v 10% with conventional chemotherapy; P = 0.01), and 5 year overall survival (52% with high dose chemotherapy v 12% with conventional chemotherapy; P = 0.03) compared with conventional chemotherapy. The first subsequent RCT (401 people aged < 65 years old with advanced stage disease) found that high dose chemotherapy plus stem cell rescue (peripheral blood stem cell, 92%; bone marrow, 8%; both, 3%) increased progression free survival (median: 31.6 months with high dose chemotherapy v 19.6 months with conventional chemotherapy; log rank P < 0.001) and overall survival (median: 54.1 months with high dose chemotherapy v 42.3 months with conventional chemotherapy; log rank P = 0.04) compared with conventional dose chemotherapy). This RCT conducted a pooled analysis of its results and those of the two RCTs identified by the review. It found that high dose chemotherapy plus stem cell rescue increased overall survival compared with conventional chemotherapy (OR for mortality 0.70, 95% CI 0.53 to 0.93). The second subsequent RCT compared high dose chemotherapy plus stem cell (peripheral blood) rescue (HDT) versus conventional chemotherapy (164 people). It found that HDT significantly increased complete remission compared with conventional chemotherapy (30% with HDT v 11% with conventional chemotherapy; P = 0.002). However, it found no significant difference in progression free survival and similar overall survival between HDT and conventional therapy (median progression free survival: 42 months with HDT v 33 months with conventional chemotherapy; P value not significant; median overall survival: 61 months with HDT v 66 months with conventional chemotherapy; significance not reported).

Harms

In the RCT identified by the review, treatment related mortality was slightly increased in the high dose chemotherapy group than in the conventional chemotherapy group (7% with high dose chemotherapy v 5% with conventional chemotherapy; significance not reported). The first subsequent RCT found similar rates of infection related mortality (35/201 [17.4%] with high dose chemotherapy v 33/200 [16.5%] with conventional chemotherapy) and early deaths (death within 60 days of randomisation: 9/201 [4.5%] with high dose chemotherapy v 8/200 [4.0%] with conventional chemotherapy; significance not reported). The second subsequent RCT found similar treatment related mortality with HDT and conventional chemotherapy (3/81 [3.7%] with HDT v 3/83 [3.6%] with conventional chemotherapy; P value not reported).

Comment

All three RCTs were well designed. Allocation concealment was adequate and the analysis was undertaken according to the intention to treat principle and a power analysis was undertaken before the beginning of the trials in the first two RCTs. The third RCT did not report details regarding allocation concealment or power analysis, but intention to treat analysis was performed. The first two RCTs randomised participants regardless of initial treatment response, whereas the third RCT only randomised people who responded to initial chemotherapy. The review identified one RCT published in abstract form only, which found no significant difference between high dose chemotherapy plus transplantation (bone marrow) and conventional chemotherapy in event free or overall survival in people aged 55–65 years old with symptomatic multiple myeloma. We identified one subsequent RCT, which found no significant difference between high dose chemotherapy plus total body irradiation plus transplantation (peripheral blood stem cells) and conventional chemotherapy in overall survival or event free survival, although there was a trend towards increased event free survival with high dose chemotherapy. As this RCT was published in abstract form only we could not fully assess study quality.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Intermediate dose chemotherapy and stem cell rescue

Summary

One RCT found that in people aged 50–70 years old, intermediate dose melphalan plus stem cell rescue improved response rate, event free survival, and overall survival compared with conventional dose chemotherapy. One RCT found that intermediate dose chemotherapy plus myeloablative therapy plus autologous stem cell rescue increased complete remission compared with intermediate dose chemotherapy alone, but it found no significant difference in survival.

Benefits

Intermediate dose chemotherapy plus stem cell rescue versus conventional chemotherapy:

We found no systematic review, but we found one RCT (194 people aged 50–70 years, with stage II or III disease), which compared intermediate dose therapy (2 courses of melphalan 100 mg/m2 ) plus stem cell support (peripheral blood) versus conventional chemotherapy (6 courses of oral melphalan 6 mg/m2 and prednisone). Intermediate dose melphalan plus stem cell rescue increased event free survival (AR: 37% with high dose chemotherapy v 16% with conventional chemotherapy; P < 0.0001) and overall survival (77% with high dose chemotherapy v 62% with conventional chemotherapy; P = 0.0005) at 3 years compared with conventional dose chemotherapy.

Intermediate dose chemotherapy plus stem cell rescue versus intermediate dose chemotherapy alone:

We found one RCT (261 people aged < 66 years with stage II or III myeloma), which compared intermediate dose chemotherapy (2 courses of melphalan at 70 mg/m2 ) plus myeloablative therapy (4 courses of cyclophosphamide 15 mg/kg) plus autologous stem cell rescue (peripheral blood) versus intermediate dose chemotherapy alone (2 courses of melphalan 70 mg/m2 ). It found that intermediate dose chemotherapy plus myeloablative therapy plus autologous stem cell rescue significantly increased complete remission compared with intermediate dose chemotherapy alone (AR: 29% with myeloablative therapy v 13% with intermediate dose chemotherapy alone; P = 0.002). It found no significant difference in overall survival (median: 47 months with myeloablative therapy v 50 months with intermediate dose chemotherapy alone; P = 0.41) and event free survival (22 months with myeloablative therapy v 21 months with intermediate dose chemotherapy alone; P = 0.28).

Harms

Intermediate dose chemotherapy plus stem cell rescue versus conventional chemotherapy:

The RCT reported that severe haematological toxicity was significantly shorter with conventional dose chemotherapy than with intermediate dose chemotherapy (with intermediate dose chemotherapy median duration of severe neutropenia 5 days, severe thrombocytopenia 3 days; no data presented for conventional dose chemotherapy; P reported as significant). The proportion of people with at least one organ toxicity was higher with intermediate dose chemotherapy than with conventional dose chemotherapy (AR: 30% with intermediate dose chemotherapy v 8% with conventional dose chemotherapy; significance not reported). Fever of unknown origin (AR: 31% with intermediate dose chemotherapy v 0% with conventional dose chemotherapy) and mucositis (AR: 23% with intermediate dose chemotherapy v 0% with conventional dose chemotherapy; P value for both comparisons reported as significant) were significantly more common with intermediate dose chemotherapy.

Intermediate dose chemotherapy plus stem cell rescue versus intermediate dose chemotherapy alone:

The RCT found that intermediate dose chemotherapy plus myeloablative therapy plus autologous stem cell rescue increased grade 3 or 4 non-haematological toxicity (45% with myeloablative therapy v 9% with first cycle of intermediate dose therapy alone v 5% with second cycle of intermediate dose therapy alone) and treatment related mortality (3.9% with myeloablative therapy v 0.8% with first cycle of intermediate dose therapy alone v 5% with second cycle of intermediate dose therapy alone; significance not reported) compared with intermediate dose chemotherapy alone.

Comment

Intermediate dose chemotherapy plus stem cell rescue versus conventional chemotherapy:

The RCT was well designed with adequate allocation concealment. Analysis was undertaken according to the intention to treat principle and a power analysis was undertaken before the beginning of the RCT. Post hoc subgroup analysis suggested that people aged over 65 years derived similar benefit from intermediate dose chemotherapy to that seen overall.

Intermediate dose chemotherapy plus stem cell rescue versus intermediate dose chemotherapy alone:

The RCT performed intention to treat analysis, but it was not clear if allocation concealment was adequate.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Adding interferon to chemotherapy

Summary

One systematic review and two subsequent RCTs found that adding interferon to chemotherapy in induction or maintenance phase increased response and progression free survival, although they found no significant difference in overall survival. The review and RCTs found that interferon increased toxicity.

Benefits

Interferon in induction phase:

We found one systematic review and one subsequent RCT. The review (search date 1997, 10 RCTs, 1323 people) found that interferon plus chemotherapy significantly improved response rates (AR at 3 years: 30% with interferon v 25% with no interferon; P = 0.0005) and progression free survival (AR for progression: 65.8% with interferon v 69.0% with no interferon; P = 0.0003) compared with chemotherapy alone. It found no significant difference in overall survival (AR for death: 66.3% with interferon v 68.9% with no interferon; P = 0.1). The subsequent RCT (485 people; 42% stages I and II, 58% stage III) found that interferon plus chemotherapy significantly increased complete response (AR: 18% with interferon v 10% with no interferon; P = 0.03) compared with chemotherapy alone. It found no significant difference in overall survival (figures displayed graphically; log rank P = 0.714).

Interferon in maintenance phase:

We found one systematic review and one subsequent RCT. The review (search date 1997, 1543 people; 12 RCTs) found that interferon improved progression free survival (AR: 71.6% with interferon v 81.8% with no interferon; P < 0.00001) and overall survival (AR for death: 62.6% with interferon v 66.9% with no interferon; P = 0.04) compared with no interferon. The subsequent RCT (81 people; 90% stages II and III) found no significant difference in duration of response (median: 1.5 years with interferon v 0.7 years with no interferon; P = 0.206) and survival (median: 4.1 years with interferon v 3.7 years with no interferon; P = 0.969) between interferon and no interferon.

Harms

Interferon in induction phase:

The systematic review did not report adverse events. The subsequent RCT found that interferon plus chemotherapy increased central nervous system toxicities compared with chemotherapy alone (26% with interferon v 10% with no interferon; significance not reported).

Interferon in maintenance phase:

The systematic review did not report adverse events. The subsequent RCT found that 5% of people on interferon had grade 3 or higher toxicities. The RCT did not report on adverse effects in the no therapy group.

Comment

In the systematic review, there was heterogeneity between study designs. In the two subsequent RCTs, the method of allocation concealment was unclear, and analysis was not intention to treat.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Thalidomide and thalidomide derivatives

Summary

We found no systematic review or RCTs of thalidomide or its derivatives, published as a full paper, for the first line treatment of advanced stage multiple myeloma.

Benefits

We found no systematic review or RCTs of thalidomide or its derivatives, published as a full paper, for first line treatment of advanced stage multiple myeloma.

Harms

We found no RCTs.

Comment

We found one RCT, which was published in abstract form, so we could not fully assess study quality. It found that thalidomide plus dexamethasone increased response rate compared with dexamethasone alone. The abstract did not report on survival, disease free survival, or quality of life. The RCT found a greater frequency of grade 3 or greater haematological toxicities with thalidomide plus dexamethasone compared with dexamethasone alone. Several RCTs are underway testing the feasibility of using thalidomide to treat multiple myeloma. (Kumar A, Djulbegovic B, personal communication, 2005).

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Bortezomib

Summary

We found no systematic review or RCTs of bortezomib as first line treatment for multiple myeloma.

Benefits

We found no systematic review or RCTs of bortezomib as first line treatment for multiple myeloma.

Harms

We found no RCTs.

Comment

There are ongoing trials of bortezomib for first line treatment of multiple myeloma (Kumar A, Djulbegovic B, personal communication, 2005).

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Single agent chemotherapy

Summary

We found no systematic review comparing chemotherapy versus placebo solely in people with multiple myeloma who had not received previous treatment, although we found two RCTs in people who had received previous treatment. There is consensus that chemotherapy is beneficial for the treatment of multiple myeloma.

Benefits

Chemotherapy versus placebo:

We found no systematic review or RCTs comparing chemotherapy versus placebo solely in people who had not received any previous treatment (see comment below).

Melphalan versus cyclophosphamide:

We identified no systematic review, but found two RCTs comparing melphalan versus cyclophosphamide. The first RCT found no significant difference in median survival between groups (130 people with advanced stage disease, see comment below: 15.5 months with melphalan v 13 months with cyclophosphamide; P = 0.65). Overall response, in people who completed the 6 week treatment period, was similar in both groups (AR for response: 15/54 [27.8%] with melphalan v 14/49 [28.6%] with cyclophosphamide; significance not reported; see comment below). The second RCT (276 people with advanced stage disease) found no significant difference in survival between cyclophosphamide and melphalan (median survival: 18 months in both groups; P reported as not significant).

Melphalan versus lomustine or carmustine:

We identified no systematic review, but found one RCT, which randomised people to three initial single treatments: melphalan, lomustine, or carmustine (see comment below). It found no significant difference in median survival according to initial treatment (361 people; 94.2% stages II and III; 27.0 months with melphalan v 21.3 months with lomustine v 20.9 months with carmustine; P reported as not significant). However, melphalan significantly increased overall response compared with lomustine or carmustine (59/100 [59%] with melphalan v 57/136 [42%] with lomustine v 50/124 [40%] with carmustine; P = 0.001 for comparisons v melphalan; lomustine v carmustine reported as not significant).

Single agent chemotherapy versus combination chemotherapy:

See benefits of combination chemotherapy

Single agent chemotherapy versus single agent chemotherapy plus corticosteroids:

See benefits of single agent chemotherapy plus corticosteroids.

Single agent chemotherapy versus combination chemotherapy plus corticosteroids:

See benefits of combination chemotherapy plus corticosteroids.

Harms

Chemotherapy versus placebo:

See other subheadings in this section for harms of chemotherapy.

Melphalan versus cyclophosphamide:

The first RCT found a higher incidence of thrombocytopenia and haemorrhage with melphalan than with cyclophosphamide (thrombocytopenia: 31 cases with melphalan v 18 cases with cyclophosphamide; thrombocytopenia with haemorrhage: 5 cases with melphalan v 0 cases with cyclophosphamide; P = 0.04 for both comparisons). There was no significant difference in overall toxicity between groups (71 cases with melphalan v 63 cases with cyclophosphamide; P reported as not significant). In second RCT there were five treatment related deaths in the melphalan arm. Treatment related deaths in the cyclophosphamide group were not reported.

Melphalan versus lomustine or carmustine:

The RCT found that severe thrombocytopenia was more common with lomustine than with carmustine or melphalan, but this difference was not significant (11% with lomustine v 7% with carmustine v 7% with melphalan; P reported as not significant). There was one treatment related death with carmustine and one treatment related death with lomustine, both were owing to infections after leukopenia.

Single agent chemotherapy versus combination chemotherapy:

See harms of combination chemotherapy.

Single agent chemotherapy versus single agent chemotherapy plus corticosteroids:

See harms of single agent chemotherapy plus corticosteroids.

Single agent chemotherapy versus combination chemotherapy plus corticosteroids:

See harms of combination chemotherapy plus corticosteroids.

Comment

Chemotherapy versus placebo:

We found two studies published in the 1960s that compared chemotherapy versus placebo. The first RCT (83 people) compared urethane versus placebo; most people in this trial (64%) had already received treatment. In subgroup analysis of people who had received no prior treatment, survival was shorter with urethane than with placebo (median survival: 5 months with urethane v 12 months with placebo; significance not reported). The second study (60 people) compared cyclophosphamide versus placebo, but it was unclear whether participants were randomised, and how many people had received prior treatment. It found that cyclophosphamide significantly increased median survival compared with placebo (49 weeks with cyclophosphamide v 15 weeks with placebo; P = 0.03). The methodological quality of these studies was unclear as few details were reported. Current consensus is that chemotherapy is beneficial as a first line treatment for people with multiple myeloma, and it is unlikely that further placebo controlled RCTs will be conducted.

Melphalan versus cyclophosphamide:

The first RCT included people with extramedullary plasmacytomas and people who had received prior treatment, but it was unclear what proportion of participants had these characteristics. Fourteen people (10.8%) were excluded from the survival analysis in the first RCT because of protocol violations or not meeting trial inclusion criteria, and 33 people (25%) were excluded from the analysis of overall response because they did not complete a full 6 weeks of treatment, in most cases this was because the person died. Neither of the studies reported intention to treat analyses or undertook power analysis before the beginning of the trial.

Melphalan versus lomustine or carmustine:

In week 22 of this RCT, people in each group were randomised to continued single agent chemotherapy or to added vincristine plus prednisolone. Adding vincristine plus prednisolone was found to not affect response or survival, therefore results were pooled based on which initial treatment was received, regardless of whether vincristine was received subsequently. It was unclear if the study had adequate allocation concealment. Although the study described withdrawals it was not clear if the study was analysed according to intention to treat principle.

Single agent chemotherapy versus combination chemotherapy:

See comments of combination chemotherapy.

Single agent chemotherapy versus single agent chemotherapy plus prednisolone:

See comments of single agent chemotherapy plus corticosteroids.

Single agent chemotherapy versus combination chemotherapy plus prednisolone:

See comments of combination chemotherapy plus corticosteroids.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Single agent chemotherapies compared with each other

Summary

Two RCTs found no significant difference between cyclophosphamide and melphalan in survival. One RCT provided limited evidence that melphalan increased overall response but not survival compared with lomustine or carmustine.

Benefits

Melphalan versus cyclophosphamide:

We identified no systematic review, but found two RCTs comparing melphalan versus cyclophosphamide. The first RCT found no significant difference in median survival between groups (130 people with advanced stage disease, see comment below: 15.5 months with melphalan v 13 months with cyclophosphamide; P = 0.65). Overall response, in people who completed the 6 week treatment period, was similar in both groups (AR for response: 15/54 [27.8%] with melphalan v 14/49 [28.6%] with cyclophosphamide; significance not reported; see comment below). The second RCT (276 people with advanced stage disease) found no significant difference in survival between cyclophosphamide and melphalan (median survival: 18 months in both groups; P reported as not significant).

Melphalan versus lomustine or carmustine:

We identified no systematic review, but found one RCT, which randomised people to three initial single treatments: melphalan, lomustine, or carmustine (see comment below). It found no significant difference in median survival according to initial treatment (361 people; 94.2% stages II and III; 27.0 months with melphalan v 21.3 months with lomustine v 20.9 months with carmustine; P reported as not significant). However, melphalan significantly increased overall response compared with lomustine or carmustine (59/100 [59%] with melphalan v 57/136 [42%] with lomustine v 50/124 [40%] with carmustine; P = 0.001 for comparisons v melphalan; lomustine v carmustine reported as not significant).

Harms

Melphalan versus cyclophosphamide:

The first RCT found a higher incidence of thrombocytopenia and haemorrhage with melphalan than with cyclophosphamide (thrombocytopenia: 31 cases with melphalan v 18 cases with cyclophosphamide; thrombocytopenia with haemorrhage: 5 cases with melphalan v 0 cases with cyclophosphamide; P = 0.04 for both comparisons). There was no significant difference in overall toxicity between groups (71 cases with melphalan v 63 cases with cyclophosphamide; P reported as not significant). In second RCT there were five treatment related deaths in the melphalan arm. Treatment related deaths in the cyclophosphamide group were not reported.

Melphalan versus lomustine or carmustine:

The RCT found that severe thrombocytopenia was more common with lomustine than with carmustine or melphalan, but this difference was not significant (11% with lomustine v 7% with carmustine v 7% with melphalan; P reported as not significant). There was one treatment related death with carmustine and one treatment related death with lomustine, both were owing to infections after leukopenia.

Comment

Melphalan versus cyclophosphamide:

The first RCT included people with extramedullary plasmacytomas and people who had received prior treatment, but it was unclear what proportion of participants had these characteristics. Fourteen people (10.8%) were excluded from the survival analysis in the first RCT because of protocol violations or not meeting trial inclusion criteria, and 33 people (25%) were excluded from the analysis of overall response because they did not complete a full 6 weeks of treatment, in most cases this was because the person died. Neither of the studies reported intention to treat analyses or undertook power analysis before the beginning of the trial.

Melphalan versus lomustine or carmustine:

In week 22 of this RCT, people in each group were randomised to continued single agent chemotherapy or to added vincristine plus prednisolone. Adding vincristine plus prednisolone was found to not affect response or survival, therefore results were pooled based on which initial treatment was received, regardless of whether vincristine was received subsequently. It was unclear if the study had adequate allocation concealment. Although the study described withdrawals it was not clear if the study was analysed according to intention to treat principle.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Combination chemotherapy

Summary

One RCT found that combination chemotherapy (adriamycin plus carmustine plus cyclophosphamide plus melphalan) increased survival compared with melphalan.

Benefits

Combination chemotherapy versus melphalan:

We identified no systematic review, but found one RCT, which compared melphalan alone versus combination chemotherapy (adriamycin plus carmustine plus cyclophosphamide plus melphalan). It found that combination chemotherapy significantly increased survival compared with melphalan alone (644 people; 91% with Durie Salmon stage II or III disease; median survival: 32 months with combination chemotherapy v 24 months with melphalan alone; log rank P = 0.0003). Overall response was similar in both groups (192/314 [61%] with combination chemotherapy v 186/316 [59%] with melphalan alone; significance not reported).

Harms

Combination chemotherapy versus melphalan:

The RCT found no significant difference between combination chemotherapy and melphalan alone in the proportion of people withdrawing from assigned treatment owing to myelotoxicity (19% with combination chemotherapy v 22% with melphalan alone; P = 0.35).

Comment

Combination chemotherapy versus melphalan:

The RCT had adequate allocation concealment, and it described withdrawals, but it was unclear if analysis was intention to treat.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Single agent chemotherapy plus corticosteroids versus single agent chemotherapy alone

Summary

One RCT found that adding prednisolone to melphalan increased survival compared with melphalan alone. Another RCT found that in people with favourable prognostic features adding prednisolone to melphalan increased median survival compared with melphalan. However, it found that in people with poor prognostic features adding prednisolone to melphalan reduced median survival and increased severe and fatal infections compared with melphalan alone, although the significance of these findings was unclear. A third RCT found no significant difference in survival between melphalan plus prednisolone and cyclophosphamide.

Benefits

Melphalan plus prednisolone versus melphalan alone:

We found no systematic review, but found two RCTs. The first RCT compared four treatments: daily melphalan alone, intermittent melphalan alone (183 people; 4 days every 6 weeks), intermittent melphalan plus alternate day prednisolone (1.0 mg/kg/day on 3 alternate weekdays), and intermittent melphalan plus concurrent prednisolone (2.0 mg/kg/day for 4 days every 6 weeks). The RCT pooled results for the melphalan alone groups (daily or intermittent dosing) and the melphalan plus prednisolone (alternate day and concurrent) groups. It found that adding prednisolone to melphalan significantly increased median survival (24 months in melphalan plus prednisolone groups v 18 months in melphalan alone groups; P < 0.05). The second RCT classified participants as “poor risk” (75 people with poor prognostic features) or “good risk” (114 people with favourable prognostic indicators), and randomised within these risk strata. The RCT compared three treatments: melphalan alone, melphalan plus prednisolone, and melphalan plus prednisolone plus testosterone. The RCT found that, in good risk participants, melphalan plus prednisolone significantly increase response (AR: 23/42 [55%] with melphalan plus prednisolone v 8/35 [23%] with melphalan alone; P < 0.01) and median survival (53 months with melphalan plus prednisolone v 30 months with melphalan alone; P reported as significant). It found that in poor risk people, adding prednisolone to melphalan did not significantly increase response (AR: 9/29 [31%] with melphalan plus prednisolone v 7/24 [28%] with melphalan alone; P reported as not significant), although the significance of this reduction was not reported, and reduced median survival (9 months with melphalan plus prednisolone v 21 months with melphalan alone; significance not reported).

Melphalan plus prednisolone versus cyclophosphamide:

We found one RCT (485 people with confirmed myeloma), which stratified and randomised people to two treatment regimens according to blood urea levels: less than 10 mmol/l (not azotaemic) – melphalan plus prednisolone versus cyclophosphamide; or 10 mmol/l or higher (azotaemic) – cyclophosphamide plus melphalan plus prednisolone plus lomustine versus cyclophosphamide. In people without azotaemia, the RCT found no significant difference in survival between melphalan plus prednisolone and cyclophosphamide (mortality: 94/179 [53%] with melphalan plus prednisolone v 105/174 [60%] with cyclophosphamide; OR 0.73, 95% CI 0.48 to 1.11).

Melphalan plus prednisolone versus combination chemotherapy plus prednisolone:

See benefits of combination chemotherapy plus corticosteroids.

Harms

Melphalan plus prednisolone versus melphalan alone:

The first RCT reported a higher incidence of serious infection with melphalan plus alternate day prednisolone than with melphalan alone or melphalan plus concurrent prednisolone, but the significance of this difference was not reported (AR: 5/35 [14.3%] with daily melphalan alone v 11/69 [15.9%] with intermittent melphalan alone v 7/28 [25.0%] with intermittent melphalan plus low dose prednisolone v 5/51 [9.8%] with intermittent melphalan plus high dose prednisolone; significance not reported). Ninety per cent of people in the melphalan plus alternate day prednisolone group had Cushingoid changes, and three (10.7%) people withdrew because of serious steroid toxicity. In the melphalan plus concurrent prednisolone group some people experienced transient facial flushing and fullness (figures not reported), and one person (2.0%) experienced serious steroid toxicity. The second RCT found, in the good risk population, a similar incidence of severe or fatal septicaemia (2% with melphalan plus prednisolone v 3% with melphalan alone) and lung infections (7% with melphalan plus prednisolone v 9% with melphalan alone) with both treatments, and it found a higher incidence of urinary tract infection with melphalan alone (0% with melphalan plus prednisolone v 3% with melphalan alone; significance of comparisons not reported). The second RCT found, in the poor risk population, more severe or fatal cases of septicaemia (7% with melphalan plus prednisolone v 0% with melphalan alone) and urinary tract infection (14% with melphalan plus prednisolone v 0% with melphalan alone; significance not reported) with melphalan plus prednisolone than with melphalan alone.

Melphalan plus prednisolone versus cyclophosphamide:

The RCT did not report on harms.

Melphalan plus prednisolone versus combination chemotherapy plus prednisolone:

See harms of combination chemotherapy plus corticosteroids.

Comment

Melphalan plus prednisolone versus melphalan alone:

It is not clear if the analysis in the RCTs was undertaken according to the intention to treat principle. Although the difference between melphalan and melphalan plus prednisolone is reported as not significant in the poor risk category of the second RCT, it is not clear if a power analysis was undertaken, and therefore it is not clear if this result could be owing to a lack of power. The contradictory results for good and poor risk populations might be an artefact attributable to the small sample size, which increases the risk of false positive findings by chance.

Melphalan plus prednisolone versus cyclophosphamide:

The RCT did not report power analysis.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Different single agent chemotherapy plus corticosteroids regimens versus each other

Summary

One RCT found that bendamustine plus prednisolone increased complete response and progression free survival compared with melphalan plus prednisolone. Median overall survival was similar in both groups. Another RCT found no significant difference in survival between melphalan plus prednisolone and melphalan plus dexamethasone. One systematic review found no significant difference in survival between melphalan plus prednisolone and combination chemotherapy plus prednisolone.

Benefits

Melphalan plus prednisolone versus bendamustine plus prednisolone:

We found one RCT, which compared bendamustine plus prednisolone versus melphalan plus prednisolone. It found that bendamustine increased the proportion of people achieving a complete response and increased progression free survival compared with melphalan (136 people with stage II or III disease; AR for complete response: 22/68 [32%] with bendamustine plus prednisolone v 8/63 [13%] with melphalan plus prednisolone; P < 0.01; median progression free survival: 14 months with bendamustine v 10 months with melphalan; P < 0.03). However, overall survival was similar in both groups (median overall survival: 32 months with bendamustine plus prednisolone v 33 months with melphalan plus prednisolone; significance not reported).

Melphalan plus prednisolone versus melphalan plus dexamethasone:

We found one RCT. It found no significant difference in overall response, event free survival, and overall survival between melphalan plus prednisolone and melphalan plus dexamethasone (201 people aged ≥ 70 years; > 95% stage II or III; overall response: 49.4% with melphalan plus prednisolone v 46.1% with melphalan plus dexamethasone; P = 0.75; event free survival: 15.9 months with melphalan plus prednisolone v 23.3 months with melphalan plus dexamethasone; P = 0.35; overall survival: 29.4 months with melphalan plus prednisolone v 27.2 months with melphalan plus dexamethasone; P = 0.26).

Harms

Melphalan plus prednisolone versus bendamustine plus prednisolone:

The RCT found that severe (grade 3 or 4) nausea and vomiting were significantly more common with bendamustine than with melphalan (AR: 11.8% with bendamustine v 0% with melphalan; P < 0.01).

Melphalan plus prednisolone versus melphalan plus dexamethasone:

The RCT found no significant difference in grade 3 and 4 haematological toxicity between melphalan plus prednisolone and melphalan plus dexamethasone (cycles 1–6: 14.9% with melphalan plus prednisolone v 25.4% with melphalan plus dexamethasone; cycles 7–12: 11.1% with melphalan plus prednisolone v 17.9% with melphalan plus dexamethasone; P value reported as not significant). It found higher grade 3 and 4 non-haematological toxicity with melphalan plus dexamethasone (cycles 1–6: 3.0% with melphalan plus prednisolone v 12.5% with melphalan plus dexamethasone; cycles 7–12: 0% with melphalan plus prednisolone v 7.7% with melphalan plus dexamethasone; P < 0.05).

Comment

Melphalan plus prednisolone versus bendamustine plus prednisolone:

The analysis was conducted according to the intention to treat principle. The study also described withdrawals. However, any information regarding a priori sample size calculation, allocation concealment, alpha error, and beta error was not reported.

Melphalan plus prednisolone versus melphalan plus dexamethasone:

The RCT performed intention to treat analysis, but it was not clear if there was adequate allocation concealment.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Combination chemotherapy plus corticosteroids

Summary

One RCT found that adding increased dose cyclophosphamide and prednisolone to a regimen of vincristine plus carmustine plus melphalan plus cyclophosphamide plus prednisolone did not improve overall response or survival. One RCT found that adding ranimustine to a regimen of cyclophosphamide plus vincristine plus melphalan plus prednisolone did not improve response or survival. One RCT found no significant difference between combination chemotherapy plus corticosteroids (cyclophosphamide plus melphalan plus prednisolone plus lomustine) and cyclophosphamide. One systematic review and two subsequent RCTs found no significant difference in survival between melphalan plus prednisolone and combination chemotherapy plus prednisolone.

Benefits

Different combination chemotherapy plus corticosteroids regimens versus each other:

We found four RCTs comparing various combination chemotherapy plus corticosteroid regimens. The first RCT (511 people aged < 70 years; 41% stages I and II, 59% stage III) compared three treatments: vincristine plus carmustine plus melphalan plus cyclophosphamide (400 mg/m2 iv on day 1 of cycle) plus prednisolone (40 mg/m2 orally on days 1–4 of cycle) (VBMCP); VBMCP plus interferon; and VBMCP plus increased dose cyclophosphamide (600 mg/m2 iv) plus increased dose prednisolone (100 mg/m2 orally) on days 1–4 of cycles 3 and 5 (VBMCP-HiCy). It found no significant difference between VBMCP and VBMCP-HiCy in objective response (67% with VBMCP v 70% with VBMCP-HiCy; P reported as not significant) or survival (displayed graphically; log rank P = 0.5). The second RCT (210 people; 87.6% stages II and III) compared cyclophosphamide plus vincristine plus melphalan plus prednisolone (CVMP) versus CVMP plus ranimustine (CVMP-R). It found no significant difference between treatments in response rate (AR: 45/103 [43.7%] with CVMP v 60/107 [56.1%] with CVMP-R; P = 0.097) or survival (median: 50 months with CVMP v 44 months with CVMP-R; log rank P = 0.75). The third RCT (485 people with confirmed myeloma) stratified and randomised people to two treatment regimens according to blood urea levels: less than 10 mmol/l (not azotaemic) – melphalan plus prednisone versus cyclophosphamide; or 10 mmol/l or more (azotaemic) – cyclophosphamide plus melphalan plus prednisone plus lomustine versus cyclophosphamide. In people with azotaemia, the RCT found no significant difference in survival between cyclophosphamide and cyclophosphamide plus melphalan plus prednisone plus lomustine (mortality: 49/61 [80%] with combination chemotherapy v 62/71 [87%] with cyclophosphamide; OR 0.59, 95% CI 0.23 to 1.52). The fourth RCT compared three treatments: melphalan plus prednisolone; vincristine plus doxorubicin plus dexamethasone alternating with melphalan plus prednisolone (VAD-MP); and vincristine plus mitoxantrone plus dexamethasone alternating with melphalan plus prednisolone (VND-MP). It did not specifically present statistical comparisons of the two combination chemotherapy regimens, however, overall it found no significant difference between the three treatments in objective response or median survival.

Combination chemotherapy plus corticosteroids versus single agent chemotherapy plus corticosteroids:

We identified one systematic review, and two subsequent RCTs. The review (search date not reported, 30 RCTs, 6633 people; including 20 RCTs with individual participant data, 4930 people, 6% with stage I disease, 67% stage II or III disease, and 27% stage unknown; 65% symptomatic) compared combination chemotherapy plus prednisolone versus melphalan plus prednisolone. It found that combination chemotherapy significantly increased overall response rates (20 RCTs, total number of people not reported; AR for complete or partial response: 60.0% with combination chemotherapy plus prednisolone v 53.2% with melphalan plus prednisolone; P < 0.00001). However, the review found no significant difference in survival between melphalan plus prednisone and combination chemotherapy plus prednisolone (30 RCTs, 6633 people; AR for mortality: 2525/3601 [70.1%] with combination chemotherapy plus prednisolone v 2183/3032 [72.0%] with melphalan plus prednisolone; OR 0.99, CI displayed graphically; P = 0.6; no significant heterogeneity P = 0.2). The first subsequent RCT compared three treatments: melphalan plus prednisolone; vincristine plus doxorubicin plus dexamethasone alternating with melphalan plus prednisolone (VAD-MP); and vincristine plus mitoxantrone plus dexamethasone alternating with melphalan plus prednisolone (VND-MP). It found no significant difference between treatments in objective response or median survival (527 people with symptomatic multiple myeloma, about 86% stages II and III; AR for objective response: 95/179 [53%] with melphalan plus prednisolone v 82/174 [47%] with VAD-MP v 86/174 [49%] with VND-MP; P reported as not significant; median survival: 36.5 months with melphalan plus prednisolone v 29.0 months with VAD-MP v 32.5 months with VND-MP; P reported as not significant). The second RCT compared oral melphalan plus prednisolone plus recombinant interferon alfa versus combination chemotherapy with vincristine plus carmustine plus melphalan plus cyclophosphamide plus prednisolone plus recombinant interferon alfa. It found no significant difference between groups in overall response or survival (89 people, 77.5% with Durie Salmon stage II or III disease; AR for complete or partial response: 67.4% with melphalan plus prednisolone v 69.1% with combination chemotherapy plus prednisolone; P = 0.59; estimated 5 year survival: 66% with melphalan plus prednisolone plus interferon alfa v 62% with combination chemotherapy plus prednisolone plus interferon alfa; log rank P = 0.79).

Harms

Different combination chemotherapy plus corticosteroids regimens:

The first RCT found that neutropenia (57% with VBMCP v 85% with VBMCP-HiCy; P = 0.001) and severe (grades 3 and 4) infections (13% with VBMCP v 25% with VBMCP-HiCy; significance not reported) were more common with VBMCP-HiCy than with VBMCP. The second RCT found that grade 3 and 4 haematological toxicities were more common with the ranimustine containing regimen (anaemia: 39% with CVMP v 55% with CVMP-R; neutropenia: 44% with CVMP v 70% with CVMP-R; thrombocytopenia: 3% with CVMP v 11% with CVMP-R; P values not reported). The third RCT did not report on harms. The fourth RCT found that granulocytopenia and infection were more common with VND-MP than with vincristine plus mitoxantrone plus melphalan plus prednisone (no significance data reported for comparison of combination regimens; see harms of combination chemotherapy).

Combination chemotherapy plus corticosteroids versus single agent chemotherapy plus corticosteroids:

The systematic review did not report harms. The first subsequent RCT found that granulocytopenia was significantly more common with combination chemotherapy regimens than with melphalan plus prednisolone, the risk was greatest with the vincristine plus mitoxantrone plus melphalan plus prednisolone regimen (AR per chemotherapy cycle: 15% with melphalan plus prednisolone v 18% with VAD-MP v 39% with VND-MP; P = 0.001 for VAD-MP v melphalan plus prednisolone; P < 0.001 for VND-MP v melphalan plus prednisolone). It found that infections were significantly more common with vincristine plus mitoxantrone plus melphalan plus prednisolone that with either alternative regimen (AR: 10% with melphalan plus prednisolone v 14% with VAD-MP v 23% with VND-MD; P = 0.009 for between group comparison). Combination chemotherapy was associated with greater World Health Organization grade 3 and 4 cardiac toxicity than melphalan plus prednisolone (AR: 1.1% with melphalan plus prednisolone v 3.4% with VAD-MP v 5.2% with VND-MD; P = 0.04). The second subsequent RCT found that neutropenia was more common with combination chemotherapy than with single agent chemotherapy, but this difference was not significant (AR: 49% with single agent chemotherapy v 62% with combination chemotherapy; P = 0.52)..

Comment

Different combination chemotherapy plus corticosteroids regimens:

Only the second RCT was analysed according to intention to treat principle and had adequate allocation concealment. The third RCT did not report power analysis. The fourth RCT was of good methodological quality, however, its method of allocation concealment was unclear.

Combination chemotherapy plus corticosteroids versus single agent chemotherapy plus corticosteroids:

The review did not specify whether the people in the included RCT were previously untreated. The RCTs included in the review were heterogeneous in design, but subgroup analyses by type of combination chemotherapy, by dose of drugs received, or according to the presentation features of the participants did not identify any particular forms of therapy that were either clearly beneficial or clearly adverse in terms of survival. There was no evidence that poor risk participants (i.e. those with poor prognostic features) benefited more from combination chemotherapy plus prednisolone. The first subsequent RCT was of good methodological quality. However, its method of allocation concealment was unclear. It was unclear whether the second subsequent RCT conducted a power analysis, and therefore whether the lack of a significant difference reflects a true equivalence of effect or a lack of power.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Bortezomib

Summary

We found one RCT of bortezomib for salvage treatment of advanced multiple myeloma. It found that bortezomib increased response rate, time to progression, and overall survival compared with dexamethasone.

Benefits

We found one RCT (669 people) of bortezomib for salvage treatment of advanced multiple myeloma, which compared bortezomib versus dexamethasone in refractory myeloma. It found that bortezomib significantly increased response rate (complete plus partial response: 38% with bortezomib v 18% with dexamethasone; P < 0.001), time to disease progression (6.22 months with bortezomib v 3.49 months with dexamethasone; HR 0.55, CI not reported; P < 0.001), and overall survival (80% with bortezomib v 66% with dexamethasone; HR 0.57, CI not reported; P = 0.001) compared with dexamethasone.

Harms

The RCT found that bortezomib increased withdrawal because of adverse events (37% with bortezomib v 29% with dexamethasone) compared with dexamethasone, but rates of grade 4 events (14% with bortezomib v group and the 16% with dexamethasone) and serious adverse events (44% with bortezomib v 43% with dexamethasone) were similar.

Comment

The trial was randomised, power calculations were undertaken a priori, and intention to treat analysis was performed. However, details of allocation concealment were not reported. This RCT has been criticised because it had a short follow up (median: 8.3 months) and excessive censoring (about 70–80% of people were censored at the time of report). A longer follow up is needed to ensure that the results will remain stable.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Salvage therapy regimens

Summary

Eleven RCTs found no significant difference in response and survival between different salvage therapy regimens.

Benefits

We found eleven RCTs, which compared various regimens as salvage therapy in refractory or relapsed multiple myeloma. The first RCT (83 people) compared epirubicin versus cyclophosphamide as salvage chemotherapy (third line chemotherapy). Both groups also received prednisone and interferon. The RCT found no significant difference between treatments in overall response (AR: 14/37 [38%] with epirubicin v 16/33 [48%] with cyclophosphamide; P reported as not significant) or overall survival (median: 13.9 months with epirubicin v 14.3 months with cyclophosphamide; log rank P reported as not significant). The second RCT (120 people) found no significant difference between vincristine plus doxorubicin plus dexamethasone (VAD) and VAD plus verapamil in overall survival (median: 10 months with VAD v 13 months with VAD plus verapamil; P = 0.22) and similar response (41% with VAD v 36% with VAD plus verapamil; significance not reported). The third RCT (47 people) found no significant difference in overall survival (median: 8.4 months with VAD v 8.1 months with VAD plus interferon; difference reported as not significant) and similar objective response (6/24 [25%] with VAD v 7/23 [30%] with VAD plus interferon; significance not reported). The fourth RCT (59 people) compared double hemi-body irradiation plus supportive care plus interferon versus double hemi-body irradiation plus supportive care alone. It found no significant difference in survival between groups (median: 10 months for both groups combined; P = 0.221). The fifth RCT (72 people resistant to or relapsed after melphalan treatment) compared cyclophosphamide plus doxorubicin plus prednisone versus carmustine plus doxorubicin plus prednisone. It found no significant difference between groups in objective response (AR: 2/30 [7%] with cyclophosphamide regimen v 7/32 [22%] with carmustine regimen; P = 0.22) or overall survival (median: 7.7 months with cyclophosphamide regimen v 8.4 months with carmustine regimen; log rank P = 0.75). The sixth RCT (41 people) found similar response rates with cyclophosphamide plus prednisone and cyclophosphamide plus prednisone plus chloroquine (good or limited response: 8/20 [40%] with cyclophosphamide plus prednisone v 8/18 [44%] with cyclophosphamide plus prednisone plus chloroquine; significance not reported). The seventh RCT (108 people) found no significant difference between cyclophosphamide plus vincristine (VCR) given on day 1 and cyclophosphamide plus VCR given on day 9 in survival (5.5 months with cyclophosphamide plus VCR on day 1 v 8.6 months with cyclophosphamide plus VCR on day 9; P = 0.28) and response (objective response: 9/51 [17.6%] with cyclophosphamide plus VCR on day 1 v 12/51 [23.5%] with cyclophosphamide plus VCR on day 9; P = 0.68). The eighth RCT (103 people resistant to or relapsed after cyclophosphamide treatment) compared VAD versus vincristine plus melphalan plus carmustine plus cyclophosphamide plus prednisone (VMBCP). It found no significant difference between treatments in overall survival (median: 16.0 months with VAD v 17.5 months with VMBCP; log rank P = 0.75). The ninth RCT (67 people resistant or relapsed after at least 1 chemotherapy regimen) compared VAD versus mitozantrone plus vincristine plus dexamethasone (MOD). It found no significant difference between treatments in overall survival (results displayed graphically; log rank P > 0.5). The tenth RCT (75 people) found that VAD plus cyclosporine A increased complete response, although the significance of this was not reported (9/34 [26.5%] with VAD plus cyclosporine A v 4/34 [9.8%] with VAD alone; significance not reported). However, it found no significant difference in overall survival between treatments (median overall survival: 13.0 months with VAD plus cyclosporin A v 14.6 months with VAD alone; HR 0.96, 95% CI 0.62 to 1.72). The eleventh RCT (98 people resistant to or relapsed after melphalan treatment) compared cyclophosphamide plus prednisone versus carmustine plus cyclophosphamide plus prednisone. It found that adding carmustine to cyclophosphamide plus prednisone increased objective response, although the significance of this was not reported (3/46 [7%] without carmustine v 7/41 [17%] with carmustine; significance not reported). However, it found no significant difference between treatments in overall survival (median: 9.6 months without carmustine v 9.5 months with carmustine; log rank P = 0.78).

Harms

The first RCT found no significant difference between epirubicin and cyclophosphamide in febrile neutropenia (15% with epirubicin v 10% with cyclophosphamide), grade 3 anaemia (7% with epirubicin v 6% with cyclophosphamide), thrombocytopenia (4% with epirubicin v 2% with cyclophosphamide), or grade 2 emesis (20% with epirubicin v 9% with cyclophosphamide; P values reported as not significant). However, it found that grade 2 or 3 alopecia was significantly more common with epirubicin than with cyclophosphamide (55% with epirubicin v 9% with cyclophosphamide; P < 0.01). The second RCT found similar toxicity with vincristine plus doxorubicin plus dexamethasone (VAD) and VAD plus verapamil (grade 3 or 4 leukopenia: 11/61 [18.0%] with VAD v 10/58 [17.2%] with VAD plus verapamil; grade 3 or 4 thrombocytopenia: 3/61 [4.9%] with VAD v 3/58 [5.2%] with VAD plus verapamil) and treatment related mortality (1/61 [1.6%] with VAD v 2/58 [3.4%] with VAD plus verapamil; significance not reported) with VAD and VAD plus verapamil. The third RCT found similar toxicity and treatment related mortality with VAS and VAD plus interferon (severe or life threatening leukopenia: 17/26 [65.4%] with VAD v 17/26 [65.4%] with VAD plus interferon; severe or life threatening thrombocytopenia: 5/26 [19.2%] with VAD v 9/26 [34.6%] with VAD plus interferon; severe or life threatening anaemia: 13/26 [50.0%] with VAD v 13/26 [50.0%] with VAD plus interferon; severe or life threatening infection: 9/26 [34.6%] with VAD v 4/26 [15.4%] with VAD plus interferon; treatment related mortality: 3/26 [11.5%] with VAD v 1/26 [3.8%] with VAD plus interferon; significance not reported). The fourth RCT found that interferon increased influenza like symptoms (World Health Organization grade 1 fever, myalgia, arthralgia, and lethargy: 15/15 [100%] with interferon v 0/23 [0%] with supportive care), hypothyroidism (3/15 [20%] with interferon v 0/23 [0%] with supportive care), and transient mild elevation in hepatic transaminases (13/15 [87%] with interferon v 0/23 [0%] with supportive care; significance not reported) compared with supportive care alone. The fifth RCT reported that the frequency and severity of haematological adverse effects were similar with both the cyclophosphamide based regimen and the carmustine based regimen (median leukocyte count nadir: 2300 cells/mm3 with cyclophosphamide regimen v 2200 cells/mm3 with carmustine regimen; median platelet count nadir: 86 000 cells/mm3 with cyclophosphamide regimen v 80 000 cells/mm3 with carmustine regimen; P values not reported). The sixth RCT found no significant difference in toxicity between cyclophosphamide plus prednisone and cyclophosphamide plus prednisone plus chloroquine (leukopenia: 5/20 [25%] with cyclophosphamide plus prednisone v 6/18 [33%] with cyclophosphamide plus prednisone plus chloroquine; thrombocytopenia: 12/20 [60%] with cyclophosphamide plus prednisone v 11/18 [61%] with cyclophosphamide plus prednisone plus chloroquine; infection: 5/20 [25%] with cyclophosphamide plus prednisone v 8/18 [44%] with cyclophosphamide plus prednisone plus chloroquine; differences reported as not significant). The seventh RCT found no significant difference in leukopenia, infection, or anaemia, but it found that cyclophosphamide plus VCR day 1 significantly increased thrombocytopenia compared with cyclophosphamide plus VCR on day 9 (life threatening or lethal toxicities: leukopenia: 47/53 [89%] with cyclophosphamide plus VCR on day 1 v 47/53 [89%] with cyclophosphamide plus VCR on day 9; P = 1.00; thrombocytopenia: 35/53 [66%] with cyclophosphamide plus VCR on day 1 v 23/53 [43%] with cyclophosphamide plus VCR on day 9; P = 0.03; infection: 17/53 [32%] with cyclophosphamide plus VCR on day 1 v 11/53 [21%] with cyclophosphamide plus VCR on day 9; P = 0.27; anaemia: 1/53 [2%] with cyclophosphamide plus VCR on day 1 v 0/53 [0%] with cyclophosphamide plus VCR on day 9; P = 1.00). The eighth RCT reported a similar frequency of deaths from infection in both groups (2/50 [4.0%] with VAD v 2/53 [3.8%] with VMBCP; significance not reported). Four other serious adverse effects occurred in the VAD group (pancreatitis, mycotic oesophagitis, cardiotoxicity, and haematological toxicity). The ninth RCT found that thrombocytopenia, haematuria, and cutaneous toxicity were more common with VAD than with MOD (figures are mean number of cycles/person affected: thrombocytopenia: 1.7 with VAD v 0.7 with MOD; P = 0.04; cutaneous toxicity: 0.6 with VAD v 0.3 with MOD; P = 0.017; haematuria: 0.4 with VAD v 0.0 with MOD; P = 0.023; significance level not adjusted for multiple comparisons). The tenth RCT found similar adverse effects with VAD plus cyclosporine A versus VAD alone, except for nausea, which was increased with VAD alone (haemorrhage: 8% with VAD plus cyclosporin A v 12% with VAD; mucositis: 5% with VAD plus cyclosporin A v 18% with VAD; nausea: 8% with VAD plus cyclosporin A v 30% with VAD; P = 0.015; arrhythmia: 5% with VAD plus cyclosporin A v 3% with VAD; peripheral neuropathy: 10% with VAD plus cyclosporin A v 18% with VAD; central neuropathy: 0% with VAD plus cyclosporin A v 3% with VAD; constipation: 10% with VAD plus cyclosporin A v 15% with VAD; pain: 35% with VAD plus cyclosporin A v 51% with VAD; performance status after treatment: 15% with VAD plus cyclosporin A v 18% with VAD; presence of infection: 35% with VAD plus cyclosporin A v 45% with VAD; significance not reported apart from nausea). The eleventh RCT found that the platelet count nadir was lower with the carmustine containing regimen (98 000 cells/mm3 without carmustine v 60 000 cells/mm3 with carmustine; significance not reported). Severe infections were less common in the carmustine containing regimen (5/46 [10.9%] without carmustine v 2/41 [4.9%] with carmustine; significance not reported).

Comment

Although all of the studies were RCTs, only two studies had adequate methods of allocation concealment and only one RCT undertook analysis by intention to treat.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Bisphosphonates

Summary

One systematic review found that bisphosphonates, particularly pamidronate and clodronate, reduced skeletal fractures and pain compared with placebo or no therapy. One RCT in people with multiple myeloma or breast carcinoma found no difference between zoledronic acid and pamidronate.

Benefits

We found one systematic review (search date 2004) comparing bisphosphonates versus placebo or no therapy. It found that bisphosphonates reduced pathological vertebral fractures (7 RCTs; 1116 people; OR 0.59, 95% CI 0.45 to 0.78), hypercalcaemia (8 RCTs; 2046 people; OR 0.76, 95% CI 0.56 to 1.03), and pain (8 RCTs; 1281 people; 0.59, 95% CI 0.46 to 0.76) compared with placebo or no therapy. It found no significant difference in mortality (10 RCTs; 2127 people; OR 0.99, 95% CI 0.88 to 1.12).

Harms

The review found that bisphosphonates increased gastrointestinal symptoms compared with placebo or no therapy, but the difference was not significant (110/853 [13%] with bisphosphonates v 86/863 [10%] with placebo or no therapy; OR 1.28, 95% CI 0.95 to 1.74). Non-randomised studies indicate that bisphosphonates may lead to serious complications, such as osteonecrosis of the jaw. The best of these studies, a prospective case series, found that 9.9% of people with myeloma developed osteonecrosis of the jaw (17/252 [6.7%] with all cancers included; 11/111 [9.9%] with myeloma).

Drug safety alert

FDA issues drug safety alert on severe musculoskeletal pain associated with bisphosphonates (08/01/2008).

Since the last update of this review, a drug safety alert has been issued by the FDA on severe musculoskeletal pain associated with bisphosphonates ( http://www.fda.gov/cder/drug/infopage/bisphosphonates/default.htm).

Comment

The review included 11 RCTs: six reported adequate allocation concealment, four were analysed by intention to treat, and eight were double blind. Data on quality of life and progression free survival were not reported. The analysis of the effect of bisphosphonates on pain was based on clinically heterogeneous data and should be interpreted with caution. The review found that the most reliable data was for the use of pamidronate and clodronate, but it found no direct comparisons. One RCT in people with multiple myeloma or breast carcinoma compared zoledronic acid versus pamidronate and found that they were equally effective.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Epoetin alpha

Summary

One systematic review found that epoetin alpha improved anaemia compared with placebo or no therapy.

Benefits

We found one systematic review (search date 2004), which compared epoetin alpha versus placebo or no therapy as treatment for anaemia related to multiple myeloma. It found that epoetin alpha significantly improved haematological response (4 RCTs; 272 people; RR 7.75, 95% CI 4.19 to 14.35) and mean haemoglobin levels (3 RCTs; 235 people; WMD 2.29, 95% CI 2.00 to 2.58) compared with placebo or no therapy.

Harms

The review found that epoetin alpha significantly increased hypertension compared with placebo or no therapy (4 RCTs; 290 people; RR 5.80, 95% CI 1.30 to 25.90).

Comment

The review included four published studies and two studies in abstract form only. The four published studies were randomised, but allocation concealment was unclear, and they did not perform a power calculation. None of the studies measured quality of life. It was not possible to assess the quality of the two studies in abstract form.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Infection prophylaxis

Summary

One systematic review found that trimethoprim–sulphamethoxazole and immunoglobulin reduced infections, although they may increase toxicity.

Benefits

We found one systematic review (search date 2004; 4 RCTs; 208 people), which compared infection prophylaxis versus placebo or no therapy. The first RCT evaluated the effect of ranitidine and placebo on cellular immunity, but it did not report patient related health outcomes (20 people). The second RCT found that trimethoprim–sulphamethoxazole reduced bacterial infection compared with no therapy at 3 months (57 people; 2/28 [7%] with trimethoprim–sulphamethoxazole v 11/26 [42%] with no therapy; P = 0.004). The third RCT found no difference in proportion of people with infections between gamma globulin and albumin control at 19 months (48 people; 7/17 [41%] with gamma globulin v 8/24 [33%] with albumin control; significance not reported). The fourth RCT found that intravenous immunoglobulin significantly reduced serious infections compared with placebo at 1 year (83 people; number of episodes: 19 with immunoglobulin v 38 with placebo; P = 0.019).

Harms

The first RCT did not report data on harms. The second RCT found that withdrawal because of toxicity was higher with trimethoprim–sulfamethoxazole than with no therapy (25% with trimethoprim–sulphamethoxazole v 0% with no therapy; significance not reported). The third RCT found that gamma globulin increased systemic reactions compared with placebo (3/17 [18%] with gamma globulin v 2/24 [8%] with placebo; significance not reported). The fourth RCT found more adverse reactions with immunoglobulin than with placebo (proportion of infusions: 12% with immunoglobulin v 5% with placebo; significance not reported).

Comment

The review did not present a meta-analysis because of heterogeneity between the included RCTs. All of the RCTs had small sample size and described withdrawals, but only two RCTs used intention to treat analysis.

Substantive changes

No new evidence

2006; 2006: 2403.
Published online 2006 April 1.

Plasmapheresis

Summary

Two small RCTs found that plasmapheresis improved renal function in people with multiple myeloma.

Benefits

We found no systematic review, but we found two RCTs, which investigated plasmapheresis as treatment for acute renal failure related to multiple myeloma. The first RCT compared forced diuresis plus chemotherapy plus plasmapheresis versus forced diuresis plus chemotherapy. It found that adding plasmapheresis to chemotherapy and forced diuresis significantly increased the proportion of people with a 50% reduction in urinary M-protein compared with no plasmapheresis (21 people; 71% with plasmapheresis v 50% without plasmapheresis; P < 0.001). However, it found no significant difference in survival between groups at 2 years (26% with each treatment; reported as not significant). The second RCT compared plasmapheresis plus corticosteroids plus cytotoxic drug plus haemodialysis when needed versus peritoneal dialysis plus corticosteroids plus cytotoxic drug. It found that plasmapheresis reduced the proportion of people requiring dialysis compared with no plasmapheresis at 2 months (29 people; requiring dialysis initially: 13/15 [87%] with plasmapheresis v 11/14 [79%] without plasmapheresis; no dialysis at 2 months: 11/13 [85%] with plasmapheresis v 2/11 [18%] without plasmapheresis; P < 0.01). It found that plasmapheresis significantly improved survival compared with no plasmapheresis at 1 year (66% with plasmapheresis v 28% without plasmapheresis; P < 0.01).

Harms

The first RCT did not report on harms. The second RCT found that harms of plasmapheresis were rare and mild (data not reported).

Comment

Both RCTs had a small sample size and did not perform intention to treat analysis. Only one of the RCTs described withdrawals. We found no RCTs on the effects of plasmapheresis in hyperviscosity syndrome.

Substantive changes

No new evidence


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