Updates
[Last Update: 21/02/2012]
Recent interesting articles
Denosumab, anti-RANKL monoclonal antibody, an additional weapon against myeloma bone disease; accumulating evidence
Denosumab (Amgen) is a fully humanised monoclonal antibody against RANKL and has been in development over the last decade as an alternative to bisphosphonates as an anti-resorptive strategy in myeloma bone disease, other tumours that metastasize to bone (eg breast, prostate) and in osteoporosis. Recently, certain key trials have reported evidence to suggest superiority of denosumab over zoledronic acid (Novartis) in a variety of settings. A debate is thus ongoing between Amgen sponsored trials showing superiority, or at least non-inferiority of denosumab and other Novartis sponsored studies which suggest that denosumab is not cost effective. Administration of denosumab does have some attractive features including lack of renal toxicity and monthly sub-cutaneous administration likely to facilitate easier, quicker and possibly domicilliary administration.
Download the full article as a pdf document.
Myeloma XI Newsletter Issue 4
Download a pdf of the Myeloma XI Newsletter Issue 4
Myeloma XI Newsletter Issue 2
Download a pdf of the Myeloma XI Newsletter Issue 2
Myeloma X Newsletter No19 February 2012
Download a pdf of the Myeloma X Newsletter No19 February 2012
Targeting adhesion molecules in myeloma – (Podar et al, BJH Nov-II, 2011)
There is increasing interest in the therapeutic potential of targeting adhesion molecules in myeloma. Strategies include targeting surface antigen adhesion molecules including integrins, cadherins, immunoglobulin like cell adhesion molecules, selectins and CD44 and their relative down-stream signalling pathways. Adhesion molecules mediate cell to cell adhesion and cell adhesion to various components of the extra-cellular matrix. It is hypothesized that disruption of adhesion using so-called selective adhesion molecule (SAM) inhibitors will prevent ‘cancer defining processes’ including adhesion initiated signalling cascades, tumour cell proliferation, survival, homing, migration, metastases and cell adhesion mediated drug resistance.
Podar et al (BJH Nov-II, 2011) recently report some promising results using Natalizumab, a recombinant humanised monoclonal antibody directed against the cellular adhesion molecule α4, a sub-unit of VLA-4. They successfully demonstrate the ability of Natalizumab to prevent adhesion of myeloma cells to cellular and non-cellular components of the bone marrow micro-environment, reduced proliferation of myeloma cells, reduced angiogenesis and increased chemo-sensitivity, (albeit in an in vitro ‘therapeutically representative human co-culture system’) of myeloma cells to Bortezomib. Proven efficacy in clinical trials is required but this interesting indirect approach may well have substantial therapeutic potential. Expect more focus on adhesion molecules in myeloma!
CyBorD superior to RD and CRD in newly diagnosed multiple myeloma but note increased neuropathy (Khan et al, BJH Feb-I 2012)
Across the pond, lenalidomide and Bortezomib have been used as front line agents for many years. Khan et al (BJH Feb-I 2012) present a retrospective comparative analysis of lenalidomide/dexamethasone (RD), cyclophosphamide/lenalidomide/dexamethasone (CRD) and cyclophosphamide/Bortezomib/dexamethasone (CyBorD). Response rates after four cycles of treatment were: ≥near complete response (nCR) were 12% vs 2% vs 41% p<0.0001 and very good partial response or better, 35% vs 30% vs 65% p<0.0003. ‘With all cycles of therapy considered’ ≥nCR was 35% vs 15% vs 41%. However, no regimen was associated with increased progression free survival or overall survival possibly due to the relatively short follow-up period available with 80% of patients treated with these modern therapeutic approaches alive at 4 years. As might be expected, the incidence of neuropathy was substantially increased in the CyBorD group 21% vs 15% vs 59% p<0.0001. However, overall the incidence of grade3 / 4 toxicities were least in the CyBorD group and highest in the CRD group. CyBorD was recommended by Dr Rajkumar as the treatment of choice for intermediate risk non-transplant eligible patients at last years IMW, Paris.
CD48 as a target for antibody therapy in multiple myeloma (Hosen et al, BJH Jan-II 2012)
This group, from Osaka Japan, provide some intriguing pre-clinical data to suggest that CD48 is a viable target for monoclonal antibody therapy. CD48 is a 47kDa glycophosphatidylinositol-linked glycoprotein strongly expressed on mature lymphocytes and monocytes and weakly expressed on CD34+ haemopoietic stem cells. They show that a monoclonal antibody to CD48 mildly enhances antibody-dependant cytotoxicity but substantially enhanced complement-dependant cell mediated cytotoxicity. Anti tumour effects were seen in SCID mice (lymphocyte depleted) and NOD/SCID mice (lack lymphocyte and complement activity) in both sub-cutaneously implanted tumour and tumour inoculated directly into tibiae. However, anti tumour activity was greater in SCID mice suggesting that complement mediated cytotoxicity is an important mechanism. Although CD48 is weakly expressed on haemopoietic stem cells, treatment with the anti CD48 monoclonal antibody did not appear to deplete haemopoietic stem cells in ex-vivo assays. Further studies combining this anti CD48 monoclonal antibody with conventional and novel myeloma treatments are eagerly awaited.
Dr Andy Chantry
Senior Clinical Lecturer in Haematology/Honorary Consultant in Haematology
University of Sheffield/Sheffield Teaching Hospitals Foundation Trust
Report on the Multiple Myeloma and Related Malignancies Meeting, Bari, Nov 2011
Meeting organisers, Professors Franco Dammacco and Angelo Vacca, assembled an impressive group of speakers for this enjoyable and informative meeting in the southern Italian Adriatic coastal city of Bari. Europe and the US were well represented by familiar key note speakers including Michel Attal, Herve Avet-Loiseau, Jean-Luc Harrouseau, Hartmut Goldschmidt, Michel Cavo, Antonio Palumbo, Pieter Sonneveld, David Roodman and Kenneth Anderson. Unfortunately, only the UK lacked senior representation from the UK myeloma community.
Michel Attal espoused once more the ‘new European emerging paradigm’ for intensive treatment comprising induction, autograft (+/- 2nd autograft), consolidation and maintenance. His other familiar proposition, strongly endorsed by Antonio Palumbo, was that achieving CR is becoming an increasingly feasible and desirable objective providing additional rationale for the use of the newer agents as first line induction therapy. He conceded that the optimal combination regimen for induction therapy was not yet established but did propose that Bortezomib and IMID based combinations may well prove superior. He also conceded that it is currently unproven whether a second autograft is worthwhile, although in many cases it is clearly feasible. Furthermore, controversy continues as to whether the second autograft should be given early or late ie after relapse and re-induction. The UK Myeloma X trial will provide important evidence in this debate. Maintenance strategies have compared Bortezomib and lenalidomide although the latter agent appears the preferred option. Given these considerations, with the possible exception of the consolidation issue, the UK Myeloma XI Trial appears well designed and likely to address many of these issues.
Kenneth Anderson summarised novel therapies and new targets under development at the Dana Faber Cancer Institute. Key approaches included immunotherapy approaches including elotuzumab, an IgG1 mab against CS1 target, expressed on MM cells and interestingly, up regulated by lenalidomide. His team are also targeting plasmacytoid dendritic cells (pDCs), key promoters of early myeloma cell colonization and expansion. Next generation proteosome inhibitors are in development including agents that target different proteosome components. Carfilzomib warranted a special mention due to the lack of peripheral neuropathy observed. Oral proteosome inhibitors are also under development and Dr Anderson concluded ‘I strongly believe the future of proteosome inhibitors is oral.’ Another exciting approach under development is to target protein homeostasis using aggresome inhibitors. The aggresome, is an intracellular organelle that forms when there is an accumulation of protein requiring disposal often seen if protein clearance is not fully effected by the proteosome. Hence inhibiting aggresome function is another method of inducing apoptosis. Furthermore, normal aggresome function is also mediated via HDAC activity providing a rationale for the use of HDAC inhibitors to disrupt this process.
This meeting delivered a broad curriculum of current myeloma clinical practice and cutting edge new therapeutic strategies giving credence to Dr Anderson prediction that ‘myeloma will become a chronic illness with complete responses in a significant fraction’
Dr Andy Chantry
Senior Clinical Lecturer in Haematology/Honorary Consultant in Haematology
University of Sheffield/Sheffield Teaching Hospitals Foundation Trust
UKMF
Website
Review
June
2011 –
What
hope
is
there
for
myeloma
bone
disease?
Click here to download the UKMF website review June 2011.
MRC Myeloma IX Newsletter
Click here to download the MRC Myeloma IX Newsletter.
Zoledronic acid now the bisphophonate of choice?
The UK MRC Myeloma IX trial has provided striking evidence to show that zoledronic acid is superior to clodronate not only in the reduction of myeloma related skeletal events (27% vs 35%) but also in its association with a survival advantage. Even after a relatively short median follow-up of 3.7 years, patients receiving zoledronic acid survive 5.5 months longer than those receiving clodronate. Progression free survival is also increased by 2 months (19.5 months vs 17.5 months) (Morgan, Davies et al. 2010).
Zoledronic acid is associated with a survival advantage
Intriguing evidence dating back over the last 15 years from animal models and in vitro studies have suggested that bisphosphonates exert an anti tumour effect. The MRC Myeloma IX trial is the first major randomised controlled trial to show an apparent anti tumour effect in human subjects with myeloma. However, despite this striking evidence, the mechanism of the anti tumour effect is not entirely clear.
Potential anti-tumour mechanisms
Various mechanisms have been proposed to account for the anti tumour effects of bisphosphonates ranging from relatively simple mechanisms to more complex interactions. Perhaps most simply, it has been proposed that because less bone is destroyed following bisphosphonate treatment, there is less volume available for tumour expansion. Furthermore, boney barriers to tumour expansion remain intact ie tumour is less likely to break out of its locale, expand and spread (Fleisch H 2001). Similarly, the bone marrow microenvironment has often been perceived as a hospitable environment for tumour growth especially when enriched by growth factors such as TGF-β, ILGF liberated from the bone matrix during bone resorption – the so called ‘seed and soil’ concept. Because treatment with bisphosphonates inhibits bone resorption, this favourable environment would be rendered relatively more inert (Mundy and Yoneda 1995). It has also been suggested that bisphosphonate treatment can inhibit tumour cell adhesion to mineralised surfaces(van der Pluijm, Vloedgraven et al. 1996). Also similar to their effects on osteoclasts, bisphosphonates have now been shown to have pro-apoptotic and anti-proliferative effects on myeloma cells (Shipman, Croucher et al. 1998). Anti-angiogenic effects have also been proposed (Croucher P.I. 2003). More complex interactions have also been proposed including enhanced γδ T-cell mediated immunosurveillance (Kunzmann, Bauer et al. 2000).
Intriguing data has also emerged suggesting synergy between bisphosphonates and various chemotherapeutic agents including doxorubicin, paclitaxel and cyclophosphamide(Vogt, Bielawski et al. 2004; Neville-Webbe, Rostami-Hodjegan et al. 2005; Neville-Webbe, Evans et al. 2006). Most recently, sequential administration of doxorubicin followed 24 hours later by zoledronic acid has been shown to decrease tumour burden in a mouse model of breast cancer. The authors propose that this is mediated by a complex interaction of increased pro-apoptotic factors and decreased cell cycle proteins (Ottewell, Woodward et al. 2009). Further studies are required to confirm which of these mechanisms are most important.
Most studies have focussed on the nitrogen containing bisphosphonates. Most commentators now conclude that the anti tumour effect of bisphosphonates is probably attributable to the inhibition of the mavelonate pathway unique to the nitrogen containing bisphosphonates and in particular, to the inhibition of the enzyme inhibits farsenyl pyrophosphate synthase (FFP synthase) which prevents the formation of isoprenoid lipids eg geranyl geranyl pyrophosphate (GGPP); these are required for the post translational prenylation (ie transfer of long-chain isoprenoid lipids) of proteins especially Ras, Rho, Rab, Rac – common intracellular proteins required for many cellular functions; reduction in these almost certainly interferes with cellular function and increases apoptosis and may well decrease concentrations of functional cell cycle proteins inhibiting proliferation (Fleisch H 2001). Thus these pro-apoptotic and anti proliferative properties, first proposed to act on osteoclasts may well also act on tumour cells.
Implications for clinical practice including notes of caution
Rajkumar makes some interesting observations in his editorial in The Lancet concerning the anti tumour effects of zoledronic acid reported in MRC MMIX including some words of caution (Rajkumar 2010). Firstly, he observes that in most countries other than the UK, the alternative bisphosphonate to zoledronic acid is pamidronate not clodronate and that pamidronate, which is ten times less expensive than zoledronic acid has not been associated with a survival disadvantage and may also have a lower incidence of ONJ. Secondly, he points out that it remains unclear whether patients without bone disease at presentation do better or not. However, the probability of an anti tumour effect does add weight to the argument to treat early plasma cell dyscraias ie asymptomatic myeloma with bisphosphonates eg yearly zoledronic acid in order to retard tumour progression and the development of myeloma bone disease. Thirdly, although the observation that most survival benefit appears to be derived early ie within the first 4 months of treatment is clealy important, mortality at this juncture is quoted at 8%. This compares less favourably with mortality at this juncture in patients treated with lenolidomide or Bortezomib which is quoted as 1% or less. Finally, he observes that the median duration of treatment with zoledronic acid is 12 months; given most benefit appears to be gained early, he suggests that this should not be used to justify indefinite treatment with zoledronic acid.
Pragmatic approach favours zoledronic acid where feasible
Inspite of these important caveats, zoledronic acid is increasingly becoming the bisphosphonate of choice in the UK and is recommended in the recent BCSH Guidelines (Bird, Owen et al. 2010). Further studies are required to answer the issues discussed above. In particular, the potential to maximise an anti tumour effect and to determine the role of bisphosphonates in the era of the newer anti myeloma remain key clinical and research objectives. Comments from clinicians concerning the way they use bisphosphonates and in response to issues discussed here are welcomed.
Dr Andy Chantry
Clinician Scientist
References
Bird, J., R. Owen, et al. (2010). "Guidelines on the diagnosis and management of multiple myeloma."
Croucher P.I., R.DeHendrik, M.J.Parry, A.Hijzen, C.M.Shipman, J.Lippitt, J.Green, E. Van Marck, B. Van Camp, K. Vanderkerken (2003). "Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreases osteolysis, tumour burden and angiogenesis, and increased survival." J. Bone Miner. Res. 18 (2003) 482-492.
Fleisch H (2001). "Development of Bisphosphonates." Breast Cancer Research, Vol 4 No 1.
Kunzmann, V., E. Bauer, et al. (2000). "Stimulation of gamma delta T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma." Blood 96(2): 384-392.
Morgan, G. J., F. E. Davies, et al. (2010). "First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial." Lancet 376(9757): 1989-1999.
Mundy, G. R. and T. Yoneda (1995). "Facilitation and suppression of bone metastasis." Clin Orthop Relat Res(312): 34-44.
Neville-Webbe, H. L., C. A. Evans, et al. (2006). "Mechanisms of the synergistic interaction between the bisphosphonate zoledronic acid and the chemotherapy agent paclitaxel in breast cancer cells in vitro." Tumour Biol 27(2): 92-103.
Neville-Webbe, H. L., A. Rostami-Hodjegan, et al. (2005). "Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells." Int J Cancer 113(3): 364-371.
Ottewell, P. D., J. K. Woodward, et al. (2009). "Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone." Mol Cancer Ther 8(10): 2821-2832.
Rajkumar, S. V. (2010). "Zoledronic acid in myeloma: MRC Myeloma IX." Lancet 376(9757): 1965-1966.
Shipman, C. M., P. I. Croucher, et al. (1998). "The bisphosphonate incadronate (YM175) causes apoptosis of human myeloma cells in vitro by inhibiting the mevalonate pathway." Cancer Res 58(23): 5294-5297.
van der Pluijm, G., H. Vloedgraven, et al. (1996). "Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro." J Clin Invest 98(3): 698-705.
Vogt, U., K. P. Bielawski, et al. (2004). "Breast tumour growth inhibition in vitro through the combination of cyclophosphamide/metotrexate/5-fluorouracil, epirubicin/cyclophosphamide, epirubicin/paclitaxel, and epirubicin/docetaxel with the bisphosphonates ibandronate and zoledronic acid." Oncol Rep 12(5): 1109-1114.
UKMF Website Review Update 26/03/2010
Welcome to the first update to the UKMF website for 2011!
‘Dear Dr Jones,
The tube contains urine of very high specific gravity. When boiled it becomes slightly opaque. On the addition of nitric acid, it effervesces, assumes a reddish hue, and becomes quite clear; but as it cools, assumes the consistence and appearance which you see. Heat reliquifies it. What is it?’ (Bence Jones, 1847)
Kyle’s fascinating historical review of myeloma entitled ‘Multiple Myeloma; an odyssey of discovery’ highlights intriguing elements to the history of myeloma including the description of classical lytic lesions in the skeletons of American Indians dating from AD200, Victorian patients crippled with bone disease, treated with an infusion of orange peel, a rhubarb pill and, when necessary, an opiate, and a certain grocer ‘of temperate habits and exemplary conduct’ whose unfolding misfortunes are highly suggestive of the disease we now know as myeloma and whose urine was sent to Dr Henry Bence Jones by an observant local GP, Dr Thomas Watson (Kyle 2000).
The last decade has seen substantial improvements in outcomes for patients with myeloma heralded by the introduction of thalidomide therapy (Palumbo, Giaccone et al. 2001; Morgan 2009), bortezomib (Richardson, Barlogie et al. 2003; Richardson, Sonneveld et al. 2007; Dimopoulos, Richardson et al. 2009) and lenolidomide, an immunomodulatory agent (IMID) derived from thalidomide (Richardson, Schlossman et al. 2002; Dimopoulos, Chen et al. 2009). Newer agents include the alkylating agent, bendamustine (Cheson, Wendtner et al. 2010) and the next generation IMID, pomalidomide (Lacy MQ 2010), now both accumulating impressive outcome data in the relapse setting. Mean overall survival for patients with myeloma treated with conventional intensive therapy followed by autologous stem cell transplantation (ASHT) is quoted as 62 months (Gulbrandsen, Wisloff et al. 2001) . However, in the era of the new agents, overall survival is likely to prove substantially longer. Provisional analysis of UK MRC MM IX trial suggests a median survival of approximately 7 years in patients treated in the thalidomide arm of the trial (Morgan 2009). The challenge for clinicians is to choose how best to use these new agents.
Cancer treatment in the UK tends to be more cautious than that offered in the US. Myeloma treatment is a case in point. Growing experience with novel agents such as bortezomib and lenolidomide, point to improved outcomes for patients. The current debate hinges on whether novel agents should be offered as first line therapy or whether the novel agents should be saved for use down the line in patients at first relapse (bortezomib) and second relapse (lenolidomide) as per recent UK practice. The management of side effects of the new agents now comprises a critical component of treatment. For example, bortezomib frequently causes severe peripheral neuropathy. Many now suggest reducing bortezomib to once weekly based on studies that demonstrate that this strategy reduces toxicity whilst enabling therapy to continue (Richardson, Barlogie et al. 2003).
The most intense regimen trialled to date in the US is Total Therapy 3. This reduces the number of induction cycles to 2 only but uses an intense combination of new and old agents comprising VTD-PACE (bortezomib, thalidomide, dexamethasone plus 4-day continuous cycles of cisplatin, doxorubicin, cyclophosphamide and etoposide. Further cycles of all of these agents, albeit at reduced doses are administered as consolidation after melphelan-based tandem autografts. Thalidomide and dexamethasone pulses are also administered to bridge between induction cycles and between autografts and consolidation phases. Maintenance therapy comprises bortezomib, thalidomide and dexamethasone for 1 year and thalidomide and dexamethasone for 2 years. The intensity of this regimen usually makes UK clinicians flinch. However, the outcome data is impressive with overall survival and event free survival at 5 years of 72% and 69% respectively. Trial organisers also contend that despite the intensity of the regimen, compliance is increased due to reducing the number of induction cycles from 4 (as in their previous Total Therapy 2 protocol) to 2 and that the addition of bortezomib up front improved outcomes. Furthermore, their analysis indicates that the use of bortezomib up front does not shorten post relapse survival (van Rhee, Szymonifka et al.) ie does not prohibit subsequent use at relapse.
The current UK MRC Myeloma XI Trial comprises randomisations and overall treatment pathways that are less intense than TT3 but does provide a design that allows the key issues to be addressed including a comparison of thalidomide and lenolidomide based induction regimens and whether the use of bortezomib at induction in non responders is advantageous. The MRC Myeloma IX trial, although its formal report on this matter is eagerly awaited, is likely to provide compelling evidence that the oral regimen CTD is superior to VAD (Morgan 2009). MRC Myeloma XI now compares CTD and RCD, a straightforward comparison which should generate a clear indication of which regimen is superior. UK experience with lenolidomide used at second relapse is encouraging. Furthermore, with a significantly more favourable side effect profile than thalidomide, lenolidomide is regarded as a ‘cleaner’ drug compared to its’ ‘dirtier’ forbear. However, some believe that it is has a reduced anti tumour effect due to its lack of anti-angiogenic effects, a trade off for its improved side effect profile. An additional benefit of thalidomide compared to bortezomib and lenolidomide is lack of myelosuppression. Mehta et al suggest that thalidomide should not be overlooked in this age of newer agents especially in patients with compromised marrow function (Mehta, Cavo et al.). Similarly, myelosuppression associated with bortezomib and lenolidomide is a threat to subsequent stem cell mobilisation, an issue that MRC MMIX which includes both lenolidomide and bortezomib in induction randomisations, will have to assess.
The role of stem cell transplantation is also under scrutiny. Allogeneic transplantation is currently the only treatment for myeloma with the potential for complete cure. However, its’ high treatment related mortality (TRM) has led clinicians to use this approach only in younger, fitter patients willing to accept the higher risk. Full intensity conditioning allogeneic stem cell transplantation is associated with a treatment related mortality of 34-54% (Lokhorst, Segeren et al. 2003; Hunter, Peggs et al. 2005; Barlogie, Kyle et al. 2006). The introduction of reduced intensity conditioning regimens has reduced TRM and intriguingly demonstrated that the best outcomes are associated with limited GVHD implying a significant graft versus myeloma effect (Crawley, Lalancette et al. 2005).
Autologous haemopoietic stem cell transplant (AHSCT) remains the gold standard in the majority of younger patients. In order to maximise the benefit of AHSCT, most now agree that complete remission (CR) post induction chemotherapy is desirable and imparts best prognosis prior to ASCT. However, with higher CR rates associated with the newer agents, some are questioning whether consolidating CR with AHSCT is necessary.
‘This is an area of debate because it is unknown whether the depth of CR achieved with novel agent-based induction therapy when not followed by AHSCT is equivalent to the depth of CR attained with novel agents and consolidated with AHSCT. Limited data suggest that the outcome of patients in CR after thalidomide or lenolidomide-based induction chemotherapy improves further with AHSCT consolidation. Prospective randomised studies designed to address this question are ongoing.’ (Mehta, Cavo et al.).
The current approach remains committed to induction therapy followed by high dose melphelan and AHSCT but is also seeking to utilise the newer more targeted approaches including bortezomib and lenolidomide whilst trying to ascertain the optimum time for the use of these newer agents.
‘All this indicates that, in the era of novel agents, high dose therapy should be optimised rather than replaced’ (Blade, Rosinol et al.).
A further issue for clinicians in choosing the best therapy for their patients is to decide whether or not to offer high dose therapy to patients over 65. The decision is invariably based on an assessment of biological age, considering performance status and co-morbidities rather than chronological age. Thus there is a trend to offer high dose therapy to an increasing number of older patients.
‘Our approach is to offer AHSCT to patients 65 to 70 years of age who are fit and motivated. In such patients, we favour the incorporation of novel agents in induction as well as in post transplantation consolidation/maintenance therapy’ (Mehta, Cavo et al.).
The importance of achieving CR has been also demonstrated in patients ineligible for high dose therapy. The recent phase 3 VISTA study comparing bortezomib, melphelan and prednisolone vs melphelan and prednisolone only not only demonstrated superiority in the bortezomib arm in all endpoints considered but also demonstrated that the achievement of CR was associated with significantly longer time to progression (Dimopoulos, Richardson et al. 2009). Interestingly, overall survival was not shown to be improved in patients achieving CR compared to other patients. However, the authors contend that this may be because patients failing to achieve CR are subsequently offered additional therapy often including novel agents in the relapse setting with good effect. Nevertheless, CR now appears to be a desirable treatment goal for all patients. This study demonstrated improved outcomes for patients achieving CR compared with VGPR and PR. This provides a rationale for continuing therapy until CR is achieved. Furthermore, authors contend that the more stringent definition of CR, termed sCR by IMWG criteria, based on normalisation of the free light chain ratio and disappearance of the monoclone by immunofixation and electrophoresis may be ‘the ultimate treatment goal’ (Harousseau, Palumbo et al.).
One of the most striking conclusions from the MRC MMIX trial is the clear superiority of zoledronic acid over clodrenate not only in terms of reduction in the number of skeletal events but also the demonstration of a survival advantage in patients receiving zoledronic acid compared with those receiving clodrenate (Morgan, Davies et al. ; Rajkumar). This gives clinicians clear guidance concerning optimal choice of bisphosphonate but has problematic consequences for the delivery of zoledronic acid which is usually administered via Day Case services which are often operating at capacity making the transfer of all patients with myeloma from oral clodronate to intravenous zoledronic acid logistically difficult.
In their recent review entitled ‘How I treat elderly patients with myeloma’ Mehta et al, from Bologna emphasize a proactive approach to investigating and monitoring older patients in order to enable maximal therapy without undue toxicity. This approach includes monitoring antidiuretic hormone in patients with compromised cardiac function assessed using echocardiography, Hb1c in diabetic patients, urine protein in patients with renal impairment, LDH, skeletal MRI, bone densitometry and PET CT in addition to the usual baseline diagnostic investigations used in the UK to confirm myeloma. These authors also routinely offer fluconazole, septrin and acyclovir prophylaxis in all patients receiving corticosteroids. Thus measures ranging from the simple to the complex are recommended to optimise treatment of myeloma in older patients. Whilst the desired benefits of such interventions are usually obvious, clinicians in the UK do not universally employ all of these measures probably both to reduce costs and to avoid unduly complex regimens.
They frequently request cytogenetics and FISH to assess prognosis and to determine choice of therapy (Mehta, Cavo et al.). Some prognostic information has already been established in correlation with cytogenetics in myeloma eg translocations involving the heavy chain locus on chromosome 14 including the t(4;14) and t(14;16) translocations and 17p deletion infer a poor prognosis (Fonseca, Van Wier et al. 2006; Munshi 2009). However, no consensus in exists concerning choice of treatment in the presence of various cytogenetic abnormalities and a recent international consensus report advocates further research before treatment decisions may be made on the basis of cytogenetic or molecular stratifications (Munshi 2009). MRC MMXI is collecting bone marrow aspirate samples for genetic analysis in order to assess whether such choices based on genetic information is possible in myeloma.
This will build on the work of analysis of samples collected from patients recruited to MRC MMIX performed by Walker et al who have recently defined frequently occurring chromosomal copy number abnormalities associated with prognostic significance in myeloma and attempted to assess global methylation patterns and the methylation status of specific genes of interest. They identify key gene deletions including those located at 1p (FAF1, CDKN2C), 1q (ANP32E) and 17p (TP53). Intriguingly, they also track the progression of plasma cell dyscrasias by methylation status identifying striking hypomethylation of the entire genome at the transition between MGUS and myeloma. However, specific genes of interest exhibit hypermethylation including GATA4 and CDKN2B at the transition from MGUS to myeloma and MMSET and FGFR3 at the transition between myeloma and plasma cell leukaemia (Walker, Leone et al. ; Walker, Wardell et al.).
Thus we live in interesting times. It is exciting to reflect on recent substantial advances in the understanding and treatment of myeloma. This inspires us to continue research into our ultimate treatment goal of complete cure. In the meantime, priorities include determining the optimal combination of therapies, drawing up algorithms for different combinations of treatment for the special circumstances often encountered in patients with myeloma and enhancing long term quality of life whilst minimising distress caused by the side effects of treatments.
This editorial aims to discuss current topics relevant to the treatment of myeloma in the UK mindful of international developments. It is intended to advance and provoke debate and reflect the philosophy of UKMF. Comment is therefore actively encouraged either to shed further light on topics discussed or to raise new issues of importance. Subsequent editorials will focus on key areas of myeloma management and review exciting new research.
Andy Chantry is a Clinician Scientist at the University of Sheffield and a Haematology trainee with a specialist interest in myeloma bone disease. He has recently volunteered to update the UKMF website on a regular basis. Feedback, contributions and suggestions would be gratefully received.
Dr Andy Chantry
Clinician Scientist
Mellanby Centre for Bone Research
University of Sheffield
a.d.chantry@sheffield.ac.uk
References
Barlogie, B., R. A. Kyle, et al. (2006). "Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321." J Clin Oncol 24(6): 929-936.
Blade, J., L. Rosinol, et al. "Hematopoietic stem cell transplantation for multiple myeloma beyond 2010." Blood 115(18): 3655-3663.
Cheson, B. D., C. M. Wendtner, et al. (2010). "Optimal use of bendamustine in chronic lymphocytic leukemia, non-Hodgkin lymphomas, and multiple myeloma: treatment recommendations from an international consensus panel." Clin Lymphoma Myeloma Leuk 10(1): 21-27.
Crawley, C., M. Lalancette, et al. (2005). "Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT." Blood 105(11): 4532-4539.
Dimopoulos, M. A., C. Chen, et al. (2009). "Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma." Leukemia 23(11): 2147-2152.
Dimopoulos, M. A., P. G. Richardson, et al. (2009). "VMP (Bortezomib, Melphalan, and Prednisone) is active and well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function, and results in reversal of renal impairment: cohort analysis of the phase III VISTA study." J Clin Oncol 27(36): 6086-6093.
Fonseca, R., S. A. Van Wier, et al. (2006). "Prognostic value of chromosome 1q21 gain by fluorescent in situ hybridization and increase CKS1B expression in myeloma." Leukemia 20(11): 2034-2040.
Gulbrandsen, N., F. Wisloff, et al. (2001). "Cost-utility analysis of high-dose melphalan with autologous blood stem cell support vs. melphalan plus prednisone in patients younger than 60 years with multiple myeloma." Eur J Haematol 66(5): 328-336.
Harousseau, J. L., A. Palumbo, et al. "Superior outcomes associated with complete response in newly diagnosed multiple myeloma patients treated with nonintensive therapy: analysis of the phase 3 VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone." Blood 116(19): 3743-3750.
Hunter, H. M., K. Peggs, et al. (2005). "Analysis of outcome following allogeneic haemopoietic stem cell transplantation for myeloma using myeloablative conditioning--evidence for a superior outcome using melphalan combined with total body irradiation." Br J Haematol 128(4): 496-502.
Kyle, R. A. (2000). "Multiple myeloma: an odyssey of discovery." Br J Haematol 111(4): 1035-1044.
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The UKMF welcome Sue Bell from Leeds Clinical Trial Office to the Executive, following the recent retirement of Prof. Curly Morris and Dr Judith Behrens.
MERIT trial [19-Feb-2004]
The MERIT trial closed on Jan 15th 2009. Analysis and publication of data will follow.
Joint Nordic and UKMF MGUS Guideline
The Joint Nordic and UKMF MGUS Guideline has been submitted to BCSH for entry on their website.