Guidelines on the diagnosis, investigation and initial treatment of myeloma: a British Society for Haematology/UK Myeloma Forum Guideline

Abstract

The objective of this guideline is to provide healthcare professionals with clear guidance on the anti-myeloma management of patients with newly diagnosed multiple myeloma. In all cases, individual patient circumstances may dictate an alternative approach. This guideline was compiled according to the BSH process at https://b-s-h.org.uk/media/16732/bsh-guidance-development-process-dec-5-18.pdf. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Recommendations are based on a review of the literature using Medline, PubMed, Embase, Central, Web of Science searches from the beginning of 2013 up to July 2019. The following search terms were used: myeloma; plasma cell leukaemia; AND risk; prognosis; cytogenetics; FISH; PCR; molecular; imaging; response; residual disease OR [chemotherapy; autologous; autograft; HDT/ASCT; allogeneic; allograft; stem cell; bone marrow; cord blood; haploidentical; tandem transplant; bortezomib; carfilzomib; ixazomib; melphalan; thalidomide; lenalidomide; pomalidomide; cyclophosphamide; dexamethasone; prednisolone; doxorubicin; bendamustine; immunotherapy; daratumumab; PDL1 inhibitor; CAR-T; frail; elderly; renal failure; renal impairment; kidney disease; maintenance; consolidation AND survival; outcome; relapse; progression; remission; response; residual disease; mortality; morbidity; side effects; adverse events; complication; neuropathy; thromboembolism; infection; quality of life; cost-effective] Review of the manuscript was performed by the British Society for Haematology (BSH) Guidelines Committee Haematology Oncology Task Force, the BSH Guidelines Committee and the Haematology Oncology sounding board of BSH. It was also on the members section of the BSH website for comment. It has also been reviewed by UK Charity Myeloma UK. These organisations do not necessarily approve or endorse the contents. Patients with suspected myeloma should be investigated using the tests listed in Table I. A bone marrow biopsy should be undertaken in patients in whom there is a clinical concern for end organ damage and/or those with a significantly elevated monoclonal protein (M-protein). The monoclonal protein should be quantified by densitometry of the monoclonal peak. Quantification of monoclonal immunoglobulin (Ig) A by electrophoresis can be complicated by migration into the beta region. International Myeloma Working Group (IMWG) guidance recommends that for IgA and IgD myelomas, quantitative immunoglobulin measurements are preferred.1 NICE guidance now recommends the use of serum free light chains (SFLC) rather than urinary Bence Jones protein (BJP), and studies have validated this.2 SFLC replaces BJP in these guidelines, although it is noted that BJP may still be required for some clinical trials. Urine albumin:creatinine ratio along with troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) can be a useful screening tool for detecting amyloid. Skeletal survey has been replaced by cross-sectional imaging, including low-dose, whole-body computed tomography (CT), or ideally functional imaging such as computed tomography-positron emission tomography (CT-PET) or diffusion weighted whole body magnetic resonance imaging (MRI). Focal imaging (e.g., dedicated MRI scan of the spine and pelvis, or plain films of long bones) should be performed to look at specific sites in more detail if required. Imaging in myeloma is discussed in detail in recent UK and international guidelines.3, 4 All diagnoses should be reviewed at a multidisciplinary team (MDT) meeting. Myeloma should be diagnosed using the 2014 IMWG updated criteria.5 Table II shows the diagnostic criteria for myeloma, smouldering (asymptomatic) myeloma and monoclonal gammopathy of undetermined significance (MGUS). Table III summarises myeloma-defining events. The latest guidance reflects a number of changes compared to the previous 2003 criteria.6 End organ damage is no longer required to diagnose myeloma. Three biomarkers have been added to the myeloma-defining events, each of which is associated with an approximately 80% probability of the development of CRAB features (hypercalcaemia, renal impairment, anaemia and bone disease). These biomarkers (≥60% clonal plasma cells in the bone marrow, involved:uninvolved light chain ratio ≥100 and ≥2 focal lesions on MRI) are referred to as the SLiM criteria. Studies have shown the rate of progression to myeloma within 2 years is approximately 95%7, 8, 80%7, 9 and 70%,10, 11 respectively. Patients with a solitary focal lesion on MRI or equivocal findings should undergo interval imaging.4 The 2003 criteria did not specify the percentage of clonal bone marrow cells required for a diagnosis of symptomatic myeloma. Current guidance confirms 10% clonal plasma cells or biopsy-proven plasmacytoma is required. Current guidance also clarifies that the presence of osteolytic bone lesions >5 mm seen on CT or PET-CT (and not on skeletal radiography) is consistent with a myeloma-defining event. Increased uptake on PET-CT alone, without a corresponding lytic lesion, is insufficient to be a myeloma-defining event, but is associated with an increased risk of progression to myeloma.5 If there is doubt regarding equivocal or small lucencies (<5 mm), repeat imaging should be performed. Bone lesions should be biopsied if there are concerns they may represent bony metastases from concurrent malignancies. Osteoporosis with compression fractures is no longer a myeloma-defining event. Criteria regarding renal failure have changed, with creatinine clearance <40 ml/min added as a myeloma-defining event. The criteria now also specify that only renal failure due to light chain cast nephropathy (biopsy proven or presumptive) is a myeloma-defining event. SFLC >500 mg/l is suggestive of cast nephropathy,12 so renal biopsy should be considered in those patients with SFLC <500 mg/l.5 Monoclonal proteins can cause other renal pathology (e.g., AL amyloidosis or monoclonal immunoglobulin deposition disease) in patients who do not meet the criteria for myeloma. Such cases are termed monoclonal gammopathy of renal significance.13 To be classed as a myeloma-defining event, CRAB events should be due to underlying myeloma and, if unclear, appropriate investigations should be performed to confirm this. Symptomatic hyperviscosity, amyloidosis and recurrent bacterial infections1 have been removed from the list of myeloma-defining events in the current guidelines, but may still require treatment. Diagnostic criteria for other related plasma cell dyscrasias, including solitary plasmacytoma with or without minimal bone marrow involvement, systemic AL amyloidosis and POEMS Syndrome can be found in the IMWG updated criteria for the diagnosis of myeloma.5 Cytogenetic analysis should be undertaken by interphase FISH (fluorescence in situ hybridization) on CD138-selected bone marrow cells. The bone marrow material used should be part of the first aspirate pull wherever possible.14 Table IV lists the cytogenetic abnormalities found to be of prognostic significance in newly diagnosed myeloma.15 Whilst t(11;14) is listed as standard risk, recent analysis of the Myeloma XI trial suggested patients with hyperdiploidy and no adverse lesions had superior outcomes compared to those with t(11;14).16 Early data suggests t(11;14) is a predictive biomarker for response to the BCL2 inhibitor venetoclax. t(4;14) is a poor risk marker, although the poor risk can be (partly) overcome by bortezomib-based therapy.17 The poor prognostic impact of del(1p) has mainly been described in patients treated with autologous stem cell transplantation.18 The number of extra copies of 1q is relevant; patients with amplification of 1q (four or more copies) having a poorer prognosis.16, 19 Del(13q) detected by FISH is no longer considered an independent prognostic factor.20-22 There is a lack of consensus internationally as to the percentage cut-off levels which should be used to signify a positive FISH result. The French group (IFM) suggested 60% was required for clinical significance in del(17p), although this has not been replicated in other studies, and sub-clonal TP53 copy number abnormalities have recently been shown to be associated with prognosis.23 The European Myeloma Network suggested 10% for translocations and 20% for copy number abnormalities.14 Less than 20% has been clearly associated with inferior outcome in the UK MRC Myeloma IX and XI trials. Smaller sub-clones may carry prognostic relevance, but data are currently limited. UK MRC Myeloma IX and XI studies found an association between the number of adverse cytogenetic lesions present and progressively shorter survival.16, 20 The International Staging System (ISS) defines three prognostic categories (Table V). The criteria reflect tumour burden and renal function (Beta-2 microglobulin) along with performance status (albumin). The ISS was initially developed in 2005.24 As such, the median overall survival (OS) associated with each stage (62 months vs. 44 months vs. 29 months) is out-dated. However, more recent studies have confirmed the prognostic significance of ISS in the era of novel agents25 and at relapse.26 The Revised-ISS (R-ISS) combines the traditional ISS with presence of high-risk cytogenetics (del(17p), t(4;14) or t(14;16)) or elevated serum lactate dehydrogenase (LDH).27 Data were pooled from 4,445 patients with newly diagnosed myeloma enrolled onto 11 international multicentre trials, 95% treated with novel agents. Three risk groups are defined, as shown in Table VI. In addition to the cytogenetic abnormalities discussed above, various recurrent genetic mutations have been associated with a poor prognosis in myeloma—for example, in CCND1, ATM and TP53.15, 28 The National Genomic Test Directory (https://www.england.nhs.uk/publication/national-genomic-test-directories) specifies the genomic tests commissioned for myeloma in the UK. Bi-allelic loss of TP53 [i.e., del(17p) plus TP53 mutation, seen in ~30% of del(17p)] has a significantly reduced OS.28 Gene Expression Profile signatures are also predictive of poor prognosis but are currently used only in the context of clinical trials.29 Plasma cell leukaemia (defined as 20% circulating plasma cells or a total plasma cell count in peripheral blood of at least 2 × 109/l) remains a poor prognostic factor,30 as does detection of low levels of circulating plasma cells by flow cytometry.31 Imaging studies can provide prognostic information; the presence and number of 18F fluorodeoxyglucose (FDG)-avid lesions on PET scanning at baseline and at response to treatment has the most data in this regard at the present time.32 Investigations should be based on the tests listed in Table I. (1C) Serum free light chain analysis should be used to investigate monoclonal light chains rather than urinary Bence Jones protein. (1B) Renal biopsy should be considered if SFLC <500 mg/l and myeloma is being considered as the cause of renal impairment. (1C) Cross-sectional imaging, ideally functional (i.e., PET-CT or diffusion weighted whole body MRI), should be used. Skeletal survey should not be used to assess bone disease in myeloma. (1B) Patients With One Solitary Focal Deposit On MRI Should Have An Interval Scan. (2C) Urine albumin:creatinine ratio along with troponin and NT-proBNP can be a useful screening tool for detecting amyloid. (2C) IMWG 2014 diagnostic criteria should be used for staging. (1A) All cases of newly diagnosed myeloma should be discussed at an MDT meeting. (1C). Cytogenetic analysis using interphase FISH on CD138-selected cells should be undertaken on all patients at diagnosis. (1A) Samples should be probed for t(4;14)(p16;q32), t(14;16)(q32;q23), t(11;14)(q13;q32), 17p−, 1q+, 1p− and testing considered for t(14;20)(q32;q11) and hyperdiploidy. (1B) Cytogenetic abnormalities found in >20% of cells should be considered significant. The significance of smaller clones is not clear. (2B) Revised ISS should be calculated on all newly diagnosed patients. (1A) Overall survival is the preferred outcome measure for assessing efficacy, using direct comparisons from Phase 3 trial data where possible. Progression-free survival (PFS) and response rate (RR) can be used as surrogate markers, although caution should be employed in their interpretation. Treatment cross-over in trials at progression means that a PFS advantage even in the absence of OS difference may still indicate a benefit from a treatment option; in this context, PFS2 (progression-free survival on the next line of treatment) can provide useful data.33 Increasingly, sustained Minimal Residual Disease (MRD) negativity is seen as a strong surrogate marker for long-term outcome.34 Myeloma predominantly affects an elderly population, many of whom are excluded from clinical trials; hence, there can be less certainty about the benefits of treatments and effects on quality of life in this group. Toxicities can be considerable, and dose modification is often necessary. Higher doses of corticosteroids35 and discontinuation due to adverse events36 are associated with worse overall survival in this population. Conversely, fitter older patients may receive inappropriate dose reductions if based solely on age. Evaluation of frailty was traditionally based on age and subjective clinician assessment. More recently, objective fitness scoring systems have been evaluated to estimate prognosis and guide dosing.37-41 The IMWG score is based on age, the Charlston Comorbidity Index and cognitive and physical conditions, while the UK Myeloma Risk Profile (UK-MRP) uses patient and disease factors.42 Prospective trial-based testing of these systems is ongoing, and consensus on their use has not yet been reached. As discussed below, autologous stem cell transplantation (ASCT) is recommended for younger, fitter patients. There is no formal definition of transplant eligibility and age alone is a poor indicator. Selected patients over the age of 70 may be suitable for ASCT with a low risk of mortality (3–5%). Transplant scoring systems can be used to assess fitness objectively and formal tests of cardiac, lung and renal function performed, although these are not currently standardised. A full discussion of side effects and dose reductions is beyond the scope of this guideline, but these have a significant bearing on drug choice and dosing. The Summary of Product Characteristic datasheets should be referred to. Patient preferences, including duration of therapy, and practical issues such as the need to travel to a day unit for parenteral treatments are important considerations, especially in the frailer patient population where quality of life as well as OS is important. Local familiarity with regimens can play an important role. Licensing and funding varies between countries and regions, and will change over time. The criteria for assessment of response continue to evolve and are defined based on paraprotein, bone marrow and imaging responses as: Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), Minimal Response (MR), Stable Disease (SD) and Progressive Disease (PD), with the more recent inclusion of MRD-based assessments by flow cytometry or sequencing and imaging.1 Outside of a clinical trial, light chain assessments can be made by SFLC assay rather than urine BJP quantification.2 Future trials will explore using MRD and functional imaging responses, but these are not currently used to make routine treatment decisions. This section discusses choice of drug treatment for newly diagnosed myeloma patients. Treatment decisions should be made within an MDT context, and may involve supportive care, surgery and radiotherapy, although these areas are not covered within these guidelines. The aim of treatment for all patients is to maximise the depth and duration of response while minimising toxicity in order to lengthen survival, improve quality of life, alleviate symptoms and prevent further organ damage. Drug regimens referred to in the text are listed in Table VII. Proteasome inhibitors (PIs) act by altering the degradation of proteins essential for cell cycle and growth.43 The first in class, bortezomib, was originally given on an intravenous, biweekly schedule, but appears to be equally efficacious with reduced peripheral neuropathy when given weekly and subcutaneously.44-47 A biweekly schedule may be used as initial therapy to try to achieve rapid tumour control in highly proliferative disease or with cast nephropathy-induced acute kidney injury. Carfilzomib is a second-generation PI with irreversible proteasome binding which has significant efficacy but higher rates of cardiac toxicity.48 Carfilzomib is given intravenously, and dosing schedules vary: 70 mg/m2 once weekly is better tolerated, with improved efficacy compared to 27 mg/m2 twice a week in the relapsed setting,49 but optimal dosing remains to be determined in the frontline setting. The oral PI ixazomib has limited data in the first line setting at this time. Immunomodulatory drugs (IMiDs) are oral agents that cause myeloma cell apoptosis primarily by interaction with cereblon. Mechanisms of action include degradation of the transcription factors IKZF1 and IKZF3,50 and immune modulation.51 The first drug in class, thalidomide, shows clinical efficacy, but is associated with high rates of venous thromboembolism (VTE) when used in with as well as neuropathy and The and have a risk and are better tolerated, but have a higher of often All require and for as well as a due to their These a part of myeloma therapy, with oral and being the most used in UK toxicity can be and doses should be reviewed and reduced if with long-term There are data that can be once patients a of treatment with PFS and weekly dosing rather than initial therapy is associated with toxicity and Higher dose treatments may be given in patients with highly proliferative disease or with cast nephropathy-induced acute kidney injury. agents (e.g., may be used in with other agents. The doses used are suitable for although and can still More such as are used in Monoclonal the response in with and and are to be in frontline Toxicities are but include first dose with blood and of monoclonal including and have limited data in the first line setting. In direct regimens with or PFS and, in some trials and OS benefit compared to The of first line studies have used in various in the transplant (Table and (Table Carfilzomib has been in patients (Table the of these data are predominantly in with OS data not However, response rates and PFS are all at least as as with bortezomib-based have been but the is in a population. In data in patients vs. have not shown an or PFS advantage over The addition of a often although this has not into a survival The addition of an in the and although in direct the addition of to has not shown a survival has not been compared to other bortezomib-based in Phase 3 trials, a analysis did indicate a survival advantage with over or and Phase 2 trial data PFS and OS at least as as this an in and As noted above, is clearly superior to for PFS and OS in the and a reduced dose is in older this a treatment agents are an alternative for patients who receive an can be used for although is than with is that may be used in fitter although is a is in patients due to the risk of stem cell In and are used with the schedule and a survival advantage over and The benefit for alone compared to or the of the as was shown in a Phase 2 of and has been added to various improved and PFS for patients in with and PFS and OS with and PFS for patients in with OS data but PFS data provide evidence of and it is to be into the frontline setting. are an in frailer patients for whom an all oral is preferred (Table patients without high-risk cytogenetic these may be more and more for long-term In this context, has been shown to be more than due to efficacy and better long-term The addition of an to an (e.g., can although survival benefits have not been are preferred to with improved survival in compared to in and responses but better shown with in treatment is to response with minimal between and and With should be performed 4 to prevent stem cell there is a to example, with and This is based on improved PFS in the Myeloma and although there remains as to the benefit in terms of overall The for a as the The aim should be treatment and using reduced doses if necessary. Patients less than a may benefit from to an alternative The Myeloma XI trial data that patients less than a following or benefit from to a bortezomib-based However, most patients will now receive as initial use or without or regimens in patients to achieve a response to although there is a lack of data in this As above, high-risk myeloma is defined by a number of of which cytogenetics have the impact on initial treatment There is evidence that therapy may the risk of t(4;14) and 17p−, and should be used in these patients if In older this should the use of a (e.g., an oral (e.g., where This is by a pooled analysis of trials of and patients with cast nephropathy-induced acute kidney plasma cell or with a proliferative biweekly with high dose of can be used for initial treatment. regimens such as are used for rapid and for more in patients. Treatment should be according to individual patient factors to maximise the depth and duration of response while minimising in order to lengthen survival, improve quality of life, alleviate symptoms and prevent further organ damage. (1A) Treatment should be for individual patients based on efficacy, patient and as well as and and criteria. (1A) patients should receive a PI or (1A) regimens response and are recommended for patients with the addition of an preferred to (e.g., (1A) the aim should be to achieve response with to of an to consolidation with Patients a should receive a to stem cell (1C) should be in patient due to concerns about reduced at stem cell (1C) the aim should be to treatment and minimising still using (1C) patients may receive a PI or treatment Patients with high-risk cytogenetics should receive a if possible. a is also and may be preferred for (1B) an or or or may be added to a is preferred to (2B) including the use of objective scoring should be for older and less patients. A multidisciplinary with from of the elderly may be (1B) should be considered for all less patients. (1A) patients less than a an alternative may be considered in order to (2C) is well and response rates and It can be added to as should be given on a weekly (1A) Patients with proliferative plasma cell leukaemia or cast nephropathy should receive biweekly for initial treatment a more schedule such as (2C) stem cell transplantation following high dose has been standard of for consolidation following treatment in those considered it was first to PFS and OS with low levels of mortality trials have shown improved response compared to A of these have also shown improved and although a significant OS advantage was not in all trials, this is related to in and consolidation and the use of ASCT in those not it up On ASCT has efficacy as consolidation (Table More recently, given the in the rates and of with the of novel agents given in and the of high dose in the management of myeloma has been recent trials have to the of ASCT following and it be for a line of The trial patients following to ASCT or All patients for PFS months vs. rate and MRD negativity were all significantly longer in the ASCT all risk There no OS benefit at 4 years vs. In the a of ASCT or with consolidation ASCT was associated with improved PFS vs. at 3 but not OS vs. at 3 These trials that ASCT

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