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Multiple Myeloma (BSH 2017, BSH 2021)
Diagnosis
Table - IMWG 2014 Diagnostic Criteria. See below for comments on SLiM criteria.
Frequency of presenting features in newly diagnosed myeloma (2016 Yong et al)
61% bone pain, 39% anaemia, 21% vertebral fracture, 20% renal dysfunction, 19% hypercalcaemia, 9% other fracture, 7% incidental diagnosis, 3% infections, 1% spinal cord compression.
9% prev. known MGUS, 7% prev. known smouldering myeloma
Screening Tests
FBC, U&E, Calcium
Immunoglobulins + Serum electrophoresis (i.e. M-band = M-protein = paraprotein)
Serum free light chains (has largely replaced urine bence jones protein (BJP)
Urine ACR + Troponin + ProBNP (screening for amyloid)
Diagnostic Tests
Bone marrow aspirate + trephine
Immunofixation of serum
Imaging (BSH 2024):
Whole-body MRI (WB-MRI) & PET-CT provide info about medullary disease and myeloma activity.
Low-dose CT Skeletal Survey (CTSS) only records cortical damage that has already occurred.
—> MRI or PET-CT recommended over CTSS, however resource limitations prevent take up.
Prognostic Tests
B-2-microglobulin, LDH, Albumin
Peripheral blood plasma cell count (>5% = Plasma cell leukaemia, as of Dec 2021)
FISH (see below)
Other genetic mutations - CCND1, ATM, TP53
Myeloma-Defining Events
This used to mean CRAB (Calcium, Renal, Anaemia, Bone), but the SLiM biomarkers were added in 2014, as thought to indicate an ~80% risk of progression to symptomatic myeloma within 2 yrs, based on:
BM PC >60% - NEJM 2011 - Retrospective review. 650 patients. 21 pts had >60%, and 95% of these progressed within 2 years. Confirmed in subsequent smaller studies.
LC Ratio >100 - Blood 2008 - Retrospective review. 270 pts in 1970-1995. 72% risk of progression in 2 yrs if ratio >100. BUT, since IMWG 2014, a 2021 paper contradicts this. Blood 2021 retrospective review. 800 pts in 2000-2020. 13-36% risk of progression at 2 years (13 v 36% depended on urinary light chain quantification). Discrepancy suggested to be due to lack of modern imaging techniques in 2008 study misclassifying patients as asymptomatic. Time to remove LC ratio from SLiM?
2+ MRI lesions - JCO 2010 - whole body MRI of 149 pts with smouldering myeloma. Those with >1 focal lesion had 70% risk of progression at 2 yrs.
Only renal failure due to LC cast nephropathy is a myeloma-defining event - this is suggested by SFLC >500mg/l. If <500mg/l, consider renal biopsy to prove cause of renal impairment.
Hyperviscosity, amyloidosis and recurrent bacterial infections are no longer myeloma-defining events.
Causes of Renal Failure in Myeloma
1. Light Chains:
Distal tubules - Light chain cast deposition —> obstruction
Proximal tubules - Direct toxic effect of light chains
Glomeruli – immunoglobulin deposition —> non-selective proteinuria and nephropathy
Aggravating factors that promote light chain precipitation – dehydration, hypercalcaemia, acidosis, drugs (cyclophosphamide, Abx, NSAIDs, furosemide)
2. Hypercalcaemia
Causes vasoconstriction —> enhances diuresis —> hypovolaemia and pre-renal kidney injury —> then becomes concentrated urine and reduced urine flow —> increases cast formation.
prognosis
Prognostic Cytogenetics (BSH2021 + BSH2024)
What defines high risk?
UK (BSH), US (mSMART), International (IMWG) and European guidelines broadly agree but there is variation in the detail
Definition of high risk = An estimated OS of <3 years (<2yrs if not transplant eligible)
Definition of ultra-high risk = An estimated OS of <2 years (Alt: 2+ high risk cytogenetic abnormalities)
Frequency of cytogenetic abnormalities
Majority (>95%) of myeloma patients have a detectable cytogenetic abnormality
Frequency of particular abnormalities
50% Hyperdiploidy
40% 1q Gain (Prognosis gets poorer with increasing copy numbers of 1q)
15% t(4;14)
15% t(11;14)
10% del(17p)
2-3% t(14;16)
1% t(14;20)
Other Cytogenetics Notes
The poor risk of t(14;16) may be partly overcome by use of bortezomib-based therapy
The risk of t(11;14) may be higher than previously thought, but may also be a biomarker for predicting response to venetoclax (BCL2 inhibitor)
If patients achieve MRD-negativity (by flow) —> 3-yr PFS similar regardless of cytogenetic risk group
Gene Expression Profiling (GEP)?
Not currently routinely available but recommended that all transplant-eligible patients should have RNA stored from diagnostic marrow samples for potential future testing
International Staging System (ISS) 2005
Stage 1 – B2M <3.5 mg/dL + Albumin ≥35 g/l
Stage 2 – Neither Stage I or III
Stage 3 – B2M ≥5.5mg/liss calc
Revised International Staging System (R-ISS) 2015
Stage I - ISS 1 + Standard risk cytogenetics + normal LDH (5-yr OS 82%)
Stage II - Neither Stage I or II (5-yr OS 62%)
Stage III - ISS 3 + high risk cytogenetics + high LDH (5-yr OS 40%)
second revision of the ISS (R2-ISS) 2022
Six Factors
ISS Stage II (1 pt), ISS Stage III (1.5 pts), del(17p) (1 pt), high LDH (1 pt), t(4:14) (1 pt), 1q gain (0.5 pt)
Groups
0 = Low - 5yr OS 88%
0.5-1.0 = Low-intermediate - 5yr OS 75%
1.5-2.5 = Intermediate-High - 5yr OS 56%
3-5 = High - 5yr OS 37%
Treatment
To note:
The 2021 guideline has comprehensive tables of outcomes for many different regimens
Treatment options in myeloma are changing frequently as new drugs become available / NHS funding and NICE appraisals make them available for us. This section last reviewed: Sept 2023.
transplant eligible first line Therapy
Standard Upfront (2023):
DVTD --> Autograft —> DVTD consolidation —> Lenalidomide maintenance
(or clinical trial)
DVTD
Daratunumab-VTD. Approved by NICE Jan 2022
First quadruplet approved in UK
4 cycles —> Autograft —> 2 cycles consolidation
CASSIOPEIA 2019 - 1000 pts, DVTD vs VTD, 39% vs 26% CR at 100 days post autograft
Maintenance post-autograft
Lenalidomide maintenance at 10mg OD approved by NICE in March 2021
Myeloma XI 2018 - maintenance improves PFS and OS (88% vs 80% at 3yrs)
High Risk / Ultra High Risk / Plasma Cell Leukaemia (BSH 2024)
N.B. BSH 2024 guideline makes several recommendations that are not currently NICE approved
IMWG definition of PCL is >5% PC in peripheral blood as counted by microscopy (IMWG 2021)
Treatment should not be delayed waiting for molecular results. Instead, pathways should allow later treatment amendments as results become available.
Offer clinical trial
Preferred Rx for HRMM would be as per OPTIMUM, CONCEPT, IFM2018-04 or EMN12
Preferred Rx for PCL would be as per OPTIMUM or EMN12
Preferred subsequent lines of Rx would be based on refractoriness, not ‘n’ lines of therapy
Where preferred treatment is not accessible (all of UK as of 2024), options include:
(V)DT-PACE, tandem autografts, post-auto consolidation, allograft
Non-transplant eligible first line Therapy
Typical Options (2023):
Daratunumab, Lenalidomide & Dex (DRD) (NICE 2023) (MAIA 2019)
Lenalidomide/Dex (Rd) only if thaliomide if contraindicated or not tolerated (NICE 2019)
Bortezomib/Cyclo/Dex (VCD) (NICE 2011)
Bortezomib/Dex (VD) (NICE 2011)
Relapse
After 1 previous treatment
Daratumumab/Bortez/Dex (DVD) only if 1 previous treatment that did include lenalidomide or lenalidomide is unsuitable as a second line treatment (updated NICE 2023)
Carfilzomib/Len/Dex (KRd) only if 1 previous treatment that did include bortezomib (NICE 2021)
Carfilzomib/Dex (Kd) only if 1 previous treatment (NICE 2020)
Lenalidomide/Dex (Rd) only if 1 previous treatment that did include bortezomib (NICE 2019)
Selinexor/Bortezomib/Dex only if 1 prev. treatment and now refractory to both dara + len (NICE 2024)
After 2+ previous treatments
Ixaz/Len/Dex only if 2 or 3 previous treatments (updated NICE 2023)
Panobinostat/Bortez/Dex only if at least 2 prev. treaments, that did include an IMiD & bortez (NICE 2016)
Selinexor/Bortezomib/Dex only if 2 prev. treatments and now refractory to lenalidomide (NICE 2024)
After 3+ previous treatments
Elranatamab only if already received IMID, PI + Anti-CD38 (NICE 2024)
Teclistamab only if already received IMID, PI + Anti-CD38 (NICE 2024)
Ixazomib/Len/Dex only if 2 or 3 previous treatments (updated NICE 2023)
Daratumumab monotherapy only after 3 previous treatements, that did include an IMID and a proteomsome inhibitor (NICE 2022)
Isatuximab/Pomalidomide/Dex only if 3 previous treatments, that did include lenalidomide and a proteosome inhibitor (ICARIA-MM trial, NICE Nov 2020)
Pomalidomide/Dex only if 3 prev. treatments, that did include lenalidomide and bortezomib (NICE 2017)
Panobinostat/Bortez/Dex only if at least 2 prev. treaments, that did include an IMiD & bortez (NICE 2016)
After 4+ previous treatments
Selinexor/Dex only if 4 prev. treatments and refractory to 2x PI + 2x IMID + 1x Anti-CD38 (NICE 2024)
Trial options, e.g. CAR-T, Bi-specific antibodies
Compassionate access schemes for new / non-NICE approved drugs (see below)
Melphalan/Pred
Re-treatment
2nd Autograft?
Variable practice - Consider for patients with long remissions lasting >1yr following 1st transplant.
Allogeneic Stem Cell Transplant?
High TRM and morbidity. Long-term (10yr) comparisons with autograft fail to show a benefit to allograft in myeloma. There may individual patient exceptions, consider discussion with transplant centres.
Emerging Therapies
Venetoclax – BCL2 inhibitor – Phase 3 CANOVA trial completed, Ven vs Pom-Dex for t(11;14) myeloma, publication awaited (as of Jan 2024)
CAR-T Cell therapy - e.g. anti-BCMA under invesitgation. Useful 2021 review article.
Bispecific Antibodies
e.g. Talquetamab (CD3xGPRC5D), Elranatamab (CD3xBCMA), Teclistamab (CD3xBCMA)
NICE approved elranatamab + teclistamab in 2024, decision on talquetamab awaited (as of june 2024)
Belantamab mafodotin - anti-BCMA (CD269) antibody conjugated with a cytoxic agent. Severe, frequent occular toxicities limit its use.
Selinexor – XPO1 inhibitor – activates tumour suppression proteins. See BOSTON trial below.
Elotuzumab – Anti-SLAM7 monoclonal antibody
Eloquent 2 study combined elotuzumab with Len/Dex.
GMMG-HD6 2024: lenalidomide, bortezomib, dex (RVd) with or without elotuzumab prior to autograft in >500 newly diagnosed patients. No difference in 3-yr PFS. Negative trial.
Pembrolizumab – Anti-PD1 – synergistic with IMiDs
Outcomes
General Points
Outcomes in myeloma have improved with each passing decade
—> By its nature, currently published data may not apply to a newly diagnosed patient today.
The hope and expectation is that newly diagnosed patients will exceed current statistics.
Outcomes affect by many factors, e.g.
Disease biology, e.g. cytogenetics
Severity of complications at diagnosis, e.g. renal failure, spinal cord compression
Fitness to receive treatment / intensity of treatment
Depth of response to treatment, MRD-, CR, VGPR etc
Cancer Research UK Stats (as of 2024)
10yr OS for patients diagnosed in 2013-2017
All patients = 29%
<54yo at diagnosis = 55%
>75 yo at diagnosis = 14%
Real-World Outcomes in 1st line Myeloma Treatment, Richter et al 2023
6000 patients treated in USA between 2011 and 2022 —> treatment was largely with combinations including both a proteasome inhibitor + an IMID (Bortez/Len/Dex). ~20% underwent an autograft.
Time to progression (from start of treatment)
52mo (autograft)
20mo (no autograft)
Median Overall survival
Not reached (autograft)
50 months (no autograft)
N.B. This difference is of course not due solely to the autograft, rather a reflection of underlying patient fitness.
Real-World Outcomes in Myeloma, Yong et al 2016
5000 patients treated in European countries in the years leading up to 2014 —> 1st line treatment was largely bortezomib-based triplets (VMP, VTD, VCD)
Treatment-free interval
Median treatment-free interval post 1st line treatment = 10 months (16mo with Auto, 7mo without)
Proportion of patients reaching each line of treatment
95% 1st line, 61% 2nd line, 38% 3rd line, 15% 4th line, 1% 5th line
Time to progression (from start of a line of treatment)
Differs depending on degree of response
Medians: 18mo 1st line, 13mo 2nd line, 7mo 3rd line, 5mo 4th line
extra Trial notes (chronological)
Phase 3, 700 patients, transplant-eligible
DVRD vs VRD —> Auto —> Consolidation —> Maintenance (DR vs R)
Large PFS advantage for DVRD, 48 month PFS 84% vs 67%
Phase 2. 120 patients. Newly diagnosed, PS 0-2, transplant elegible.
4x Dara-KRd —> Autograft —> 2x Dara-KRd —> Len maintenance
But MRD adapted so treatment stopped if gained MRD negativity —> move to surveillance.
81% reached MRD negativity, some prior to autograft.
2-yr PFS from time of treatment cessation was 9% for pts with 0 or 1 high risk cytogenetic abnorm. (HRCA)
Myeloma XIV FiTNEss - Still recruiting as of sept 2023
comparing two different dosing regimens of IRD as first line treatment for transplant ineligible newly diagnosed myeloma. Followed by len vs len+ixa maintenance.
Myeloma XII Trial (ACCoRD) - Results pending (as of sept 2023)
Recruitment now closed (2023), results pending, three questions:
1. Ixazomib / Thal /Dex (ITD) v.s. VTD
2. Autograft vs Autograft + Ixazomib
3. ITDx2 consolidation vs Ixazomib maintenance
Selinexor/Bortez/Dex vs Bortez/Dex for patients treated with 1-3 previous lines of treatment
400 patients
In 2nd line, PFS better with selinexor (21mo va 11mo) but no difference in OS
In 3rd line, no difference in PFS or OS
DRD vs Rd for newly diagnosed, transplant ineligible patients. 740 patients.
30 month PFS 71% vs 56%, median OS not yet reached for either arm
56 month median PFS not reached for DRD, vs 34 months for Rd. Median OS not reached (Lancet 2021 f/up).
Myeloma XI Trial ~2019
High intensity Arm
Carfilzomib/Cyclo/Len/Dex (KCRD) v.s. Cyclo/Len/Dex (CRD) vs CTD
CTD & CRD get VCD if poor response
Followed by Autograft
Randomised to maintenance or no maintenance
Low intensity Arm
Cyclo/Len/Dex (CRD) vs CTD
VCD if poor response
Randomised to Len maintenance, Len/Vorinostat maintenance or no maintenance
1st Line High Intensity Results
Significantly improved PFS and PFS2 with KRCD
KCRD higher rates of VGPR or better, and higher rate of MRD negativity (77%) post autograft
1900 patients, randomised Len vs No Len. Median PFS 39 vs 20 months. 3yr OS 78.6 vs 75.8%.
Subsequent analysis of early relapse patients
14% of patients progressed within 12 months. This group has a 3-yr OS 28% compared to 53% for those with remission >12 months.
More likely to be in early relapse group if any of the following at diagnosis: Lambda LC, higher marrow PC %, anaemia or stage 3 ISS.
33% of early relapse group had 1 high risk genetic abnormality, 31% ³2.
i.e. 1/3 had standard risk genetics à more to be learnt about risk assessment.
Phase 3, placebo controlled. >650 patients.
Ixazomib maintenance vs placebo post-autograft. 2 years treatment then stop.
39% improvement in PFS, 6 month increase in PFS. Also of benefit in MRD-neg patients.
No OS data yet
Real-World Outcomes in Myeloma, Yong et al 2016
Real-world outcomes for 5000 patients treated in European countries
Patient’s charts reviewed in 2014 —> 1st line treatment was largely bortezomib-based triplets (VMP, VTD, VCD) and others (Bortez/Dex, CTD, MPT, PAD)
Nevertheless, paper is stuffed full of useful data!
For pts diagnosed in 2013/2014, frequency of presenting symptoms
61% bone pain, 39% anaemia, 21% vertebral fracture, 20% renal dysfunction, 19% hypercalcaemia, 9% other fracture, 7% incidental diagnosis, 3% infections, 1% spinal cord compression.
9% prev known MGUS, 7% prev known smouldering myeloma
Treatment-free interval
Median treatment-free interval post 1st line treatment = 10 months (16mo with Auto, 7mo without)
Proportion of patients reaching each line of treatment
95% 1st line, 61% 2nd line, 38% 3rd line, 15% 4th line, 1% 5th line
Time to progression (from start of a line of treatment)
Differs depending on degree of response
Medians: 18mo 1st line, 13mo 2nd line, 7mo 3rd line, 5mo 4th line
Ixazomib/Lenalidomide/Dex vs Placebo/Len/Dex
722 R/R patients with 1-3 prior lines of therapy
Improved PFS, 20 months vs 14 months
Median overall survival not reached, i.e. survival benefit not demonstrated yet
SE: Thrombocytopenia, rash, diarrhoea
CDF approved Jan 2018 as 3rd or 4th line treatment, provided not refractory to Bortez
Evidence for Bortezomib
APEX trial – Bortez monotherapy v Dex monotherapy in relapsed disease
VISTA trial – VMP vs MP tested. 44% reversal of renal dysfunction. Prolongs OS.