Myeloma, Supportive Care, Plasmacytomas & Late Complications

(BSH 2004, BSH 2011, BSH 2017, BSH 2017(2))

  

Diagnosis

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Prognostic Cytogenetics

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N.B. Novel therapies (proteasome inhib & IMID’s) appear to overcome the prev. poor prognosis of t(14;16).

Minimal Residual Disease & Prognosis

If achieve MRD-negativity (by flow) —> 3-yr PFS similar regardless of cytogenetic risk

International Staging System (ISS)

 

Stage 1 – B2M <3.5 mg/dL + Albumin ≥35 g/l

Stage 2 – Neither Stage I or II

Stage 3 – B2M ≥5.5mg/l

 

When to treat Asymptomatic Myeloma

 

Any one of:

  • Plasma cells >60% on trephine

  • SFLC ratio >100

  • Any lytic lesion on CT (+ MRI spine)

  • Adverse cytogenetics

 

Causes of Renal Failure in Myeloma

 

1. Light Chains:

Distal tubules - Light chain cast deposition à obstruction

Proximal tubules - Direct toxic effect of light chains

Glomeruli – immunoglobulin deposition à non-selective proteinuria and nephropathy

Aggravating factors that promote light chain precipitation – dehydration, hypercalcaemia, acidosis, drugs (cyclophosphamide, Abx, NSAIDs, furosemide)

 

2. Hypercalcaemia

Causes vasoconstriction à enhances diuresis à hypovolaemia and pre-renal kidney injury à then becomes concentrated urine and reduced urine flow à increases cast formation.

 

Treatment

 

Intensive Therapy

Standard Upfront: VCD / VTD / CTD / BD --> Autograft

No UK upfront trial currently open

VCD vs VTD?

  • 2014 meta-analysis showed VTD > VCD for CR and VGPR. Higher rate of neuropathy

Evidence for Bortezomib

  • APEX trial – Bortez monotherapy v Dex monotherapy in renal failure

  • VISTA trial – VMP vs MP tested. 44% reversal of renal dysfunction

 

Consolidation / Maintenance post-autograft?

  • May prolong PFS post-autograft

 

Non-Intensive Therapy

Frail elderly --> Bortez/Dex

Fit elderly

  • Renal impairment --> VMP

  • Normal renal function --> MPT / CTDa

 

Relapse

Funding and guidance changing frequently at present

NICE as of Jan 2019

  • Bortezomib monotherapy after 1 previous treatment

  • Carfilzomib + Dex after only 1 previous treatments that did not include bortezomib

  • Lenalidomide after 2 previous treatments

  • Ixaz/Len/Dex after 2 or 3 previous treatments

  • Panobinostat/Bortez/Dex after 2 or more previous treatments

  • Daratunumab monotherapy after 3 previous treatments

  • Pomalidomide + Dex after 3 more previous treatments

Anglia Network 2017 Algorithm

  • Had Bortez 1st line

    • VGPR & 12 month remission --> Re-treat with Bortez —> Lenalidomide

    • Inadequate response --> CTDa --> Lenalidomide

  • Did not have Bortez 1st line

    • Bortez —> Lenalidomide

 

Emerging Therapies

 

Carfilzomib – Proteosome inhibitor - IV twice weekly, combined with Len/Dex à 70% MRD negative post-autograft. Aspire & Endeavour trials

Ixazomib – Proteosome inhibitor – oral – due to be reported on from Myeloma XI

Panobinostat – pan-deacetylase inhibitor – Given in combo with Vel/Dex à response in 30% of relapsed patients – NICE approved if 2 prior therapies including IMiD – SE: diarrhoea, prolonged QT, drug interactions (clarithromycin)

Daratumumab – Anti-CD38 – causes direct and indirect CD38+ cell death – Blood 2016 showed 30% response rate in patients with 5 prior therapies – CASTOR study combined daratumumab with Vel/Dex. POLLUX Study combined daratumumab with Len/Dex

Elotuzumab – Anti-SLAM7 – Eloquent 2 study combined elotuzumab with Len/Dex

Pembrolizumab – Anti-PD1 – synergistic with IMiDs

Venetoclax – BCL2 inhibitor – Phase 1 study showing safety profile and benefit in t(11;14)

Selinexor – XPO1 inhibitor – activates tumour suppression proteins

AMG420 – BiTE antibody, anti-BCMA + anti-CD3. Early phase trials for relapse post autograft

 

Trials

 

Myeloma XI Trial (ASH 2018, publication awaited)

1274 patients. High and Low intensity arms

High intensity

  • 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

  • KCRD higher rates of VGPR or better, and higher rate of MRD negativity (77%) post autograft, which translates to a 2 year PFS advantage over CRD.

 Low intensity

  • CTD v.s. Cyclo/Len/Dex

  • VCD if poor response

  • Randomised to Len maintenance, Len/Vorinostat maintenance or no maintenance

 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.

 

Myeloma XII Trial (ACCoRD)

Opening soon, three questions:

  • 1. Ixazomib / Thal /Dex (ITD)  v.s. VTD

  • 2. Autograft vs Autograft + Ixazomib

  • 3. ITDx2 consolidation   vs Ixazomib maintenance

 

Tourmaline-MM1 Trial 2016

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

MAIA Study (ASH 2018, publication awaited)

Phase 3. Daratunumab-Lenalidomide (D-Rd) vs Rd mono in transplant-ineligible newly diagnosed myeloma.

30 month PFS 71% vs 56%

MRD negativity 24% vs 7%

?New first choice treatment for older patients (outside UK)

Tourmaline-MM3 2018

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

 

Plasmacytomas

 

Epidemiology & Clinical Features

 

Male:Female 2:1, median age 55

Occur in spine twice as often as other sites

Presents as pain or cord/nerve root compression

Base of skull lesions can cause cranial nerve palsies

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Solitary Bone Plasmacytoma (SBP)

  

Majority with apparent SBP develop myeloma after 2-4 years

  • i.e. undetected myeloma at diagnosis (MRI spine may increase pick-up rate)

Increased likelihood of progression to myeloma with:

  • Low uninvolved Ig, Axial disease, Older age, Size >5cm, monoclonal band post-Rx

Diagnostic criteria

  • Single area of bone destruction due to clonal plasma cells + normal BM biopsy + normal skeletal survey + no myeloma ROTI + absent or low monoclonal Ig

Treatment

  • Radical radiotherapy of approx. 40 Gy with a 2cm margin

  • Post-treatment regular review and monitoring for myeloma development

 

Solitary Extramedullary Plasmacytoma (SEP)

 

Less common than SBP but better prognosis

90% occur in head and neck but can be anywhere in body

Diagnostic criteria

  • Single extramedullary mass of clonal plasma cells + normal BM biopsy + normal skeletal survey + no myeloma ROTI + absent or low monoclonal Ig

  • Due to soft tissue mass and rarity, can be confused with Non-hodgkin lymphomas

Treatment

  • High cure rates with radiotherapy of approx. 40 Gy with 2cm margin

  • Surgery may be considered if not ‘mutilating’

 

 

Supportive Care

 

MDT Approach – Palliative Care, Pain Management, Clinical Oncology, Orthopaedics

 

Anaemia

Present in 75% patients at diagnosis

Blood transfusion and/or Erythropoiesis-Stimulating Agents (ESAs)

ESAs recommended for anaemia in myeloma with associated renal impairment

E.g. Darbepoetin 6.25ug/kg every 3 weeks

True or functional iron deficiency occurring during ESA therapy should be treated with      IV iron infusions

 

Bleeding

Rare at presentation, usually occurring later as a result of:

  • Thromobocytopenia (immune or marrow infiltration), renal failure, infection, therapy toxicity, acquired von Willebrands, fibrin defects, hyperfibrinolysis, heparin-like anticoagulants and factor X deficiency (in AL amyloidosis)

No consensus on treatment of acquired VWD in myeloma – desmopression, IVIg and factor concentrates have all been used.

 

Thrombosis

Highest VTE risk is in newly diagnosed patients treated with lenalidomide and dex

Introduction of LMWH prophylaxis reduced rate of VTR from 17% à 3% with MPT

In patients receiving lenalidomide

  • Aspirin may be considered if patient is otherwise low risk

In patients receiving lenalidomide or thalidomide

  • LMWH

 

Infection

10% of patients die of infection within 60 days of diagnosis

Myeloma patients have inadequate responses to a variety of vaccines, esp polysaccharide

‘Flu, Step pneumonia and Haemophilus vaccines are recommended

Consider prophylactic IVIg

Aciclovir prophylaxis for bortezomib-based regimens or post-autograft

 

Pain

Multifactorial – destructive bone disease, plasmacytoma, co-morbidities, drug side effects (e.g. GCSF), mucositis, neuropathies

Cause may not be clear – e.g. neuropathy ?Chemo ?Diabetes ?Carpal tunnel

Titrating opiates

  • Normal release can be increased by 30-50% daily

  • Sustained release every 2-3 days

  • Patches every 3 days

Patches work well in myeloma – give anti-emetic for first 7 days of buprenorphine

Opioid-induced hyperalgesia

  • Increased pain with increasing dose, usually at original site of pain + adjacent dermatomes

Radiotherapy

  • Myeloma is usually radio-responsive

  • 8 Gy single fraction often an appropriate dose for pain control

 

 

Bisphosphonate Bone Protection

Zometa

  • >60ml/min:               4.0mg

  • 50-60ml/min:           3.5mg

  • 40-49ml/min:           3.3mg

  • 30-39ml/min:           3.0mg

  • <30ml/min:               Do not give

Pamidronate

  • Consider if Zometa contraindicated

 

Peripheral Neuropathy

Causes

  • Disease-associated – spinal cord or nerve root compression, POEMS

  • M-protein-associated – seen in MGUS more than myeloma

  • Co-morbidities – diabetes, carpal tunnel, CIDP, renal failure, B12 deficiency

  • Chemotherapy

    • Thalidomide – cumulative effect, mild-moderate, improves with stopping

    • Bortezomib – length-dependent distal sensory neuropathy with suppression of reflexes + motor & autonomic neuropathies. May take 2 years to resolve

Management

  • Correct the cause

  • Dose-adjust chemo as per SPC

  • L/S BP prior to bortez dose detects autonomic neuropathy before severe

  • Capsaicin cream acts on peripheral nerve TRPV1 (menthol on TRPM8)

  • Lidocaine patch

 

Nausea and Vomiting

Many causes – hypercalcaemia, analgesia, chemotherapy

Pro-kinetcs good for acute emesis

Consider ondansetron (5HT3 antagonist) for severe chemo nausea

 

Bisphosphonate osteonecrosis of the jaw

Presence of exposed necrotic bone in the mandible that does not heal after 2 months

RF – LT bisphos use, dental surgery, prior malignancies, smoking

Management is supportive, occasionally debridement required

 

End of Life

See guideline for more info. All the standard procedures.

 

Others to be aware of

Anorexia

Constipation/diarrhoea

Mucositis

Sedation

Fatigue – treatable causes include anaemia, low testosterone, thyroid def, drugs

 

Late Complications of Myeloma

 

Myeloma survival is increasing and so need to address side effects of treatment, co-morbidities and the impact of the physical disease and its treatments on psychological and social wellbeing.

 

Late Effects = A health problem that occurs months or years after a disease is diagnosed or after treatment has ended. Late effects may be caused by cancer or cancer treatment. They include physical, mental and social problems.

 

Survivorship = a focus on the health and life of a person with cancer post treatment until the end of life. It covers physical, psychosocial and economic issues of cancer, beyond the diagnosis and treatment phases.

 

Myeloma Survival – 5-year relative survival rate rose from 20% in 1995 to 40% in 2011.

 

Long-term Physical consequences

 

Infection and Immunity

Quantitative and qualitative defects in B cells, T cell subsets, NK and dendritic cells

Compounded by treatment-induced immunosuppression, neutropenia, immobility

Most myeloma patients die from infection, included 10% within 60 days of diagnosis

Management

  • Pomalidomide ass. w/ 30% risk of infection à prophylactic Abx for 1st 3 months

    • Levofloxacin or moxifloxacin should be used (cipro contraindicated)

  • Aciclovir if bortezomib, lenalidomide or previous shingles

  • Fluconazole with high dose steroids (prevention of oesophageal candidiasis)

  • IVIg replacement on a patient-by-patient basis

  • Vaccination

    • Aim to vaccinate between courses of treatment, more effective then

    • Flu + Pneumococcal (PCV13 and PPV23) + Hib are recommended

    • Other available in activated vaccines include: DTP, Hep A, Hep B, Meningococcal, Typhoid, Pertussis

 

Renal and Urogenital

50% of patients have renal impairment at presentation

Causes: Cast nephropathy, infection, dehydration, hypercalcaemia, hyperuricaemia, NSAIDs, AL amyloidosis

Management

  • Optimise diabetes and blood pressure control to prevent further renal injury

  • Appropriate dose reductions

  • ESAs

 

Bone, Endocrine and Metabolic

Bone loss causes – lytic lesions, chemotherapy, steroids, vit D deficiency, inactivity, hypogonadism, renal failure and 2o hyperparathyroidism, radiotherapy

Bone Loss Management

  • Zolendronic acid – reduces fractures, preserves density and prolongs PFS / OS

  • Calcium and Vit D supplementation, hormone replacement

Endocrine

  • 9% hypothyroidism, 65% hypogonadism in male patient, sarcopenic obesity

  • Management – active screening

    • BMI, waist circumference, strength, BP, HbA1c, lipid profiles

    • Weight bearing exercises as part of a structured rehab course

Neurological and Eye Complications

  • Spinal Cord or nerve root compression is the most common neurological presenting Sx

  • Chemotherapy-Induced Peripheral Neuropathy (CIPN) most common LT neuro problem

  • Polyneuropathies may be 2o to myeloma, POEMS, AL amyloidosis

  • 2o to co-morbidities – diabetes, carpal tunnel, CKD, Vitamin deficiencies

  • Eyes – cataracts post steroids and transplant conditioning, diabetic retinopathy

  • Management

    • Pain specialist, gabapentin

 

Cardiovascular & respiratory

50% of patients have ECG / Echo / BNP / Lung function test abnormalities

Associated with a poorer QoL

Resp function – recurrent infection, PE, chemotherapy, radiotherapy, hypoventilation due to bone pain, smoking

Cardiac function – sodium and fluid retaining effects of steroids and IMiDs, cardiac amyloid, anaemia, raised BMI

Management

  • Lifestyle management

  • ESAs / transfusion to correct anaemia

 

Oral and Dental Hygiene

Bisphosphonate-related osteonecrosis of the jaw (BRONJ)

Oral dryness 2o to chemoradiotherapy, supportive meds

  • Leads to dental infection, altered taste, speaking and swallowing difficulty

Management

  • Annual dental review, artificial saliva

 

Gastrointestinal and Nutritional problems

Bowel disturbance is a persistent side effect of many chemotherapies

Diarrhoea with lenalidomide due to bile acid malabsorption and responds to bile acid sequestrants (cholestyramine)

Common nutritional deficiencies

  • Vit B12, Vit D, Folate

Management

  • Monitor weight, involve dietitians, routinely assess drug and alcohol history

 

Second Primary Malignancies

8-11 fold increased risk of MDS & AML over general population

Management

  • Encourage participation in NHS cancer screening

  • Skin care

 

Frailty, Psychosocial and Rehabilitation Considerations

 

Three aims of assessment

1.     Predict toxicity (à dose modification)

2.     Provide prognostic information

3.     Detect disability (à support it)

 

Geriatric Assessment (GA) Tools

Many available, no one tool shown to be best in oncology

GA tools detect age-related problems missed in history&exam in 50% of patients

Performance status underestimates the degree of disability

A frailty score includes age, comorbidities and GA

 

Definitions

Frailty – A phenotype (3 or more of weakness, poor endurance, weight loss, low physical activity, slow gait speed) (2001) or the cumulative effect of individual deficits (2007)

Disability – difficulty or dependency in carrying out activities essential to independent living including task needed for self-care and desired activities important to one’s quality of life

Comorbidity – concurrent presence of 2 or more medically diagnosed disease in the same person, with the diagnosis of each contributing disease based on established criteria

 

Psychological Wellbeing

At time of diagnosis, 8% anxiety and 24% depression reported

50% of these patients had a desire for psychosocial interventions including relaxation techniques, counseling and peer support groups

 

A suggested “Late Effects MDT”

Core team – lead clinician, nurse specialist, physio, OT and psychologist

Associates – GP, Geriatrician, Psychiatrist, Endocrinologist, Cardiologist, Immunologist, Renal, Gastro, REsp, Neuro, Ophthal, Dermaholiday, Pscyhosexual counselor, Palliative care

Social / voluntary – Social worker, patient support group, cancer information services, Citizens Advice, Cancer /Elderly charities, complementary therapies.