Myeloma group

BENDAMUSTINE, BORTEZOMIB &

DEXAMETHASONE (BVD)
INDICATIONS

Relapsed multiple myeloma in bortezomib naïve patients where other treatments are
contraindicated or inappropriate.
Bendamustine Funding from Cancer Drugs Fund. Requires Blueteq application.
Bortezomib Funding from Cancer Drugs Fund. Requires Blueteq application.

TREATMENT INTENT

Disease modification

GENERAL PRE-ASSESSMENT

1. Ensure all the following staging investigations are done:

o FBC & film
o Clotting screen
o U&Es
o LFTs
o Calcium
o Albumin
o Uric acid
o CRP
o Baseline random blood glucose level
o Virology : HIV, Hepatitis B (including core antibody), and Hepatitis C
o Calculated creatinine clearance (CrCl), urine protein/ creatinine ratio
o Electrophoresis and immunofixation for quantitation of serum paraprotein and
immunoglobulins.
o Serum free light chain assay (Freelite)
o β2 microglobulin
o LDH
o Myeloma FISH should be performed in all patients at diagnosis, and in selected patients at
relapse/progression to help guide treatment decisions Samples should be sent to Wessex
Regional Genetics Laboratory (address below)
o Urine pregnancy testing for pre-menopausal women younger than 55 before each cycle.
o Send a "group and save" sample to transfusion and inform patient and transfusion
laboratory that they will require irradiated blood products for all future transfusions.
Ensure irradiation card is attached to the patient's notes.
o Imaging as per NICE/network guidance and clinical presentation
o Bone marrow aspirate and trephine (and immunophenotype if appropriate)

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Wessex Regional Genetic Laboratory

Salisbury NHS Foundation Trust
Salisbury Disctrict Hospital
Salisbury
Wiltshire
SP2 8BJ

Additional Investigations
o Plasma viscosity if hyperviscosity suspected
o If allogeneic transplant an option: Tissue typing of patient and siblings and CMV serology
2. Hydration - fluid intake of at least 3 litres/ day should be attempted
3. Fertility - all patients should be offered fertility advice, asappropriate.
4. Consent - ensure patient has received adequate verbal and written information regarding their
disease, treatment and potential side effects. Document in medical notes all information that
has been given. Obtain written consent for the treatment.
5. Document patient’s height and weight
6. Document patient’s performance status.
7. Treatment must be agreed at the relevant MDT.

REGIMEN SPECIFIC PRE- ASSESMENT

1. Evaluate for presence of neuropathy. This is usually done by clinical assessment although
nerve conduction studies may be useful in occasional patients to document the extent of
neurological damage prior to treatment with Bortezomib.
2. Baseline lying and standing blood pressure should be recorded prior to administration of
cycle #1.

DRUG REGIMEN

Dexamethasone 20 mg PO once daily On the days of and day after

bortezomib days 1,2, 8,9 15,16 and
22, 23
Bortezomib 1.3 mg/m2 given as S/C bolus Days 1, 8, 15 and 22.
2
Bendamustine 70 mg/m IV infusion in 500 ml Days 1, 8.
sodium chloride 0.9% over 30 - 60
min.

At least 72 hours should elapse between consecutive doses of bortezomib.

CYCLE FREQUENCY

The cycle is repeated every 28 days for a minimum of 6 cycles and a maximum of 8 cycles
depending on response.

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DOSE MODIFICATIONS

Haematological toxicity:

Bendamustine: Dose reductions in bendamustine may be necessary. Treatment related fall in

neutrophil count below 1.0 x 109/L or platelets below 75 x 109/L, bendamustine should be
temporarily withheld until counts recover with G-CSF therapy + transfusions. If the cytopaenias are
disease related, please use G-CSF cover and platelet support.

Bortezomib:Withhold at G3 non-haem or G4 haem toxicities. Once resolved, re-initiate at 25%

reduced dose (1.3 mg/m2 reduced to 1.0 mg/m2; 1.0 mg/m2 reduced to 0.7 mg/m2). If the toxicity is
not resolved or if it recurs at the lowest dose, discontinue unless benefit outweighs risk.

Peripheral neuropathy

Patients with pre-existing severe neuropathy may be treated with bortezomib only after careful
risk/benefit assessment.
Severity of neuropathy Posology modification
G1 with no pain or loss of function None
G1 with pain or G2 Reduce to 1.0 mg/m2 or change treatment
schedule to 1.3 mg/m2 once per week
G2 with pain or G3 Withhold treatment until symptoms of toxicity
have resolved. When toxicity resolves re-
initiate treatment at 0.7 mg/m2 once per week.
G4 and/or severe autonomic neuropathy Discontinue

Hepatic /renal Impairment:

Bortezomib
Renal Hepatic
For dialysis patients, bortezomib Bili > 1.5 x ULN Reduce to 0.7 mg/m2 in the first
should be given after dialysis treatment cycle. Consider dose escalation to 1.0 mg/m2
No dose reduction necessary or further dose reduction to 0.5 mg/m2 in subsequent
cycles based on patient tolerability.

Bendamustine
Renal Hepatic
> 10 ml/min – no dose adjustment Mild: Bili <20 micromol/L Give 100%
≤ 10 ml/min – limited data Moderate: Bili 20 – 51micromol/L Give 70% dose
Severe: Bili > 51micromol/L Contraindicated

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INVESTIGATIONS – during treatment

 Urine pregnancy testing for pre-menopausal women younger than 55 before each cycle.
 FBC, U&Es, LFTS, Ca++, glucose – every 3 - 4 weeks.
 Clinical assessment of neuropathy should be undertaken and documented prior to each cycle
of bortezomib.
 Ig's, paraprotein, usually monthly after first 2 months, Freelite assay if appropriate.
 Consider bone marrow assessment after four cycles for non-secretory Myeloma.
 Consider blood glucose monitoring in patients with diabetes and those with signs of glucose
intolerance

CONCURRENT MEDICATIONS

 Allopurinol 300 mg daily for 6 days, from day 2 – 7 of first cycle only. Skin rash has been
reported in patients taking concomitant Allopurinol and Bendamustine It is suggested that
allopurinol is omitted on the days of Bendamustine administration.
 Prophylactic fluconazole 50mg OD
 Prophylactic aciclovir 200 mg TDS (consider reducing to 200mg BD if CrCl<10ml/min)
 Consider prophylactic co-trimoxazole 960mg OD on M/W/F if heavily pre-treated or previous
autograft.
 Proton pump inhibitor or H2 antagonist at clinician’s discretion.
 Bone protection as per NSSG Bone Protection protocol MM3.

Patients on bortezomib should be closely monitored if on CYP3A4-inhibitors (e.g. ketoconazole,

ritonavir). The concomitant use of bortezomib with strong CYP3A4-inducers (rifampicin,
carbamazepine, phenytoin, phenobarbital, and St John’s wort) is not recommended as efficacy
may be reduced.

EMETIC RISK

Moderate emetic risk on weekly bendamustine days, otherwise low risk.

EXTRAVASATION RISK

Bendamustine- vesicant/irritant

ADVERSE EFFECTS/REGIMEN SPECIFIC COMPLICATIONS

 Peripheral neuropathy: Patients should be advised to report pain hypersensitivity prickling,

numbness and paraesthesia. If these occur see above dose reductions and consider use of
Amitriptyline, Gabapentin and Pain Team referral. Neuropathy assessment tools are available
in DTU. Caution in patients with existing peripheral neuropathy (> Grade 2).
 Dizziness and orthostatic hypotension: Patients should be advised that Bortezomib may
cause orthostatic hypotension and that they should sit upright for a few minutes prior to
standing up from a recumbent position. Caution in patients with history of syncope, receiving
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medications associated with hypotension and patients who are dehydrated. Management of
orthostatic/postural hypotension may include adjustment of antihypertensive medicinal
products, rehydration or administration of mineralocorticosteroids and/or sympathomimetics.
Patients should be instructed to seek medical advice if they experience symptoms of dizziness,
light-headedness or fainting spells. Patients who experience dizziness or low blood pressure
may benefit from 500ml intravenous 0.9% sodium chloride with each dose of bortezomib.

 Gastrointestinal: Nausea, diarrhoea, vomiting and constipation are very common and ileus
has been reported.

 Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported
in patients who received bendamustine and allopurinol simultaneously. If patients
experience any skin reactions during treatment, they should be monitored closely and, in the
case of any suspicion of the skin reaction evolving to a serious muco-cutaneous reaction,
treatment with bendamustine should be withheld until complete resolution of the event or
discontinued. Other potential causes of skin toxicity should be evaluated and suspected agents
discontinued accordingly.

 Herpes zoster virus reactivation, progressive multifocal leukoencephalopathy (PML)

 Bendamustine MHRA Alert (20 July 2017): Hepatitis B virus (HBV) reactivation has been
reported; monitor known carriers of HBV for signs and symptoms of active HBV infection.
Increased mortality mainly due to opportunistic infections was observed in recent clinical
studies when bendamustine was used in combination treatment outside the approved
indications. Infections include bacterial (sepsis, pneumonia) and opportunistic infections such
as Pneumocystis jirovecii pneumonia, varicella zoster virus, and cytomegalovirus infection.
Some fatal cardiac, neurological, and respiratory toxicities were also reported.

REFERENCES

1. Offidani M, Corvatta L, Maracci L, Liberati AM, Ballanti S, Attolico I, Caraffa P, Alesiani F,

Caravita di Toritto T, Gentili S, Tosi P, Brunori M, Derudas D, Ledda A, Gozzetti A, Cellini C,
Malerba L, Mele A, Andriani A, Galimberti S, Mondello P, Pulini S, Coppetelli U, Fraticelli P,
Olivieri A, Leoni P. Efficacy and tolerability of bendamustine, bortezomib and dexamethasone
in patients with relapsed-refractory multiple myeloma: a phase II study. Blood Cancer J. 2013
Nov 22;3:e162.
2. Ludwig H, Kasparu H, Leitgeb C, Rauch E, Linkesch W, Zojer N, Greil R, Seebacher A, Pour L,
Weißmann A, Adam Z. Bendamustine-bortezomib-dexamethasone is an active and well
tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood. 2014 Feb
13;123(7):985-91.
3. Pönisch W, Moll B, Bourgeois M, Andrea M, Schliwa T, Heyn S, Schmalfeld M, Edelmann T,
Becker C, Hoffmann FA, Schwarzer A, Kreibich U, Egert M, Stiegler R, Krahl R, Remane Y,
Bachmann A, Lindner T, Weidhase L, Petros S, Fricke S, Vucinic V, Al Ali H, Niederwieser D.
Bendamustine and prednisone in combination with bortezomib (BPV) in the treatment of
patients with relapsed or refractory multiple myeloma and light chain-induced renal failure. J
Cancer Res Clin Oncol. 2013 Nov;139(11):1937-46.

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4. Pratt G, Bowcock S, Lai M, Bell S, Bird J, D'Sa S, Cavenagh J, Cook G, Morgan G, Owen R,
Snowden JA, Yong K, Davies F. United Kingdom Myeloma Forum (UKMF) position statement
on the use of bendamustine in myeloma. Int J Lab Hematol. 2013 Apr 25. [Epub ahead of print]
5. Berenson JR, Yellin O, Bessudo A, Boccia RV, Noga SJ, Gravenor DS, Patel-Donnelly D,
Siegel RS, Kewalramani T, Gorak EJ, Nassir Y, Swift RA, Mayo D. Phase I/II trial assessing
bendamustine plus bortezomib combination therapy for the treatment of patients with relapsed
or refractory multiple myeloma. Br J Haematol. 2013 Feb;160(3):321-30.
6. Rodon P1, Hulin C2, Pegourie B3, Tiab M4, Anglaret B5, Benboubker L6, Jardel H7, Decaux
O8, Kolb B9, Roussel M10, Garderet L11, Leleu X12, Fitoussi O13, Chaleteix C14, Casassus
P15, Lenain P16, Royer B17, Banos A18, Benramdane R19, Cony-Makhoul P20, Dib M21,
Fontan J22, Stoppa AM23, Traullé C24, Vilque JP25, Pétillon MO12, Mathiot C26, Dejoie T27,
Avet-Loiseau H10, Moreau P27. Phase II study of bendamustine, bortezomib and
dexamethasone as second-line treatment for elderly patients with multiple myeloma: the
Intergroupe Francophone du Myelome 2009-01 trial. Haematologica. 2015 Feb;100(2):e56-9.
7. Bendamustine Levact® eMC UK Summary of Product Characteristics, Napp Pharmaceuticals
ltd, February 2015.
8. Velcade ® Bortezomib, eMC UK Summary of Product Characteristics, Janssen, March 2017

REVIEW

Name Revision Date Version Review date

Nadjoua Maouche Formatting, adverse effects May 2016 1.3 May 2018
Pharmacist and pre assessment
section
Dr Jaimal Kothari Regiment specific section May 2016 1.3 May 2018
Consultant included
Manuela Sultanova Formatting, standardisation July 2017 1.4 May 2018
Service Coordinator of pre-assessment section
Network Protocol Review Funding. Dosing. June 2.0 June 2020
Extravasation risk. MHRA 2018
alert. Standardisation of
supports, dose
modifications and
investigations
Quality manager Addition of nursing care April 2.1 June 2020
plan 2021

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Nursing Care Plan

Bendamustine Bortezomib Dexamethasone (BVD)

Indication: Relapsed Myeloma.

Frequency: 6-8 cycles of 28 days.
Alopecia: Possible thinning of hair.
Send a group and save sample to blood transfusion and inform patient and laboratory that
they will require irradiated blood products for all future transfusions due to Bendamustine
treatment. Give patient an irradiated blood product booklet and card

BENDAMUSTINE: Alkylating agent.

Administered as intravenous infusion over 30-60 minutes on days 1 and 8.
Classification of extravasation: vesicant/irritant.
Emetic risk: moderate.
Side effects: infusion reactions: fever, chills, itchy skin, nausea and vomiting, anorexia,
bone marrow depression, diarrhoea, constipation, mucositis, fatigue, raised LFT’s,
hypokalaemia, cardiac impairment, hypo/hypertension, insomnia, skin disorders.

BORTEZOMIB (VELCADE): Proteasome inhibitor

Administered subcutaneously on days 1, 8, 15, 22. Minimum of 72 hours required between
doses.
Emetic risk: Low.
Classification of extravasation: irritant
Side effects: tachycardia, diarrhoea, constipation, anorexia, nausea/vomiting,
thrombocytopenia, neutropenia, peripheral neuropathy (sensory and motor), headache,
rash, fatigue, postural hypotension, dizziness, shingles, inflammation at injection site,
infections, bone marrow depression.

DEXAMETHASONE: corticosteroid tablets

Administered orally on the day of each bortezomib dose and the day after. Taken with or
after food preferably at breakfast
Side effects: restlessness, insomnia, mood changes, gastritis, hyperglycaemia, increased
appetite, fluid retention, weight gain, immunosuppression.

Regime Specific Considerations

 Lying and standing Blood pressure to be recorded pre cycle 1, advise patients that
velcade can cause orthostatic hypotension and counsel them to sit upright for a
moment before standing from a sitting/lying position.
 Risk of skin reactions (Steven-Johnson Syndrome ) when Allopurinol is given
concomitantly with Bendamustine. For patients with a low risk of tumour lysis
syndrome Allopurinol to be started on day 2. Check prescription on Aria for start
dates of Allopurinol.
 Bloods are required at the start of each cycle. Patients with unstable blood counts
may require more frequent monitoring.

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 Advise patients to maintain a fluid intake of 2-3 litres and avoid dehydration through
the prompt management of diarrhoea and nausea/vomiting.
Assess for presence of peripheral neuropathy before starting treatment and prior to the
start of each cycle.

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