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Bortezomib 1.3 / Daratumumab 16 / Dexamethasone (20/20), Multiple Myeloma, Cycle 1

Protocol-ID: 817 V2.1 (Complete), BORT1.3/DRTM16/DEXA(20/20), MM, C1

Indication(s)

Multiple Myeloma; ICD-10 C90.-, C90.0-

Protocol classification

Classification: current standard
Intensity: Standard dose
Therapy mode: Relapse therapy
Therapy intention: disease control

Cycles

Cycle length 21 days, recommended cycles: 1

Protocol sequences

CASTOR: BORT1.3/DRTM16/DEXA(20/20), MM, C1 (PID817) -|- C2-3 (PID818) -|- C4-8 (PID819) -|- C9+ (PID820)

Risks

Emetogenicity (MASCC/ESMO): minimal (<10%)
Neutropenia: moderate (11-20%)
Thrombocytopenia below 50 000/µl: very high (>41%)
Anemia Hb below 8g/dl: moderate (6-15%)
Diarrhea: CTC AE °3-4: 4%
Hypertension: CTC AE °3-4: 7%
Dyspnea: CTC AE °3-4: 4%
Fatigue: CTC AE °3-4: 5%
Neuropathy: CTC AE °3-4: 5%
Pneumonia: CTC AE °3-4: 8%

Therapy

Day	Substance	Dosage	Appl.	Inf. time	Procedure
HYD Hydration: Balanced Crystalloid Solution
Access: peripheral venous
Hydration before, during, or after antitumor therapy
1	Balanced Crystalloid Solution	500 ml	i.v.	60 min	60 min before Daratumumab (d1)

8	Balanced Crystalloid Solution	500 ml	i.v.	60 min	60 min before Daratumumab (d8)

15	Balanced Crystalloid Solution	500 ml	i.v.	60 min	60 min before Daratumumab (d15)

Day	Substance	Dosage	Solution	Appl.	Inf. time	Procedure
AP Allergy prophylaxis: Daratumumab allergy prophylaxis with dexamethasone
Access: peripheral venous
Preinfusion Medication: To reduce the risk of IRRs, premedication should be given to all patients approximately 1 hour before each infusion.
1	Dexamethasone	20 mg	NaCl 0.9% 50 ml	i.v.	5 min	60 min before Daratumumab (d1)
1	Dimetinden	4 mg	NaCl 0.9% 50 ml	i.v.	5 min	60 min before Daratumumab (d1)
1	Paracetamol	1000 mg		p.o.		60 min before Daratumumab (d1)
1	Montelukast	10 mg		p.o.		60 min before Daratumumab (d1)
8	Dexamethasone	20 mg	NaCl 0.9% 50 ml	i.v.	5 min	60 min before Daratumumab (d8)
8	Dimetinden	4 mg	NaCl 0.9% 50 ml	i.v.	5 min	60 min before Daratumumab (d8)
8	Paracetamol	1000 mg		p.o.		60 min before Daratumumab (d8)
15	Dexamethasone	20 mg	NaCl 0.9% 50 ml	i.v.	5 min	60 min before Daratumumab (d15)
15	Dimetinden	4 mg	NaCl 0.9% 50 ml	i.v.	5 min	60 min before Daratumumab (d15)
15	Paracetamol	1000 mg		p.o.		60 min before Daratumumab (d15)

Day	Substance	Dosage	Solution	Appl.	Inf. time	Procedure
CTX Antineoplastic therapy: BORT1,3/DRTM16/DEXA(20/20)
Access: peripheral venous
Bortezomib, daratumumab, and dexamethasone in multiple myeloma
1,4,8,11	Bortezomib	1.3 mg/m² BSA	none	subc	Bolus	Sequence
1	Daratumumab	16 mg/kg bw	NaCl 0.9% 1000 ml	i.v.	6.5h	Sequence
Initial rate 50 ml/h, increase infusion rate by 50 ml/h every 60 minutes. Maximum infusion rate: 200 ml/h
8	Daratumumab	16 mg/kg bw	NaCl 0.9% 500 ml	i.v.	4 h	Sequence
Initial rate 50 ml/h, increase infusion rate by 50 ml/h every 60 minutes. Maximum infusion rate: 200 ml/h
15	Daratumumab	16 mg/kg bw	NaCl 0.9% 500 ml	i.v.	3.25h	Sequence
Initial rate 100 ml/h, increase infusion rate by 50 ml/h every 60 minutes. Maximum infusion rate: 200 ml/h
2,4-5,9,11-12	Dexamethasone	20 mg		p.o.		1-0-0-0
Patients with BMI below 18.5 or over 75 years of age received 20mg of dexamethasone per week.

Day	Substance	Dosage	Appl.	Inf. time	Procedure
HW Hematopoietic growth factors: G-CSF prophylaxis MM, low/intermediate risk
Access: - none -
Neutrophils < 1000/µl at start of therapy + 1 additional risk factor (Palumbo et al. 2012)
2-3,5-7,9-10,12-14,16-19	Filgrastim	5 µg/kg bw	subc	Bolus	1-0-0-0
Neutrophils below 1000/µl at start of therapy + 1 additional risk factor: age > 65 yrs, female gender, comorbidities, decreased immune function, body surface area less than 2m², low performance status; daily until neutrophils > 1000/µl

Day	Substance	Dosage	Appl.	Procedure
IP Infection prophylaxis: Herpes prophylaxis
Access: - none -
Aciclovir administration for herpes prophylaxis under proteasome inhibitor therapy. DGHO recommendation 07/2015
1-21	Aciclovir	400 mg	p.o.	1-0-1-0

Concomitant therapy supplements

Dexamethasone for antitumor therapy is covered by dexamethasone of allergy prophylaxis on days 1,8 and 15. The use of methylprednisolone p.o. at a low dose (less than 20 mg) or equivalent should be considered on day 3 after infusion of daratumumab. Montelukast in allergy prophylaxis is optional starting on day 8. Levofloxacin infection prophylaxis (2 x 250mg/day) is recommended for the first 3 months after initiation of therapy in patients at high risk of infection (ESMO Guideline 02/2020). In obstructive lung disease, the use of short- and long-acting bronchodilators and inhaled corticosteroids should be considered after daratumumab infusion. If no significant IRRs occur, inhaled agents may be discontinued after the first four infusions.

Cycle diagram

Hydration: Balanced Crystalloid Solution

Substance	1	8	15
	Week 1 / d	Week 2 / d	Week 3 / d
Balanced Crystalloid Solution (i.v.)
Balanced Crystalloid Solution (i.v.)
Balanced Crystalloid Solution (i.v.)

Allergy prophylaxis: Daratumumab allergy prophylaxis with dexamethasone

Substance	1	8	15
	Week 1 / d	Week 2 / d	Week 3 / d
Dexamethasone (i.v.)
Dimetinden (i.v.)
Paracetamol (p.o.)
Montelukast (p.o.)
Dexamethasone (i.v.)
Dimetinden (i.v.)
Paracetamol (p.o.)
Dexamethasone (i.v.)
Dimetinden (i.v.)
Paracetamol (p.o.)

Antineoplastic therapy: BORT1,3/DRTM16/DEXA(20/20)

Substance	1	8	15
	Week 1 / d	Week 2 / d	Week 3 / d
Bortezomib (subc)
Daratumumab (i.v.)
Daratumumab (i.v.)
Daratumumab (i.v.)
Dexamethasone (p.o.)

Hematopoietic growth factors: G-CSF prophylaxis MM, low/intermediate risk

Substance	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19	20	21
	Week 1 / d							Week 2 / d							Week 3 / d
Filgrastim (subc)

Infection prophylaxis: Herpes prophylaxis

Substance	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19	20	21
	Week 1 / d							Week 2 / d							Week 3 / d
Aciclovir (p.o.)

Cycles

Cycle length 21 days, recommended cycles: 1

Controls:

Blood count: on day 1 and subsequently weekly
Day 1: IgG
Coombs test Before starting treatment with daratumumab, patients should be typed and screened. Interference with indirect antiglobulin test (indirect Coombs test): Daratumumab binds to CD38, which is also found on erythrocytes. This may result in a positive indirect Coombs test up to 6 months after therapy. It should be noted that daratumumab bound to erythrocytes may mask the detection of antibodies against minor antigens in the serum of patients (risk of hemolysis).
Blood group Blood grouping before the 1st cycle
Hepatitis (B) screening Risk of hepatitis B reactivation under daratumumab.
X-ray thorax Bortezomib: as a baseline finding before possible pulmonary changes with therapy (pneumonitis, interstitial pneumonia, ARDS).
Echocardiography, ECG Bortezomib: Occurrence/worsening of heart failure possible with therapy. Decrease in LVEF possible. Isolated cases of QT prolongation. Monitoring of LVEF and ECG during therapy.
Blood pressure regular control under therapy
Day 1: GOT, GPT, GGT, Bilirubin, AP, Cholinesterase Bortezomib: Patients with moderate or severe hepatic impairment should be treated with 0.7 mg/m², then increased to 1 mg/m² or further dose reduction to 0.5 mg/m² if necessary. Monitor liver enzymes during therapy.
Day 1: Creatinine, glomerular filtration rate (GFR) Bortezomib: close monitoring of renal values in patients with renal impairment.
Day 1-3,8-10,15-17: Infusion reactions Signs of nasal congestion, cough, chills, allergic rhinitis, throat irritation, dyspnea, nausea, bronchospasm, hypertension, and hypoxia

Dose adjustment

Aciclovir

for Renal Failure: Glomerular Filtration Rate (GFR)
Depending on creatinine clearance or serum creatinine, the dose may need to be adjusted (due to renal elimination of Aciclovir) (from summary of product characteristics)

Original indication

recurrent or refractory multiple myeloma

Original author

Palumbo A (2016)

Origin

Department of Hematology, University of Turin, Italy, CASTOR

References

Palumbo A, Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med 2016 Aug 25;375(8):754-66. doi: 10.1056/NEJMoa1606038. PMID: 27557302. [PMID]
Richardson PG, A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003 Jun 26;348(26):2609-17. doi: 10.1056/NEJMoa030288. PMID: 12826635. [PMID]
Nooka AK, Managing Infusion Reactions to New Monoclonal Antibodies in Multiple Myeloma: Daratumumab and Elotuzumab. J Oncol Pract 2018 Jul;14(7):414-422. doi: 10.1200/JOP.18.00143. PMID: 29996069. [PMID]
Spencer A, Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica 2018 Dec;103(12):2079-2087. doi: 10.3324/haematol.2018.194118. PMID: 30237264. [PMID]
Palumbo A, How to manage neutropenia in multiple myeloma. Clin Lymphoma Myeloma Leuk 2012 Feb;12(1):5-11. doi: 10.1016/j.clml.2011.11.001. PMID: 22178143. [PMID]

Recommendations

07/2017: European Society for Medical Oncology
05/2020: National Comprehensive Cancer Network

Status

Valid since 2021-04-15, Version 2.1, last updated 2021-06-17

Last modification: V2.1: Cato test done. Insertion of hematopoietic growth factors module according to Palumbo et al. 2012. V2.0: Cato test done Montelukast added at day 1, adjustment of durations of Daratumumab, Protocol name changed, added note on dexamethasone dosing, V1.0: Cato test done. V0.1: Duration Daratumumab according to the SmPC.

Important notice

The copyrighted protocols are treatment recommendations. The information contained in this compilation on cytostatic drugs, concomitant medication and other therapeutic procedures, as well as dosage and application information, is continuously reviewed with all due care by the authors and editors involved. Nevertheless, the publishers and authors do not assume any liability for the correctness - also with regard to possible printing errors.

The protocols may not be changed in terms of content.

Diagnosis, indication for therapy and treatment of malignant diseases must be carried out in each individual case by the hematologist and oncologist on his or her own responsibility. The treating physician is obligated to this personal responsibility to weigh in each case before a diagnostic or therapeutic measure, indication, contraindications, dosage and application under consideration of the specialized information or other documents of the manufacturers. This applies in particular to rarely used preparations or preparations that are new to the market.

The publishers and authors assume no liability for the accuracy of the contents. The application is at the own responsibility of the treating physician. ©Onkopti.

Bortezomib 1.3 / Daratumumab 16 / Dexamethasone (20/20), Multiple Myeloma, Cycle 1

Indication(s)

Protocol classification

Cycles

Protocol sequences

Risks

Therapy

Concomitant therapy supplements

Cycle diagram

Hydration: Balanced Crystalloid Solution

Allergy prophylaxis: Daratumumab allergy prophylaxis with dexamethasone

Antineoplastic therapy: BORT1,3/DRTM16/DEXA(20/20)

Hematopoietic growth factors: G-CSF prophylaxis MM, low/intermediate risk

Infection prophylaxis: Herpes prophylaxis

Cycles

Controls:

Dose adjustment

Original indication

Original author

Origin

References

Recommendations

Links

Status

Important notice