Tumour lysis syndrome in multiple myeloma after bortezomib (VELCADE) administration.
J Cancer Res Clin Oncol. 2004 Oct;130(10):623-5.
Terpos E, Politou M, Rahemtulla A

Severe irreversible bilateral hearing loss after bortezomib (VELCADE) therapy in a multiple myeloma (MM) patient.
Leukemia. 2005 May;19(5):869-70.
Engelhardt M, Müller AM, Maier W, Wäsch R.

Severe pulmonary complications in Japanese patients after bortezomib treatment for refractory multiple myeloma.
Blood. 2006 May 1;107(9):3492-4.
Miyakoshi S, Kami M, Yuji K, Matsumura T, Takatoku M, Sasaki M, Narimatsu H, Fujii T, Kawabata M, Taniguchi S, Ozawa K, Oshimi K.
The authors report the occurrence of severe lung toxicity in 13 patients with multiple myeloma treated with bortezomib. Two patients died of respiratory failure.

Rapid response to high-dose steroids of severe bortezomib-related pulmonary complication in multiple myeloma.
J Clin Oncol. 2007 Aug 1;25(22):3380-1.
Zappasodi P, Dore R, Castagnola C, Astori C, Varettoni M, Mangiacavalli S, Lazzarino M, Corso A.
A 66-year-old man with myeloma treated with bortezomib developed severe acute respiratory failure after the second cycle. CT of the chest showed bilateral pulmonary lesions and consolidation, and pleural effusions, with a pattern suggesting bronchiolitis obliterans organizing pneumonia. A rapid improvement was achieved with corticosteroids, starting with methylprednisolone 500 mg/24 hours for 2 days.

Recurrent capillary leak syndrome following bortezomib therapy in a patient with relapsed myeloma.
Ann Pharmacother. 2010 Mar;44(3):587-9.
Hsiao SC, Wang MC, Chang H, Pei SN.

Chalazia associated with bortezomib therapy for multiple myeloma.
Ophthalmology. 2014 Sep;121(9):1845-1847.e3.
Grob SR, Jakobiec FA, Rashid A, Yoon MK.

Development of acute pulmonary hypertension after bortezomib treatment in a patient with multiple myeloma: a case report and the review of the literature.
Am J Ther. 2015 May-Jun;22(3):e88-92.
Akosman C, Ordu C, Eroglu E, Oyan B.

Bortezomib-induced acute pancreatitis: Case report and review of the literature.
Talamo G, Sivik J, Pandey MK, Mir MA.
J Oncol Pharm Pract. 2016 Apr;22(2):332-4.

A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma.
Br J Haematol. 2017 Aug;178(4):547-560.
Laubach JP, Moslehi JJ, Francis SA, San Miguel JF, Sonneveld P, Orlowski RZ, Moreau P, Rosiñol L, Faber EA Jr, Voorhees P, Mateos MV, Marquez L, Feng H, Desai A, van de Velde H, Elliott J, Shi H, Dow E, Jobanputra N, Esseltine DL, Niculescu L, Anderson KC, Lonial S, Richardson PG.
After analyzing data from  2509 myeloma patients treated with bortezomib-containing regimens, and 1445 control patients, the incidence of cardiac events was low: arrhythmias 1-6%, ischemic heart disease 1-3%, CHF (grade 3 or 4) 1-5%, and cardiac death about 1%. More importantly, there were no significant differences between the bortezomib-treated patients and the controls.



Therapeutic measures that can be attempted:
  - Gabapentin, pregabalin, tricyclic antidepressants
  - Opioid analgesics (e.g., extended-release oxycodone)
  - Local application of lidocaine or menthol-based analgesic creams

Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib.
J Clin Oncol. 2006 Jul 1;24(19):3113-20.
Richardson PG, Briemberg H, Jagannath S, Wen PY, Barlogie B, Berenson J, Singhal S, Siegel DS, Irwin D, Schuster M, Srkalovic G, Alexanian R, Rajkumar SV, Limentani S, Alsina M, Orlowski RZ, Najarian K, Esseltine D, Anderson KC, Amato AA.
In this study of 256 myeloma patients enrolled in 2 phase II studies, bortezomib-induced peripheral neuropathy developed in 35% of patients. The rate of neuropathy was 37% (84 of 228 patients) when bortezomib was given at 1.3 mg/m2, and 21% (6 of 28 patients) when bortezomib was given at 1.0 mg/m2.
Severity of peripheral neuropathy:
  - Grade 1-2: 22%
  - Grade 3: 13%
  - Grade 4: 0.4%
Neuropathy required dose reductions of bortezomib in 12% of patients, and discontinuation of it in 5% of patients. After dose reduction or discontinuation of bortezomib, neuropathy of grade 3 or 4 improved or completely resolved in 71% of patients.

Features and risk factors of peripheral neuropathy during treatment with bortezomib for advanced multiple myeloma.
Clin Lymphoma Myeloma. 2008 Jun;8(3):146-52.
El-Cheikh J, Stoppa AM, Bouabdallah R, de Lavallade H, Coso D, de Collela JM, Auran-Schleinitz T, Gastaut JA, Blaise D, Mohty M.
Among 100 myeloma patients treated with bortezomib for a median of 8 months (range: 0.1-32 months), 38% developed bortezomib-induced peripheral neuropathy. This was grade 3 in 5 patients and grade 4 in 1 patient. Median time to onset of neuropathy was 53 days (range: 11-182 days). Neuropathy improved or completely resolved in 53% of cases, at a median of 3 months (range: 1-8 months). The incidence of bortezomib-induced peripheral neuropathy was significantly higher in patients who received > 4 cycles of bortezomib, and in patients previously treated with thalidomide.

Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature.
Blood. 2008 Sep 1;112(5):1593-9.
Argyriou AA, Iconomou G, Kalofonos HP.



The subcutaneous administration of bortezomib can induce injection site reactions. It is recommended that injections are rotated among 8 different sites on the abdomen and thigh.
Most reactions disappear within 10 days without sequelae.
Treatment: often not necessary. Topical steroids can be used.

Higher incidence of injection site reactions after subcutaneous bortezomib administration on the thigh compared with the abdomen.
Eur J Haematol. 2013 Feb;90(2):157-61.
Kamimura T, Miyamoto T, Yokota N, Takashima S, Chong Y, Ito Y, Akashi K.
In a series of 15 patients, the authors demonstrated that injection site reaction were more frequent in the thigh compared with the abdomen (grade II: 9% vs 1%).
   Grade I =  tenderness with or without symptoms (pruritus, erythema, warmth)
   Grade II = pain, edema, phlebitis, lipodystrophy
It is possible that the more frequent occurrence in the thigh is due to the fact that the abdomen has more abundant adipose tissue, and therefore the local concentration of bortezomib in the subcutaneous tissues of the abdomen is more diluted.


Example of a site reaction after subcutaneous injection of bortezomib (my personal archive):




Bortezomib and the increased incidence of herpes zoster in patients with multiple myeloma.
Clin Lymphoma Myeloma. 2008 Aug;8(4):237-40.
Kim SJ, Kim K, Kim BS, Lee HJ, Kim H, Lee NR, Nam SH, Kwon JH, Kim HJ, Sohn SK, Won JH, Lee JH, Suh C, Yoon SS, Kim HJ, Kim I, Do YR, Lee WS, Joo YD, Shin HJ; Korean Multiple Myeloma Working Party.
This is a retrospective analysis of 282 myeloma patients treated with bortezomib-containing regimens. The incidence of herpes zoster was 11% (31 of 282 patients) without bortezomib, but after treatment with bortezomib, the incidence increased to 22% (63 of 282 patients). In the vast majority of cases, herpes zoster developed during the the first 3 cycles of bortezomib.

Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study.
J Clin Oncol. 2008 Oct 10;26(29):4784-90.
Chanan-Khan A, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Neuwirth R, Anderson KC, Richardson PG.
The authors evaluated the incidence of VZV reactivation in 663 patients with relapsed myeloma enrolled in the APEX trial (phase III trial comparing bortezomib vs dexamethasone). They found that bortezomib treatment was associated with a significantly higher incidence of VZV reactivation compared with dexamethasone treatment (13% vs 5%, p =0.0002). Time to onset of VZV reactivation and absolute lymphocyte counts at baseline were similar between the two arms. The incidence of other (non-VZV) herpes viral infections was similar between the two arms. The authors concluded that the use of antiviral prophylaxis considered in all patients treated with bortezomib.



Giampaolo Talamo, M.D.