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Velzomib is a proteasome inhibitor indicated for treatment of patients with multiple myeloma and treatment of patients with mentle cell lymphoma who have received at least 1 prior therapy.
Velzomib is recommended by guidelines such as NCCN and ESMO as Preferred Regimen in multiple myeloma. Bortezomib has been used to treat an estimated 350,000 patients worldwide*.

*Bortezomib; Highlights of prescribing information. 2012. Refrence ID: 3209067
Bortezomib
Manitol
Nitrogen
1. Name of the medicinal product:
Bortezomib 3.5 mg powder for solution for injection

2. List of excipients:
Manitol, Nitrogen

3. Pharmaceutical form:
Sterile Lyophilized Powder for solution for injection. Each single use vial contains 3.5 mg Bortezomib as a white to off-white cake or powder
Side Effects
Hematological Toxicity
Neuropathy
Hepatic Impairment
Table 1 : Dose Modifications during Cycles of Combination Velzomib, Melphalan and Prednisone Therapy 1
Toxicity Dose modification or delay
Hematological toxicity during a cycle: if prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle Consider reduction of the melphalan dose by % 25 in the next cycle
If platelet count is not above 30x109/L or ANC is not above or 0.75x109/L on a Velzomib dosing day (other than day 1 ) Withhold Velzomib dose
If several Velzomib dose in consecutive cycles are withheld due to toxicity Reduce Velzomib dose by 1 dose level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2
Grade 3 or higher non-hematological toxicities3Grade Withhold Velzomib therapy until symptoms of toxicity have resolved to Grade 1 or baseline. Then, Velzomib may be reinitiated with one dose level reduction (from 1.3 mg/m2 to 1 mg/m2 , or from 1 mg/m2 to 0.7 mg/m2 ). For Velzomib- related neuropathic pain and/or peripheral neuropathy, hold or modify Velzomib as outlined in Table 2.
Table 2 : Recommended Dose Modification for Velzomib related Neuropathic Pain and/or Peripheral 1
Sensory or Motor Neuropathy
Severity of Peripheral Neuropathy Signs and Symptoms * Modification of Dose and Regimen
Grade 1 (asymptomatic: loss of deep tendon reflexes or paresthesia) without pain or loss of function No action
Grade 1 with pain or Grade 2 (moderates symptoms; limiting instrumental Activities of Daily Living (ADL)**) Reduce Velzomib to 1 mg/m2
Grade 2 with pain or Grade 3 (severesymptoms; limiting self care ADL***) Withhold Velzomib therapy until toxicity resolves.When toxicity resolves reinitiate with a reduceddose of Velzomib at 0.7 mg/m2 once per week
Grade 4 (Life- threatening consequences; urgent intervention indicated) Discontinue Velzomib
*Grading based on NCI Common Terminology Criteria CTCAE v4.0
** Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money etc;
***Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet,taking medications, and not bedridden
Table 3 : Recommended Starting Dose Modification for Velzomib in Patients with Hepatic Impairment 1
Bilirubin Level SGOT (AST) Levels Modification of Starting Dose
Mild Less than or equal to 1.0X ULN More than ULN None
More than 1.0X - 1.5X ULN Any None
Moderate More than 1.5X - 3X ULN Any Reduce Velzomib to 0.7 mg/m2 in the first cycle. Consider dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability.
Severe More than 3X ULN Any
1) Bortezomib; Highlights of prescribing information. 2012. Refrence ID: 3209067
Administration*
Route of administration Velzomib (mg/vial) Diluent (0.9% sodium chloride) Final Bortezomib conecentration (mg/mL)
Intravenous 3.5 mg 3.5 mL 1 mg/mL
Subcutaneous 3.5 mg 1.4 mL 2.5 mg/mL
Dose must be individualized to prevent overdosage. After determining patient body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of reconstituted Velzomib to be administered:
Intravenous Administration [1 mg/mL concentration]
Velzomib dose (mg/m2) x patient BSA (m2)
1 mg/mL
= Total Velzomib volume (mL) to be administered
Subcutaneous Administration [2.5 mg/mL concentration]
Velzomib dose (mg/m2) x patient BSA (m2)
2.5 mg/mL
= Total Velzomib volume (mL) to be administered
Dosing and Adjustment
Once Weekly Velzomib (Cycles 5-9 when used in combination with Melphalan and Prednisone) 1
Once Weekly Velzomib (Cycles 5-9)
Week 1 2 3 4 5 6
Velzomib (1.3 mg/m2) Day 1 - - Day 4 Day 8 - rest period day 22 - day 29 - rest period
Melphalan (9 mg/m2)
Prednisone (60 mg/m2)
Day 1 Day 2 Day 3 Day 4 - - rest period - - - - rest period
Dosage Regimen for Patients with Previously Untreated Multiple Myeloma 1
Once Weekly Velzomib (Cycles 1-4)
Week 1 2 3 4 5 6
Velzomib (1.3 mg/m2) Day 1 - - Day 4 Day 8 Day 11 rest period day 22 day 25 day 29 day 32 rest period
Melphalan (9 mg/m2)
Prednisone (60 mg/m2)
Day 1 Day 2 Day 3 Day 4 - - rest period - - - - rest period
1) Bortezomib; Highlights of prescribing information. 2012. Refrence ID: 3209067
Once Weekly Velzomib
Twice Weekly Velzomib
Various calculations have been published to arrive at the BSA without direct measurement.
In the following formulas, BSA is in m2, W is weight in kg, and H is height in cm.
Height (cm)
Weight (kg)
Severty, Symptoms and Grade
 
Calculate (mg)
Recommended Dose
( Adjusted )
Recommended Dose
( No Adjustment Needed )
Table 1 : Dose Modifications during Cycles of Combination Velzomib, Melphalan and Prednisone Therapy 1
Toxicity Dose modification or delay
Hematological toxicity during a cycle: if prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle Consider reduction of the melphalan dose by % 25 in the next cycle
If platelet count is not above 30x109/L or ANC is not above or 0.75x109/L on a Velzomib dosing day (other than day 1 ) Withhold Velzomib dose
If several Velzomib dose in consecutive cycles are withheld due to toxicity Reduce Velzomib dose by 1 dose level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2
Grade 3 or higher non-hematological toxicities3Grade Withhold Velzomib therapy until symptoms of toxicity have resolved to Grade 1 or baseline. Then, Velzomib may be reinitiated with one dose level reduction (from 1.3 mg/m2 to 1 mg/m2 , or from 1 mg/m2 to 0.7 mg/m2 ). For Velzomib- related neuropathic pain and/or peripheral neuropathy, hold or modify Velzomib as outlined in Table 2.
ESMO
NCCN
Multiple myeloma: ESMO Clinical Practice Guidelines
for diagnosis, treatment and follow-up
These Clinical Practice Guidelines are endorsed by the Japanese Society of Medical Oncology (JSMO)

Incidence and epidemiology

Multiple myeloma (MM) accounts for 1% of all cancers and ~10% of all haematological malignancies. The incidence in Europe is 4.5–6.0/100 000/year with a median age at diagnosis of between 65 and 70 years; the mortality is 4.1/100 000/year. Almost all patients with MM evolve from an asymptomatic pre-malignant stage termed monoclonal gammopathy of undetermined significance (MGUS). MGUS progresses to MM at a rate of 1% per year. In some patients, an intermediate asymptomatic but more advanced pre-malignant stage termed smouldering (or indolent) multiple myeloma (SMM) can be recognised. SMM progresses to myeloma at a rate of 10% per year over the first 5 years following diagnosis, 3% per year over the following 5 years and 1.5% per year thereafter.
NCCN Guidelines Version 2.2014*
Multiple Myeloma
MYELOMA THERAPY
Exposure to myelotoxic agents (including alkylating agents and nitrosoureas) should be limited to avoid compromising stem-cell reserve prior to stem-cell harvest in patients who may be candidates for transplants.
Preferred Regimens Other Regimens
Primary Therapy for Transplant Candidates (Assess for response after 2 cycles)
  • Bortezomib/dexamethasone (category 1)
  • Bortezomib/cyclophosphamide/dexamethasone
  • Bortezomib/doxorubicin/dexamethasone (category1)
  • Bortezomib/lenalidomide/ dexamethasone
  • Bortezomib/thalidomide/dexamethasone (category 1)
  • Lenalidomide/dexamethasone (category1)
  • Carfilzomib/lenalidomide/dexamethasone
  • Dexamethasone (category2B)
  • Liposomal doxorubicin/vincristine/dexamethasone (DVD)
  • doxorubicin/vincristine/dexamethasone (DVD) (category 2B)
  • Thalidomide/dexamethasone (category 2B)
Primary Therapy forNon-Transplant Candidates(Assess for response after2 cycles)
  • Bortezomib/dexamethasone
  • Lenalidomide/low-dose dexamethasone (category 1)
  • Melphalan/prednisone/bortezomib (MPB) (category 1)
  • Melphalan/prednisone/lenalidomide (MPL) (category1)
  • Melphalan/prednisone/thalidomide (MPT) (category 1)
  • Dexamethasone (category 2B)
  • Liposomal doxorubicin/vincristine/dexamethasone (DVD) (category 2B)
  • Melphalan/prednisone (MP)
  • Thalidomide/dexamethasone (category 2B)
  • Vinccristine/doxorubicin/dexamethasone (VAD) (category 2B)
Maintenance Therapy
  • Bortezomib
  • Lenalidomide (category1)
  • Thalidomide (category 1)
  • Bortezomib + prednisone (category 2B)
  • Bortezomib + Lenalidomide (category 2B)
  • Interferon (category 2B)
  • Steroids (category 2B)
  • Thalidomide + prednisone (category 2B)
* Bortezomib; Highlights of prescribing information. 2012. Reference ID: 3209067
ARTICLES
  • 1. Bortezomib Plus Melphalan and Prednisone Compared With Melphalan and Prednisone in Previously Untreated Multiple Myeloma: Updated Follow-Up and Impact of Subsequent Therapy in the Phase III VISTA Trial
    Purpose
    The purpose of this study was to confirm overall survival (OS) and other clinical benefits with bortezomib, melphalan, and prednisone (VMP) versus melphalan and prednisone (MP) in the phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial after prolonged follow-up, and evaluate the impact of subsequent therapies.

    Patients and Methods
    Previously untreated symptomatic patients with myeloma ineligible for high-dose therapy received up to nine 6-week cycles of VMP (n = 344) or MP (n = 338).

    Results
    With a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P  .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Response rates to subsequent thalidomide- (41% v 53%) and lenalidomide-based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%. Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months.

    Conclusion
    VMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent antimyeloma therapy. First-line bortezomib use does not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib- and other novel agent–based treatment until relapse.

    J Clin Oncol 28:2259-2266. © 2010 by American Society of Clinical Oncology
  • 2. Bortezomib Plus Dexamethasone Is Superior to Vincristine Plus Doxorubicin Plus Dexamethasone As Induction Treatment Prior to Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: Results of the IFM 2005-01 Phase III Trial
    Purpose
    To compare efficacy and safety of bortezomib plus dexamethasone and vincristine plus doxorubicin plus dexamethasone (VAD) as induction before stem-cell transplantation in previously untreated myeloma.

    Patients and Methods
    Four hundred eighty-two patients were randomly assigned to VAD (n = 121), VAD plus dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) consolidation (n = 121), bortezomib plus dexamethasone (n = 121), or bortezomib plus dexamethasone plus DCEP (n = 119), followed by autologous stem-cell transplantation. Patients not achieving very good partial response (VGPR) required a second transplantation. The primary end point was postinduction complete response/near complete response (CR/nCR) rate.

    Results
    Postinduction CR/nCR (14.8% v 6.4%), at least VGPR (37.7% v 15.1%), and overall response (78.5% v 62.8%) rates were significantly higher with bortezomib plus dexamethasone versus VAD; CR/nCR and at least VGPR rates were higher regardless of disease stage or adverse cytogenetic abnormalities. Response rates were similar in patients who did and did not receive DCEP. Post first transplantation, CR/nCR (35.0% v 18.4%) and at least VGPR (54.3% v 37.2%) rates remained significantly higher with bortezomib plus dexamethasone. Median progression-free survival (PFS) was 36.0 months versus 29.7 months (P = .064) with bortezomib plus dexamethasone versus VAD; respective 3-year survival rates were 81.4% and 77.4% (median follow-up, 32.2 months). The incidence of severe adverse events appeared similar between groups, but hematologic toxicity and deaths related to toxicity (zero v seven) were more frequent with VAD. Conversely, rates of grade 2 (20.5% v 10.5%) and grades 3 to 4 (9.2% v 2.5%) peripheral neuropathy during induction through first transplantation were significantly higher with bortezomib plus dexamethasone.

    Conclusion
    Bortezomib plus dexamethasone significantly improved postinduction and post-transplantation CR/nCR and at least VGPR rates compared with VAD and resulted in a trend for longer PFS. Bortezomib plus dexamethasone should therefore be considered a standard of care in this setting.

    J Clin Oncol 28. © 2010 by American Society of Clinical Oncology
  • 3. Bortezomib, melphalan, prednisone (VMP) versus melphalan, prednisone, thalidomide (MPT) in elderly newly diagnosed multiple myeloma patients: A retrospective case-matched study
    Novel agents in combination with melphalan and prednisone (MP) significantly improved progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM). Randomized trials comparing MP plus bortezomib (VMP) versus MP plus thalidomide (MPT) are lacking. Nine hundred and fifty-six elderly (>65 years) newly diagnosed MM patients from six European randomized trials were retrospectively analyzed and matched for age, albumin, and beta2-microglobulin at diagnosis, 296 patients were selected from the VMP groups, and 294 from MPT. Complete response rate was 21% in the VMP patients and 13% in the MPT patients (P50.007). After a median follow-up of 34 months (range, 1–92), VMP significantly prolonged both PFS (median 32.5 vs. 22.9 months, HR 0.65; 95% CI 0.52–0.82; P < 0.001) and OS (median 79.7 vs. 45.1 months, HR 0.44; 95% CI 0.32–0.59; P < 0.001) in comparison with MPT. The benefit in terms of OS of the VMP group was quite similar among patients with different risk factors defined by sex, ISS, ECOG performance status, or serum creatinine but not among patients 75 years. Multivariate analysis confirmed that VMP was an independent predictor of longer PFS and OS. In a control-case matched analysis, PFS and OS were prolonged in patients who received VMP in comparison with those treated with MPT.

    Am. J. Hematol. 00:000–000, 2013. VC 2013 Wiley Periodicals, Inc.
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PO Box: 1516673115
CONTACT US
مولتیپل میلوما
مولتیپل میلوما یا میلوم متعدد تکثیری بدخیم در پلاسماسل‌ها است که از یک کلون منفرد ایجاد می‌شود. تظاهرات آن به صورت درداستخوان یا شکستگی، نارسایی کلیه، استعداد به عفونت، کم خونی،هیپرکلسمی می‌باشد.
رشدهای ناهنجار پلاسماسل، بیماری‏هایی هستند که در آن‏ها نوع خاصی از سلول‏های خونی به نام "پلاسماسل" (Plasma cell) سرطانی می‌شوند. این سلول‏ها از نوعی گلبول‏های سفید خون به نام لنفوسیت B ساخته می‌شوند، پلاسماسل‌ها تولید‏کننده پادتن یا آنتی‏بادی‌ها هستند. هنگامی که این سلول‌ها سرطانی می‌شوند ممکن است مقادیر معتنابهی پادتـــن و ماده‌ای به نام "پروتئین - M" تولید کنند که در خون و ادرار یافت می‌شود. انواع متعددی از بدخیمی‌های پلاسماسل وجود دارد. شایع‌ترین آن "مولتیپل میلوما" نامیده می‌شود. پلاسماسل‌های بدخیم می‌توانند در استخوان تجمع کرده و توده‌های کوچکی به نام "پلاسموسیتوم" بوجود آورند.
علائم بالینی
در مولتیپل میلوما پلاسماسل‌های سرطانی در مغز استخوان یافت می‌شوند. مغز استخوان مولد گلبول‏های قرمز، گلبول‏های سفید و پلاکت‏ها می‌باشد. افزایش سلول‏های سرطانی باعث کاهش سلول‏های خونی و نهایتاً کم خونی می‌شود. همچنین ممکن است پلاسما‏سل‏ها باعث شکسته شدن استخوان شوند. علائم شایع درد شدید و عمیق در استخوان‌های درگیر، کاهش وزن، علایم کم‌خونی نظیر ضعف، رنگ پریدگی، خستگی و تنگی نفس است. سندرم هیپرویسکوزیته (افزایش ویسکوزیته خون) از تظاهرات نادر است. کرایوگلبولین‌ها، ایمونو گلبولین‌هایی هستند که در درجه حرارت کمتر از 37 درجه سانتیگراد تمایل به رسوب دارند. کرایوگلبولین‏های مونوکلونال معمولاً با یک اختلال هماتولوژیک مشخص همراه هستند و غالباً بدون علامت اند.
شیوع
این بیماری می‌تواند مغز همه استخوان‌ها را درگیر سازد ولی شایع‌ترین مکان‌های درگیری عبارتند از ران، کمر، لگن یا بالای بازو. این بیماری در مردان سنین 70-50 سال شایع‌تر است.
مرحله‏ بندی مولتیپل میلوما
I
در این مرحله، نسبتاً تعداد کمی از سلول‏های سرطانی در بدن پخش شده‌اند . تعداد گلبول‏های قرمز خون و میزان کلسیم خون طبیعی است . هیچ توده‌ای (پلاسموسیتوم) در استخوان یافت نمی‌شود. مقدار پروتئین - M در خون و ادرار بسیار ناچیز است . ممکن است بیماری علامت و نشانه بالینی نداشته باشد.
II
در این مرحله سلولهای سرطانی به تعداد نه کم و نه زیاد در بدن پخش شده‌اند.
III
تعداد نسبتاً زیادی سلول‏های سرطانی در بدن پخش شده‌اند. همچنین ممکن است یک یا تعداد بیشتری از موارد زیر دیده شود:
  1. کاهش تعداد گلبول‏های قرمز که منجر به کم خونی شده‌است.
  2. میزان کلسیم خون بدلیل آسیب استخوان‏ها بسیار افزایش یافته‌است.
  3. بیش از 3 توده استخوانی ( پلاسماسیتوم ) یافت می‌شود.
  4. مقادیر بالای پروتئین - M در خون یا ادرار دیده می‌شود.
تهران، میدان آرژانتین، خیابان الوند، پلاک 39
کدپستی: 1516673115
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