Cancer Treatment Today » Amyloidosis

Velcade First Line in Multiple Myeloma – pro

M Levin, MD — Mon, 13 Aug 2012 18:03:36 +0000

There are relatively few effective treatment options for patients with multiple myeloma. Traditional treatment includes combination chemotherapy with melphalan/prednisone and vincristine/doxorubicin/dexamethasone. Myeloablation with high-dose chemotherapy and subsequent rescue with ASCT is a mainstay for patients fit enough to withstand the regimen, usually patients less than 65 years of age. The immunomodulators, thalidomide and lenalidomide, alone or in combination with dexamethasone, have been shown to be effective in multiple myeloma.

Bortezomib is a first-in-class proteasome inhibitor that has shown remarkable efficacy in multiple myeloma. Bortezomib specifically targets the ubiquitin-proteasome pathway; the proteasome plays a key role in the degradation of ubiquinated proteins in general, and specifically proteins that control tumor cell growth and survival. By targeting the proteasome and acting on the multiple myeloma cells as well as the microenvironment, bortezomib has been shown to increase response in patients with multiple myeloma, especially in patients with relapsed and refractory disease. Bortezomib was first indicated for the treatment of relapsed and refractory multiple myeloma, including use as second-line treatment after first relapse.

Bortezomib has shown activity as first-line treatment in newly diagnosed, untreated multiple myeloma in two phase II studies. In one study, overall response after more than 2 cycles of therapy (n = 22) was 64%. Peripheral neuropathy occurred in 21% of patients and was mainly grade 2 and managed with dose modification.

In the second study, patients (completed, n = 23) received single-agent bortezomib with added dexamethasone for less than PR after 2 cycles or less than CR after 4 cycles of treatment [33]. Overall major response was 83%. Best response was recorded for 43% of patients after cycle 2, 39% after cycle 4, and 13% after cycle . The addition of dexamethasone (61% of patients) increased response in 9 patients. Peripheral neuropathy (grades 1-3) occurred in 56% of patients; 12% had neuropathic pain, which resolved when treatment was discontinued.

A number of phase I/II clinical trials have investigated the use of bortezomib in combination with chemotherapy, including dexamethasone, for induction treatment prior to ASCTThe conclusion from these studies is that bortezomib is an effective adjunct to standard induction regimens, with excellent response, successful mobilization of peripheral blood stem cells, and good tolerance. Based on this data, NCCN recommends bortezomib/dexamethasone as primary (front-line) therapy for transplant candidates. Newer studies suggest that it is a superior front line treatment and FDA approval has been granted.

Rami Manochakian, Kena C. Mis iller, Asher A. Chanan-Khan Clinical Impact of Bortezomib in Frontline Regimens for Patients with Multiple Myeloma The Oncologist, Vol. 12, No. 8, 978-990, August 2007;

Mario Dicatoa et al, Management of Multiple Myeloma with Bortezomib: Experts Review the Data and Debate the Issues Oncology Vol. 70, No. 6, 2006

http://nccn.org/professionals/physician_gls/PDF/myeloma.pdf

Revised: 10/5/08

Reece DE, Rodriguez GP, Chen C, et al. Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. Journal of Clinical Oncology 2008;26:4777-4783.

Melphalan for Amyloidosis – pro

M Levin, MD — Mon, 13 Aug 2012 18:00:07 +0000

Treatment for systemic amyloidosis targets the aberrant plasma cell clone to prevent further synthesis and deposition of the amyloid protein. Conventional therapy usually combines oral melphalan with prednisone (MP), shown to yield higher response rates and longer survival than colchicine or prior therapies. This was investigated in a three arm study in 1997. The patients were randomly assigned to receive colchicine (72 patients), melphalan and prednisone (77), or melphalan, prednisone, and colchicine (71). They were stratified according to their chief clinical manifestations: renal disease (105 patients), cardiac involvement (46), peripheral neuropathy (19), or other (50). Therapy with melphalan and prednisone results in objective responses and prolonged survival as compared with colchicine in patients with primary amyloidosis. Guidelines on the diagnosis and management of AL amyloidosis. Br J Haematol 2004; 125:681–700.

Alastair Smith Finn Wisloff Diana Samson on behalf of the UK Myeloma Forum, Nordic Myeloma Study Group and British Committee for Standards in Haematology. (2006) Guidelines on the diagnosis and management of multiple myeloma 2005. British Journal of Haematology 132:4, 410-451

Wechalekar, A. D., Lachmann, H. J., Goodman, H. J. B., Bradwell, A., Hawkins, P. N., Gillmore, J. D. (2008). AL amyloidosis associated with IgM paraproteinemia: clinical profile and treatment outcome. Blood 112: 4009-4016

Velcade for Amyloidosis – pro

M Levin, MD — Sat, 30 Jun 2012 18:04:17 +0000

Bortezomib is a first-in-class proteasome inhibitor that has shown remarkable efficacy in multiple myeloma. Bortezomib specifically targets the ubiquitin-proteasome pathway; the proteasome plays a key role in the degradation of ubiquinated proteins in general, and specifically proteins that control tumor cell growth and survival. By targeting the proteasome and acting on the multiple myeloma cells as well as the microenvironment, bortezomib has been shown to increase response in patients with multiple myeloma, especially in patients with relapsed and refractory disease. Bortezomib is currently indicated for the treatment of multiple myeloma, including use as first line or in second-line treatment after first relapse.Bortezomib can be combined with other agents and much investigation is going on.

For amyloidosis, several studies show that bortezomib is a active drug with high response rates in various lines of therapy. These include 1 phase II clinical study (Kastritis et al, 2007), small case series (Wechalekar et al, 2008), and case reports (Borde et al, 2008). Data showing hematologic overall response rate exceeding 66 percent and complete response rates of up to 37 percent seen with single agent VELCADE were presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO) held in Chicago, Illinois, June 4-8, 2010.

NCCN’s Drug and Biologics Compendium lists systemic light chain amyloidosis as an indication for bortzomib as do NCCN guidelines (2011).

Carlson, Robert H. Amyloidosis: High Hematologic Response Rates with Bortezomib, Oncology Times: 10 August 2010 – Volume 32 – Issue 15 – pp 16-17

Mario Dicatoa et al, Management of Multiple Myeloma with Bortezomib: Experts Review the Data and Debate the Issues Oncology Vol. 70, No. 6, 2006

Sitia R, Palladini G, Merlini G. Bortezomib in the treatment of AL amyloidosis: Targeted therapy? Haematologica. 1007;92(10):1302-1305.

National Comprehensive Cancer Network (NCCN). Bortezomib. In: NCCN Drugs & Biologics Compendium. Fort Washington, PA: NCCN; 2008.

National Comprehensive Cancer Network (NCCN). Multiple myeloma. NCCN Clinical Practice Guidelines in Oncology v.2.2009. Fort Washington, PA: NCCN; 2009.

Comenzo RL. Managing systemic light-chain amyloidosis. J Natl Compr Canc Netw. 2007;5(2):179-187.

Kastritis E, Anagnostopoulos A, Roussou M, et al. Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone. Haematologica. 2007;92(10):1351-1358.

Wechalekar AD, Lachmann HJ, Offer M, et al. Efficacy of bortezomib in systemic AL amyloidosis with relapsed/refractory clonal disease. Haematologica. 2008;93(2):295-298.

Revised: 1/29/2012

Suboxone, a Sublingual Preparation of Buprenorphine in Treatment of Chronic Cancer Pain – pro

M Levin, MD — Tue, 19 Jun 2012 21:14:52 +0000

Buprenorphin comes in a sublingual and transdermal formulation. In October 2002, the Food and Drug Administration (FDA) approved buprenorphine monotherapy product, Subutex®, and a buprenorphine/naloxone combination product, Suboxone®, for use in opioid addiction treatment. The combination product is designed to decrease the potential for abuse by injection.

The transdermal form is well-established for treatment of chronic cancer pain and. It was recommended for this purpose by a consensus conference(Pergolizzin et al). The sublingual form is much less studied in this setting. Notably, it was started as longer go us 1979 by Robbie. He concluded that this sublingual preparation seems worthy of addition to the commercially available range of analgesics in clinical practice. Other publications appeared occasionally over the next 20 years and have been generally supportive. in 2005, Malinoff found it to be well tolerated and safe and appeared to be effective in the treatment of chronic pain patients refractory to other pain medications. It continued to be mildly recommended in more recent reviews.

Pergolizzi JV Jr, Mercadante S, Echaburu AV, Van den Eynden B, Fragoso RM, Mordarski S, Lybaert W, Beniak J, Orońska A, Slama O; Euromed Communications meeting.Curr Med Res Opin. 2009 Jun;25(6):1517-28.

D. S. Robbie A trial of sublingual buprenorphine in cancer pain. Br J Clin Pharmacol. 1979; 7(Suppl 3): 315S–317S.

Hotz G. Oral and maxillofacial cancer pain therapy with sublingual buprenorphine.Schmerz. 1988 Mar;2(1):38-41.

Malinoff HL, Barkin RL, Wilson G. Sublingual buprenorphine is effective in the treatment of chronic pain syndrome.Am J Ther. 2005 Sep-Oct;12(5):379-84.

Yokell MA, Zaller ND, Green TC, Rich JD. Buprenorphine and buprenorphine/naloxone diversion, misuse, and illicit use: an international review.Curr Drug Abuse Rev. 2011 Mar 1;4(1):28-41.

Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone). Pain Pract. 2008 Jul-Aug;8(4):287-313.

Pergolizzi J, Böger RH, Budd K, Dahan A, Erdine S, Hans G, Kress HG, Langford R, Likar R, Raffa RB, Sacerdote P. The role of transdermal buprenorphine in the treatment of cancer pain: an expert panel consensus.Pain Pract. 2008 Jul-Aug;8(4):287-313.