The recently published American Society of Clinical Oncology clinical practice guidelines for the use of bisphosphonates (BPs) in multiple myeloma do not recommend use of these drugs in patients with monoclonal gammopathies not requiring specific treatments, such as smoldering/indolent myeloma or monoclonal gammopathies of undetermined significance. The guidelines were updated in 2007 and continue to recommend that bisphosphonates not be given to myeloma patients with solitary plasmacytoma, smoldering or indolent disease, and monoclonal gammopathy of undetermined significance. The 2006 Mayo Clinic Consensus reached the same conclusion.

The most recent guideline is a European one from 2012. The panel recommends the use of biphoopshanates(BP)s in Multiple Myeloma patients suffering from lytic bone disease or severe osteoporosis. Intravenous administration may be preferable; however, oral administration can be considered for patients unable to make hospital visits. The panel agrees that BPs should be given for 2 years, but this may be extended if there is evidence of active myeloma bone disease. A recent article in 2013 New England of Medicine  ( Mateos et al) suggested that high risk smoldering myeloma should be aggressively treated.  This is  remains controversial.

Smith A, Wisloff F, Samson D, UK Myeloma Forum, Nordic Myeloma Study Group, British Committee for Standards in Haematology. Guidelines on the diagnosis and management of multiple myeloma 2005. Br J Haematol 2006 Feb;132(4):410-51. [292 references]

NCCN.ORG, Myeloma, 2012

Lacy MQ, Dispenzieri A, Gertz MA, et al. Mayo Clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc. 2006;81:1047-1053.

Terpos E, Sezer O, Croucher PI, et al. The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol 2009; 20:1303.
María-Victoria Mateos, M.D., Ph.D., Miguel-Teodoro Hernández, M.D., Pilar Giraldo, M.D., Javier de la Rubia, M.D., Felipe de Arriba, M.D., Ph.D., Lucía López Corral, M.D., Ph.D., Laura Rosiñol, M.D., Ph.D., Bruno Paiva, Ph.D., Luis Palomera, M.D., Ph.D., Joan Bargay, M.D., Albert Oriol, M.D., Felipe Prosper, M.D., Ph.D., Javier López, M.D., Ph.D., Eduardo Olavarría, M.D., Ph.D., Nuria Quintana, M.D., José-Luis García, M.D., Joan Bladé, M.D., Ph.D., Juan-José Lahuerta, M.D., Ph.D., and Jesús-F. San Miguel, M.D., Ph.D.
N Engl J Med 2013; 369:438-447August 1, 2013

Patients with melanomas less than or equal to 1.0 mm in thickness are at lower risk for nodal involvement (2-5%), and there is debate as to whether they would benefit from evaluation of their nodal basin. Currently, the National Comprehensive Cancer Network (NCCN) recommends against SLND for patients with melanoma in situ or melanoma less than 1.0 mm in thickness. Patients with melanoma between 0.76 mm and 1.0 mm in thickness may be considered for SLND if they have adverse features such as positive deep margins, lymphovascular invasion, age less than 40 years, significant vertical growth face, increased mitotic rate, and Clark’s level IV or higher. Those with melanoma that exhibits regression may also be considered, but this is more controversial. Some recent studies have indicated that there may be no association between regression and positive SLN status. SLND is also offered to patients with deep (>4 mm) melanoma and clinically negative nodes because it has proven to yield valuable prognostic information, with rates of positive SLNs ranging from 30-40%.

Similarly, ASCO 2012 recommends: ” SLN biopsy is recommended for patients with intermediate-thickness melanomas (1-4mm Breslow thickness) of any anatomic site; use of SLN biopsy in this population provides accurate staging. While there are few studies focusing on patients with thick melanomas (T4; >4mm Breslow thickness), SLN biopsy may be recommended for staging purposes and to facilitate regional disease control. There is insufficient evidence to support routine SLN biopsy for patients with thin melanomas (T1; <1mm Breslow thickness), although it may be considered in selected cases with high risk features when staging benefits outweigh risks of the procedure. Completion lymph node dissection (CLND) is recommended for all patients with a positive SLN biopsy and achieves good regional disease control. Whether CLND following a positive SLN biopsy improves survival is the subject of the ongoing Multicenter Selective Lymphadenectomy Trial II.”
Stadelmann WK. The role of lymphatic mapping and sentinel lymph node biopsy in the staging and treatment of melanoma. Clin Plast Surg. Jan 2010;37(1):79-99.

Morris KT, Busam KJ, Bero S, Patel A, Brady MS. Primary cutaneous melanoma with regression does not require a lower threshold for sentinel lymph node biopsy. Ann Surg Oncol. Jan 2008;15(1):316-22. [Medline].

Socrier Y, Lauwers-Cances V, Lamant L, Garrido I, Lauwers F, Lopez R, et al. Histological regression in primary melanoma: not a predictor of sentinel lymph node metastasis in a cohort of 397 patients. Br J Dermatol. Apr 2010;162(4):830-4.

http://www.asco.org/ASCOv2/Practice+%26+Guidelines/Guidelines/Clinical+Practice+Guidelines/Melanoma

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.

This is relatively unpublished regimen, although it is in extensive use at University of Arkansas. In general, conditioning regimens have been established on the basis of phase II studies; there are only few comparative studies of different conditioning regimen. This Super-BEAM regimen is ahead of the “curve” and should be considered experimental. Very little had been published on it as of yet.

Sarah Waheed, MD et al, abs3421 SUPER- BEAM (SB): Incorporation of Bortezomib, Thalidomide, Dexamethasone, Cisplatin and Rapamycin Into the BEAM Regimen for Multiple Myeloma (MM)
Poster Session: Clinical Results – Autologous Transplantation Poster III
ASH 2009

http://myeloma.uams.edu/upload/docs/Myeloma/PACMEd%20v3.pdf

nccn.org myeloma 2012

Read the Layperson version here.

These recommendations are intended to apply only to newly diagnosed cases of myeloma or frank relapse cases. The use of FISH to monitor response to high dose therapy, or to study diseases such as MGUS or primary amyloidosis where only a small proportion of the plasma cells may belong to the abnormal clone is still considered to be a research tool, and different criteria may need to be used.

The purpose of the workshop was to agree rules for FISH in myeloma but consideration was also given to conventional cytogenetic studies. It was agreed that these should not be discouraged but that, especially in a multi-centre setting, full cytogenetic studies were often impracticable due to the poor quality of samples and the poor ratio of number of man-hours required for the analysis to the number of patients on whom an abnormal result is obtained.

It was felt very strongly that much still needs to be learned about the significance of chromosome abnormalities in myeloma. For this reason, FISH results should not yet be used to make treatment decisions, except in the context of a clinical trial. The workshop also made 14 technical recommendations which are not applicable to this issue.

In conclusion, FISH for myeloma is still an investigational modality. A number of guidelines and reviews mention FISH but do not definitively address its place in myeloma diagnosis and management.

At present, in multiple myeloma, the use of conventional cytogenetics is currently restricted to clinical research studies and the differential diagnosis of unusual cases, because it tends to represent cells that admix rather than myelooma cells. However, certain FISH markers correlate well with prognosis and can be used in treatment decisions. Specifically, translocations involving the immunoglobulin heavy chain gene (IGH) at 14q32 and either monosomy or deletions of chromosome 13 (which can also be picked up on cytogenetics)  have been reported in a significant number of patients from both cytogenetic and interphase fluorescence in situ hybridization (FISH) studies. The CPT codes refer to the technical components of tests and panels of different markers and individual better established tests are difficult to separate from less established ones. Medicare currently covers cytogenetics and FISH for multiple myeloma. NCCN also recommends cytogenetics and FISH.

In conclusion, cytogenetics and FISH(88271) are tepidly supported by the workshop. Only one special stain(88313), iron, is documented.

More recenlty, it is recommended by Bird et al that a diagnosis of myeloma be confirmed by the demonstration of an aberrant plasma cell phenotype and/or monoclonality. Plasma cell phenotyping may be performed by flow cytometry and/or immunohistochemistry on trephine sections. Using an aspiratewith various cell types in it  confounds the results.

Jennifer M. Bird et al, Guidelines for the diagnosis and management of multiple myeloma 2011. British Journal of Haematology Volume 154, Issue 1, pages 32–75, July 2011

Fonseca R, Barlogie B, Bataille R, Bastard C, Bergsagel PL, Chesi M, Davies FE, Drach J, Greipp PR, Kirsch IR, Kuehl WM, Hernandez JM, Minvielle S, Pilarski LM, Shaughnessy JD Jr, Stewart AK, Avet-Loiseau H.Genetics and cytogenetics of multiple myeloma: a workshop report.Cancer Res. 2004 Feb 15;64(4):1546-58.

N. C. Gutierrez, J. L. Garcia, J. M. Hernandez, E. Lumbreras, M. Castellanos, A. Rasillo, G. Mateo, J. M. Hernandez, S. Perez, A. Orfao, et al.
Prognostic and biologic significance of chromosomal imbalances assessed by comparative genomic hybridization in multiple myeloma
Blood, November 1, 2004; 104(9): 2661 – 2666.

Harrison, Christine J. (2003) Cytogenetics of multiple myeloma: interpretation of fluorescence in situ hybridization results. British Journal of Haematology 120(6) Br J Haematol. 2009 Oct;147(1):22-42. Epub 2009 Aug 10.