Cancer Treatment

DVD (Doxil) for myeloma

The VAD regimen has long been used for myeloma. It includes infusional Adriamycin but a newer drug, Doxil, may replace it. A multi-center trial is ongoing involving over 200 patients, comparing Doxil, Vincristine, and decadron (DVd) versus Vincristine, Adriamycin, and Dexamethasone (VAD). DVD is faster, does not require a prolonged infusion and is less cardiotoxic; it is more cost effective. It is supported by phase II trials and has been widely adopted in the place fo VAD.It is recommended by several guidelines and The Consensus

Statement.http://myeloma.org/pdfs/MyelomaManagementGuidelines.pdf

http://www.bcshguidelines.com/pdf/UKNordic_070705.pdf

http://www.aspb.ro/documente/protocoaleclinice/Oncologie/myeloma.pdf, p.17

Maintenance in myeloma

The role of maintenance therapy in multiple myeloma is controversial. A number of different maintenance strategies have been evaluated without clear benefit for one therapy versus another or, a clear benefit of any specific therapy in terms of prolonging remission or overall survival.

Recently, a study by the Southwest Oncology Group (SWOG) noted that patients receiving prednisone at a starting dose of 50 mg three times a week had excellent remission duration and survival, indicating that this could be a good maintenance strategy. In the 1980s, Franco Mandelli published results suggesting that using interferon could prolong the disease-free interval for patients with multiple myeloma. Subsequent studies have failed to confirm this effect, although not all the studies have been negative.Aredia is anotehr agent that is being studied.

Total 3 regimens include a multidrug regimen maintenance phase with Revlimid and Velcade. This continues to be investigated. Guidelines currenlty do not recommend routine maintenance, except that NCCN menions interferon and steroids as level 2B evidence.

The Myeloma Trialists' Collaborative Group. Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol. 2001;113:1020-1034.

NCCN.org, myeloma

Rituxan for Waldenstrom's macroglobulinemia

Waldenström's macroglobulinemia (WM) is a CD20 expressing B-cell malignancy represented by the pathological diagnosis of IgM secreting lymphoplasmacytic lymphoma. Since 1999, there have been many reprts and several  phase II studies of Rituxan in this disease. Major response rates of 30% have been reported in most studies with standard dose rituximab, i.e. 4 weekly infusions at 375 mg/m2/week.  A recent guideline states: "Rituximab is active in the treatment of WM but associated with the risk of transient exacerbation of clinical effects of the disease and should only be used with caution especially in patients with symptoms of hyperviscosity and/or IgM levels > 40g/L. Level of evidence IIb, Grade of recommendation B." In light of this guidelien, Rituxan should not be considered experiemntal since it is recognized by exp[ert opinon to be useful in the form of the guideline.

A. Vijay and M. A. Gertz
Waldenstrom macroglobulinemia
Blood, June 15, 2007; 109(12): 5096 - 5103.

S. P. Treon, C. Emmanouilides, E. Kimby, A. Kelliher, F. Preffer, A. R. Branagan, K. C. Anderson, S. R. Frankel, and On behalf the Waldenstrom's Macroglobulinemia Clin
Extended rituximab therapy in Waldenstrom's macroglobulinemia
Ann. Onc., January 1, 2005; 16(1): 132 - 138.

J. Boye, T. Elter, and A. Engert
An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab
Ann. Onc., April 1, 2003; 14(4): 520 - 535.

Johnson SA, Birchall J, Luckie C, Oscier DG, Owen RG, Haemato-Oncology Task Force of the British Committee for Standards in Haematology. Guidelines on the management of Waldenstrom macroglobulinaemia. Br J Haematol 2006 Mar;132(6):683-97. [108 references]

AVN944

Lay Summary: AVN-944 is reviewed.

AVN-944 is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme that catalyzes the rate-limiting step in guanine nucleotide synthesis, and induces apoptosis in malignant hematopoietic cell lines in vitro.

Pre-clinical studies showed that AVN944 is a highly specific inhibitor of IMPDH, suppresses pools of GTP, and in cultured cells has a selective growth inhibition effect on cancer cells vs. normal cells.

An earlier single-dose, dose-escalation, healthy volunteer clinical trial conducted in the United Kingdom showed that AVN944 was well tolerated at all tested doses with no notable side effects; had good pharmacokinetic properties; and had a significant inhibitory effect on IMPDH enzyme activity.

A recent phase I study is a repeat-dose dose escalation trial in patients with advanced hematologic malignancies. Patients are dosed for 21 days on a 28-day cycle. A minimum of three patients are treated at each dose level. The study is divided into two arms, one for treatment of leukemia patients and the other for treatment of patients with lymphoma and myeloma. For the leukemia arm of the study, patients are currently being treated at the fourth dose level, 100 mg twice daily. For the lymphoma and myeloma arm, patients are currently being treated at the fifth dose level, 125 mg twice daily. There have been no drug-related Serious Adverse Events (SAEs), indicating that AVN944 is being well tolerated thus far at all dose levels. Pharmacokinetics measurements indicate dose proportional plasma levels of AVN944 during treatment and sustained plasma concentrations at the dose levels tested thus far.

Early Activity Indicators: This Phase I study has also been designed to evaluate several pharmacodynamic and efficacy-related endpoints. Upon entering the trial, all patients have refractory, progressive disease and have failed all prior therapies. Thus far, 12 of 24 patients have had stabilized disease after one cycle of treatment with AVN944. These include patients with both leukemia and multiple myeloma. Patients who have achieved stable disease following completion of a one-month treatment cycle with AVN944, as determined by the clinical investigator, may be advanced to a subsequent cycle.

Four multiple myeloma patients in the study have maintained stabilized disease for several months of treatment with AVN944; two of these patients completed five months of treatment and two others completed eight successive cycles. These two patients continue to have stable disease and are in their ninth month of treatment.  it is clearly experimental.

Author(s): R. B. Klisovic, G. Tricot, S. Coutre, T. Kovacsovics, F. Giles, T. Genna, D. K. Bol, J. W. Strovel, J. M. Hamilton, B. Mitchell A phase I trial of AVN944 in patients with advanced hematologic malignancies.  Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 14026

IVIG post transpalntation

Lay Summary: Intravenous gammaglobulin is often adminsitered after bone maroow/ stem cells transplantation to prophylax for infections.

Antibiotics and intravenous gamma globulin are often adminstered for at least 100 days months after transplant to decrease the risk of bacterial infection immediately following transplant. Although there are no randomized studies of this strategy, it is recommended by the joint guidelines of CDC, the Infectious Disease Society of America, and the American Society of Blood and Bone Marow Transplantation. For actually hypogammaglobulinemic patients a higher dose is used than than is standard for non-HSCT recipients because the IVIG

half-life among HSCT recipients (generally 1–10 days) is much

shorter than the half-life among healthy adults (generally 18–23

days) (therefore, the IVIG dose for a hypogammaglobulinemic

recipient should be individualized to maintain trough serum IgG

concentrations >400–500 mg/dl (should monitor trough serum IgG concentrations among

these patients approximately every 2 weeks and adjust IVIG doses

as needed

Stanley C. Jordan, Ashley A. Vo, Mieko Toyoda, Dolly Tyan, Cynthia C. Nast (2005)
Post-transplant therapy with high-dose intravenous gammaglobulin: Applications to treatment of antibody-mediated rejection Pediatric Transplantation 9 (2), 155–161.

Antin, JH. Long-term care after hematopoietic-cell transplantation in adults. N Engl J Med. 2002; 347(1):36-42.

http://mmserver.cjp.com/gems/bbmt/7-83.pdf

Velcade first line in Multiple Myeloma

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 is currently 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 adn FDA approval is expected this year.

Rami Manochakian, Kena C. Miller, 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: 3/5/08

Revlimid for induction of myeloma

Lenalidomide is an immunomodulatory drug and a structural analogue of thalidomide which has been developed by Celgene. Potential clinical applications investigated for lenalidomide include CNS cancer, inflammation, malignant melanoma, chronic lymphocytic leukaemia, myelodysplastic syndromes, and multiple myeloma (MM). It is FDA approved in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma patients who have received at least one prior therapy. Off-label, however, Revlimid with dexamethasone is considered an appropriate induction regimen for potential transplant candidates since it does not possess bone marrow toxicity. It is listed as such, for example, by the NCCN.

The consensus that Revlimid is appropriate for first line therapy is reflected in a Phase III ECOG trial that investigates high versus low dose dexamethason with Revlinid in first line therapy. On 4/5, Celgene Corporation (Nasdaq: CELG) announced that the Eastern Cooperative Oncology Group (ECOG) has reported that its Data Monitoring Committee's (DMC) review of preliminary results from a large, randomized clinical trial for patients with newly diagnosed multiple myeloma has found that the use of a low dose of dexamethasone (Decadron) in combination with lenalidomide suggests survival advantage for patients when compared to the higher, standard-dose of dexamethasone that is used in combination with lenalidomide to treat.

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

Matthew Strobeck From the analyst's couch: Multiple myeloma therapies Nature Reviews Drug Discovery 6, 181-182 (March 2007)

Weber D, Chen C, Niesvizky R, et al. Lenalidomide Plus High-Dose Dexamethasone Provides Improved Overall Survival Compared to High-Dose Dexamethasone Alone for Relapsed or Refractory Multiple Myeloma (MM): Results of a North American Phase III Study (MM-009). Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. June 2006. Abstract # 7521.

PET for myeloma

Lay Summary: PET is not recommended in myeloma in general but is NCCN recommended for non-secretory plasmacytoma.

While PET can be useful for evaluation for  diagnosis of plasmacytoma and is so noted on the NCCN guidelines, its role for non-secretory myeloma is controversial. In a recent exchange of letters, a correspondent made the claim that such use of PET should have been listed in a review article in teh New Engalnd Journal of Medicine. However, the authors resonded: " We agree that in the setting of nonsecretory myeloma, PET scanning and measurement of free light chains can be helpful in establishing the extent of disease, particularly if protocol participation or intensive therapy is planned. However, the routine use of these tests is not supported by the clinical practice guidelines of the National Comprehensive Cancer Centers Network."  This exchange can be found at http://content.nejm.org/cgi/content/full/352/15/1610

A 2005 guidelines states: "MR and positron emission tomography (PET) scanning may aid disease evaluation in individual patients (grade C recommendation; level III evidence)." This level of evidence falls short of ehat the Plan requires. There are no randomized studies or good cohort studies of PEt in myeloma in general or for non-secretory myeloma in particular. As noted above, there is no consensus on its utility in that setting.

Durie BG, Waxman AD, D'Agnolo A, Williams CM. Whole-body (18)F-FDG PET identifies high-risk myeloma. J Nucl Med 2002;43:1457-1463.

http://www.myeloma.org/pdfs/MyelomaManagementGuidelines.pdf

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

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)

Autologous stem cell transplantation for Amyloidosis

Lay Summary: AuSCT is supported by credible evidence for amylod for patients without organ damage.

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. Initial results of HDC/AuSCS in uncontrolled patient series were published in 1998. Clinical response rates (50% to 60%) were nearly twice those reported for conventional therapy, and two-year survival reportedly ranged from 56% to 68%. However, two issues tempered initial enthusiasm for these favorable results. First, early series reported procedure-related mortality of 15% to 43%, substantially higher than after HDC/AuSCS for multiple myeloma (less than 5%). Studies that evaluated risk factors for early death identified involvement of more than two organ systems and symptomatic cardiac involvement as significant predictors of treatment-related mortality.
In addition to longer survival, there is evidence suggesting improvement in symptoms and quality of life for amyloidosis patients treated with HDC/AuSCS. Skinner and colleagues  reported the largest retrospective series of amyloidosis patients eligible for transplant (n=394). Of the 394 eligible patients, 63 declined treatment and 19 lost eligibility when their disease progressed before treatment started. Estimated median survival for 312 patients who initiated stem-cell mobilization was 4.6 years, but median follow-up was not reported. Of 181 evaluable patients (alive and followed for one year or more), 40% achieved complete hematologic response, defined as no evidence of plasma cell dyscrasia at one year after transplant. They reported functional improvement in at least one affected organ for 44% of evaluable patients: 66% of 73 patients with complete hematologic response and 30% of 108 patients with an incomplete or no hematologic response.

Skinner and colleagues also reported that of 277 patients who completed the transplant protocol, 36 (13%) died of treatment related toxicity before day 100 post-transplant, 21 (8%) died between day 100 and one year, and 39 are alive but had not reached one year since transplant. (13) Note that this series included all patients transplanted between July 1994 and June 2002, of which half (n=196) had three or more organs involved and 43% had some cardiac involvement. Patients with these poor prognostic features likely predominate among the 21% who died within the first year. For example, median survival for those with cardiac involvement (n=137) was significantly shorter (1.6 versus 6.4 years; p=0.001) than for those without cardiac involvement (n=175).

Additional support comes from a registry analysis of 114 amyloidosis patients transplanted between 1995 and 2001 at 50 centers, thus far published only as an abstract. (15) Only 35% of patients reported to the registry were transplanted for initial therapy of amyloidosis, while 25% were transplanted after two years or more prior therapies. With a median follow-up of 29 months after transplant, overall survival at one and three years was 68% and 57%, respectively. Among 77 patients with data available on organ function, investigators reported improvement in 28 (35%). For those with no or one organ involved at transplant, survival at one year was 70%, while for those with two or more organs involved survival at one year was 60%. Survival at one year was also greater for those without cardiac involvement (72% versus 54%). Mortality at 100 days was 25%, but this likely included patients with cardiac and/or multiple organ involvement.

In summary, biologic similarity of the two plasma cell dyscrasias led to inferences that evidence of longer survival after HDC/AuSCS than after conventional-dose therapy in multiple myeloma patients might also be relevant to those with systemic amyloidosis. This hypothesis was questioned based on a retrospective analysis and a simplified matched-pair analysis suggesting similar survival after either therapy for amyloidosis.  A subsequent study with more thorough matching of cases and controls reports significantly longer survival after HDC/AuSCS for amyloidosis. Additionally, recent large series and registry analysis report evidence that HDC/AuSCS improves organ function and quality of life. Taken together, these data support the hypothesis that HDC/AuSCS improves outcomes for amyloidosis patients with two or fewer involved organs and without cardiac symptoms.

However, there are experts who do not recommend autologous transplantation for this disease and there is no credible literature to support tandem transplantation.

Hugh J. B. Goodman, Julian D. Gillmore, Helen J. Lachmann, Ashutosh D. Wechalekar, Arthur R. Bradwell and Philip N. Hawkins. (2006) Outcome of autologous stem cell transplantation for AL amyloidosis in the UK. British Journal of Haematology 134:4, 417-425

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

Guidelines on the diagnosis and management of AL amyloidosis.
British Journal of Haematology 125 (6), 681-70, 2004

Skinner M, Sanchorawala V, Seldin DC et al. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med 2004;140(2):85-93

Seldin DC, Anderson JJ, Malek K et al. Treatment of AL amyloidosis patients with high dose melphalan and autologous stem cell transplantation (HDM/SCT) produces durable remissions and improvement in quality of life. Blood 2003;102(11 pt. 1):452a (abstract 1651)

H. J. B. Goodman, P. N. Hawkins, A. Dispenzieri, M. A. Gertz, R. A. Kyle, and J. Mehta
The role of PBSCT in treatment of AL amyloidosis is far from settled
Blood, November 1, 2004; 104(9): 2991 - 2994.

Third transplant for myeloma

A single autologous transplant is considered medically necessary for mulitple myeloma. Tandem transplants or second transplant are investigational at this time. While there is some literature supporting effectiveness of a tandem approach, the current guidelines do not recommend it.
Autologous stem cell transplantation has emerged as standard therapy for patients with multiple myeloma, primarily as a result of randomized trials performed in France over the past decade. Recent guidelines agree on several recommendations.  An autologous stem cell transplant is recommended for patients with stage II or III multiple myeloma who have a good performance status. They state that evidence of benefit is strongest for patients who are younger than 55 years of age and have a serum creatinine level less than 1.7 mg/dL. They recommend using clinical judgement for patients who do not fit these criteria. Importantly, they advise early and integrated treatment with collection of stem cells before exposure to alkylating agents. They also support the use of peripheral blood stem cells over bone marrow. They suggest that early transplant produces the best results. They recommend a single transplant with high-dose Alkeran®, with or without total-body irradiation unless patients are on a clinical trial. A second autologous stem cell transplant is sometimes performed in patients who have relapsed after an initial stem cell transplant. Some myeloma centers automatically collect enough stem cells for two transplants and reserve them for a possible second transplant. Analysis of data on 96 myeloma patients who received a second transplant following relapse, which was presented at the IXth International Workshop on Myeloma, showed that a second (salvage) transplant is a feasible option for refractory/relapsed disease. (Powles et al. Hematology J. 2003;4(suppl 1):S62. Abstract P10.3.1.) The median survival in patients receiving the salvage transplant (6.4 years) was equivalent to that typically seen with a planned tandem transplant. However, these patients represent a select subgroup of patients with relatively good prognosis.

I was only able to find an fairly dated report of two patients treated with a third autologous transplant.

Two issues remain: 1. the status of allogeneic after autologus transplants for myeloma, and of non-myeloablative form of transplant.

NCCN advises allogeneic transplant on a clinical trial after relapse from an autologous transplant. It says that allogneic transpolant includes the non-myeloablative form. Underlying this recommendation is lack of studies that compare this aproach to salvage chemotherapy alone, especially since availability of Revlimid and Velcade.

The only guidelines that address a situation similar to this patient are the recently released Duthc guidelines say the following: These include upfront induction therapy followed by autologous transplantation for patients aged up to 65 years and oral melphalanprednisone treatment for patients with severe co-morbidities and patients over the age of 65 years. Patients under the age of 66 with an HLA-identical (family) donor are candidates for non-myeloablative stem-cell transplantation following autologous stem-cell transplantation. For second-line treatment, thalidomide, combined with dexamethasone is recommended. Younger patients responding to second-line treatment are candidates for a second autologous transplant. Bortezomib is indicated for those patients refractory to the previous two lines of treatment. All patients should receive long-term bisphosphonates."

Jourdan E, Blaise D, Fegueux N, Navarro R, Rossi JF, Maraninchi D, Navarro M.Third autologous stem cell transplants for late relapse of multiple myeloma.Bone Marrow Transplant. 1996 May;17(5):885-6

NCCN -  http://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf

J Mehta et al, Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft? Bone Marrow Transplantation May 1998, Volume 21, Number 9, Pages 887-892

Lokhorst H, Huijgens PC, Raymakers R, Bos GM, Vellenga E, Wijermans PW, Sonneveld PModern treatment methods for multiple myeloma: guidelines from the Dutch Haemato-Oncology Association (HOVON), Ned Tijdschr Geneeskd. 2005 Apr 9;149(15):808-13.