Cancer Treatment Today » Multiple Myeloma

Carfilzomib(Kyprolis), a new drug for myeloma – pro

M Levin, MD — Fri, 12 Oct 2012 12:14:23 +0000

Carfilzomib(Kyprolis) is a newly approve drug for multiple myeloma. (Onyx Pharmaceuticals) is similar to Velcade. KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. It is a proteasome inhibitor that inhibits the breakdown of proteins in cancer cells, thereby triggering their death. The approval was based on several clinical trials that were presented at the 2012 American Society of Clinical Oncology (ASCO) annual meeting in 2012. Three Phase 1/2 clinical trials showed that several carfilzomib (Kyprolis) combinations are effective for newly diagnosed multiple myeloma patients. Researchers involved in each of these clinical trials presented the results during oral presentations at the ASCO meeting.

One trial was of a combination of carfilzomib, Revlimid, and dexamethasone, whcih was highly effective and well tolerated in newly diagnosed myeloma patients. Another was cyclophosphamide(Cytoxan), thalidomide, and dexamethasone – known as “CYCLONE” – is tolerable and effective in newly diagnosed multiple myeloma patients. The phase II part of the study included 24 patients who faield an autologosu transplant, with a median age of 65 years. All patients received 20 mg/m2 of carfilzomib on days 1, 2, 8, 9, 15, and 16 of the first 28-day cycle, and 27 mg/m2 of carfilzomib in subsequent cycles. Moreover, all patients received 300 mg/m2 of oral cyclophosphamide on days 1, 8, and 15; 100 mg of oral thalidomide daily; and 40 mg of oral dexamethasone on days 1, 8, 15, and 22 of each cycle. After four cycles of treatment, 29 percent achieved a complete response, 46 percent a very good partial response, and 21 percent a partial response.

Another Phase 1/2 study was conducted in France. The results show that a frontline combination of carfilzomib, melphalan (Alkeran), and prednisone is tolerable and effective in newly diagnosed myeloma patients over the age of 65. The maximum tolerated dose of carfilzomib was defined as 36 mg/m2. at thsi time, 43 patients had been treated on the phase II of the study, and 35 patients, with a median age of 74 years, were evaluated for response.

After a median of eight cycles of treatment, 89 percent of patients responded to the treatment regimen, with 3 percent achieving a complete response, 40 percent a very good partial response, and 46 percent a partial response. The progression-free survival was 81 percent and overall survival was 94 percent after a median follow-up of one year.

These are all remarkable results for multiply treated myeloma patients.

Two posters defiend single agents activity. One analyzed outcomes of 228 patients (86 percent) who were either intolerant or refractory (resistant) to Velcade as well as Revlimid or thalidomide (referred to as “double refractory/intolerant”) and a subgroup of 44 patients (17 percent) who were refractory to all classes of myeloma treatments. This includes alkylators such as melphalan, anthracyclines such as doxorubicin (Adriamycin), corticosteroids such as dexamethasone, immunomodulatory agents such as Revlimid and thalidomide, and proteasome inhibitors such as Velcade. The results show that patients refractory to prior myeloma therapies had responses overall response rates of 23 percent overall, 21 percent for those who were double refractory/intolerant, and 20 percent for those refractory to all classes of myeloma therapies. Responses lasted 7.8 months for the entire study group, 7.4 months for the double refractory/intolerant group, and 7.8 months for those refractory to all classes of treatment. Anotehr poster presented results of a Phase 1/2 clinical trial on the safety and efficacy of carfilzomib as a replacement therapy for Velcade in patients who progressed while taking Velcade-containing regimens. Early results of the study suggest that carfilzomib is an effective and tolerable replacement for Velcade in these patients.

The study included 27 patients who had received a median of six previous lines of therapy, with a median of 2.5 of those containing Velcade. After progression, patients continued on their same treatment regimens, except intravenous carfilzomib was given in place of Velcade.

Twenty-two of the patients were evaluated for a response after a median of three cycles of carfilzomib therapy. The overall response rate was 51 percent, with 23 percent of patients achieving a complete response, 5 percent a very good partial response, and 23 percent a partial response. The median progression-free survival time was 9.8 months.

FDA Approval:

Kyprolis is indicated in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy [see Clinical Studies].
Kyprolis is indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy [see Clinical Studies].

“PX-171-003-A1, an open-label, single-arm, phase (Ph) II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (R/R MM): Long-term follow-up and subgroup analysis”. ASCO 2011; Abstract 8027. 2011. http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=81812.

Interim results from PX-171-006, a phase (Ph) II multicenter dose-expansion study of carfilzomib (CFZ), lenalidomide (LEN), and low-dose dexamethasone (loDex) in relapsed and/or refractory multiple myeloma (R/R MM)”. ASCO 2011; Abstract 8025. 2011. http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=82679.

The effect of carfilzomib (CFZ) in patients (Pts) with bortezomib (BTZ)-naive relapsed or refractory multiple myeloma (MM): Updated results from the PX-171-004 study”. ASCO 2011; Abstract 8026. 2011. http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=77577.

Siegel DS, Martin T, Wang, M, et al. Results of PX-171- 003-A1, an open-label, single-arm, phase 2 study of carfilzomib in patients with relapsed and refractory multiple myeloma. Presented at: 52nd ASH Annual Meeting and Exposition; December 4-7, 2010; Orlando, Florida.”.

Final Results of a Frontline Phase 1/2 Study of Carfilzomib Lenalidomide, and Low-Dose Dexamethasone (CRd) in Multiple Myeloma (MM)”. ASH 2011; Abstract 631. http://ash.confex.com/ash/2011/webprogram/Paper39029.html.

Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120:1801-1809.

Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-152.

Kyprolis, Prescribing Information 2018

NCCN, Myeloma 2018

Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-152.

Kyprolis, Prescribing Information 2018

NCCN, Myeloma 2018

Multiple Myeloma, Tandem vs Second Transplants and Total Therapy – pro

M Levin, MD — Sat, 01 Sep 2012 20:59:43 +0000

Lay Summary: I review the current status of tandem versus second transplant and Total Therapy.

One needs to differentiate between tandem transplants, a planned sequence of two high dose treatments with HSCT salvage, and a second transplant, an approach of consolidating the first autologous HSCT with another HSCT ONLY if the first one appears partially effective.

A tandem autologous transplant, also known as a double autologous transplant, requires the patient to undergo two planned autologous stem cell transplants within 6 months. Stem cells are collected once before the initial transplant and half are used for each procedure. The followup transplant is performed after recovery from the first procedure whatever the results of the initial transplant. Tandem transplant is now NCCN recommended but only as 2a recommendation. On the other hand, for patients who have not responded completely, NCCN recommends second transplant.

Various strategies are being evaluated to improve the outcome of tandem transplants. One such strategy is intensification of therapy, such as that implemented in the Total Therapy program (see below), which is showing promising results. Another strategy is the incorporation of novel agents, such as thalidomide, Velcade, or Revlimid, into the treatment regimen either before or after transplant. A second transplant is an intensification approach.

Two hundred thirty-one patients with symptomatic myeloma were enrolled in Total Therapy I between 1990 and 1995 (Barlogie et al. Blood. 1997;89(3):789-793; Barlogie et al. Blood. 1999;93:55-65.) The Total Therapy I regimen included induction therapy with 3 cycles of VAD (vincristine, doxorubicin, dexamethasone). High-dose cyclophosphamide plus granulocyte-macrophage colony-stimulating factor (GM-CSF) was then used to mobilize stem cells prior to peripheral blood stem cell (PBSC) collection. After stem cell collection, EDAP (etoposide, dexamethasone, cytarabine, cisplatin) was given to enhance reduction of tumor cells prior to high-dose therapy (melphalan 200 mg/m²) and autologous transplant. The second course of high-dose therapy and transplant was performed 3 to 6 months later. Patients then received interferon maintenance until disease recurrence. There are now trials up to Total Therapy 5.
The final analysis of the landmark French IFM-94 trial demonstrated that double transplantation led to improved survival compared with single transplantation in patients with previously untreated myeloma. (Attal et al. N Engl J Med. 2003;349(26):2495-2502.) Boith of these studies suggested benefit; however, the benefits were not apparent for several years and the overall suvival remained a paltry 20% at 7 years.

Preliminary results of several randomized trials comparing tandem and single autologous transplants, which have not been followed as long, have also shown superior event-free survival with the tandem regimen in most studies. In one study (Bologna 96), significantly improved event-free survival with double transplants was seen among patients <60 years of age, particularly those who had not achieved a near CR after the first transplant. However, only the IFM-94 study has demonstrated improvement in overall survival with the tandem approach. The designs of these studies vary, so comparisons are difficult. In addition, it has yet to be determined which patients benefit most from a tandem transplant. It appears that in patients with poor prognostic features, outcome is not improved with tandem transplants, so additional strategies need to be evaluated in this patient population. Many of these studies are reviewed at http://66.223.50.155/main.jsp?type=article&id=1012

The issue of allogeneic after autologous transplant is reviewed under a separate heading.

Nordic – http://www.bcshguidelines.com/pdf/UKNordic_070705.pdf#search=%22myeloma%2C%20guidelines%22

Chemotherapy and stem-cell transplantation in patients with multiple myeloma: a practice guideline of the Cancer Care Ontario Practice Guidelines Initiative. Annals of Internal Medicine. 2002;136:619-629

Nordic – http://www.bcshguidelines.com/pdf/UKNordic_070705.pdf#search=%22myeloma%2C%20guidelines%22

NCCN.org, Multiple Myeloma

Revised: 2/20/08

Single or Tandem Autologous Transplant for Multiple Myeloma, outpatient stem cell transplants – pro

M Levin, MD — Sat, 01 Sep 2012 20:57:53 +0000

Lay Summary: Single or tandem autologous transplant is standard of care for multiple myeloma. Other types of transplants are discussed under separate rubrics.

Single or tandem autologous transplant is standard of care for multiple myeloma. 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. In terms of treatment regimen, at the present time, there is no convincing evidence that total body irradiation adds anything to Alkeran® alone regimens. More recent studies suggest that tandem transplants are as or more effective than single transplants. A second transplant, after inadequate response to the first cycle of high dose therapy, is also recommended by the more recent guidelines.A single or tandem autologous transplant is a reasonable option and it is supported by guideines, such as NCCN. Since this consensus, new and more effective drugs had been introduced for myeloma. It is possible that future studies will result in modification of these recommendations in favor of drug therapy alone, without transplant. However, at this time, the guidelines continue to stand as the guide to clinical decision making.

There were two studies supporting maintenance presented at ASCO 2010, and one, the CALGB, was actually stopped after benefit was demonstrated. Maintenance afer transplant appears to be beneficial. two studies presented at 2010 ASCO, showed that maintenance is beneficial and the CALGB study was stopped based on positive results. NCCN aready incorporated Revlimid maintenance, as well as interferon, steroids and thalidomide with or without prednisone into its guideline on p. 17.

Some forward-looking institutions have begun performing transplants on the outpatient basis. They arrange a place for these patients to stay, daily visiting nurse service and close oversight. Under such conditions, it has been found that autologous stem transplants van be safely performed.

According to the NCCN guidelines for transplant eligible patients autologous stem cell transplant (SCT) is an option after primary induction therapy (category 1) and
for treatment of progressive/refractory disease after primary treatment.

Lauren W. Veltri MD Denái R. Milton MS Ruby Delgado BS Nina Shah MD Krina Patel MD Yago Nieto MD, PhD Partow Kebriaei MD Uday R. Popat MD Simrit Parmar MD Betul Oran MD Stefan Ciurea MD Chitra Hosing MD Hans C. Lee MD Elisabet Manasanch MD Robert Z. Orlowski MD, PhD Elizabeth J. Shpall MD Richard E. Champlin MD Muzaffar H. Qazilbash MD Qaiser Bashir MD, Outcome of autologous hematopoietic stem cell transplantation in refractory multiple myeloma Cancer Volume123, Issue18 September 15, 2017

NCCN.org, Multiple Myeloma 2020

Morie A. Gertz and David Dingli,How we manage autologous stem cell transplantation for patients with multiple myeloma. Blood 2014 124:882-890

Jean-Luc Harousseau, M.D., and Philippe Moreau, M.D.
Autologous Hematopoietic Stem-Cell Transplantation for Multiple Myeloma N Engl J Med 2009; 360:2645-2654

S Giral et al, International myeloma working group (IMWG) consensus statement and guidelines
regarding the current status of stem cell collection and high-dose therapy for multiple
myeloma and the role of plerixafor (AMD 3100), Leukemia (2009), 1–9

Shah N et al, Inpatient vs outpatient autologous hematopoietic stem cell transplantation for multiple myeloma.Eur J Haematol. 2017 Dec;99(6):532-535

Third transplant for myeloma – pro

M Levin, MD — Sat, 01 Sep 2012 20:56:07 +0000

A single autologous transplant is considered medically necessary for mulitple myeloma. I was only able to find one fairly dated report of two patients treated with a third autologous transplant.

NCCN advises allogeneic transplant on a clinical trial after relapse from an autologous transplant. It says that allogneic transplant 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.

One guideline that address a situation similar to this patient are the Dutch 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.”

NCCN does allow an option of a repeat autologous transplant for salvage on p. MYEL-5 and recommends considering the time between transplants and documented progression.

Most transplant centers would do an allogeneic transplant for patients relapsing after an autologous transplant.

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.

http://onlinelibrary.wiley.com/doi/10.1002/ajh.20641/pdf

Revised:9/1/2011

Autologous stem cell transplantation for Amyloidosis – pro

M Levin, MD — Sat, 01 Sep 2012 20:54:51 +0000

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. There is recent credible literature to support tandem transplantation. NCCN on AMYL-2 recommends high dose chemotherapy with stem cell transplantation.

Because most patients with amyloidosis are for advanced age, studies of allogeneic transplantation have focused on reduced conditioning regimens. NCCN recommends only autologus stem cell transplant with high dose melphalan conditioning, but also recommend all treatment of whatever kind to be in clinical trials.

NCCN, Amyloidosis, MS-7 2016

Shameem Mahmood, Giovanni Palladini, Vaishali Sanchorawala, Ashutosh Wechalekar, Update On Treatment Of Light Chain Amyloidosis. Haematologica February 2014 99: 209-221

Michael Rosenzweig and Heather Landau, Light chain (AL) amyloidosis: update on diagnosis and management. Journal of Hematology & Oncology 2011, 4:47

Sanchorawala V, Wright DG, Quillen K, Finn KT, Dember LM, Berk JL, et al. Tandem cycles of high-dose melphalan and autologous stem cell transplantation increases the response rate in AL amyloidosis. Bone Marrow Transplant. 2007 (b) Sep;40(6):557-562.

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

Sanchorawala V, Skinner M, Quillen K, Finn KT, Doros G, Seldin DC. Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation. Blood. 2007 (a) Aug 2;

PET for myeloma – pro

M Levin, MD — Sat, 01 Sep 2012 20:53:12 +0000

While PET can be useful for evaluation for diagnosis of plasmacytoma and initially that was the only indication lsited by NCCN guidelines, its role for non-secretory myeloma is more controversial. However, NCCN now includes it, which makes it not experimental. 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 the 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 what insurers generally require. However, in its 2010 guidelines, PET/CT is now listed by NCCN.

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.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)

Revlimid for myeloma treatment – pro

M Levin, MD — Sat, 01 Sep 2012 20:51:48 +0000

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 and for first line. 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.

For maintenance, please see here

Palumbo A, Falco P, Gay F, et al. Bortezomib-doxorubicin-dexamethasone as induction prior to reduced intensity autologous transplantation followed by lenalidomide as consolidation/maintenance in elderly patients. Blood. 2008;112:66, abstract number 159.

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.

IVIG post transplantation – pro

M Levin, MD — Sat, 01 Sep 2012 20:49:01 +0000

Intravenous gammaglobulin is often administered after bone marrow/ stem cells transplantation to prophylax for infections. Antibiotics and intravenous gamma globulin are often adminstered for at least 100 days 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 Marrow 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.

In their recently published meta-analysis of prophylactic intravenous immunoglobulin (IVIG) in allogeneic stem cell transplantation (alloSCT), Raanani et al concluded that IVIG does not have a role in SCT. The debate continues but guidelines currently recommend it.

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.

Uptodate, Prevention of infections in hematopoietic cell transplant recipients, 2016
.
Andrew J. Ullmann et al, Published online 2016 Jun 24. Infections in haematopoietic stem cell transplantation: prevention and prophylaxis strategy guidelines 2016. Ann Hematol. 2016; 95: 1435–1455

Raanani P, Gafter-Gvili A, Paul M, et al: Immunoglobulin prophylaxis in hematopoietic stem cell transplantation: Systematic review and meta-analysis. J Clin Oncol 27:770-781, 2009

AVN944 – pro

M Levin, MD — Sat, 01 Sep 2012 20:47:49 +0000

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

Rituxan for Waldenstrom’s macroglobulinemia – pro

M Levin, MD — Sat, 01 Sep 2012 20:45:21 +0000

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.

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