Cancer Treatment

CYBORD regimen for multiple myeloma: Velcade, Cytoxan and dexamethasone.

The CYBORG regimen is in interesting attempt to combinae Cytoxan with Velcade. A recent phase II trial enrolled thirty-seven patients. At the dose levels defined in the trial, the overall response rate was 95% (complete responses
[CR] plus partial response plus minimal response), with CR observed in more than 50% of patients.
The authors state: "Further evaluation of this promising regimen is warranted both in relapsed and newly diagnosed disease."

In 2010 ASCO, the was a study presented that compared CyBorD with Revlimid (lenalidomide)-dexamethasone treatment (abbreviated RD) and cyclophosphamide-Revlimid-dexamethasone treatment (abbreviated CRD). The results of the Phase 2 trials indicate that RD and CyBorD treatment were similar in efficacy and safety. CRD, however, was not as effective and had more severe side effects than RD and CyBorD.

NCCN in teh section on myeloma therapy lists this regimen for first line.

Donna E. Reece, Giovanni Piza Rodriguez, Christine Chen, Suzanne Trudel, Vishal Kukreti, Joseph Mikhael,
Mariela Pantoja, Wei Xu, and A. Keith Stewart Phase I-II Trial of Bortezomib Plus Oral Cyclophosphamide
and Prednisone in Relapsed and Refractory Multiple Myeloma J Clin Oncol VOLUME 26
NUMBER 28
OCTOBER 1 2008

M. L. Khan, C. B. Reeder, S. Kumar, M. Lacy, D. E. Reece, K. M. Laumann, J. Mikhael, R. Fonseca, V. Rajkumar, A. K. Stewart; Mayo Clinic, Scottsdale, AZ; Mayo Clinic, Rochester, MN; University Health Network, Toronto, ON, Canada  Comparison of lenalidomide/dexamethasone (RD) versus cyclophosphamide/lenalidomide/dexamethasone (CRD) versus  cyclophosphamide/bortezomib/dexamethasone (CyborD) in newly diagnosed multiple myeloma (MM).  J Clin Oncol 28:15s, 2010 (suppl; abstr 8131)

 

MGUS: Monclonal Gammopathy of Unknown Significance

Monoclonal gammopathy of undetermined significance (MGUS) is the most common of a spectrum of diseases called plasma cell dyscrasias. Its prevalence increases with increasing age and it is in majority clinically slient. The term MGUS denotes the presence of a monoclonal immunoglobulin (Ig), also called an M-protein, in the serum or urine in persons without evidence of multiple myeloma (MM), Waldenström macroglobulinemia (WM), amyloidosis (AL) or other lymphoproliferative disorders. Once these conditions have been ruled out, no farther workup or investigation is routinely recommended. Inital and subsequent testing is limited to:
•Include baseline measurements of serum vitamin B12 and RBC folate levels and a hypercoagulation profile.
•In addition, specific workup relative to the gammopathy should include a bone marrow examination, skeletal radiography (including single views of the humeri and femurs and complete spinal with optional lateral views), and a 24-hour urine collection for protein quantitation.
•Serum protein electrophoresis should be repeated in 3 months after diagnosis. If the results are stable, medical assessment should be performed every 6-12 months.
If a patient has an IgM M-protein, aspiration and biopsy of the bone marrow and CT scanning of the abdomen may be useful in detecting WM or other lymphoproliferative disorders. If all these results are satisfactory, serum electrophoresis should be repeated in 2-3 months at the earliest, and, if the finding is stable, the test should be repeated at 6- to 12-month intervals. Serum and urine electrophoresis with immunofixation should be performed if the serum M-protein value increases or if other evidence of evolving MM or WM is observed. No treatment is recommended for patients with MGUS, until and if, it evolves into another plasma cell dyscrasia. Recently various subtypes are being defined based on advanced tests but this had not reached clinical use.

REFERENCES:
http://www.bcshguidelines.com/documents/MGUS_bjh_28092009.pdf - Monoclonal Gammopathy
•Guidelines for the investigation of newly detected M-proteins and the management of Monoclonal Gammopathy of Undetermined Significance (MGUS) UK Myeloma Forum and Nordic Myeloma Study Group (February 2009)

Bida JP, Kyle RA, Therneau TM, Melton LJ 3rd, Plevak MF, Larson DR, et al. Disease associations with monoclonal gammopathy of undetermined significance: a population-based study of 17,398 patients. Mayo Clin Proc. Aug 2009;84(8):685-93.

Kyle RA, Therneau TM, Rajkumar SV, et al. Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. Blood. Nov 15 2003;102(10):3759-64.

Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. Feb 21 2002;346(8):564-9.

8.Kristinsson SY, Bjorkholm M, Andersson TM, et al. Patterns of survival and causes of death following a diagnosis of monoclonal gammopathy of undetermined significance (MGUS): a population-based study. Haematologica. Jul 16 2009;

Revlimid for myeloma maintenance

Lenalidomide is an immunomodulatory drug and a structural analogue of thalidomide which has been developed by Celgene. REVLIMID (lenalidomide) in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM) 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.

It can also be used as maintenance, which has been studied in the post-transplant setting. Italian researchers presented the results of a study where Revlimid was administered as consolidation/maintenance therapy after a reduced-intensity autologous stem cell transplants in elderly patients with newly diagnosed myeloma. This study included over 100 patients aged 65-75 years with newly diagnosed myeloma. All received induction therapy with Velcade, dexamethasone, and doxorubicin followed by tandem autologous stem cell transplants with 100 mg/m2 of melphalan. Peripheral blood stem cells were harvested after Cytoxan and Neupogen® (figrastim). Revlimid was given after recovery from tandem autologous transplants. Starting dose was 10 mg/day, escalated to 15 mg/day after 3 months. Drug was held for ≥ Gr 3 toxicity, restarted at resolution to ≤ Gr 2 and was de- escalated by 5 mg or maintained at 5, 10 or 15 mg/day as tolerated. After consolidation/maintenance Revlimid, 88% of patients achieved at least a very good partial remission, and 53% a complete remission. One-year survival was 92%.

Results of the fifth interim analysis of this CALGB ECOG BMT-CTN 100104 trial showing data out to a median of 18 months were presented in Paris, France, at the 13th International Myeloma Workshop by principal investigator Philip McCarthy Jr, MD, director of the Blood & Marrow Transplant Program at Roswell Park Cancer Institute in Buffalo, New York in 2011. In this latest analysis, there continued to be a significantly longer time to progression in the patients who received lenalidomide therapy when compared with placebo. As of April 17, 2011, 69 of the original 231 lenalidomide patients experienced an event — disease progression or death — compared with 116 of the original 229 patients randomized to placebo (P < .0001), for a 56% reduction in the risk for disease progression in the lenalidomide arm (hazard ratio, 0.44; 95% confidence interval, 0.32 – 0.60).With regard to overall survival, patients receiving continuous lenalidomide therapy demonstrated an overall survival rate of 90% at more than 2 years after transplantation, compared with 83% for patients receiving placebo (P = .018).

However, this trial raised concerns because there appears to be a higher incidence of cancers in the Revlimid group.

I consider Revlimid maintenance to still be investigational because that study is continuing and the results will continue to be update, because the increased cancer incidence in the experimental arm needs to be understood and explained.

P. L. McCarthy, K. Owzar, K. C. Anderson, C. C. Hofmeister, H. Hassoun, D. D. Hurd, E. A. Stadtmauer, S. Giralt, V. Hars, C. A. Linker, for CALGB, ECOG and BMT-CTN; Roswell Park Cancer Institute, Buffalo, NY; Duke University Medical Center, Durham, NC; Dana-Farber Cancer Institute, Boston, MA; The Ohio State University, Columbus, OH; Memorial Sloan-Kettering Cancer Center, New York, NY; Wake Forest University, Winston Salem, NC; University of Pennsylvania Cancer Center, Philadelphia, PA; University of Texas M. D. Anderson Cancer Center, Houston, TX; University of California, San Francisco, San Francisco, CA Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant (ASCT) for multiple myeloma (MM): CALGB 100104. J Clin Oncol 28:15s, 2010 (suppl; abstr 8017)

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.

Velcade for Waldenstrom's

Waldenström's macroglobulinemia (WM) is a CD20 expressing B-cell malignancy represented by the pathological diagnosis of IgM secreting lymphoplasmacytic lymphoma.

Chen, et al. (2007) found bortezomib to be an active agent in Waldenstrom's macroglobulinemia but it was an uncontrolled phase II clinical trial in which untreated or previously treateds ymptomatic patients with Waldenstrom's macroglobulnemia (n = 27) received bortezomib on a 21-day cycle until two cycles .

Treon, et al. (2007) reported on an uncontrolled clinical study which found bortezomib to be an active agent in relapsed and refractory Waldenstrom's macroglobulinemia. The overall response rate was 85%, with 10 and 13 patients achieving minor and major responses, respectively. The investigators observed that sensory neuropathies resolved or improved in nearly all patients following cessation of therapy.

Guidelines from the National Comprehensive Cancer Network (p. WLMPL-B, 2011) indicates bortezomib with rituximab "particularly" for primary treatment of symptomatic hyperviscosity in Waldenstrom's macroglobulinemia. However, NCCN appears to accept the combination with Rituxan without hyperviscosity also.

Velcade is currenlty under a French study for this diagnosis: Efficacy of Bortezomib (Velcade(R)) in Patients With Advanced Waldenström Macroglobulinemia (WM2), NCT00777738. This trial is designed to evaluate the efficacy and toxicity in patients with advanced Waldenström's Macroglobulinemia disease. A Belgian study, NCT00142129, was completed in 2007 and not yet published.

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

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]

Chen CI, Kouroukis CT, White D, et al; National Cancer Institute of Canada Clinical Trials Group. Bortezomib is active in patients with untreated or relapsed Waldenstrom's macroglobulinemia: A phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(12):1570-1575.

Treon SP, Hunter ZR, Matous J, et al. Multicenter clinical trial of bortezomib in relapsed/refractory Waldenstrom's macroglobulinemia: Results of WMCTG Trial 03-248. Clin Cancer Res. 2007;13(11):3320-3325.

Rituxan for CD20 positive myeloma

Interest in using Rituxan for subsets of myeloma with CD20 positivity, was provoked by a Phase II study of Moreau et al evaluating four weekly infusions of single-agent rituximab (375 mg/m2) therapy in a cohort of patients with CD20+ multiple myeloma (MM) with either stage I, never treated disease, or stage III MM in relapse, or refractory after two lines of therapy. The authors concluded that rituximab as a single agent had minor activity in this cohort of patients with CD20 expression on at least 33% of tumor cells. A 2008 review concluded: "Clinical trials show that anti-CD20 therapy with rituximab elicits a partial response in approximately 10% of CD20+ patients with multiple myeloma. In addition, there is preliminary evidence of disease stabilization in 50-57% of CD20+ patients for a period of 10-27 months. Further large-scale clinical trials are therefore needed to establish the role of this promising strategy in the treatment of myeloma." There are several other reports in different settings, including in maintenance.

All in all, there is sufficient literature to consider it supported.

J M Bergua, C Cabrera, E G Arteta and J Prieto
Rituximab in CD20 positive multiple myeloma, Letter to the Editor, Leukemia 22, 1082-1083 (May 2008)

P Moreau, L Voillat, L Benboukher, C Mathiot, C Dumontet, N Robillard, O Hérault, F Garnache, R Garand, N Varoqueaux, H Avet-Loiseau, J L Harousseau and R Bataille
Rituximab in CD20 positive multiple myeloma, Leukemia 21, 835-836 (April 2007)

Kapoor P, Greipp PT, Morice WG, Rajkumar SV, Witzig TE, Greipp PR.
Anti-CD20 monoclonal antibody therapy in multiple myeloma.
Br J Haematol. 2008 Apr;141(2):135-48. Epub 2008 Mar 3.

Long-term response to maintenance treatment with rituximab in CD20+ multiple myeloma
Hitoshi OhnoLeukemia & Lymphoma
November 2010, Vol. 51, No. 11 : Pages 2144-2146

 

Zolinza and Valcade for myeloma

Zolinza is approved in the USA for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. However, it mayb e effective in myeloma as well.Results from two Phase 1 studies of ZOLINZA® (vorinostat), Merck's oral histone deacetylase (HDAC) inhibitor, administered in combination with bortezomib, showed early anti-tumor activity in patients with relapsed and/or refractory multiple myeloma, including those previously treated with and no longer responding to bortezomib. Results of these studies, which were designed primarily to determine the maximum tolerated dose of the combination regimen, were presented at the 50th Annual Meeting of the American Society of Hematology (Abstract #871). 

Based on this information, Merck initiated phase II studies, VANTAGE 088 and VANTAGE 095, as well as a Phase III, global, randomized, double-blind, placebo-controlled, 742-patient multicenter trial investigating Zolinza plus Velcade in relapsed MM after one to three prior anti-myeloma. However, the therapy remains investigational so far.

Weber D, Badros AZ, Jagannath S, et al. Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: Early clinical experience. Blood. 2008;112:322, abstract number 871.

nccn.org, myeloma

Acyclovir prophylaxis for Velcade based therapies

The bortezomib and dexamethasone treatment is myelosupressive. The APEX trial demonstrated an incidence of H. Zoster of 13% in the bortezomib-treated arm compared with 5% in the dexamethasone-treated arm (p<0.001)in patients treated for myeloma. Some subsequent studies showed lower H. Zoster infection rates and others showed similar rates. For this reason, many experts recommend routine acyclovir prophylaxis for high-risk patients treated with bortezomib. National Comprehensive Cancer Network guidelines recommend that herpes zoster prophylaxis be considered for patients receiving bortezomib or bortezomib-based therapies.

Routine acyclovir prophylaxis is not guideline recommended in transplant patients. MMWR says: "Prophylaxis or preemptive therapy with acyclovir is not recommended because of lack of efficacy". Supressive therapy because of previous shingles is noto prospectively studied in this setting, to my knowedge.

Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Eng J Med. 2005a;352:2487–98.

Dasanu CA, Alexandrescu DTDoes bortezomib induce de facto varicella zoster virus reactivation in patients with multiple myeloma? J Clin Oncol, doi: 10.1200/JCO.2008.21.0138.

Chanan-Khan A, Sonneveld P, Schuster MW, et al.(2008) Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol 26:4784–4790.

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4910a1.htm

Revlimid maintenance for myeloma

As per the 2010 ASCO meeting and the two studies presented there, maintenance treatment is beneficial after an autologous transplant for multiple myeloma and the CALGB s100104 study was stopped based on positive results. That trial of  568 multiple myeloma patients ages 18 to 70 included  participants who had an autologous stem cell transplant. 460 patients were randomized to receive Revlimid maintenance therapy or placebo. Due to the significant difference in time to progression between the two groups, the study has been stopped, patients have been informed about which maintenance therapy they were receiving, and all patients have been given the option to receive Revlimid.  

There is also randomized and phase II evidence to support maintenance thalidomide. NCCN has incorporated lenalidomide maintenance, as well as interferon, steroids and thalidomide with or without prednisone into its guidelines.

NCCN.org, Multiple Myeloma

P. L. McCarthy, K. Owzar, K. C. Anderson, C. C. Hofmeister, H. Hassoun, D. D. Hurd, E. A. Stadtmauer, S. Giralt, V. Hars, C. A. Linker, for CALGB, ECOG and BMT-CTN; Roswell Park Cancer Institute, Buffalo, NY; Duke University Medical Center, Durham, NC; Dana-Farber Cancer Institute, Boston, MA; The Ohio State University, Columbus, OH; Memorial Sloan-Kettering Cancer Center, New York, NY; Wake Forest University, Winston Salem, NC; University of Pennsylvania Cancer Center, Philadelphia, PA; University of Texas M. D. Anderson Cancer Center, Houston, TX; University of California, San Francisco, San Francisco, (ASCT) for multiple myeloma (MM): CALGB 100104. CAJ Clin Oncol 28:15s, 2010 (suppl; abstr 8017)

M. Attal, C. Cristini, G. Marit, D. Caillot, T. Facon, C. Hullin, P. Moreau, C. Mathiot, H. Avet-Loiseau, J. L. Harousseau, Intergroupe Francophone du Myelome; Hematology Department, CHU Purpan, Toulouse, France; CHU Toulouse, Toulouse, France; Service d'Oncologie Médicale, Hôpital du Haut Leveque CHU de Bordeaux, Bordeaux, France; Hematology Department, CHU Le Bocage, Dijon, France; Hôpital Claude Huriez, Lille, France; Hematology Department, CHU Brabois, Nancy, France; Hematology Department, University Hospital, Nantes, France; Hematology Laboratory, Institut Curie, Paris, France; Hematology Laboratory, University Hospital, Nantes, France; IFM, Nantes, France , Lenalidomide maintenance after transplantation for myeloma. J Clin Oncol 28:15s, 2010 (suppl; abstr 8018)

Chang JE, Juckett MB, Callander NS, Kahl BS, Gangnon RE, Mitchell TL, Longo WL. Thalidomide maintenance following high-dose melphalan with autologous stem cell support in myeloma. Clin Lymphoma Myeloma. 2008 Jun;8(3):153-8.

Abdelkefi A, Ladeb S, Torjman L, Othman TB, Lakhal A, Romdhane NB, Omri HE, Elloumi M, Belaaj H, Jeddi R, Aissaouï L, Ksouri H, Hassen AB, Msadek F, Saad A, Hsaïri M, Boukef K, Amouri A, Louzir H, Dellagi K, Abdeladhim AB; Tunisian Multiple Myeloma Study Group. Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood. 2008 Feb 15;111(4):1805-10.

Harousseau JL, Moreau P. Evolving role of stem cell transplantation in multiple myeloma. Clin Lymphoma Myeloma. 2005 Sep;6(2):89-95.

Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, Gill DS, Horvath N, Reynolds J, Kennedy N. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009 Apr 10;27(11):1788-93.

Kumar A, Kharfan-Dabaja MA, Glasmacher A, Djulbegovic B. Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis. J Natl Cancer Inst. 2009 Jan 21;101(2):100-6. Epub 2009 Jan 13.

 

 

Revlimid for myeloma - first line.

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). REVLIMID® (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy.

The consensus that Revlimid is appropriate for first line therapy is reflected in a Phase III ECOG trial that investigated high versus low dose dexamethasone 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. NCCN lists it as 2B recommendation of p. 17 of NCCN guidelines for myeloma. On this basis, it can be considered to be medically necessary.

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.

Extramedullary completely resected plasmacytoma

Diagnosis of a solitary plasmacytoma requires a full workup to rule out myeloma elsewhere.  This is because many patients  are ultimately found to have evidence of myeloma. Following complete evaluation, patients with a solitary plasmacytoma can be treated with radiation therapy alone, as studies have indicated that the addition of chemotherapy to radiation does not improve overall survival in patients with solitary plasmacytoma. This was done in this case

Radiation therapy for solitary plasmacytoma typically delivers between 40 and 50 Gy. Treatment with radiation is associated with up to 50% of patients with solitary bone plasmacytoma being alive without evidence of recurrence 10 years from treatment, suggesting that many patients with solitary plasmacytoma can be cured. Prognosis may be even better for patients with solitary extramedullary plasmacytoma. Both osseous and extraosseous or extramedullary plasmacytomas are treated with radiation therapy.

WHen plasmacytoma was completely excised, guidelines do not recommend adjuvant radiation. From p.3 of reference 2: "...if patients have been treated by primary surgery, radiotherapy would only be required in patients with inadequate surgical margins".

Rajkumar SV, Dispenzieri A, Kyle RA. Monoclonal gammopathy of undetermined significance, Waldenström macroglobulinemia, AL amyloidosis, and related plasma cell disorders: diagnosis and treatment. Mayo Clinic Proceedings. 2006;81:693-703.

Guidelines on the diagnosis and management of solitary plasmacytoma of bone and solitary extramedullary plasmacytoma
(2004) Clinical Oncology, 16 (6), pp. 405-413.  See it at: http://www.bcshguidelines.com/pdf/Plasmacytoma080304.pdf