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 Doxil, Vincristine,  Decadron and Thalidomide (DVd-T) for Newly Diagnosed & Relapsed/Refractory Multiple Myeloma

 

1.     Objectives:

 

Primary

  1. The role of Thalidomide in increasing the CR rate to DVd in newly diagnosed multiple myeloma
  2. The role of Thalidomide in improving the response rate to DVd in Relapsed/Refractory Myeloma

Secondary

1.      Evaluate toxicity of Doxil, Vincristine and Decadron with Thalidomide.

2.      The role of Thalidomide in maintaining the anti-angiogenic activity of DVd

3.      All patients will be followed for survival

 

2.     Background and Rationale:

 

Cytokines in the Pathophysiology of Multiple Myeloma

 

Interleukin-6 (IL-6) is a major survival factor for malignant plasma cells. In patients with multiple myeloma (MM), cell lines have been obtained whose survival and proliferation are dependent upon addition of exogenous IL-6. Tumor necrosis factor-alpha (TNF-alpha) is also a survival factor for myeloma cell lines, although less potent than IL-6. The survival activity of TNF-alpha is not affected by anti-IL-6 or anti-gp130 monoclonal antibodies (mAbs). TNF-alpha also induces myeloma cells in the cell cycle and promotes the long-term growth of malignant plasma cell lines. As TNF-alpha is produced in patients with MM and associated with a poor prognosis, these results suggest that anti-TNF-alpha therapies could be useful in this disease[1].

 

Drug Resistance and Multiple Myeloma

 

Multiple myeloma is not a curable disease, and most patients relapse after plateau phase. Drug resistance is a major problem in effective chemotherapy in this kind of disease. Current approaches are aimed at reversing or preventing drug resistance late in the disease. A drug resistance marker, P-glycoprotein (P-gp), was studied by the Mayo group in a total of 43 patients with monoclonal gammopathy. This group included eight with monoclonal gammopathy of undetermined significance (MGUS), five with plasmacytoma (PCM), nineteen with multiple myeloma (MM; six newly diagnosed, seven plateau, five refractory, one relapse) and eleven amyloidosis (seven newly diagnosed, four previously treated). P-gp expression was positive on marrow plasma cells in 42/43 patients. The resistance index (RI) in these cases (range 2.0-7.07) is comparable to that in the positive cell line KG-1A (3.05-3.08). In 2 of 5 patients with refractory MM, the RI for P-gp (5.4-6.36) was higher than in plateau phase. These data suggest that relative resistance due to the P-gp mechanism is likely to be an intrinsic property of plasma cells in monoclonal gammopathies and may provide a partial explanation as to why these diseases always relapse. The results support strategies for MDR reversal earlier in the course of the disease[2].

 

Role of TNF in Drug Resistance and Tumorogeneisis

 

Studies by Licht et al suggest that in mesothelioma cells the transcription from the MDR-1 promotor gene is very responsive to regulation by TNF, IL-1, and IL-6[3].

Multiple myeloma secretes its own TNF. This TNF has been shown to act as an autocrine growth factor for these cells. Complex interactions between tumor associated macrophages and stromal cells can also result in autocrine and paracrine growth enhancement utilizing downstream IL-1 and IL-6[4]. Tumor cells can also use TNF from tumor-associated macrophages to stimulate the production of VEGF from epithelial cells[5]. TNF also increases the expression of VCAM-1 on endothelial cells, which are also key to angiogenic growth[6]. TNF increase the production of matrix metalloproteinases, which are essentially collagenases that break down the extracellualar matrix. This phenomenon has been noted in multiple myeloma cells[7].

 

Thalidomide; an Immune and Cytokine Modulator

 

 Reports of increased bone marrow (BM) angiogenesis in multiple myeloma[8], [9]coupled with the known antiangiogenic properties of Thalidomide[10], provided the rationale for its use to treat MM[11]. Importantly, Thalidomide induced clinical responses in 32% of MM patients, whose disease was refractory to conventional and high-dose therapy, suggesting that it can overcome drug resistance because of its alternative mechanisms of anti-MM activity11. Besides alkylating agents and corticosteroids, Thalidomide now, represents the third distinct class of agents useful in the treatment of MM. Given its broad spectrum of activities; Thalidomide may be acting against MM in several ways[12]. First, Thalidomide may have a direct effect on the MM cell and/or BM stromal cell to inhibit their growth and survival. For example, free radical–mediated oxidative DNA damage may play a role in the teratogenicity of Thalidomide and may also have anti-tumor effects[13]. Second, adhesion of MM cells to BM stromal cells both triggers secretion of cytokines that augment MM cell growth and survival[14],[15][16] and confers drug resistance[17]; Thalidomide modulates adhesive interactions and, thereby, may alter tumor cell growth, survival, and drug resistance[18]. Third, cytokines secreted into the BM microenvironment by MM and/or BM stromal cells, such as interleukin (IL)-6, IL-1b, IL-10, and tumor necrosis factor (TNF)–a, may augment MM cell growth and survival16.

 

Doxil, Vincristine, and Decadron (DVd) In the Management of Multiple Myeloma

 

Doxil is doxorubicin HCl encapsulated in long circulating “STEALTH®” liposome with a long circulation time. The long exposure to the drug could overcome the MDR over-expression in plasma cells. Also, the liposomes can extravasate through the abnormally permeable vessels characteristic of the bone marrow of MM patients, especially the group with advanced/refractory disease. In our phase II trial with DVd for newly diagnosed patients, we treated 33 myeloma patients. A CR rate of 15% and overall response rate of 96% has been achieved with minimal toxicity. Median time to failure is currently estimated to be 23.1 months.  We were impressed by the high CR (15%), overall response rate (96%), low toxicity profile (10% cytopenias), and the simplicity of administering the regimen. We then proceeded to evaluate the regimen in myeloma patients who have failed other regimens, including VAD, to assess response and toxicity. Patients received Doxil (40 mg/m2/d1) IV, Bolus Vincristine (2.0 mg d 1), and Decadron (40 mg PO qd x 4d, as a one time bolus). The regimen was administered in the outpatient setting every 4 weeks for a minimum of 6 cycles and 2 cycles after best response. When plateau phase was achieved, patients were initiated on prednisone at 50mg every other day until disease progression. All patients received pyridoxine 200mg PO QD if they developed grade 1/2 PPE. Responses were based on the modified ECOG MM criteria. 24 patients are currently enrolled and evaluable for toxicity/response. Median age was 59 & performance status < 2. Patients received a median of 6 cycles (1-12). Myelosuppression has been more frequent than what was noted in the newly diagnosed group, with Grade 3/4 granulocytopenia and thrombocytopenia in 50% of the patients. However the latter did not require any hospitalizations or transfusions. None of the patients experienced greater than grade 1 mucositis or PPE. 50% of the patients experienced progressive disease. Sixteen patients have relapsed. Median follow-up time for the patients who have not failed is 16 months. No deaths have been reported. Even though DVd appeared to have activity in this group of advanced patients, 50% of the patients did not respond to therapy, and the toxicity was significant when compared to the same regimen in newly diagnosed. The latter was related to previous chemotherapy, as well as disease compromising the bone marrow, but also, the presence of high cytokine levels suppressing the bone marrow.

 

Anti-Angiogenic activity of DVd

 

Angiogenesis is important for the proliferation and metastasis of tumors and has prognostic value in several malignancies. A recent study by Rajkumar et al showed that increased angiogenic activity in the form of high micro-vessel density (MVD) is found in the bone marrow of multiple myeloma patients. Of interest is the persistence of the increased MVD after stem cell transplant, and even after CR. In our Phase II Study of 33 newly diagnosed MM patients treated with DVd encouraging results have been shown, a CR (15%) and overall response rate of 96% has been achieved with minimal toxicity.  Median time to failure is currently estimated to be 23.1 months.  We evaluated the effect of this therapy on the angiogenic process in the BM of these pts. Pre- and post-therapy bone marrow biopsies from 20 patients were evaluated for MVD using immunohistochemistry for CD34 to highlight vascular spaces. MVD counts were performed on CD34-stained slides using a 100x oil objective counting 10 fields at two different levels. No statistical difference in MVD was seen between the two levels either pre-treatment (p=.95) or post-treatment (p=.91).Post-treatment MVD was significantly less than pre-treatment (mean + s.d. of 1.6+2.30 vs. 3.8 + 3.34, p<0.001).We also evaluated the prognostic implications of MVD pre- and post-treatment. Using Cox proportional hazards models, increased pre-treatment MVD was associated with poorer progression free survival (p=0.04), however, the change in MVD (p=0.86) was not. Pre-treatment MVD also correlated with response. That is, mean pre-treatment MVD for patients achieving CR or major response was significantly lower than  that of patients achieving less than a major response (p=0.004) as shown in the table below.

 

CR or Major Response

<Major Response

N

15

5

Mean±SD

2.7±2.39

7.5±3.61

 

DVd is the only chemotherapeutic regimen reported to significantly reduce angiogenesis in the bone marrow of MM Patients. Increased MVD may be an adverse prognostic finding in myeloma patients. Although this is a relatively small trial, the absence of correlation between the degree of angiogenic reduction and progression free survival suggests that the angiogenic process is an epiphenomenon. The high response rate (96%) and significant anti-angiogenic activity suggests that this regimen would be beneficial in combination with immunomodulatory agents such as Thalidomide[19]

 

Maximal Tolerated Cumulative Dose of Doxil

 

A meta-analysis was conducted on 1716 AIDS-KS patients (Karnofsky status 60) enrolled and treated in 10 multicenter phase II/III studies 1991--1997. A 1 hour infusion of CAELYX was administered every 2--3 weeks at doses of 10--40 mg/m2) with most patients receiving 20 mg/m2 (cumulative dose: median 1207 mg/m2; range 250--2664 mg/m2). Of a total of 10,817 adverse events reported after the administration of 15,711 doses, 1588 (14.7%) were classified as "serious". Leucopenia was the most common AE, seen in 52.6% of patients, with serious (grade 3 or 4) leucopenia in only 6%, despite concomitant use of various potentially myelotoxic drugs. Other adverse events included fever (25%), infection, anemia or diarrhea (20% each), nausea (16.5%), nausea & vomiting (6.8%), alopecia (7.9%), and infusion-related reactions (3.3%). 0.3% of patients experienced anaphylactoid-type reactions (believed to relate to infusion rate; a proportion of these patients were retreated successfully at lower infusion rates). Cardiotoxicity is expected with conventional doxorubicin at cumulative doses 550 mg/m2. 82 patients received 500 mg/m2 of CAELYX and endomyocardial biopsies performed on 9 of these patients showed a Billingham score 0.5. Only one had a score >0.5 (score of 1.0) [20].

 

Prednisone for Maintenance Therapy in Multiple Myeloma

 

SWOG evaluated vincristine, doxorubicin, and dexamethasone (VAD) regimen alone or with chemosensitizers for remission induction and interferon (IFN) versus IFN plus prednisone for remission maintenance in previously untreated multiple myeloma patients.  Patients who achieved remission were randomized to maintenance therapy with IFN-a 3 MU in the evening three times weekly, or IFN plus 50 mg of prednisone (IFN/P) on the morning after IFN, until relapse. Eighty-nine eligible patients who achieved remission were randomized to maintenance. Patients who received IFN/P had improved progression-free survival (median, 19 v 9 months for IFN; P = .008). After 48 months, progression-free survival on IFN/P was at the thirtieth percentile, whereas it was below the tenth percentile on IFN alone. Improved relapse-free survival may be attributable to IFN/P or to the use of prednisone for maintenance. This latter alternative is currently being studied and preliminary data suggest that prednisone is responsible for the difference [21]

 

Rationale for the combination & safety

 

Plasma cell resistance to therapy in myeloma is multifactorial. As shown the different cytokines, and integrins that are modulated by Thalidomide, in addition to the synergism with steroids could result in improving the response rate as well as the quality of response. Moreover, DVd results in an anti-angiogenic activity that Thalidomide might maintain, resulting in a prolonged PFS. With all these factors, such a combination is an attractive approach, if safety is confirmed. Relative to the neuropathy associated with Vincristine, and Thalidomide, we believe that these side effects are exaggerated in myeloma patients because of overlooking the 40% of the myeloma patients experiencing vitamin B12/folate deficiency[22]. Correcting this deficiency has resulted in decreasing this side effect significantly.

 

 

3.     Patient selection

 

Inclusion Criteria

 

The patient will be evaluated within 28 days before study entry. Each patient must meet these criteria to be considered for enrollment.

 

  1. Newly diagnosed MM or relapsed/refractory patients who have failed at least one regimen.
  2. Patients must have an Eastern Cooperative Group (ECOG) Performance Status of 0-4. Performance status of 3 & 4 will be allowed if related to myeloma, and or bony disease related to myeloma.
  3. No limitations will be applied to the WBC or the platelet count.
  4. Bilirubin < 2x institutional upper limits of normal. 
  5. Liver enzymes (ALT or AST) <2 Xs normal (unless >1/3 of liver is involved by tumor, in which case ALT or AST must be < 5 x normal).

 

 

Exclusion Criteria

 

Any one of the following conditions eliminates a patient from participating in this protocol.

 

  1. Severe infection requiring active intravenous antibiotic treatment.
  2. Patients with a life expectancy of less than 3 months
  3. Pregnant or lactating patients.
  4. Men or women of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.
  5. No prior malignancy is allowed, except for adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, or other cancer from which the patient has been disease-free for at least 5 years.
  6. Patients with solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia.
  7. Patients who have received > 500mg/m2 of Adriamycin
  8. Patients who have received > 500mg/m2 of Doxil 20
  9. ECHO and /or MUGA showing the LVEF less than the institutions normal standards

 

 

Pre-treatment Screening Procedures

 

The patient must be evaluated within twenty-eight days of study entry.  Must be preformed before enrollment, unless otherwise specified.

           

  1. History and physical examination, performance status determination.
  2. CBC with differential, Chemistry profile 16 (including total protein, albumin, calcium, phosphate, glucose, uric acid, total bilirubin, alkaline phosphatase, AST {SGOT}, ALT {SGPT}, sodium, potassium, chloride, carbon dioxide, Blood Urea Nitrogen, and creatinine)
  3. Serum protein electrophoresis, Myeloma typing of serum and urine, Beta-2 microglobulin.
  4. A 24-hour urine collection for total protein, Myeloma typing, and urine protein electrophoresis.
  5. Serum B12, RBC Folate, methylmalonic acid, and serum homocysteine.  The latter two values only if the serum creatinine is <1.5.
  6. Bone marrow aspirate, biopsy, and cytogenetics within 28 days.
  7. Complete bone survey, if not performed within 3 months, or if new symptoms have developed.
  8. ECHOcardiogram must be performed; however, to expedite workup a normal MUGA scan will suffice to start therapy.

 

 

On Study Evaluation

 

  1. Interim history and physical exam, and blood work before each cycle.  Laboratory values include CBC, Chemistry profile 16, SPEP, Beta 2 microglobulin, and 24-hour urine for protein quantitation with UPEP, if monoclonal protein is detected in the urine.
  2. Bone marrow aspirate, biopsy and cytogenetics at the completion of chemotherapy.
  3. CBC with diff on day 21 for first 5-10 patients. This could be extended to the remaining patients if severe neutropenia is observed.
  4. All patients will be followed for survival.
  5. Bone survey will be performed every 6 month or sooner, if clinically indicated.
  6. Patients who achieve plateau phase and are stable for 2 months will be followed every 3 months
  7. ECHO, or MUGA scan will be performed every 2 cycles, after a total dose of 300mg/m2 of Doxil is reached.

 

 References:

 

[1] Jourdan M. Tarte K. Legouffe E. Brochier J. Rossi JF. Klein B. Tumor necrosis factor is a survival and proliferation factor for human myeloma cells. European Cytokine Network. 10(1):65-70, 1999 March

 

[2] Mongkonsritragoon W. Kimlinger T. Ahmann G. Greipp PR. Is multidrug resistance (P-glycoprotein) an intrinsic characteristic of plasma cells in patients with monoclonal gammopathy of undetermined significance, plasmacytoma, multiple myeloma and amyloidosis? Leukemia & Lymphoma. 29(5-6):577-84, 1998 May.

 

[3] Licht Thomas, Von Schlling, Christoph, Lubert, Michael. Tumor Necrosis Factor-Alpha and Interleukin-6 Induce MDR in PXF1118L Pleural Mesothelioma Blood, (XX), 276, 1999.

 

[4] Klein B. Li XY. Lu ZY. Jourdan M. Tarte K. Brochier J. Claret E. Wijdenes J. Rossi JF. Activation molecules on human myeloma cells. Current Topics in Microbiology & Immunology. 246:335-41, 1999.

 

[5] Xiong M. Elson G. Legarda D. Leibovich SJ. Production of vascular endothelial growth factor by murine macrophages: regulation by hypoxia, lactate, and the inducible nitric oxide synthase pathway. American Journal of Pathology. 153(2):587-98, 1998 Aug

 

[6] Sheski FD. Natarajan V. Pottratz ST. Tumor necrosis factor-alpha stimulates attachment of small cell lung carcinoma to endothelial cells. [Journal Article] Journal of Laboratory & Clinical Medicine. 133(3):265-73, 1999 Mar.

 

[7] Kelly T. Borset M. Abe E. Gaddy-Kurten D. Sanderson RD. Matrix metalloproteinases in multiple myeloma. Leukemia & Lymphoma. (3-4):273-81, 2000 Apr.

 

[8] Ribatti D, Vacca A, Nico B, et al. Bone marrow angiogenesis and mast cell density increase si-multaneously with progression of human multiple myeloma. Br J Cancer. 1999;79:451-455.

 

[9] Vacca A, Ribatti D, Presta M, et al. Bone marrow neovascularization, plasma cell angiogenic po-tential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood. 1999;93:3064-3073.

[10] D’Amato RJ, Loughman MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994;91:4082-4085.

[11] Singhal S, Mehta J, Desikan R, et al. Anti-tumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341:1565-1571.

[12] Raje N, Anderson KC. Thalidomide: a revival story. N Engl J Med. 1999;341:1606-1609.

[13] Parman T, Wiley MJ, Wells PG. Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity. Nat Med. 1999;5: 582-585.

[14] Uchiyama H, Barut BA, Mohrbacher AF, Chauhan D, Anderson KC. Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates IL-6 secretion. Blood. 1993;82:3712-3720.

[15] Chauhan D, Uchiyama H, Akbarali Y, et al. Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kB. Blood. 1996;87:1104-1112.

[16] Hallek M, Bergsagel PL, Anderson KC. Multiple myeloma: increasing evidence for a multisteptransformation process. Blood. 1998;91:3-21.

[17] Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS. Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood. 1999;93:1658-1667.

[18] Geitz H, Handt S, Zwingengerger K. Thalidomide selectively modulates the density of cell surface molecules involved in the adhesion cascade. Immunopharmacology. 1996;32:213-221.

[19] ASH 2000

[20] M. Opravil, D. Tomlinson, J.R. Bogner, O. Loch, S.D. Hill, J. Whittaker. Caelyx® (Doxil®; Liposomal Doxorubicin) Is Tolerated Well Long-Term At High Cumulative Dose In Aids-Related Kaposi's Sarcoma (Aids-Ks) Patients- A Meta-Analysis Of 1716 Patients. ASCO Proceedings, 257, 1999

 

[21] Salmon SE. Crowley JJ. Balcerzak SP. Roach RW. Taylor SA. Rivkin SE. Samlowski W. Interferon versus interferon plus prednisone remission maintenance therapy for multiple myeloma: a Southwest Oncology Group Study. Journal of Clinical Oncology. 16(3): 890-896, 1998.

 

[22] Beckmann MJ, Hussein MA, Lichtin A, Jacobsen DW, Manteuffel L and Green R.  Low Serum Vitamin B12 in Patients with Plasma Cell Myeloma Is Associated with True Functional Cobalamin Deficiency.  American Journal of Clinical Pathology, 1995, 140:350

 
 
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