[suzierose]

True or False Statements regarding multiple myeloma therapy

by suzierose on Fri May 04, 2012 6:26 pm

1. True or False:
Early treatment of patients defined as high risk for progression to multiple myeloma (multiple myeloma) from smoldering multiple myeloma (SMM) with lenalidomide (Revlimid, Celgene) and dexamethasone exhibited a trend toward improvement in overall survival (OS).

2. True or False:
The combination of carfilzomib (Onyx Pharmaceuticals), lenalidomide and low-dose dexamethsone (CRd) regimen has very high and stable response rates with fewer dose modifications due to peripheral neuropathy in contrast to bortezomib (Velcade, Millennium Pharmaceuticals) combinations with similar agents.

3. True or False:
In a Phase I trial with marizomib (Nereus Pharmaceuticals), a highly potent proteasome inhibitor, once-a-week dosing of 0.4 to 0.5 mg/m2 appears to be the optimal dosing schedule for relapsed/refractory multiple myeloma.

4. True or False:
In patients with multiple myeloma, the Phase II study of bortezomib in combination with panobinostat (Novartis) demonstrated activity in approximately one-third of patients who were truly refractory to bortezomib.

5. True or False:
Perifosine (Keryx Biopharmaceuticals) and bortezomib with or without dexamethasone demonstrated encouraging activity with an overall response rate (ORR; defined as minimal response or better) of 41% in 73 evaluable patients, including an ORR of 65% and 32% in bortezomib-relapsed and bortezomib-refractory patients, respectively.

6. True or False:
pomalidomide (Celgene) with or without dexamethasone is active in heavily pretreated patients with multiple myeloma, including those refractory to bortezomib but not to lenalidomide.

7. True or False:
Elotuzumab (Abbott Laboratories) in combination with lenalidomide and low-dose dexamethasone exhibited 92% ORR in relapsed/refractory patients with multiple myeloma.

8.True or False:
The retrospective data on 2,283 patients with multiple myeloma suggest that observed and expected secondary primary malignancy (SPM) rates are higher with induction with both an alkylating agent and an immunomodulatory agent.

9. True or False

The combination of MLN9708 (Millennium), lenalidomide, dexamethasone in patients with multiple myeloma who were not previously treated demonstrated 100% (n=15) partial or better response, including four complete responses and five very good partial responses.


10.. True or False:
Persistent minimal residual disease by multiparameter flow cytometry at day 60+ predicted unsustained complete response (CR) after autologous stem cell transplantation (ASCT) in multiple myeloma.

11.
True or False:
In multiple myeloma, prediction of complete response by gene expression profiling (GEP) is likely to be an important goal for prospectively selecting those patients who are more likely to benefit from a given therapy.



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1. True.
Higher three-year (from study inclusion) and five-year (from diagnosis) OS rates compared with observation (hazard ratio [HR] for five-year OS from diagnosis: 5.01; 95% confidence interval [CI], 1-22; P=0.03) were observed. Similar to this Spanish trial, the ECOG (Eastern Cooperative Oncology Group) trial involved accrual of patients with high-risk SMM for randomization to either single-agent lenalidomide or observation (ClinicalTrials.gov identifier: NCT01169337).
Mateos MV, López-Corral L, Hernández M, et al. Smoldering multiple myeloma (SMM) at high-risk of progression to symptomatic disease: a phase III, randomized, multicenter trial based on lenalidomide-dexamethasone (Len-Dex) as induction therapy followed by maintenance therapy with Len alone vs no treatment. ASH Annual Meeting Abstracts. 2011;118(21):991.

2 True.
The majority of patients did not require dose modifications, either in the initial or in the maintenance phase of the treatment.
Jakubowiak AJ, Dytfeld D, Jagannath S, et al. Final results of a frontline Phase 1/2 study of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in multiple myeloma (multiple myeloma). ASH Annual Meeting Abstracts. 2011;118(21):631.

3. False.
Marizomib in combination with dexamethsone demonstrated encouraging responses of 15% to 20% in heavily pretreated patients. Marizomib 0.4 to 0.5 mg/m2 twice weekly appears to be the optimal dosing schedule without reports of significant peripheral neuropathy.
Richardson PG, Spencer A, Cannell P, et al. Phase I clinical evaluation of twice-weekly marizomib (NPI-0052), a novel proteasome inhibitor, in patients with relapsed/refractory multiple myeloma (multiple myeloma). ASH Annual Meeting Abstracts. 2011;118(21):302.

4. True.
The combination of panobinostat and bortezomib seems to be promising for patients with bortezomib-refractory multiple myeloma. A Phase III Spanish trial with panobinostat/placebo plus bortezomib plus dexamethasone in patients with relapsed multiple myeloma (PANORAMA 1) will further define the potential role of panobinostat in the treatment of patients with multiple myeloma.
Richardson PG, Alsina M, Weber DM, et al. Phase II study of the pan-deacetylase inhibitor panobinostat in combination with bortezomib and dexamethasone in relapsed and bortezomib refractory multiple myeloma (PANORAMA 2). ASH Annual Meeting Abstracts. 2011;118(21):814.

San-Miguel JF, de Moraes Hungria VT, Yoon SS, et al. Update on a Phase III study of panobinostat with bortezomib and dexamethasone in patients with relapsed multiple myeloma: PANORAMA 1. ASH Annual Meeting Abstracts. 2011;118(21):3976.

5. True.
Perifosine, an orally bioavailable, novel signal transduction modulator has multiple pathway effects including inhibition of Akt, NFkB and activation of JNK. A Phase III trial is under way comparing perifosine with bortezomib plus dexamethasone with bortezomib plus dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib.

Richardson PG, Wolf JL, Jakubowiak AJ, et al. Perifosine plus bortezomib and dexamethasone in relapsed/refractory multiple myeloma patients previously treated with bortezomib: final results of a Phase I/II trial. ASH Annual Meeting Abstracts. 2011;118(21):815.

6. False.
In a Phase II study with 221 multiple myeloma patients who had previously received a median of five prior therapies including lenalidomide and bortezomib, pomalidomide was administered at 4 mg for 21 days of a 28-day cycle. For patients refractory to both lenalidomide and bortezomib, median progression-free survival was two months for pomalidomide alone and 3.9 months for pomalidomide and low-dose dexamethasone. The regimen is now being investigated in combination with pegylated liposomal doxorubicin (ClinicalTrials.gov identifier: NCT01541332) and bortezomib (NCT01497093).

Richardson PG, Siegel DS, Vij R, et al. Randomized, open label Phase 1/2 study of pomalidomide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): Phase 2 results. ASH Annual Meeting Abstracts. 2011;118(21):634.

7, True.
Elotuzumab is a humanized monoclonal immunoglobulin G1 antibody directed against the cell surface glycoprotein CS1, which is highly expressed on tumor cells in more than 95% of multiple myeloma patients. Phase III clinical trials with similar combinations are ongoing—ELOQUENT2 trial—for relapsed/refractory multiple myeloma (NCT01239797) and the ELOQUENT1 trial for front-line multiple myeloma (NCT01335399).

Lonial S, Jakubowiak AJ, Jagannath S, et al. A Phase 2 study of elotuzumab in combination with lenalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma. ASH Annual Meeting Abstracts. 2011;118(21):303.

8. False.
The observed and expected SPM rates are similar, even for treatment that includes induction with both an alkylating agent and an immunomodulatory agent. For all patients, the rate of SPM was 2.1% (n=48); it was 0.6% (n=2) with lenalidomide and dexamethasone or cyclophosphamide, 2.4% (n=23) with lenalidomide and melphalan, 3.1% (n=17) with melphalan and thalidomide, and 1.4% (n=6) with melphalan and no immunomodulatory agent.

Palumbo A, Larocca A, Zweegman S, et al. Second primary malignancies in newly diagnosed multiple myeloma patients treated with lenalidomide: analysis of pooled data in 2459 patients. ASH Annual Meeting Abstracts. 2011;118 (21):996.

9. True.
MLN9708 is an oral, specific, reversible inhibitor of the 20S proteasome. The combination with lenalidomide and dexamethasone yielded rapid responses, with 14 of 15 patients achieving at least 50% reduction in M-protein in cycle 1. Two patients discontinued the therapy following cycle 6 to undergo transplantation (one in very good partial remission and one in complete remission [CR]).

Berdeja JG, Richardson PG, Lonial S, et al. Phase 1/2 study of oral MLN9708, a novel, investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (multiple myeloma). ASH Annual Meeting Abstracts. 2011;118 (21):479.

10. False
Dr. Bruno and colleagues investigated which prognostic markers can predict unsustained CR in a series of 241 patients in CR at day 100+ after high-dose therapy (HDT)/ASCT who were enrolled in the Spanish GEM2000 (n=140) and GEM2005 (<65 years old, n=101) trials. Twenty-nine (12%) of the 241 patients showed unsustained CR and a dismal outcome (median OS, 39 months). The presence of baseline high-risk cytogenetics by fluorescence in situ hybridization (HR, 17.3; P=0.002) and persistent minimal residual disease by multiparameter flow cytometry at day 100+ after HDT/ASCT (HR, 8.0; P=.005) were the only independent factors that predicted unsustained CR.

Paiva B, Gutierrez NC, Rosiñol L, et al. High-risk cytogenetics and persistent minimal residual disease (MRD) by multiparameter flow cytometry (MFC) predict unsustained complete response (CR) after autologous stem cell transplantation (ASCT) in multiple myeloma (multiple myeloma). ASH Annual Meeting Abstracts. 2011;118 (21):630.

11. True.
GEP analysis of a subgroup of patients who received bortezomib, thalidomide and dexamethasone (VTD) induction therapy provided a 41-gene signature that was able to predict attainment of CR/near complete remission (nCR) and, conversely, failure to achieve at least nCR in 91% and 95% of cases, respectively.

Terragna C, Remondini D, Durante S, et al. A 41-gene signature predicts complete response (CR) to bortezomib-thalidomide-dexamethasone (VTD) as induction therapy prior to autologous stem-cell transplantation (ASCT) in multiple myeloma (multiple myeloma). ASH Annual Meeting Abstracts. 2011;118(21):805.

http://www.clinicaloncology.com//ViewArticle.aspx?ses=ogst&d=PRN&d_id=155&i=ISSUE%3a+April+2012&i_id=836&a_id=20689