Phase II Clinical and Correlative Study Of Carfilzomib, Lenalidomide, and Dexamethasone Followed By Lenalidomide Extended Dosing (CRD-R) Induces High Rates Of MRD Negativity In Newly Diagnosed Multiple Myeloma (MM) Patients

Abstract Background An irreversible proteasome inhibitor with decreased peripheral neuropathy compared to bortezomib, Carfilzomib (Cz) has potent anti-MM effects resulting in deep clinical responses and durable remissions. In this two-stage phase II trial of 45 planned patients, we treat newly diagnosed MM patients with Cz, lenalidomide(Ln), and dexamethasone (Dx) followed by 2 years of Ln maintenance. Methods Eight 28-day cycles of combination therapy comprises: Cz IV 20/36 mg/m2 on days 1, 2, 8, 9, 15, 16; Ln oral 25 mg days 1-21; and Dx IV or oral 20/10 mg (C1-4/5-8) on days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients undergo stem cell collection after 4 cycles of CRd and continue with treatment. After 8 cycles of combination therapy, patients with SD or better receive up to 24 cycles of Ln extended dosing 10 mg days 1-21. Primary endpoint is ≥ grade 3 neuropathy. Bone marrow samples are collected at baseline, C1D2 (single agent Cz exposed), CR/end of cycle 8 (cycles 1-8), CR/end of cycle 20 (cycles 9-20), and CR/end of cycle 32/treatment termination (cycles 21-32). Patients are evaluated for clinical biomarkers, FDG-PET CT, and MRD studies (flow cytometry and PCR) at regular time points. Flow cytometry utilizes 8-color flow panel and analyzes ≥ 3 x 106 events (sensitivity 1 x 10-5). Results Forty-one patients meeting eligibility criteria have been enrolled (24 male, 17 female; median age 60; range 40-88). Among patients enrolled, median M-spike is 2.9 (1.0-7.6 g/dL) and isotypes included 26-IgG, 10 – IgA, 4 – free kappa, and 1 – free lambda. Thirty-eight patients are evaluable for response and toxicity. No patients have had ≥ grade 3 neuropathy. The mean decline in serum M-protein (n=33) was 72% after 1 cycle of CRd received. Best responses after a median of 9 cycles (range 2-20) completed, include 17–sCR/1-CR/6-nCR (63%), 10-VGPR (26%), 3-PR (8%), and 1-SD (3%). Among 18/38 (47%), median time to sCR/CR was 5 cycles. Among 14 CR/sCR + 3 nCR patients who underwent MRD assessment, all were negative. Among patients with ≤ VGPR at the end of 8 cycles of CRd, 5/8 (63%) had evidence of immunophenotypically abnormal plasma cells defined by flow cytometry, and 3 patients had undetectable abnormal plasma cells (1 achieved sCR after 8 additional Ln cycles). After median follow-up of 10 months (3-22), PFS rate was 83.3%. Twenty-five patients have completed 8 cycles of CRd, while 24/25 continued to Ln extension and 1 patient opted to exit study after CRd. Patients with non-hematologic toxicity events (≥ grade 3) include: electrolyte disturbances - 7(18%), LFT elevation - 5(13%), rash/pruritus – 4(11%), fatigue – 4(11%), cardiovascular – 3(8%), dyspnea/respiratory – 3(8%), constitutional symptoms – 2(5%), infections – 2(5%), VTE - 2(5%), and anxiety – 1(3%). Patients with hematologic toxicity events (≥ grade 3) include: lymphopenia –24(63%), anemia – 6(16%), leukopenia - 5(13%), and thrombocytopenia - 4(11%). All patients with baseline FDG avid lesions or extramedullary disease showed decrease or resolution of FDG avidity at MRD assessment time points. Conclusions Beyond traditional clinical response criteria, using a functional imaging and highly sensitive MRD assays, we consistently show high rates of deep remission and MRD negativity among newly diagnosed MM patients treated with carfilzomib, revlimid, dexamethasone (CRd) combination therapy. The results were very similar across age-groups and the oldest patient on this trial was 88 years old. If deep remissions are maintained with a delayed ASCT strategy incorporating extended dosing revlimid therapy, this may be a future strategy available to all patients irrespective of age. Disclosures: Off Label Use: Abstract is in newly diagnosed Multiple Myeloma patients. Carfilzomib is approved for relapsed/refractory patients.

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Prognostic impact of kinetics of circulating plasma cells before and after induction therapy in newly diagnosed multiple myeloma patients undergoing early transplantation.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.8020 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 8020-8020

Author(s):

Rajshekhar Chakraborty ◽

Eli Muchtar ◽

Angela Dispenzieri ◽

Martha Lacy ◽

Francis Buadi ◽

...

Keyword(s):

Multiple Myeloma ◽

Flow Cytometry ◽

Induction Therapy ◽

Plasma Cells ◽

Progression Free Survival ◽

Prognostic Impact ◽

Newly Diagnosed ◽

Color Flow ◽

Course Of Illness ◽

The Impact

8020 Background: Circulating plasma cells (CPCs) at diagnosis, prior to transplant and at relapse have a negative prognostic impact on survival in multiple myeloma (MM). However, the impact of changes in CPCs along the course of illness has not been defined. Methods: We evaluated 247 patients with newly diagnosed MM (NDMM) undergoing early autologous stem cell transplantation (ASCT) in the era of novel agents (2007 to 2015), who had serial evaluation of CPCs at diagnosis and pre-ASCT by 6-color flow cytometry. Results: The median age at transplant was 62 years.A total of 117 (47%) patients had no detectable CPCs at both time points (CPC-/-), 82 (33%) had CPCs at diagnosis followed by complete eradication after induction therapy (CPC+/-) and 48 (19%) had detectable clonal CPCs at transplant, with persistence of cells (CPC+/+; n=45) or emergence of new CPCs (CPC-/+; n=3) after induction. The incidence of t(11;14) by iFISH was lower in the CPC-/- group (19%) compared to CPC+/- (29%) and CPC +/+ or -/+ (39%) groups ( p=0.033). Conversely, the incidence of hyperdiploidy was significantly higher in patients with CPC-/-, compared to those with CPC+/- and CPC+/+ or -/+ (64%, 44% and 39% respectively; p=0.005). The rate of post-ASCT stringent complete response was 32% in the CPC-/- group, 30% in CPC+/- group and 12% in CPC+/+ or -/+ group ( p=0.018). At a median follow-up of 58 months from ASCT, the median progression-free survival (PFS) from transplant in the 3 respective groups was 30, 24 and 14 months and the 5-year overall survival (OS) rates were 83%, 70% and 43% ( p<0.001 for both comparisons). On a multivariate analysis, using CPC-/- group as the comparator, PFS and OS was significantly inferior in CPC+/- (RR 1.6; p=0.020 and RR 2.7; p=0.008 for PFS and OS respectively) and CPC +/+ or -/+ groups (RR 2.9; p<0.001 and RR 5.8; p<0.001 for PFS and OS respectively). Conclusions: Clonal CPCs are detectable in more than 50% of newly diagnosed MM patients undergoing upfront ASCT. Monitoring for CPCs before initiation of induction therapy and before ASCT by 6-color flow cytometry is highly predictive of outcome in NDMM and should be incorporated into prospective clinical trials.

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Phase II Clinical and Correlative Study of Carfilzomib, Lenalidomide, and Dexamethasone (CRd) in Newly Diagnosed Multiple Myeloma (MM) Patients

Blood ◽

10.1182/blood.v120.21.732.732 ◽

2012 ◽

Vol 120 (21) ◽

pp. 732-732 ◽

Cited By ~ 4

Author(s):

Neha Korde ◽

Adriana Zingone ◽

Mary Kwok ◽

Elisabet E. Manasanch ◽

Rene Costello ◽

...

Keyword(s):

Multiple Myeloma ◽

Flow Cytometry ◽

Single Agent ◽

M Protein ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Molecular Responses ◽

Pet Ct ◽

Grade 3 ◽

Fdg Pet Ct

Abstract Abstract 732 Background Carfilzomib (CFZ) is an irreversible proteasome inhibitor with potent anti-MM effects and significantly decreased peripheral neuropathy rates compared with bortezomib. In this single stage phase II trial, we plan to treat 45 newly diagnosed MM patients with 8 cycles of CRd followed by 1 year of Lenalidomide (LEN) maintenance. Unique to this study, transplant eligible patients default to “delayed” ASCT per protocol and depth of molecular responses are assessed using studies of minimal residual disease (MRD) (flow cytometry, PCR, and FDG PET-CT). Using this approach, we report the first n=18/45 patient results, showing that CRd induces rapid and deep remissions. Methods Untreated newly diagnosed non-transplant and transplant candidates are eligible for protocol. Patients are administered eight 28-day cycles of therapy including: CFZ IV 20/36 mg/m2 on days 1, 2, 8, 9, 15, 16; LEN oral 25 mg days 1–21; and Dexamethasone IV/oral 20/10 mg on days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients default to “delayed” ASCT approach per protocol by harvesting and cryopreserving stem cells after 4 cycles of CRd and continuing with cycles 5–8 of CRd thereafter. After 8 cycles of CRd, all patients with SD or better receive cycles 9–20 of LEN maintenance 10 mg days 1–21. Primary endpoint is the incidence of ≥ grade 3 neuropathy. Secondary endpoints include response rate, profiling CFZ activity to biological endpoints, and impact of MRD studies on clinical outcomes. Bone marrow samples are collected at baseline, C1D2 (single agent CFZ exposed), CR /end of cycle 8 (cycles 1–8), and CR/end of cycle 20 (cycles 9–20). MRD studies are performed on achievement of CR/end of cycle 8 (during cycles 1–8) and CR/end of cycle 20 (during cycles 9–20). Results 18 patients meeting eligibility criteria have been enrolled (10 male, 8 female; median age 60; range 42–83). Among the patients enrolled, mean M- protein 2.9 g/dL (1.0–7.2 g/dL) and isotypes included 10 IgG, 4 IgA, and 4 light chain only. 15 patients were evaluated for toxicity and response. No patients have reported ≥ grade 3 neuropathy. After completing one cycle, the mean decline in M-protein (heavy chain, n= 10 IgG + 4 IgA) and involved – uninvolved light chains (light chain only, n=4) was 74% and 73%, respectively. Best responses after median of 4 cycles of CRd (range 1–8) completed, include 4 – sCR/2-nCR (40%), 5 – VGPR (33%), 3 – PR (20%), and 1 – SD (6%). For patients who achieved sCR, median time from initiation of CRd treatment to sCR was 5 cycles. Four patients with sCR had no evidence of immunophenotypic abnormal plasma cells on multiparametric flow cytometry during MRD assesment. In addition, PET-CT results for 3 out of 4 sCR patients showed substantial decrease in max standardized uptake value (SUV) avid lytic lesion seen at MRD assessment when compared with baseline (average SUV decline was 76%). 1 sCR patient did not have any FDG avid lesions at baseline. All patients maintained their best response and have no evidence of clinical disease progression. 4 patients completed 8 cycles of CRd, while 3 (2 sCR and 1 SD) continued to maintenance Len phase and 1 opted to exit study after achieving sCR. The patient with only SD (17p deletion on FISH at baseline) achieved a 65% decrease in plasma cell tumor burden in bone marrow and no evidence of disease progression after 10 cycles of therapy. Patients with non-hematologic toxicity events (≥ grade3) include: 3 (20%) - hypophosphatemia, 2 (13%) - ALT increase, 2 (13%) – CHF, 1 (6%) – fatigue, 1 (6%) - anxiety, 1 – (6%) syncope, and 1(6%) – rash. Patients with ≥ grade 3 hematologic toxicity events include 10 (66%) – lymphopenia and 1 (6%) - thrombocytopenia. Updated results on additional patients and molecular/MRD studies (flow cytometry, PCR, and FDG PET-CT) will be presented at meeting. Conclusions Using an approach that merges functional imaging with molecular responses beyond traditional clinical biomarkers, we show that CRd followed by LEN maintenance and delayed ASCT is a highly potent and tolerable combination regimen in newly diagnosed MM patients. Disclosures: Off Label Use: In the clinical trial, we are using Carfilzomib in newly diagnosed multiple myeloma in combination with Lenalidomide and Dexamethasone. Currently, its label indication is single agent for use in relapsed/refractory multiple myeloma.

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Phase II clinical and correlative study of carfilzomib, lenalidomide, and dexamethasone (CRd) in newly diagnosed multiple myeloma (MM) patients.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e18568 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18568-e18568 ◽

Cited By ~ 2

Author(s):

Neha Korde ◽

Adriana Zingone ◽

Mary Kwok ◽

Elisabet E. Manasanch ◽

Manisha Bhutani ◽

...

Keyword(s):

Flow Cytometry ◽

Phase Ii ◽

Fdg Pet ◽

Single Agent ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Clinical Biomarkers ◽

Pet Ct ◽

Grade 3 ◽

Fdg Pet Ct

e18568 Background: Carfilzomib (Cz) is an irreversible proteasome inhibitor with potent anti-MM effects and decreased peripheral neuropathy rates compared to bortezomib. In this two-stage phase II trial of 45 planned patients, we treat newly diagnosed MM patients with Cz, lenalidomide(Ln), and dexamethasone (Dx). Methods: Eight 28-day cycles of induction comprises of Cz IV 20/36 mg/m2 on days 1, 2, 8, 9, 15, 16; Ln oral 25 mg days 1-21; and Dx IV/oral 20/10 mg on days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients undergo stem cell collection after 4 cycles of CRd and continue with induction. After 8 cycles of induction, patients with SD or better receive 12 cycles of Ln maintenance 10 mg days 1-21. Primary endpoint is ≥ grade 3 neuropathy. Bone marrow samples are collected at baseline, C1D2 (single agent Cz exposed), CR/end of cycle 8 (cycles 1-8), and CR/end of cycle 21 (cycles 9-21). Patients are evaluated for clinical biomarkers and MRD studies (flow cytometry, PCR, and FDG PET-CT) at regular time points. Results: Approximate enrollment rate is 1-2 patients/month. Six patients meeting eligibility criteria have been enrolled (2 male, 4 female; median age 58; age 42-74). Thus far, 5/6 patients are evaluable for toxicity and response (1-5 cycles, 2-4 cycles, 1-2 cycles, and 1-1 cycle). No patients have reported ≥ grade 3 neuropathy. Non-hematologic toxicity (≥ grade3) includes: 1 - LFT elevation and 1 - anxiety. One patient had ≥ grade3 hematologic toxicity with lymphopenia. After median 3 cycles of CRd, 3 patients achieved VGPR, 1 patient achieved PR, and 1 remained at SD. Mean decline in serum markers (M-protein or FLCs) was 87% (60-100%) among responders. One patient had 98% decline in FLCs after 1 cycle and a decrease in abnormal plasma cell burden to ≤ 2% by flow cytometry after 3 cycles. Updated results on additional patients and molecular/MRD studies (flow cytometry, PCR, and FDG PET-CT) will be presented at meeting. Conclusions: Combination therapy with CRd is a tolerable and effective regimen against upfront MM, evoking rapid and deep disease control.

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Results From the Phase II Dose Expansion of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.445.445 ◽

2012 ◽

Vol 120 (21) ◽

pp. 445-445 ◽

Cited By ~ 4

Author(s):

Joseph R. Mikhael ◽

Craig B. Reeder ◽

Edward N. Libby ◽

Luciano J. Costa ◽

P. Leif Bergsagel ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Phase Ii ◽

Initial Phase ◽

Stem Cell Transplant ◽

Response Rate ◽

Phase Ii Trial ◽

Cell Transplant ◽

Newly Diagnosed ◽

Grade 3

Abstract Abstract 445 Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its target and has a favorable toxicity profile that has shown significant activity in relapsed multiple myeloma (MM), leading to recent FDA accelerated approval. To achieve rapid and deep response in patients eligible for stem cell transplant, we combined carfilzomib with the regimen of cyclophosphamide-thalidomide-dexamethasone (CTD). We recently reported the results of the Phase I component of the trial (in which no MTD was reached) followed by the initial Phase II trial; however, with increasing evidence for the safe and effective use of higher doses of carfilzomib, we now report results from dose escalation extension of the Phase II trial. Methods: Newly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with Carfilzomib IV Days 1,2,8,9,15,16 (see Table 1 below for dosing per cohort) along with Cyclophosphamide 300 mg/m2 PO Days 1,8,15, Thalidomide 100 mg PO Days 1–28 and Dexamethasone 40 mg PO Days 1,8,15,22. We initially conducted a Phase I run in trial of 6 patients with no DLT observed before expanding to the Phase II portion of the study. The initial phase II regimen is shown below – as no DLTs were observed, we have now fully accrued to the Phase II dose level +1. Treatment was for 4 cycles with expected SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results: A total of 38 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II, and the remaining at dose escalated cohorts. We are reporting the 27 patients who have completed therapy and will update with the dose escalated cohorts. Median age was 65 (range 27–74) and 52% were female. ISS Stage was advanced (II-III) in 56%. Best overall response rate during 4 cycles of CYCLONE at dose level 0 is 96%: CR 29%, VGPR 46%, PR 21% (1 pt achieved MR). Adverse events of grade 3 or higher at least possibly related to CYCLONE occurred in 12 (44%). Most commonly reported non hematological toxicities (all grades) included fatigue (67%), constipation (56%), lethargy (41%) somnolence (37%), malaise (30%) depressed level of consciousness (22%); however, grade 3/4 toxicities occurring in >5% were uncommon: thromboembolic event 11%) and muscle weakness (7%). Two cases of pneumonia required hospitalization. Eight patients (30%) developed grade 1 sensory neuropathy; no higher grade or painful neuropathy was evident. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included neutropenia (15%) and lymphopenia (7%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. Conclusion: The 4 drug CYCLONE regimen is highly efficaceous with a response rate after only 4 cycles of 96% (75% ≥VGPR, 29% CR) at the current dosing level of carfilzomib IV 20/27 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. Increasing the dose of carfilzomib is feasible and updated results of dose escalated cohorts will be reported at 20/36 and 20/45 mg/m2. Disclosures: Bergsagel: onyx: Membership on an entity's Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

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NCCTG N057K phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: A North Central Cancer Treatment Group trial.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2031 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2031-2031

Author(s):

Daniel Ma ◽

Evanthia Galanis ◽

David Schiff ◽

Wenting Wu ◽

Patrick J. Peller ◽

...

Keyword(s):

Phase Ii ◽

Residual Disease ◽

Methylation Status ◽

Mtor Inhibitors ◽

Outcome Data ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Drug Induced ◽

Flt Pet ◽

Grade 3

2031 Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt pathway as a critical modulator of cell survival. Preclinical studies in GBM indicate that the combination of mTOR inhibitors, such as everolimus (RAD001), with either radiation therapy (RT) or temozolomide (TMZ) provide increased tumor cell killing. Methods: Newly diagnosed GBM pts were eligible for the study. RAD001 was dosed orally at 70 mg/week weekly, starting 1 week prior to RT/TMZ, and continued throughout RT/TMZ, adjuvant TMZ and then until progression. This was a single arm phase II design powered to detect a true overall survival at 12 months (OS12) of 73% (vs 58% in historical controls). Secondary endpoints were toxicity, response rate, and time to progression (TTP). A subgroup of patients with measurable residual disease were eligible for the PET imaging component of the study, consisting of an 18FLT-PET/CT scan performed before and after the initial two doses of RAD001 but before the first dose of RT or TMZ. Results: 103 patients were accrued to phase II of which 100 were evaluable. The median age was 60.5 years (23-81), median ECOG PS was 1, 46 patients had GTR, 33 STR, and the remainder had biopsy at diagnosis. Treatment tolerance was acceptable: 17% patient had at least one grade 3 hematologic toxicity; 14% had at least one grade 4 hematologic toxicity, 42% had at least one grade 3 non-heme toxicity, while 12% had at least one grade 4 non-heme toxicity. No increased incidence of infectious complications was observed and there were no treatment related deaths. Median PFS was 5.3 months (1.3-21.4), with 22 patients progression free. Mature OS data will be available at the meeting. MGMT methylation status analysis is ongoing. Of the pts who had evaluable FLT-PET data, three of eight (37.5%) had a drop in SUVmax >25% after two treatments of RAD001. Conclusions: RAD001 with standard of care chemoradiation had moderate toxicity. Serial 18FLT-PET was feasible for evaluating drug-induced changes in tumor proliferation following RAD001. Final outcome data and association of MGMT status with outcome will be reported at the meeting.

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Oral lenalidomide plus melphalan and prednisone (R-MP) for newly diagnosed multiple myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7518 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7518-7518 ◽

Cited By ~ 6

Author(s):

A. Palumbo ◽

P. Falco ◽

G. Benevolo ◽

L. Canepa ◽

S. D’Ardia ◽

...

Keyword(s):

Multiple Myeloma ◽

Multicenter Trial ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Cutaneous Toxicity ◽

Cutaneous Eruption ◽

Level 3 ◽

Immunomodulatory Drug ◽

Grade 3 ◽

Dose Levels

7518 Background: Lenalidomide (Revlimid) is a novel oral immunomodulatory drug active in refractory multiple myeloma (MM). In this multicenter trial, we evaluate the effect of the combination lenalidomide, melphalan and prednisone (R-MP). Methods: Patients (pts) with newly diagnosed symptomatic MM ≥ 65 years received 9 courses of lenalidomide (21 days every 4–6 weeks) plus MP (4 days every 4–6 weeks). The trial was designed to asses toxicity and efficacy of R-MP combination. Four dose levels were tested (table 1). Each cohort included 6 pts, with additional 15 pts in level 3 and 4. Dose limiting toxicity (DLT) was defined as: grade ≥ 3 non-hematologic toxicity; grade 4 hematologic toxicity (with neutropenia lasting >7 days); treatment delay due to toxicity during the first cycle. All pts received ciprofloxacin and aspirin as prophylaxis. Results: At present, 50 pts (median age 71) received at least one R-MP course. No DLTs were observed in levels 1 and 2. In level 3, 1 pt experienced DLT (grade 4 neutropenia > 7 days). In level 4, 3 pts showed DLTs (neutropenic fever, grade 3 cutaneous toxicity, pulmonary embolism and cycle 2 delay due to neutropenia). After 1 cycle, no one was in complete remission (CR) (according to the EBMT/IBMTR criteria), 51% of pts showed a response of 50–99% (PR) and 49% a response <50%, no progressive disease (PD) occurred. After 3 cycles, CR was observed in 10% of pts, PR in 60% and response <50% in 30%, no PD occured. Major grade 3–4 adverse events were hematological toxicities: neutropenia (58%) and thrombocytopenia (21%). Major grade 3–4 non-hematological toxicities were cutaneous eruption (11%), infections (5%) and febrile neutropenia (3%). Neuropathy was not observed and only one thromboembolism was recorded. Conclusions: R-MP was well tolerated with a manageable toxicity. Significant response rate was observed. It represents a feasible and promising approach for elderly newly diagnosed pts. An update of these data will be presented. [Table: see text] [Table: see text]

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Oral RevlimidR Plus Melphalan and Prednisone (R-MP) for Newly Diagnosed Multiple Myeloma.

Blood ◽

10.1182/blood.v106.11.785.785 ◽

2005 ◽

Vol 106 (11) ◽

pp. 785-785 ◽

Cited By ~ 5

Author(s):

Antonio Palumbo ◽

Patrizia Falco ◽

Pellegrino Musto ◽

Paolo Corradini ◽

Francesco Di Raimondo ◽

...

Keyword(s):

Multiple Myeloma ◽

Treatment Delay ◽

Multicenter Trial ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Cutaneous Toxicity ◽

Myeloma Protein ◽

Grade 3 ◽

Protein Reduction ◽

Dose Levels

Abstract Introduction. Lenalidomide (RevlimidR) is a novel, orally active immunomodulatory drug effective for the treatment of refractory myeloma. In this multicenter trial, we evaluate the potential additive and synergistic effect of the combination RevlimidR, melphalan and prednisone (R-MP). Materials and Methods. Patients (pts) with newly diagnosed symptomatic multiple myeloma older than 65 years were treated with 9 courses of RevlimidR (5–10 mg/day for 21days every 4–6 weeks) plus MP (melphalan 0.18–0.25 mg/kg and prednisone 2 mg/kg for 4 days every 4–6 weeks). The trial was designed to define the toxicity profile of R-MP and to analyze the efficacy of this combination. Four different dose levels were tested: 1. melphalan 0.18 mg/kg + RevlimidR 5 mg/day; 2. melphalan 0.25 mg/kg + RevlimidR 5 mg/day; 3. melphalan 0.18 mg/kg + RevlimidR 10 mg/day; 4. melphalan 0.25 mg/kg + RevlimidR 10 mg/day. Each cohort included 6 pts. Dose limiting toxicity (DLT) was defined as: any grade ≥ 3 non-hematologic toxicity; grade 4 neutropenia lasting >7 days; any other grade 4 hematologic toxicity and any treatment delay due to toxicity that occurred during the first cycle. All pts received ciprofloxacin and aspirin as prophylaxis. Results. At present, 24 pts (median age 72, range 61–77) received at least one R-MP course and were evaluated. No DLTs were observed in the first 2 dose levels; 1 DLT was observed with melphalan 0.18 mg/Kg and RevlimidR mg/kg (grade 4 neutropenia lasting> 7 days); 2 DLTs were reached with melphalan 0.25 and RevlimidR 10 mg (1 neutropenic fever, 1 grade 3 cutaneous toxicity). After 1 cycle of R-MP, no one was in complete remission (according to the EBMT/IBMTR criteria), 2 pts (9.5%) showed a myeloma protein reduction of 75–99%, 7 pts (28.6%) a response of 50–74%, and 15 (61.9%) a response of <50% (1 of these pts showed a 30% reduction in the size of soft tissue plasmacytomas), no disease progressions were observed. After 3 cycles of R-MP, myeloma protein reduction of 75–99% was detected in 1 patients (11,1%), response of 50–74% in 8 patients (55.6%) and response <50% in 5 patients (33.3%), no disease progressions were observed. Grade 3 or 4 adverse events were reported in 9 patients (35%). They included: 1 thrombo-embolism (4.2%); 5 grade 4 neutropenias (20.9%) ;4 grade 3 neutropenias (16.7%); 4 grade 3 thrombocytopenias (16.7%); 1 febrile neutropenia (4.2%); 2 grade 3 dermatological toxicities (8.3%); 1 grade 3 metabolic toxicity (4.2%) and 1grade 4 metabolic toxicity (4.2%). One pt discontinued RevlimidR because of grade 3 dermatological toxicity. Dose- reduction was required in 4 pts (1 grade 4 neutropenia >7 days, 1 treatment delay due to toxicity, 2 grade 3 dermatological toxicities). Conclusions. R-MP was well tolerated with a manageable toxicity. Significant response rate was observed. It represents a feasible and promising approach for newly diagnosed pts who are not candidates for transplant. Fifteen additional pts were treated with the fix dose of melphalan 0.18 mg/kg + RevlimidR 10 mg/day, results are too premature to assess efficacy. An update of these data will be presented.

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Combination Therapy Based on Bortezomib for Newly-Diagnosed Multiple Myeloma: a Chinese Experience

Blood ◽

10.1182/blood.v116.21.5036.5036 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5036-5036

Author(s):

Li Yang ◽

Jing-Song He ◽

WenJun Wu ◽

Xiujin Ye ◽

Jimin Shi ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Combination Therapy ◽

Combination Chemotherapy ◽

Chinese Population ◽

Conflicts Of Interest ◽

Malignant Neoplasm ◽

Chinese Patients ◽

Newly Diagnosed ◽

Grade 3

Abstract Abstract 5036 Multiple myeloma (MM) is a malignant neoplasm of plasma. With conventional chemotherapy, the rates of complete remission (CR) or very good partial remission (VGPR) are still low. Little has been reported on Bortezomib-based therapies specifically in the Chinese pateitns with MM. Here we report our results with combination therapy based on bortezomib in the Chinese population. We investigated the efficacy and safety of Bortezomib-based therapies in previously untreated MM patients. Methods: Between June 2006 and June 2010, 61 consecutive newly-diagnosed patients with symptomatic MM were treated with combination therapies based on Bortezomib. Forty-two patients were male and 19 were female. Median age was 59 years (range 37–86 years). Forty-four patients were stage 3 according to the International Staging System, 6 patients were stage 2 and 11 patients were stage 1. The conbinations included dexamethasone, dexamethasone plus subsequent thalidomide and dexamethasone plus cyclophosphamide. In detail, Bortezomib was at the dose of 1.3 mg per square meter IV on days 1, 4, 8, 11 and dexamethasone at 20 mg per square meter IV daily on the day of bortezomib and the day after, with or without daily oral thalidomide that was escalated from 100 mg to 200 mg (BD group or BDT group) or plus cyclophosphamide at 0.2 per square meter IV on days 1 to days 4 (BDC group). Thirty-four patients were in BDT group, 12 in BD group and 15 in BDC group. All patients received a median of three cycles of therapy (range 1–6). The IMWG criteria were used for response evaluation and toxicities were evluated according to the NCI Common Toxicity Criteria version 3. Results: The proportions of patients with very good partial response (VGPR) or better were 38% (13/34), 25% (3/12) and 60% (9/15) in BDT, BD and BDC group, respectively; 44% (15/34), 33% (4/12) and 33% (5/15) achieved partial response (PR). Therefore the overall response (VGPR plus PR) were 82% (28/34), 58% (7/12) and 93% (14/15). Three patients died with severe infection without disease progression. Grade 3–4 toxicities included fatigue (4/34, 1/12 and 4/15), thrombocytopenia (8/34, 3/12 and 5/15), diarrhea (4/34, 2/12 and 2/15) and infection (7/34,3/12,6/15) in BDT, BD and BDC group, respectively. Grade 1–2 neuropathy were occurred in 20 patients (59%), 6 patients (50%) and 9 patients (60%) and grade 3–4 were occurred in 6 (18%), 1 (8%) and 1 (7%) in BDT, BD and BDC group, respectively. Herpes zoster occurred in 6 patients (18%), 1 patients (8%) and 2 patients (13%) respectively. Routine anticoagulation or anti-thrombsis were not used. Only 1 patient suffered from DVT/PE but did well with treatment. Conclusions: Our preliminary experience in Chinese patients indicated that combination chemotherapy based on Bortezomib is highly effective in newly-diagnosed multiple myeloma and BDC or BDT regimens may be more superior than BD in Chinese population. There were relative lower rates of grade 3–4 neuropathy and DVT/PE in the Chinese patients with MM receved combination chemotherapy based on bortezomib. Disclosures: No relevant conflicts of interest to declare.

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Phase II Trial of Initial Safety and Toxicity Prior to the Phase III Trial of Lenalidomide Versus Observation Alone in Patients with Asymptomatic High-Risk Smoldering Multiple Myeloma (E3A06): A Trial Coordinated by the Eastern Cooperative Oncology Group

Blood ◽

10.1182/blood.v120.21.4079.4079 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4079-4079 ◽

Cited By ~ 1

Author(s):

Sagar Lonial ◽

Susanna Jacobus ◽

Matthias Weiss ◽

Rafael Fonseca ◽

Madhav V. Dhodapkar ◽

...

Keyword(s):

High Risk ◽

Phase Ii ◽

Research Funding ◽

Plasma Cells ◽

Phase Ii Trial ◽

Phase Iii ◽

Hematologic Toxicity ◽

Trial Testing ◽

Grade 3 ◽

Smoldering Myeloma

Abstract Abstract 4079 The treatment and natural history of asymptomatic or smoldering myeloma has been an area of intense preclinical and clinical study. Historical attempts to treat these patients have not demonstrated significant benefit, likely as a consequence of limited therapeutic options as well lack of attention to the vast heterogeneity contained within the diagnosis of smoldering myeloma. More recent risk criteria from both US and Spanish investigators have identified a cohort of smoldering myeloma patients at high risk for progression to myeloma in a short time. Recently the PETHEMA group has conducted a randomized clinical trial testing lenalidomide and dexamethasone vs observation among high risk smoldering patients and has demonstrated a clear benefit in terms of progression free survival and hints towards improvement in overall survival favoring early intervention. To further evaluate the potential benefit of early intervention in a high risk smoldering cohort, the ECOG myeloma group designed a phase II trial testing the safety and efficacy of single agent lenalidomide with the intent of broadening to a randomized phase III trial if toxicity was acceptable. We report here on the safety portion of the phase II trial. The phase II group of patients received lenalidomide at a dose of 25 mg days 1–21 every 28 days to evaluate the early toxicity and tolerance of this dosing. The dose of lenalidomide could be adjusted based on toxicity using a defined dose-modification guideline in the protocol. The primary endpoint for the safety study was the rate of any treatment-related grade 4–5 non-hematologic toxicity plus grade 3 non-hematologic toxicity that affects vital organ function (such as cardiac, hepatic, or thromboembolic events) observed within 6 cycles of treatment. The goal was to enroll 34 patients; if 9 or more patients experience toxicity as defined, then the study would not continue. In terms of eligibility, patients were to be diagnosed with asymptomatic high-risk smoldering multiple myeloma (SMM) within the past 12 months, as confirmed by both of the following: bone marrow plasmacytosis with >= 10% plasma cells or sheets of plasma cells and an abnormal serum free light chain ratio (<0.125 or >8.0) by serum FLC assay. Further, patients must have measurable levels of monoclonal protein (M-protein): >=1g/dL on serum protein electrophoresis or >=200 mg of monoclonal protein on a 24 hour urine protein electrophoresis. Patients must have no lytic lesions on skeletal surveys and no hypercalcemia. Among the 36 patients enrolled in the phase II study, 56% were female, and 44% were 65 years and older. Treatment and toxicity data at a minimum through cycle 6 is complete as of August 2, 2102. The last patient enrolled completed cycle 6 treatment on June 7, 2012. The median treatment duration of the entire cohort is 9 cycles (range 1–18 cycles), with 86% of patients completing at least 6 cycles of treatment. Ten patients are off treatment for the following reasons: disease progression (n=1), AE/complication (n=5), death (n=1) and patient withdrawal/refusal (n=3); 5 of the 10 patients ended treatment before completing 6 cycles. Of 36 patients assessed for toxicity, 8 patients [22.2%, 90% CI: (11.6%-36.5%)] experienced worst grade treatment-related non-hematologic toxicity of grade 3 or higher. Separately, 6 patients experienced unrelated non-hematologic toxicity of grade 3 or higher. Three patients [8.3%, 90% CI: (2.3%-20.2%)] experienced a serious adverse event as defined for the purposes of the phase II toxicity analysis (treatment-related grade 4–5 non-hematologic toxicity or grade 3 non-hematologic toxicity that affects vital organ function (such as cardiac, hepatic, or thromboembolic events). Based upon this analysis of the study, the phase II portion of the trial met the prespecified safety benchmark established to allow for phase III expansion, and accrual to the phase III portion of this study will begin. Efficacy data will be presented at the time of presentation. Disclosures: Lonial: Novartis: Consultancy; Millennium: Consultancy; Onyx: Consultancy; BMS: Consultancy; Celgene Corp: Consultancy; Merck: Consultancy. Off Label Use: Lenalidomide is not approved for treatment of smoldering MM. Fonseca:Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy; Binding site: Consultancy; Millenium: Consultancy; AMGEN: Consultancy; Celgene : Research Funding; Onyx: Research Funding; prognostication of MM based on genetic categorization of the disease: Prognostication of MM based on genetic categorization of the disease, Prognostication of MM based on genetic categorization of the disease Patents & Royalties. Dhodapkar:Celgene: Research Funding; KHK: Research Funding.

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Phase II Trial Of Initial Safety and Toxicity Prior To The Phase III Trial Of Lenalidomide Versus Observation Alone In Patients With Asymptomatic High-Risk Smoldering Multiple Myeloma (E3A06): A Trial Coordinated By The Eastern Cooperative Oncology Group

Blood ◽

10.1182/blood.v122.21.3174.3174 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3174-3174 ◽

Cited By ~ 2

Author(s):

Sagar Lonial ◽

Susanna Jacobus ◽

Matthias Weiss ◽

Rafael Fonseca ◽

Madhav V. Dhodapkar ◽

...

Keyword(s):

High Risk ◽

Phase Ii ◽

Plasma Cells ◽

Eastern Cooperative Oncology Group ◽

Phase Iii ◽

Hematologic Toxicity ◽

Organ Function ◽

Trial Testing ◽

Grade 3 ◽

Smoldering Myeloma

Abstract The treatment and natural history of smoldering myeloma has been an area of intense preclinical and clinical study. Historical attempts to treat these patients have not demonstrated benefit, likely as a consequence of lack of attention to the vast heterogeneity contained within the diagnosis. More recent risk criteria from both US and Spanish investigators have identified a cohort of smoldering myeloma patients at high risk for progression in a short time, using different methodology. Recently the PETHEMA group published a randomized clinical trial testing lenalidomide/dexamethasone vs observation among high risk smoldering patients, and demonstrated a clear benefit in terms of progression free and overall survival favoring early intervention. However, the risk criteria utilized a highly sensitive method of flow cytometry, a test not routinely available in the US. It is not clear that the group of patients defined in the PETHEMA study share similar outcomes with those defined as high risk using the ECOG/Mayo criteria. A recent publication demonstrated only 25% overlap for the highest risk smoldering patients when using either the PETHEMA or the ECOG criteria. To further evaluate the potential benefit of early intervention in a high risk smoldering cohort, the ECOG myeloma group designed a phase II/III trial testing the safety and efficacy of single agent lenalidomide. We report here on the safety and efficacy of the phase II portion of the trial. The phase II group of patients received lenalidomide alone at a dose of 25 mg days 1-21 every 28 days. The primary endpoint for the safety study was the rate of any treatment-related grade 4-5 non-hematologic toxicity plus grade 3 non-hematologic toxicity that affects vital organ function (such as cardiac, hepatic, or thromboembolic events) observed within 6 cycles of treatment. Patients were to be diagnosed with high-risk smoldering multiple myeloma (SMM) within the past 12 months, as confirmed by both of the following: bone marrow plasmacytosis with >= 10% plasma cells or sheets of plasma cells and an abnormal serum free light chain ratio (<0.125 or >8.0) by serum FLC assay. Patients must have had measurable levels of monoclonal protein. Patients must have had no lytic lesions on skeletal surveys and no hypercalcemia (i.e. >= 11 mg/dL). Among the final phase II cohort (n=44 patients), 55% were female, and 43% were 65 years and older. Enrollment began in January 2011 and lasted 2 years with the last patient completing 6 cycles of treatment in August 2013. The median treatment duration of the entire cohort is 13.5 cycles (range 1-30 cycles). Mean percentage lenalidomide dose over the first 6 cycles was 94, 89, 82, 79, 76, 72. With a median follow up of 17 months, 2 patients had progression on therapy. Fifteen patients are off treatment for the following reasons: disease progression (n=2), AE/complication (n=5), death (n=2), patient withdrawal/refusal (n=5), other (n=1); 6 of the 15 patients ended treatment before completing 6 cycles. Of 44 patients assessed for toxicity, 11 patients [25.0%, 95% CI: (13.2%-40.3%)] experienced worst grade treatment-related non-hematologic toxicity of grade 3 or higher based on CTCAE v4, with neutropenia and fatigue being the most frequent. This includes 2 fatal deaths (MI and TE). Two patients [4.6%, 95% CI: (0.1%-15.5%)] experienced a serious adverse event as defined for the purposes of the phase II toxicity analysis that included treatment-related grade 4-5 non-hematologic toxicity or any grade 3 toxicity affecting vital organ function (such as cardiac, hepatic, or thromboembolic events) during the first 6 cycles of treatment. Twelve patients achieved partial response or better [33.3%, 95% CI: (15.0%-42.8%)] along with 25 patients reporting stable disease. Lenalidomide has shown promise in the treatment of high-risk smoldering myeloma and based on this analysis, accrual to the phase III portion is ongoing. In the context of the encouraging data from the PETHEMA group, completion of the phase III portion of this study is needed to validate their findings using a different criteria, and using a steroid sparing approach. This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, M.D., Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA13650, CA32102 and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Disclosures: Lonial: Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

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