Combination Therapy With Thalidomide Plus Dexamethasone for Newly Diagnosed Myeloma

PURPOSE: Multiple myeloma is a malignancy of plasma cells and is characterized by increased marrow angiogenesis. Thalidomide, an agent with antiangiogenic properties, is effective in relapsed myeloma. We report the results of a study combining thalidomide and dexamethasone as initial therapy for myeloma. PATIENTS AND METHODS: Fifty patients with newly diagnosed myeloma were studied. Thalidomide was given at a dose of 200 mg/d orally. Dexamethasone was given at a dose of 40 mg/d orally on days 1 to 4, 9 to 12, and 17 to 20 (odd cycles) and 40 mg/d on days 1 to 4 (even cycles), repeated monthly. RESULTS: Of all 50 patients, a confirmed response was seen in 32 patients yielding a response rate of 64% (95% confidence interval, 49% to 77%). Thirty-one patients (62%) proceeded to stem-cell collection after four cycles of therapy including 26 who underwent stem-cell transplantation and five who chose stem-cell cryopreservation. Major grade 3 or 4 toxicities were observed in 16 patients (32%), and the most frequent were deep vein thrombosis (six patients), constipation (four patients), rash (three patients), and dyspnea (two patients). Three deaths occurred during active therapy because of a pancreatitis, pulmonary embolism, and infection. CONCLUSION: We conclude that the combination of thalidomide plus dexamethasone is a feasible and active regimen in the treatment of multiple myeloma. It merits further study as an oral alternative to infusional chemotherapy with vincristine, doxorubicin, and dexamethasone and other intravenous regimens currently used as pretransplantation induction therapy for myeloma.

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Rapid Control of Previously Untreated Multiple Myeloma with Bortezomib-Lenalidomide-Dexamethasone (BLD).

Blood ◽

10.1182/blood.v110.11.3611.3611 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3611-3611 ◽

Cited By ~ 2

Author(s):

Michael Wang ◽

Kay Delasalle ◽

Sergio Giralt ◽

Raymond Alexanian

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Deep Vein Thrombosis ◽

Intensive Therapy ◽

Primary Treatment ◽

Short Exposure ◽

Newly Diagnosed ◽

Vein Thrombosis ◽

Grade 3 ◽

Deep Vein

Abstract Introduction: Both bortezomib (B) and lenalidomide (L) are effective against relapsed/refractory and newly-diagnosed multiple myeloma (MM). The 3-drug combination of bortezomib-thalidomide-dexamethasone had induced remission in 87% of patients with untreated myeloma, significantly higher than the frequency of 66% observed with thalidomide dexamethasone. Patients and Method: We conducted a retrospective review of a pilot study in 17 previously-untreated patients with MM who were treated with bortezomib-lenalidomide dexamethasone between 4/06–4/07. Median age was 60 (35–71), median B2M was 3.7 mg/L (1.8–11.7) and median Hgb was 11 g/dl (6–14.7). Serum creatinine was greater than 2 mg/dl in one patient (6%). Bortezomib was given at 1.3 mg/m2 intravenously on days 1,4, 8 and 11; lenalidomide was at 25 mg orally daily for 21 days; and dexamethasone was at 20 mg/m2 daily orally for 4 days beginning on days 1, 9 and 17. Each cycle was 28 days. After the first cycle, a second cycle was given to 10 patients so that the median cycles of therapy was 2. As prophylaxis for deep vein thrombosis, all patients received warfarin with a targeted INR range between 2–3. All patients received daily orally vancyclovir to prevent herpes zoster. Results: Applying the Blade criteria of response (PR: greater than 50% reduction of serum myeloma protein and/or greater than 90% reduction of Bence Jones protein), remission of disease was observed in 14/17 patients (82%), including 2 patients (12%) with CR based on negative immunofixations and 12 patients (70%) with PR. All but one patient achieved remission after 1 cycle of treatment. Three patients were resistant to bortezomib-lenalidomide-dexamethasone after 2 cycles. One patient had deep vein thrombosis with pulmonary emboli. One patient had short-term grade 3 neuropathy. One patient had grade 3 thrombocytopenia and one patient had nonneutropenic pneumonia. Median nadir neutrophil count was 3000/ul (range 1400–5400/ul), and median nadir platelet count was 174 k/ul (range 38–270 k/ul). After a median 3.6 months (range 3.3–5.5), intensive therapy supported by autologous blood stem cells was given to 11 patients. Three of the 11 patients in PR after induction with bortezomib-lenalidomide-dexamethasone were converted to CR with intensification. Consequently, the CR rate after intensification 29%. Intensification is planned for the 3 patients with primary resistant MM. Discussion: Overall response and CR rates were similar to those observed previously among similar patients treated with bortezomib-thalidomide-dexamethasone. All reported primary treatment programs based on bortezomib-dexamethasone have induced high response rates of 82–92%, regardless of whether melphalan, lenalidomide, or thalidomide were included. Conclusions: One or two cycles of bortezomib-lenalidomide-dexamethasone were associated with rapid onset of response in patients with newly-diagnosed multiple myeloma. Toxicity was infrequent due to short exposure to bortezomib-lenalidomide-dexamethasone. There was early access to intensive therapy supported by autologous stem cells. Reduced exposure to drugs given as primary treatment should help preserve disease sensitivity to later treatment upon relapse.

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A Phase II Study of PS-341 for Patients with High Risk, Newly Diagnosed Multiple Myeloma: A Trial of the Eastern Cooperative Oncology Group (E2A02).

Blood ◽

10.1182/blood.v106.11.2546.2546 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2546-2546 ◽

Cited By ~ 2

Author(s):

Angela Dispenzieri ◽

Emily Blood ◽

David Vesole ◽

Rafael Fonseca ◽

Natalie Callander ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Peripheral Neuropathy ◽

High Risk ◽

Partial Response ◽

Progressive Disease ◽

Response Rate ◽

Cell Labeling ◽

Newly Diagnosed ◽

Grade 3

Abstract Background: Multiple myeloma (MM) is an incurable disease with a anticipated overall survival (OS) ranging from months to decades. Modest improvements in OS have been made with high-dose chemotherapy with peripheral blood stem cell transplant (PBSCT), but to date prognostic factors have a greater impact on OS than do individual therapies. Patients with adverse risk factors such as elevated beta-2 microglobulin (B2M), plasma cell labeling index, deletions of the long arm of chromosome 13 by metaphase cytogenetics (del 13q) require innovative new treatment strategies. Bortezomib has significant activity in patients with both newly diagnosed and relapsed/refractory MM, but its specific role in patients with adverse features has not yet been defined. Methods: Patients with newly diagnosed “high-risk” myeloma (B2M ≥ 5.5., PCLI ≥ 1, or del 13q) and adequate organ and functional status were eligible. Patients were treated with bortezomib 1.3 mg/m2 day 1, 4, 8, and 11 every 21 days for 8 cycles as induction. After induction, patients were scheduled to receive bortezomib 1.3 mg/m2 every other week indefinitely. Elective peripheral stem cell mobilization (growth factor alone) was allowed after 4 cycles of bortezomib. Patients relapsing on maintenance schedule were to have the full induction schedule resumed. Responses were by the EBMT criteria but a very good partial response category was included. The primary end-point was the response rate in these high-risk patients (90% power to detect a response rate of 50% or higher). The study decision rule requires that 16 or more responses, among 39 eligible patients, are seen in order to declare this treatment effective. Results: Between March 15, 2004 and March 10, 2005, 44 patients enrolled on study. Among the 43 eligible patients, median age was 63; 51% were male. All patients had high risk disease: del 13q (6/41); plasma cell labeling index ≥1% (16/34); and B2M≥5.5 (34/43). Preliminary response data are available for 18 of the 44 cases enrolled, of which 7 had partial response, 1 had minimal response, 1 had no response, 2 had progressive disease, and 5 were unevaluable. Among those patients completing induction therapy and with response information, the median number of cycles of therapy administered is 5, range (0,8). The most common non-hematologic adverse events (AEs) of grade 3 or higher included hyponatremia (9 patients) and diarrhea (6 patients). Mild sensory peripheral neuropathy was common: grade 1, 16 patients; grade 2, 2 patients. Only 1 patient had grade 3 peripheral neuropathy. One patient died after receiving 2 doses bortezomib due to heart block and asystole. Two patients had a grade 4, 25 patients had grade 3, and 13 had grade 1 or 2 as the worst grade non-hematologic adverse event. Based on data received by August 1, 2005, 18 patients have gone off study: AEs (2); death (1); progressive disease (9); and other reasons (6). Updated results on the full study population along with FISH data for IgH translocations and deletions of 13q and 17p will be presented at the meeting. Conclusions: Preliminary results suggest that upfront bortezomib has activity in patients with high-risk MM, but further follow-up is required.

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Up-Front Therapy for Multiple Myeloma: A Survey of Practice Patterns in the USA.

Blood ◽

10.1182/blood.v106.11.5172.5172 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5172-5172

Author(s):

Kavita Natarajan ◽

Gary H. Lyman ◽

Oscar F. Ballester

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

Initial Therapy ◽

Newly Diagnosed ◽

The Usa ◽

Choice Of Therapy

Abstract Introduction: Several treatment programs are available for the initial management of patients with multiple myeloma, with no clear documented advantage(s) of one regimen over the others in terms of time to progression (TTP) or overall survival (OS). Materials and Methods: A questionnaire was mailed to 540 randomly selected members of ASH during early 2005. Practitioners were asked their choice of therapy for newly diagnosed myeloma patients during 2004, based on 2005 NCCN guidelines, including: 1) melphalan/prednisone (MP), 2) vincristine / adriamycin / decadron (VAD), 3) high-dose decadron (HD), 4) thalidomide / decadron (Thal/Dex), 5) doxyl / vincristine / decadron (DVD); the options of a clinical trial (CT) or “other” were also included. Physicians were asked about factors influencing their choice of therapy for individual patients and their recommendations for autologous stem cell transplantation as part of the initial treatment schema. Results: Surveys were returned by 123 physicians(19.2%), of which 93 contained evaluable data. Among responders, 52% were in private practice and 47% in academic institutions and 74% respondants reporting having been in practice for more than 10 years. A large majority of physicians (74%) utilized 3 or more different regimens, only 10.7% of responders used a single regimen for all of their patients. Thal/Dex was used by 87% of responders, with 47% of them recommending this regimen in ≥ 50% of their patients. MP, HD and VAD were used by 67.7%, 49% and 44% of responders, but only 10.7%, 4% and 3% respectively, recommended them to ≥ 50% of their patients. DVD was used by 25% of physicians. Of respondants, 64.5% did not accrued patients to clinical trials and only 7.5% of physicians accrued ≥ 50% of their patients to clinical trials. No significant differences in the choice of regimen were apparent based on years of practice. Physicians in academic centers tended to use HD (p =.002) and accrue patients to CT (p=. 001) more often than those in private practice. Factors identified as important in selecting initial therapy for individual patients included: age (92%); performance status (95%); prognostic factors, such as β2-microglobulin and cytogenetics (75%); and candidacy for stem cell transplantation (93%). Respondants consider autologous stem cell transplantation as part of the initial therapy for all eligible patients (47%), only those with responsive disease (42%) and normal renal function (30%); only in selected cases (76%). Conclusions: Thal/Dex appears to be currently the most commonly recommended up-front therapy for multiple myeloma in the USA, in spite of the lack of published data documenting patient benefit in terms of TTP and OS. A sizable proportion of physicians do not recommend autologous stem cell transplantation as part of the initial therapy of newly diagnosed myeloma patients despite confirmed randomized clinical trials documenting benefit.

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Thalidomide Plus Dexamethasone for Untreated Newly Diagnosed Multiple Myeloma Patients and Deep Vein Thrombosis.

Blood ◽

10.1182/blood.v108.11.5093.5093 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5093-5093 ◽

Cited By ~ 2

Author(s):

Victor H. Jiménez ◽

Virginia J. Domínguez ◽

Eduardo E. Reynoso

Keyword(s):

Multiple Myeloma ◽

Deep Vein Thrombosis ◽

Oral Dose ◽

Newly Diagnosed ◽

First Line ◽

Factor V Leiden Mutation ◽

Vein Thrombosis ◽

First Line Therapy ◽

Line Therapy ◽

Deep Vein

Abstract Background The combination of thalidomide/dexamethasone (TD) induces remission in approximately 70% of previously untreated patients with low or intermediate tumor mass. TD appeared superior to previous programs because of the high response rate and reasonable survival and its low frequency of serious complications. The aim of our study was to assess the efficacy of thalidomide plus dexamethasone as first line therapy and the incidence of deep vein thrombosis. Material and methods Patients with newly diagnosed and symptomatic MM (untreated patients) were evaluated. We enrolled all patients who fulfilled entire criteria for multiple myeloma between January 1998 and December 2005. Patients were divided into 2 groups: thalidomide plus dexamethasone (TD) and VAD group. The present study is a prospective, descriptive, longitudinal and observational one. Thalidomide was prescribed in an oral dose of 100 mg qhs and increased by 50 mg every 7 days to a maximum dose of 300 mg, depending on side effects. Dexamethasone was given in an oral dose of 20 mg/m2 each morning after breakfast on days 1–4, 9–12 and 17–20, followed by 10 days without therapy prior to the next cycle. Treatment with the combination was continued for at least 6 months or until the earliest occurance of maximum plateau of myeloma protein reduction, autologous transplant-supported intensification or other treatments. VAD was given as an Out-patient regimen including: vincristine (0.4mg/day, continuous IV), doxorubicin (9mg/m2/day, continuous IV) and dexamethasone (40 mg/day PO) with a median of 6 courses. Citrate plasma was used to investigate coagulation and anticoagulation parameters. Results Sixty newly diagnosed multiple myeloma patients were included in the study, 35 (58%) male and 25 (42%) female, aged 45–85 (mean 63). Underlying diagnosis was IgG MM in 44 (73.3%), IgA in 12 (20%) and light chain disease in 4 (6.7%). Clinical characteristics were similar for both groups. According to Durie Salmon criteria patients were grouped into: IA (n6, 10%), IB (n3, 5%), IIA (n12, 20%), IIB (n6, 10%), IIIA (n19, 31.6%) and IIIB (n14, 23.4%). The frequency of response (CR, NCR/VGPR and PR) in the group of thalidomide and dexamethasone was 73% being higher than VAD (53%)p0.005. CR was observed in 5 patients treated with thalidomide/dexamethasone (16%). Thrombosis complications DVT was observed in 7 patients. DVT occurred in 4 patients treated with TD and 3 with VAD. From the last 40 patients, 5 presented APC-R and 3 of them developed DVT. A significant shorter time to DVT was observed in patients exposed to VAD chemotherapy (first 2 cycles p 0.007). Patients developing APC-R were tested for Factor V Leiden mutation resulting negative. After patients developed any response criteria were retested for acquired activated protein C resistance, all of them went back to normal. Finally we conclude TD is an effective, less toxic therapy in comparison with VAD as first line therapy and in order to reduce incidence of DVT effective prophylactic anticoagulation should be implemented in all controlled trials, at least during the first few cycles of treatment.

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Frontline Therapy with Bortezomib, Lenalidomide, and Dexamethasone (VRD) Induction Followed by Autologous Stem Cell Transplantation, VRD Consolidation and Lenalidomide Maintenance In Newly Diagnosed Multiple Myeloma Patients: Primary Results of the IFM 2008 Phase II Study

Blood ◽

10.1182/blood.v116.21.624.624 ◽

2010 ◽

Vol 116 (21) ◽

pp. 624-624 ◽

Cited By ~ 10

Author(s):

Murielle Roussel ◽

Hervé Avet-Loiseau ◽

Philippe Moreau ◽

Anne Huynh ◽

Lotfi Benboubker ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

Research Funding ◽

Response Rate ◽

Phase Ii Study ◽

Newly Diagnosed ◽

Grade 3 ◽

Stem Cell Collection

Abstract Abstract 624 Background: Autologous Stem Cell Transplantation (ASCT) is a standard of care for eligible MM patients (pts). Introduction of new drugs in this setting have markedly increased survival rates within the last 10 years. Efforts to further improve response and survival in those pts are still needed, mainly by increasing the depth of tumor reduction and the duration of response through more effective induction, consolidation and maintenance therapies. Therefore, the IFM (Intergroupe Francophone du Myélome) decided to evaluate the Bortezomib (Bor), Lenalidomide (Len) and Dexamethasone (Dex) regimen as induction and consolidation therapy followed by Len maintenance in the transplant setting for newly diagnosed pts. Methods: This open-label phase II study was conducted at 10 IFM transplant centers, with enrollment between September and December 2009. Pts under 65 with symptomatic de novo MM were enrolled to receive three 21-day induction cycles of VRD= Bor 1.3 mg/m2 (days 1, 4, 8, 11), Len 25 mg (days 1–14), and oral Dex 40 mg (days 1, 8 and 14). Stem cell collection was planned for all pts after high dose cyclophosphamide (3g/m2). All pts then proceeded to intensification prepared with melphalan 200 mg/m2 followed by ASCT. Two months after hematological recovery, pts could receive two 21-day consolidation cycles of VRD (same schedule) followed by 1 year of maintenance with Len at 10–15 mg/day. All patients received, unless contraindicated, aspirin prophylaxis or alternative anticoagulation for prevention of deep-vein thrombosis (DVT), anti-viral therapy (valacyclovir) for herpes zoster prevention. Pts with ≥ grade 2 peripheral neuropathy (PNY) were excluded. The primary endpoint was the best response achieved 1 month after consolidation. The secondary endpoints were the response rate after 3 cycles of VRD, after ASCT and after consolidation; the safety profile of the program, the feasibility and quality of stem cell collection and dthe uration of response (DOR), PFS, OS. Response was assessed according to International Uniform Response Criteria including stringent Complete Response (sCR). Flow cytometric analysis of bone marrow plasma cells was performed before and after ASCT, and after consolidation. Toxicities were graded using the CTCAEv4. Patients: Thirty-one pts with symptomatic MM were enrolled. Baseline characteristics of the pts were: median age = 58 (range 33–65); 55% were women; 55%/32%/13% had IgG/IgA/light chain MM; ISS= 1 in 52%, 2 in 32% and 3 in 16% of pts; chromosome 13q deletion in 41% over 27 assessable pts; chromosome 17p del in 18% and t(4;14) translocation in 11%. Results: All pts but one remain on study program at data cut-off (01/08/10). The one pt had discontinued treatment at time of ASCT due to mobilization failure. Therefore, 31 pts are evaluable for response rates after induction therapy, 30 after ASCT and 13 after consolidation. All results are summarized in table 1. In Intent To Treat analysis, the overall response rate (ORR) after ASCT was 94%, including 32% VGPR, 13% CR and 23% sCR. Nine serious AEs were reported. There was no treatment-related mortality. The most common toxicities were: sensory PNY (45%), including 29% grade 1 and 16% grade 2; neuropathic pain (13%); GI tract symptoms (42%) including diarrhea (16%) and constipation (10%); fatigue (10%) and erythrodermia (9%). There was no grade 3/4 PNY. Grade 3/4 hematological toxicities included neutropenia (26%), and thrombocytopenia (6%). No DVT or pulmonary embolism was reported.Six of 31 pts (19%) have had difficulty with mobilization but only 1 pt did not undergo ASCT. Stem cell collection with plerixafor was successful in 4 pts. Median stem cell collection was 7.7 × 106 CD34+ cells/kg. Conclusions: VRD induction followed by ASCT and VRD consolidation produce high quality responses and is well tolerated in newly diagnosed MM pts under 65. Updated efficacy and safety data will be presented at the meeting. Disclosures: Roussel: Janssen: Consultancy, Research Funding, orator; Celgene: Consultancy, Orator, Research Funding. Off Label Use: bortezomib, lenalidomide as induction and consolidation therapies in frontline MM pts. Leleu:Celgene: Consultancy, Research Funding; Janssen Cilag: Consultancy, Research Funding; Leo Pharma: Consultancy; Amgen: Consultancy; Chugai: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Attal:celgene: Consultancy, Research Funding; johnson and johnson: Consultancy, Research Funding.

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Phase II Trial of Intravenously Administered AMD3100 (Plerixafor) for Stem Cell Mobilization in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation Following a Lenalidomide-Based Initial Therapy

Blood ◽

10.1182/blood.v118.21.2992.2992 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2992-2992

Author(s):

Shaji Kumar ◽

Joseph R. Mikhael ◽

Martha Q Lacy ◽

Betsy R. LaPlant ◽

Francis K Buadi ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Adverse Events ◽

Research Funding ◽

Maximum Yield ◽

Early Morning ◽

Initial Therapy ◽

Cd34 Cells ◽

Rate Of Failure ◽

Stem Cell Collection

Abstract Abstract 2992 Background: Patients with myeloma receiving initial therapy with lenalidomide-based regimens can have difficulty collecting adequate stem cells for an autologous transplant. Stem cell collection in these patients can be significantly enhanced by addition of the CXCR-4 antagonist plerixafor to the mobilization regimen. Plerixafor is typically given subcutaneously (SQ), with collection approximately 11 hours after injection to obtain maximum yield. Intravenous administration can potentially allow more rapid and predictable mobilization compared to the SQ route. We designed this trial to prospectively assess the efficacy of intravenous plerixafor administration in patients undergoing lenalidomide therapy. Patients and methods: Patients who were receiving initial therapy with a lenalidomide-based regimen and were undergoing stem cell collection within 12 months of their myeloma diagnosis were enrolled. Patients received GCSF at 10 μg/kg/day for 4 days followed by addition of plerixafor at 0.24 mg/kg/dose starting on day 5. Plerixafor was administered intravenously early morning (6–7 am) followed by apheresis beginning 4–5 hours later. Plerixafor was administered for a maximum of 4 days; but patients could continue apheresis beyond the 4th day at treating physician discretion. The aims of the study were to determine the proportion of patients reaching a stem cell yield of at least 3 million CD34 cells/kg by second day of apheresis, the safety and tolerability of intravenously administered plerixafor, and the overall rate of failure to mobilize (defined as less than 2.5 million CD34 cells/kg in 4 collections). Results: Thirty-seven patients were accrued between December 2009 – April 2011, and 36 were eligible for analysis. The median age was 61 years (range; 28–73); 61% were male. The median time from start of initial therapy to enrollment was 4.6 months (range; 2.6 to 11.1) and the median cycles of lenalidomide were 4 (range; 3–11). Thirty-four (94%) of the patients achieved at least 3 million CD34 cells/kg within 2 days of apheresis. The median CD34 cells/kg after 1 day of collection was 3.9 million (range; 0.7 to 9.2) and after two days of collection was 7.02 million (range: 1.1–16.5). Two patients failed the mobilization (<2.5 million CD34 cells/kg). There were no grade 3 or 4 non-hematological adverse events and one patient experienced grade 4 thrombocytopenia. The most common grade 1 or 2 adverse events seen were gastrointestinal, namely nausea, diarrhea and abdominal pain or bloating. Grade 1 dizziness was reported in 8 patients. Overall, the infusion was well tolerated. Conclusion: Intravenously administered plerixafor is an effective strategy for mobilization in this patient group with low rate of failure to mobilize. It is well tolerated with toxicity comparable to the SQ administration. It also offers flexibility in patient scheduling with a convenient schedule for early morning infusion followed by apheresis later in the day. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding. Off Label Use: Use of the investigational agent MLN9708 for the treatment of previously untreated multiple myeloma. Lacy:Celgene: Research Funding.

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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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Elevated Levels of Circulating Nucleosomes Are Not Associated with Venous Thrombosis or Neutrophil Activation in Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.274.274 ◽

2016 ◽

Vol 128 (22) ◽

pp. 274-274

Author(s):

Mandy N. Lauw ◽

Frank W.G. Leebeek ◽

Moniek P.M. de Maat ◽

Gerard J. van Mierlo ◽

Saskia Middeldorp ◽

...

Keyword(s):

Multiple Myeloma ◽

Deep Vein Thrombosis ◽

Human Neutrophil ◽

Research Funding ◽

Neutrophil Activation ◽

Extracellular Dna ◽

Human Neutrophil Elastase ◽

Newly Diagnosed ◽

Vein Thrombosis ◽

Deep Vein

Abstract Background: Patients with multiple myeloma (MM) are at a 9-fold increased risk of venous thromboembolism (VTE). Mechanisms underlying the increased VTE risk in MM have not yet been clarified. Recently, extracellular DNA, e.g. nucleosomes, has been shown to play a central role in coagulation activation and propagation in vivo and in animal models. Increased nucleosome levels were demonstrated in patients with VTE, supporting their role in VTE development. The prothrombotic activity of nucleosomes may be of importance in systemic inflammatory states, in which activated immune cells can release nucleosomes, such as neutrophils by forming neutrophil extracellular traps (NETs). However, during inflammation and upon chemotherapy, parenchymal cells and tumor cells, respectively, can also release extracellular DNA in the form of nucleosomes, which could promote coagulation. As MM is regarded as a systemic inflammatory disease, we hypothesized to find elevated levels of nucleosomes in MM patients, with an association between the highest levels of nucleosomes and development of VTE. Therefore, we assessed levels of nucleosomes and neutrophil activation, and their association with VTE, in a cohort of patients with newly diagnosed MM. Methods: We assessed levels of circulating nucleosomes and systemic neutrophil activation, by presence of elastase-α1-antitrypsin (EA) complexes, in 131 patients with newly diagnosed MM using plasma samples. Interleukin (IL)-6 and IL-8 levels were also assessed to estimate the inflammatory state. We used a case-cohort design to investigate the association between nucleosomes, neutrophil activation and VTE, by calculating odds ratios (ORs) with corresponding 95% confidence intervals (CIs) using nucleosomes and EA complexes as categorical variables, based on the 80th percentile for MM patients without VTE, with ≤80th percentile being the reference category. To compare levels of nucleosomes and neutrophil activation complexes in MM patients with patients with other malignancies, a comparison was made with a cohort of cases with objectified deep-vein thrombosis (DVT) of the leg and screened controls without DVT, stratified by malignancy status. Results: 19 of 131 MM patients (14.5%) developed VTE during MM treatment. Levels of nucleosomes (median 39.5 U/mL; interquartile range [IQR] 7.9-156.8, vs. median 25.6 U/mL; IQR 10.9-76.4; p=0.61) and neutrophil activation, as evidenced by presence of EA complexes (median 30.1 U/mL; IQR 22.6-39.3, vs. median 31.6 U/mL; IQR 24.3-46.0; p=0.45), did not differ between MM patients with and without VTE. No association was found between high levels (>80th percentile of non-VTE MM patients) of nucleosomes or neutrophil activation, and VTE (OR 0.5; 95% CI 0.2-1.6, and OR 2.1; 95% CI 0.5-9.7, respectively) in MM patients. IL-6 and IL-8 levels were low in all MM patients, irrespective of VTE. Nucleosome levels were similarly high in MM patients compared with DVT patients with other malignancies, and significantly higher compared with DVT patient without malignancies, and with DVT controls, irrespective of malignancy status (Fig. 1A). In contrast, levels of neutrophil activation were significantly lower in MM patients in all comparisons (Fig. 1B). Conclusions: Elevated levels of nucleosomes were found in MM patients, but without correlating high levels of neutrophil activation. Nucleosome levels in MM patients with and without VTE were similar, and there was no association between high levels of circulating nucleosomes or neutrophil activation, and VTE in MM patients. Our results suggest that elevated levels of nucleosomes in MM patients are independent of neutrophil activation or inflammatory status, but rather a marker of plasma cell injury or death. This could also explain absence of a clear association with VTE. Future studies are necessary to confirm the source and the clinical relevance of high levels of nucleosomes in MM patients. Figure 1 Levels of nucleosomes and neutrophil activation (by presence of human neutrophil elastase-α1-antitrypsin (EA) complexes) in patients with multiple myeloma (MM), compared with cases with deep vein thrombosis (DVT) of the leg with other malignancies or without malignancies, and DVT controls with other malignancies or without malignancies Median levels of circulating nucleosomes (1A), and median levels of EA complexes (1B). Bars represent median with interquartile ranges (IQR). Figure 1. Levels of nucleosomes and neutrophil activation (by presence of human neutrophil elastase-α1-antitrypsin (EA) complexes) in patients with multiple myeloma (MM), compared with cases with deep vein thrombosis (DVT) of the leg with other malignancies or without malignancies, and DVT controls with other malignancies or without malignancies. / Median levels of circulating nucleosomes (1A), and median levels of EA complexes (1B). Bars represent median with interquartile ranges (IQR). Disclosures Leebeek: Baxter: Research Funding; UniQure: Consultancy; Netherlands Hemophilia Foundation: Research Funding; CSL Behring: Research Funding.

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Succesful Stem Cell Collection in Newly Diagnosed Multiple Myeloma (NDMM) Patients Over 65 Years Old

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2015.07.384 ◽

2015 ◽

Vol 15 ◽

pp. e166-e167

Author(s):

C. Cecchini ◽

N. de las Heras ◽

P. Escribano ◽

M. Fuertes ◽

V. Martínez-Robles ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Newly Diagnosed ◽

Stem Cell Collection

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Utilization of Stem Cell Transplantation in Newly Diagnosed Multiple Myeloma Patients Lacking Geographic Proximity to a Transplant Center

Blood ◽

10.1182/blood-2021-147895 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4085-4085

Author(s):

Megan B Sears-Smith ◽

Lillian Charboneau ◽

Renju Raj ◽

R. Eric Heidel

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplant ◽

Systemic Disease ◽

Age At Diagnosis ◽

Cell Transplant ◽

Newly Diagnosed ◽

First Line ◽

Transplant Center ◽

Stem Cell Collection

Abstract Introduction: Autologous stem cell transplant (ASCT) is considered standard of care in young and fit patients with newly diagnosed multiple myeloma. ASCT has shown to improve depth of response, progression free survival and overall survival compared to systemic therapy alone in myeloma patients (Harousseau et al. New England Journal of Medicine). Proximity to a stem cell transplant center may influence the utilization of this therapeutic option in transplant eligible multiple myeloma patients. Our cancer center did not have a stem cell transplant program in the 100-mile driving radius. The goal of this study was to assess the referral patterns and utilization of ASCT in newly diagnosed, young (age <65 years) multiple myeloma patients in a setting where patients are lacking proximity to a transplant center. Methods: The study was an IRB-approved retrospective cohort study. Patients between 18 and 65 years of age at the time of diagnosis who were diagnosed with multiple myeloma between January 1, 2014, and December 31, 2020, were included. Data including age at diagnosis, sex, race, zip code, treatment regimen, clinical data-including referral to a transplant center, stem cell collection and transplant-were collected and analyzed. Staging was calculated using lab values at the time of diagnosis or within 2 weeks of starting treatment. Date of diagnosis was defined as the date of bone marrow biopsy confirming systemic disease. All frequency and descriptive analyses were performed using SPSS Version 26 (Armonk, NY: IBM Corp.) Results: There were n = 62 patients that met the study inclusion criteria. Patients were mainly white (86%) and male (58%) with an average age at diagnosis of 55.9 (SD = 6.83) years. All patients (n = 62, 100%) lived at zip codes that were more than 100 miles from the closest transplant center. ISS staging showed 37% (n = 23, 95% CI 25% - 50%), 29% (n = 18, 95% CI 18% - 42%), and 18% (n = 11, 95% CI 9% - 30%) to have stage I, II, and III disease respectively. Twelve patients (n = 12, 19.4%, 95% CI 10.4% - 31.4%) had insufficient data for staging. The most common first line regimens were bortezomib, lenalidomide, and dexamethasone (n = 39, 62.9%, 95% CI 49.7% - 74.8%) and bortezomib, cyclophosphamide, and dexamethasone (n = 13, 21%, 95% CI 11.7% - 33.2%). Most patients (n = 48, 77.4%, 95% CI 65% - 87.1%) achieved a very good partial response or better. Eight (n = 8, 13%, 95% CI 5.7% - 23.9%) patients had refractory disease to first line therapy. Forty-six (n = 46, 74%, 95% CI 62% - 85%) patients were referred for HSCT evaluation, n = 16 (26%, 95% CI 15.5% - 38.5%) patients were not. Of the forty-six (n = 46) patients that were referred, n = 44 (96%, 95% CI 85% - 99.5%) patients had a clinical consultation with the transplant team. Of the entire cohort, n = 36 (58%, 95% CI 44.9% - 70.5%) patients underwent stem cell collection and n = 34 (55%, 95% CI 42% - 68%) patients underwent an ASCT after induction therapy. Conclusions: Our study found that more than one third of young patients with newly diagnosed multiple myeloma did not undergo stem cell collection or stem cell transplant. Lack of geographic access to a transplant center may be a contributing factor to the under utilization of this highly effective therapeutic strategy. Further investigation into interventions to improve ASCT referral and completion rates is imperative for improving outcomes for patients in such geographic locations. Disclosures Raj: Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz pharmaceuticals: Speakers Bureau; Glaxo-Smith Kline: Speakers Bureau.

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