Bortezomib (Velcade™) + Adriamycin™ + Thalidomide + Dexamethasone (VATD) as an Effective Regimen in Patients with Refractory or Relapsed Multiple Myeloma (MM).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2399-2399 ◽  
Author(s):  
Klaus Hollmig ◽  
Julie Stover ◽  
Giampaolo Talamo ◽  
Athanasios Fassas ◽  
Choon-Kee Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Platelet Count ◽  
Stable Disease ◽  
Progressive Disease ◽  
Single Agent ◽  
Patient Characteristics ◽  
M Protein ◽  
Ambulatory Care Setting ◽  
Pet Scans

Abstract Velcade™ (Vel) has shown promising activity as single agent and, more recently, in combination with other antimyeloma agents (dexamethasone, thalidomide) in relapsed or refractory multiple myeloma. We have now explored the efficacy and safety of adding Adriamycin™ 2.5–10.0mg/m2 continuous infusion on days 1–4 and days 9–12 to Velcade™ 1.0 or 1.3 mg/m2 administered on days 1, 4, 9 and 11; thalidomide 50 or 100 mg days 1–12; and dexamethasone 20 or 40 mg days 1–4 and 9–12 (VATD). The treatment was administered in an out-patient, ambulatory care setting to 20 patients. Of the 20 patients evaluable for toxicity, 14 are also evaluable for response. Patient characteristics are outlined in Table 1. Prior resistance to Velcade™-based treatment was demonstrated in 19 patients, with progressive disease in 13 and stable disease in 6. All patients have received systemic therapy immediately prior to the initiation of VATD, which included Vel + thal (7), VTD (5), DT-PACE (4), Revlimid (3), and dex + thal (1). Hematologic toxicities were dependent on the pre-VATD platelet count and WBC levels, as outlined in Table 2. Out of 14 evaluable patients, partial response (≤ 75% of serum M protein reduction, ≤ 75% of urinary M excretion) was obtained in 7 (50%); none had a complete response. Serum M protein decreased by a median of 57% (21–90%) and urine M decreased by a median of 93% (21–90%). Bone marrow follow-up examinations were available in 13 patients and revealed a median reduction in monoclonal plasmacytosis of 50% (range 33–94%); none had a normal bone marrow. Pre-VATD PET scans showed evidence of disease in 10 patients. Post VATD PET scans showed improvement in 5, stable disease in 1 and progressive disease in 4 patients. Our results are promising and demonstrate that administration of Adriamycin™ can be safely added to VTD, and that this addition does overcome the resistance to Velcade-based therapy even in metronomic doses. This approach is now being formally evaluated in a randomized trial comparing VTD alone versus added Adriamycin™ 2.5 mg/m2 on days 1–4 and 9–12 as a salvage protocol in patients with recurrent or progressive MM. Patient Characteristics Velcade 1.0 mg/m² Velcade 1.3 mg/m² Parameter Total Adria 2.5 mg/m² Adria 5 mg/m² Adria 10 mg/m² Adria 5 mg/m² 1: Autotransplant; 2: Thalidomide; 3: Velcade; 4: Velcade; Thalidomide, Dexamethasone N 20 7 10 1 2 % Age ≥ 65 14 14 60 100 0 % Abn Cytogen 55 43 60 100 50 % Prior Autotx1 85 86 80 100 100 % Prior Thal2 100 100 100 100 100 % Prior Vel³ 95 100 90 100 100 % Prior VTD[sup4] 45 71 20 100 50 % LDH > 190 U/l 55 57 60 100 0 Hematologic Toxicities Pre-Treatment Median WBC Nadir Platelet Count WBC < 2,000 WBC > 2,000 WBC < 2,000 WBC > 2,000 > 100k (n=6) 1 5 .65 2.07 50k-100k (n=9) 3 6 .94 1.73 < 50k (n=4) 1 3 1.98 3.44 Median Platelet Nadir > 100k 46,000 51,000 50K–100k 11,000 20,000 < 50K 36,000 47,000

Rituximab in CD20 Positive Multiple Myeloma: A Prospective Study from the IFM Group.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3577-3577
Author(s):  
Philippe Moreau ◽  
Laurent Voillat ◽  
Lotfi Benboubker ◽  
Charles Dumontet ◽  
Claire Mathiot ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Cells ◽  
Stable Disease ◽  
Plasma Cells ◽  
Single Agent ◽  
Stage I ◽  
Minor Response ◽  
Cd20 Expression ◽  
Anti Cd20

Abstract Multiple myeloma (MM) is a heterogenous disease. A strong association between small mature plasma cell morphology, t(11;14) and CD20 expression has been described in approximately 10% of the patients with MM (Robillard et al, Blood 2003). In this subgroup of patients with MM expressing CD20, rituximab (anti-CD20 chimeric monoclonal antibody) could target the antigen and could have a clinical impact. Thus we conducted a prospective phase II trial of 4 weekly IV infusions of 375 mg/m2 rituximab in patients with MM expressing CD20 on at least 33% of tumor cells. From 07/2004 to 02/2006, 14 consecutive patients, median age 65 years, with either stage I MM never pretreated (n = 7) or stage III MM in relapse or refractory after a median of 2 lines of therapy (n= 7) were treated. Immunophenotype using flow cytometry revealed that a median of 75% of tumor cells were expressing CD20 (range, 33–100%) at the onset of therapy. Responses were evaluated 3 months after therapy according to EBMT criteria. At the reference date of June 1st, 2006, a single patient, who had relapsed 8 months after a double autologous SCT, experienced a minor response, ongoing 18 months after rituximab therapy. At the time of rituximab therapy, 100% of its plasma cells were expressing CD20, and 3 months after treatment, bone marrow examination showed 0.6% of plasma cells, none of them expressing CD20. Five patients (1 with relapsed MM and 4 with stage I MM) experienced stable disease, ongoing for 3, 4, 4, 11 and 12 months, respectively. Three patients with stage I MM had stable disease but subsequently progressed 10, 11, and 15 months after therapy, respectively. The last 5 patients with relapsed MM did not respond to anti-CD20 therapy, despite partial clearance of CD20+ plasma cells in the bone marrow in 2 cases. Conversely in the 3 latter cases, the percentage of CD20+ plasma cells did not decrease despite rituximab therapy. Several factors have been described to explain resistance against rituximab in a variety of B-cell malignancies such as the level of CD20 expression, dissociated action of complement-dependent cytotoxicity and antibody-dependant cellular cytotoxicity, polymorphism in FcgammaRIIIA receptor, and may be inadequate dose schedule. These mechanisms could explain the marginal activity of rituximab as single-agent in CD20+ MM.

Preliminary Safety and Efficacy Results from an International Phase 3b Study for Expanded Access to Bortezomib in 624 Patients with Relapsed and/or Refractory Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3530-3530 ◽  
Author(s):  
Joseph R. Mikhael ◽  
Andrew Belch ◽  
Miles Prince ◽  
Maria Nambo Lucio ◽  
Angelo Maiolino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Median Time ◽  
Stable Disease ◽  
Progressive Disease ◽  
Karnofsky Performance Status ◽  
M Protein ◽  
Significant Activity ◽  
Expanded Access ◽  
Grade 3

Abstract Background: Bortezomib (VELCADE®) is a first-in-class, reversible proteasome inhibitor with activity in multiple myeloma (MM) and other malignancies. Bortezomib showed significant activity in previous phase 2 and 3 studies in patients (pts) with previously treated MM. This international multicenter open-label phase 3b study allowed expanded access to bortezomib therapy in pts with relapsed/refractory MM treated with ≥ 2 previous lines of therapy. Methods: Pts with MM were eligible if they had received ≥ 2 prior lines of therapy and required treatment due to relapsed or progressive disease. Pts with grade ≥ 2 peripheral neuropathy (PN) were excluded. Pts received 1.3 mg/m2 IV bolus bortezomib on days 1, 4, 8, and 11 of each 3-week cycle for up to 8 cycles; dexamethasone (20 mg/d PO on the day of and day after bortezomib dose) could be added after cycle 2 for progressive disease or after cycle 4 for stable disease. Adverse events (AEs) were assessed beginning at the start of treatment and continuing until 30–42 days after treatment and were graded based on NCI-CTC version 2.0. Efficacy assessment was performed based on changes in disease burden as measured by monoclonal (M)-protein concentration in serum and urine every 2 cycles (6 weeks). Response was assessed using modified SWOG criteria: complete response (CR) was a 100% reduction in M-protein; very good partial response (VGPR), 75–99% reduction; partial response (PR), 50–74% reduction; minimal response (MR), 25–49% reduction; and stable disease, < 25% reduction. Increasing M-protein levels indicated progressive disease. Results: 624 pts in 93 centers from 21 countries received at least 1 dose of treatment and were evaluable for safety (55.3% male; median age 62.7 years). 68% of pts received 3–11 lines of previous therapy. Karnofsky performance status was ≤70 in 25.6% of pts; 141 pts (22.6%) were ≥ 70 years of age. Pts completed a median of 5 cycles of therapy (range 0–13); 39.3% of pts completed all 8 planned cycles. Grade 3/4 treatment-emergent (related and unrelated) AEs were reported in 430 pts (68.9%), with thrombocytopenia (29.2%), neutropenia (13.3%), and anemia (11.7%) the most common hematologic AEs. Grade 3/4 PN was reported in 8.2% of pts. Overall, 165 pts (26.4%) discontinued therapy due to treatment-related AEs. Best responses among evaluable pts (n = 593) included 12.0% CR, 23.1% VGPR, 19.1% PR, and 16.5% MR, for an overall response rate of 70.7%. Median time to first response was 42 days (range 7–125), and median time to best response was 63 days (range 7–235). Conclusions: Bortezomib 1.3 mg/m2 administered biweekly q3 weeks was well tolerated with manageable toxicities in pts with relapsed and/or refractory MM. Response rates with bortezomib were high, even in heavily pretreated pts, inducing > 25% CR/VGPR. This study confirms results from initial clinical trials in a broader population.

Response Adapted Therapy Using Single Agent Lenalidomide in Older Adults with Newly Diagnosed Standard Risk Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4060-4060
Author(s):  
Rachid Baz ◽  
Melissa Alsina ◽  
Kenneth H. Shain ◽  
Jennifer Paleveda ◽  
Nancy Hillgruber ◽  
...  
Keyword(s):  
Older Adults ◽  
Multiple Myeloma ◽  
Stable Disease ◽  
Research Funding ◽  
Progressive Disease ◽  
Single Agent ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Standard Risk

Abstract Abstract 4060 Introduction: Rajkumar et al. reported improved survival with lenalidomide and low dose dexamethasome as compared with lenalidomide and high dose dexamethasone (Rajkumar V, Lancet Oncol 2010). In addition, we reported promising outcomes of a retrospective cohort of newly diagnosed multiple myeloma patients treated with single agent lenalidomide(Baz R Leuk Lymphoma. 2010). Accordingly, we conducted this prospective single center open label study to evaluate the efficacy of a response adapted approach using single agent lenalidomide in older adults with newly diagnosed standard risk multiple myeloma. Patients/Methods: Eligible patients had symptomatic multiple myeloma without high risk features (b2microglobulin (b2m) ≤5.5, absence of t(4;14), t(14;16), 17p deletion, aneuploidy or 13q by metaphase cytogenetics) and were not eligible or not willing to receive high-dose therapy and stem cell transplant. Patients received lenalidomide 25 mg PO D1–21 every 28 days for 2 cycles. If patients had a minimal response or better (MR, 25% reduction in serum M spike) after 2 cycles, they continued on single agent lenalidomide until progressive disease. If patients had stable disease after 2 cycles, prednisone 100 mg PO D1–5 was added to their lenalidomide. In the event of progressive disease on single agent lenalidomide or on lenalidomide/prednisone, therapy was changed to lenalidomide (at the tolerated dose) and dexamethasone 40 mg PO weekly. Thromboprophylaxis was with aspirin, warfarin or low molecular weight heparin. Responses were per IMWG response criteria. The study was approved by the institutional review board. Results: Between February 2010 and May 2012, 22 patients were screened and 19 were eligible. The median age was 75 years (range 65–83) and 12 were males. Per protocol, no patient had ISS stage 3 disease but 8 patients had ISS stage 2 and 11 stage 1 (median b2m was 3.2 mg/L (range 2.2–5.5)). 5 patients had 13q deletion by FISH alone, 4 had t(11;14), another 3 had trisomy 11, and 2 had trisomy or tetrasomy 1q. The median baseline creatinine clearance was 66.5 ml/min (range 43–109). After 2 cycles of single agent lenalidomide, 9 patients (47%) had a PR (partial response), 6 (32%) MR, 3 (16%) stable disease (SD), and 1 (5%) progressive disease. The best response to single agent lenalidomide was as follows: 3 had a stringent complete response sCR (16%), 1 (5%) a very good partial remission (VGPR), 8 PR (42%), 4 MR (21%), 2 SD (11%) and 1 PD (5%). The estimated 1 year PFS to single agent lenalidomide is 80%. Five patients required the addition of dexamethasone with the following responses: 1 VGPR, 1 PR, 1 MR, 1 SD and 1 PD; Three patients required the addition of prednisone and the response to lenalidomide prednisone was 1PR, 1 MR, 1 SD. Five patients went off study, 2 for PD and 3 withdrew consent (2 were in PR at the time and 1 in SD). The estimated 1 year PFS for the protocol therapy is estimated at 94%. Eleven patients had dose reduction in lenalidomide; 5 patients to 15mg and 6 patients to 10 mg. Grade 3/4 neutropenia, thrombocytopenia, anemia, febrile neutropenia and fatigue occurred in 58%, 5%, 10%, 5% and 5% of patients respectively. Conclusion: In this patient population, single agent lenalidomide results in an ORR (PR and better) of 63% and clinical benefit rate (MR and better) of 84% with only a quarter of patients requiring the addition of dexamethasone. A response adapted therapy using single agent lenalidomide is safe and effective in older adults with standard risk myeloma sparing dexamethasone toxicities from the majority of patients. Updated results for ongoing accrual of up to 30 evaluable patients will be presented at the meeting. Disclosures: Baz: Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding. Off Label Use: lenalidomide for newly diagnosed multiple myeloma. Alsina:Millenium: Consultancy, Research Funding. Finley-Oliver:celgene: Speakers Bureau.

Increased Bone Marrow Plasma Cell Infiltration Pre-Transplant Is Associated with Worse Outcomes in Patients Undergoing High Dose Chemotherapy and Autologous Stem Cell Transplantation for Multiple Myeloma,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4135-4135
Author(s):  
Nina Shah ◽  
Qaiser Bashir ◽  
Simrit Parmar ◽  
Yvonne T Dinh ◽  
Sofia Qureshi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Plasma Cell ◽  
Progressive Disease ◽  
Patient Characteristics ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
High Group

Abstract Abstract 4135 Multiple myeloma (MM) is the second most common adult hematologic malignancy. High dose chemotherapy (HDC) and autologous stem cell transplantation (auto-SCT) have become the standard of care for eligible patients. Though the impact of bone marrow (BM) plasma cell (PC) percentage has been explored in the post-SCT setting, its role before SCT is not yet known We performed a retrospective review of 1826 MM pts who underwent HDC and auto-SCT at our institution from 7/8/98 – 12/31/2010. We further identified patients who had post-induction, pre-SCT BM biopsy information available. Patients were divided into 2 groups: those with <10% PC infiltration (“PC low”) and those with ≥10% plasma cell infiltration (“PC high”). Additional data, such as demographics, time of diagnosis, response, time to progression and time of death were also collected. Progression-free (PFS) and overall (OS) survivals were estimated by the Kaplan-Meier method. Log-rank test was performed to test the difference in survival between groups. 1489 pts were studied, 605 female and 884 male. Patient characteristics are detailed in Table 1. Median time from diagnosis to auto-SCT was 247 days (range 45–7895). 1299 (87%) patients underwent auto-SCT after 2000. Nearly all patients received melphalan-based conditioning. 1174 patients had <10% involvement of BM by PCs and 315 had > 10% involvement. The details of best responses before and after auto-SCT are also listed in Table 1. For patients in the PC low group, 32% had a CR, 20% had a VGPR, 31% had a PR, 13% had <PR and 3% had progressive disease after auto-SCT. For patients in the PC high group, 11% had a CR, 14% had a VGPR, 48% had a PR, 21% had <PR and 5% had progressive disease (PD) after auto-SCT. Median PFS was significantly shorter for the PC high group versus the PC low group (24.8 vs 29.5 months, p=0.05), as was median OS (52.5 vs 79.4 months respectively, p<0.001). When only those patients who had a PR to induction were examined, there was again a significant difference in both PFS (24.4 vs 33.2 months, p=0.04) and OS (58.3 vs 81.2 months, p =0.002) for those patients in the PC high versus PC low groups, respectively. Finally, when looking at those patients who underwent auto-SCT in the era of novel therapeutics (after 2000), the differences between the PC high and PC low groups were maintained for both PFS (24.4 vs 29.5 months respectively (p=0.029)) and OS (54.8 vs 88.4 months respectively, p<0.001). Table 1. Patient characteristics and responses All patients (n=1489) PC <10% (n=1174) PC ≥ 10% (n=315) Male 884 (59%) 718 (61%) 166 (53%) Female 605 (41%) 456 (39%) 149 (47%) Race 988 (66%) 784 (67%) 204 (65%) Caucasian 230 (15%) 181 (15%) 49 (16%) African American 33 (2%) 24 (2%) 9 (3%) Asian Unknown/other 238 (16%) 185 (16%) 53 (17%) Durie-Salmon Stage (1440 pts)     I 218 (15%) 179 (16%) 39 (13%)     II 597 (41%) 486 (43%) 111 (37%)     III 626 (43%) 472 (42%) 154 (51%) Cytogenetics (1265) Normal 943(75%) 782 (79%) 161 (58%) Abnormal 322 (25%) 207 (21%) 115 (42%) Response prior to auto-SCT     CR 66 (4%) 66 (6%) 0 (0%)     VGPR 255 (17%) 244 (21%) 11(3%)     PR 817 (55%) 655 (56%) 162 (51%)     <PR 232 (16%) 144 (12%) 88 (28%)     PD 93 (6%) 45 (4%) 48(15%)     unknown 26 (2%) 20 (2%) 6 (2%) Median time to SCT (range) 247 days (45–7895) 239 days (45–7895) 259 days (74–5580) SCT after 2000 1299 (87%) 1037 (88%) 262 (83%) Best response after SCT     CR 384 (26%) 350 (32%) 34 (11%)     VGPR 298 (20%) 253 (20%) 45 (14%)     PR 510 (34%) 359 (31%) 151 (48%)     <PR 223 (15%) 157 (13%) 66 (21%)     PD 45 (3%) 30 (3%) 15 (5%)     Not evaluable 29 (2%) 9 (1%) 4 (1%) PFS from SCT (months) 29.5 24.8 P=0.05 OS from SCT (months) 79.4 52.5 P<0.001 PR-PFS from SCT (months) 33.2 24.4 P = 0.04 PR- OS from SCT (months) 81.2 58.3 P = 0.002 Post-2000 SCT PFS from SCT (months) 29.5 24.4 P = 0.029 Post-2000 SCT OS from SCT (months) 88.4 54.8 P<0.001 Extensive BM infiltration by PCs before auto-SCT is associated with a worse outcome in patients treated with HDC and auto-SCT. This finding persists when looking specifically at patients with a PR before auto-SCT. Thus, BM disease burden may further assist us in stratifying patients with a PR and may warrant further disease reduction before stem cell collection. Additionally, the differences between PC high and PC low groups are maintained in the modern era, despite the availability of several new salvage agents over the last 10 years. Further prospective study is warranted to determine the true impact of PC infiltration in the BM. Disclosures: No relevant conflicts of interest to declare.

Phase 2 Study of MLN8237, An Investigational Aurora A Kinase (AAK) Inhibitor In Patients with Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndromes (MDS)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3273-3273 ◽  
Author(s):  
Stuart L Goldberg ◽  
Pierre Fenaux ◽  
Michael D Craig ◽  
Emmanuel Gyan ◽  
John Lister ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stable Disease ◽  
Research Funding ◽  
Progressive Disease ◽  
Response Rate ◽  
Single Agent ◽  
Myelogenous Leukemia ◽  
Phase 2 ◽  
Investigational Agent ◽  
Grade 3

Abstract Abstract 3273 Background: AAK is essential for mitotic progression and is amplified or overexpressed in AML and other hematologic malignancies. The investigational agent MLN8237 is an orally available, potent, and selective AAK inhibitor with preclinical activity against leukemias, lymphomas, and myeloma. Phase 1–2 and pharmacodynamic results show a mechanism of selective AAK inhibition, and some durable clinical activity in patients with treatment-resistant malignancies. Methods: Open-label, multicenter, phase 2 trial (NCT00830518) of MLN8237 in patients aged ≥18 years with advanced AML or intermediate-2/high-risk MDS. Eligibility criteria included ECOG performance status 0–2, adequate organ function, and >10% blasts in bone marrow. Patients were not excluded based on number of prior therapies, treatment with hydroxyurea or steroids, prior transplant, or ongoing cytopenias. Patients received 21-day cycles of MLN8237 50 mg BID for 7 days followed by 14 days' rest until disease progression or unacceptable toxicity. The primary endpoint was response rate, defined as complete (CR) plus partial (PR) response, which included CR (CRi) or PR (PRi) with incomplete blood count recovery in AML patients and marrow CR or PRi in MDS patients. Response was evaluated by modified AML/MDS international working group (IWG) criteria; stable disease was defined as failure to achieve PRi but no evidence of progression in AML patients, and as failure to achieve PR but no evidence of progression for >8 weeks in MDS patients. Adverse events (AEs) were graded by National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) version 3.0. Results: 57 patients were enrolled; median age was 72 years (range 46–85), 56% were male, and 81% white. Forty-six (81%) patients had AML, of whom 21 (37%) had secondary leukemia. Of 11 (19%) patients with MDS, 8 had an IPSS score of intermediate-2 (1.5 or 2.0), and 3 had a high (≥2.5) score. Forty-nine (86%) patients had received prior therapies, and 9 (16%) received ≥3 prior therapies. Patients received a median of 2 cycles (range 1–16) of MLN8237. Treatment-related grade 3/4 AEs were seen in 24 (42%) patients and included febrile neutropenia (11%), thrombocytopenia (9%), anemia (9%), fatigue (7%), and neutropenia (7%). Treatment-emergent somnolence was identified in 14 (25%) patients, and grade 3/4 treatment-related somnolence was reported in 2 (4%) patients. Fourteen (25%) patients discontinued due to AEs. Twenty-two on-study deaths were reported, caused by events unrelated to MLN8237, including progressive disease (46%), and sepsis (14%); of these, 9 deaths from AML occurred within 2 months of study entry. Overall, 6 (13%) responses were observed (all AML patients; response-evaluable population n=45); 5 patients had PR. One CR was documented in a 79-year old female with AML and no prior therapy, who presented with 23% bone marrow blasts at the time of progression from MDS/RAEB-2, and remains in CR through 16 cycles (1 year). Seventeen (49%) AML and 2 MDS (20%) patients achieved stable disease. Ongoing analyses suggest that co-morbidities influenced clinical outcomes. Conclusions: Data suggest that single-agent MLN8237 has anti-leukemia activity with a 13% response rate (all AML) in this clinical study of patients with advanced, mainly pre-treated disease. In patients with rapidly progressive disease, these results indicate that improved outcomes require strategies to enhance both disease control and risk management in early cycles, allowing time needed to achieve clinical benefit from AAK inhibition. These results support further clinical studies of MLN8237 in heme-lymphatic malignancies and solid tumors. Disclosures: Goldberg: Millennium Pharmaceuticals, Inc.: Research Funding. Off Label Use: Investigational agent in clinical development for the treatment of AML/MDS. Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; GSK Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Craig:Genentech: Membership on an entity's Board of Directors or advisory committees. Gyan:Amgen: Research Funding; Janssen-Cilag: Research Funding; Celegene: Honoraria, Research Funding; Roche: Honoraria. Schiller:Millennium Pharmaceuticals, Inc.: Research Funding. Jung: Millennium Pharmaceuticals, Inc.: Employment. Leonard:Millennium Pharmaceuticals, Inc.: Employment. Fingert:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Westervelt:Novartis: Honoraria; Celgene: Honoraria, Speakers Bureau.

scholarly journals A Phase 1/2 Trial of Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin for Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4774-4774
Author(s):  
James R. Berenson ◽  
Laura V. Stampleman ◽  
Alberto Bessudo ◽  
Peter J. Rosen ◽  
Leonard M Klein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Phase 1 ◽  
Single Agent ◽  
Pegylated Liposomal Doxorubicin ◽  
Great Promise ◽  
Phase 2 ◽  
Grade 3

Abstract Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/ progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who have previously received POM treatment were ineligible. In the phase 1 portion, POM was administered at 2, 3 or 4 mg daily in three cohorts on days 1-21 of a 28-day cycle and DEX (40 mg) and PLD (5 mg/m2) were fixed and given intravenously on days 1, 4, 8, and 11. Results As of June 20th, 2014, 48 pts were enrolled in the trial and a total of 47 pts had received study drug. Pts had received a median of 4 prior treatments (range 1-18), with a median of 2 prior IMiD-containing regimens (range, 0-8). Fifty-three percent of the pts had received a prior PLD-containing regimen and 21% had received a prior IMiD and PLD combination treatment. Among all enrolled pts, 40 pts discontinued treatment and seven remain active. Pts completed a median of 3 cycles (range: 1-8), with a median follow-up time of 5.4 months (range: 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 36 pts enrolled in phase 2, 78% percent were refractory to LEN and steroids with or without other agents and 47% had previously received PLD. A median of 2 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Thirty-five pts were evaluable for response as one pt was active but had not yet had any post-baseline disease assessments. Among all pts enrolled in phase 2, the overall response rate (ORR) and clinical benefit rate (CBR) were 29% and 49%, respectively, with 6 pts (17%) showing stable disease and 12 pts (34%) demonstrating progressive disease. For all pts enrolled in phase 2, the median follow-up time was 4.7 months (range 0-12) and the median PFS was 5.3 months. ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (32% and 58%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (21 pts; 44.7%), lymphopenia (10 pts; 21.3%), and hyponatremia (4 pts; 8.5%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Consultancy, Honoraria. Vescio:Celgene: Honoraria.

scholarly journals Efficacy and Safety of Daratumumab Combined With All-Trans Retinoic Acid in Relapsed/Refractory Multiple Myeloma

2021 ◽  
Author(s):  
Kristine A. Frerichs ◽  
Monique Christina Minnema ◽  
Mark-David Levin ◽  
Annemiek Broijl ◽  
Gerard MJ Bos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stable Disease ◽  
Immune Cell ◽  
Ex Vivo ◽  
Phase 1 ◽  
Single Agent ◽  
Flow Cytometric Analysis ◽  
Optimal Dose ◽  
Efficacy And Safety ◽  
Cd38 Expression

The efficacy of daratumumab is partially dependent on CD38 expression on multiple myeloma (MM) cells. We have previously shown that ATRA upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy and safety of daratumumab combined with ATRA in daratumumab-refractory MM patients in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty daratumumab-refractory patients were subsequently enrolled in part B, and treated with daratumumab (re-intensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR≥15%) was not met. However, the majority of patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median PFS for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS, compared to those who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 versus 1.3 months). The median OS was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and re-intensification of daratumumab had limited activity in daratumumab-refractory patients, which may be explained by the transient upregulation of CD38 expression.

scholarly journals Raised ?2-Microglobulin as a Surrogate Marker in Non-Secretory Multiple Myeloma

2017 ◽  
Vol 16 (1) ◽  
pp. 142-145
Author(s):  
Bimal K Agrawal ◽  
Anshul Sehgal ◽  
Vikas Deswal ◽  
Prem Singh ◽  
Usha Agrawal
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Rare Case ◽  
Plasma Cells ◽  
Medical Science ◽  
Protein A ◽  
Surrogate Marker ◽  
M Protein ◽  
Review Of Literature ◽  
Lytic Lesions

Multiple myeloma is a neoplasm of plasma cells in the bone marrow. It is characterised by lytic lesions in the bones, marrow plasmacytosis and presence of M protein in serum and/or urine. Serum ?2 microglobulin is also raised and can be used for classification and prognostication of the disease. In the absence of M protein, the disease is known as non-secretory myeloma. It is proposed that raised ?2 microglobulin can be used for diagnosis and therapeutic guidance in the absence of M protein. A rare case of nonsecretory myeloma with neurocognitive impairment along with review of literature is being presented. The patient had multiple lytic lesions in bones with marked increase in plasma cells in bone marrow. M protein was not detectable in serum or urine but serum ?2 microglobulin was much elevated.Bangladesh Journal of Medical Science Vol.16(1) 2017 p.142-145

scholarly journals Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma

2010 ◽  
Vol 28 (18) ◽  
pp. 3015-3022 ◽  
Author(s):  
Wei-Gang Tong ◽  
Rong Chen ◽  
William Plunkett ◽  
David Siegel ◽  
Rajni Sinha ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Clinical Efficacy ◽  
Stable Disease ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Dose Escalation Study

Purpose SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy. Patients and Methods Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course. Results There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m2, and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m2, owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis. Conclusion SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.

A Multicenter, Single-Arm, Open-Label Study To Evaluate the Efficacy and Safety of Single-Agent Lenalidomide in Patients with Relapsed and Refractory Multiple Myeloma; Prelininary Results.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1565-1565 ◽  
Author(s):  
Paul Richardson ◽  
Sundar Jagannath ◽  
Mohamad Hussein ◽  
James Berenson ◽  
Seema Singhal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Stable Disease ◽  
Single Agent ◽  
Phase 2 ◽  
Open Label ◽  
Open Label Study ◽  
Label Study ◽  
Multicenter Phase ◽  
Best Response

Abstract INTRODUCTION: Lenalidomide (REVLIMID®; CC-5013) is a novel, orally active immunomodulatory drug under investigation for the treatment of multiple myeloma (MM). Phase 1 dose-escalation studies in patients (pts) with relapsed and refractory MM determined that the maximum tolerated dose (MTD) of lenalidomide was 25 mg/day, based upon myelosuppression encountered beyond 28 days, which was manageable with growth factor support and dose reduction. In a multicenter phase 2 study to determine optimal dose and schedule, 102 pts with relapsed or refractory MM were randomized to receive lenalidomide at either 15 mg bid (n=34) or 30 mg qd (n=68), for 21 days every 4 wks. Both treatment arms showed significant activity with manageable toxicity. An increased incidence of cytopenia was noted in the 15-mg bid group and thus the 30 mg qd schedule was taken forward. METHODS: The objective of this multicenter, phase 2, open-label study (CC-5013-MM-014) was to further evaluate the effectiveness and safety of single-agent lenalidomide administered at a dose of 30 mg qd for 21 days every 28 days (28-day cycle) in pts with relapsed and refractory MM. Eligible patients included those who had received prior thalidomide, bortezomib, or SCT. RESULTS: 222 pts were enrolled into the study. All patients had received at least 2 prior anti-myeloma treatments, including bortezomib (41%), thalidomide (80%), and SCT (44%). Table 1 shows Best Response data, excluding patients in whom responses were not evaluable (n=10). Partial response or better occurred in 25% of patients and SD or better in 71%. Time to Progression was a median of 22.4 wks (range 1.8– 66 wks). The median survival has not been reached (the lower bound of the 95% CI exceeds 15 months). The most common treatment-related AEs (those reported in ≥10% of patients overall) included upper respiratory tract infection, neutropenia and thrombocytopenia. AEs that most frequently led to dose reduction or interruption by percentage of cases were neutropenia (40%), thrombocytopenia (23%), fatigue (5%), and anemia (5%). CONCLUSION: Oral lenalidomide in relapsed and refractory MM patients achieved PR+CR in 25%, stable disease or better in 71%, a median TTP of approximately 6 months and a median survival that has not been reached. Toxicity has been manageable with a very low incidence of DVT and minimal treatment-emergent neuropathy. Table 1. Best Response Best Response* n (%) *Excluding patients not evaluable (n=10); CR=complete response and PR=partial response (EBMT criteria) ≥PR (CR + PR) 53 (25) Stable disease 152 (71)

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