Bortezomib Plus Thalidomide Treatment of Newly Diagnosed Patients with Multiple Myeloma - Efficacy and Neurotoxicity: Results of a Multicenter Study.

Abstract Introduction: The standard first-line treatment for patients with multiple myeloma (MM) has been melphalan plus prednisone (MP). However, complete responses (CRs) are rare. As single agents, bortezomib (V) and thalidomide (T) achieved responses in <50% of newly diagnosed MM patients, whereas combinations of V or T with dexamethasone (D), designated VD and TD, demonstrated response rates of 85% and 63%, respectively. We examined the anti-MM activity and neurotoxicity of VT, a steroid-free regimen. Methods: In this phase II study in 30 untreated MM patients, bortezomib 1.3mg/m2 was administered intravenously on days 1, 4, 8, and 11 of a 21-day cycle for up to 8 cycles. Thalidomide 100mg was administered orally at bedtime on days 1 through 21 for up to 8 cycles. Response was assessed with European Group for Blood and Marrow Transplantation (EBMT) criteria. Newly diagnosed MM patients (including Phase IB, II and III according to the International Myeloma Working Group [IMWG] criteria) were eligible if they were 18–80 years of age, had anticipated life expectancy >6 months, and had an age-adjusted creatinine clearance of ≥15 mL/min within 14 days before enrollment. Results: Median age was 56.6 years (range, 30–77), albumin was <3.5g/dL in 18 patients (60%), b2-microglobulin was ≥3.5mg/L in 20 patients (66%), and hemoglobin was ≥100g/L only in 9 patients (30%). International Staging System I/II/III were 3%/50%/47% respectively; all patients had stage III MM according to the IMWG criteria. There were 26 patients (87%) who completed at least two cycles of therapy and were evaluable for response; 18 (60%) completed the planned 8 cycles. Treatment was discontinued in 4 patients due to renal failure. Rates of overall response (ORR), CR, near CR (nCR), partial response (PR), and stable disease (SD) are summarized in Table 1. Median time to response was 35.6 days (range, 7–60). The best response occurred within the first 4 cycles in 96% of patients. Side effects were predictable and manageable. The main toxicities were hematologic (53%), fever (47%), gastrointestinal (40%), fatigue (37%), and peripheral neuropathy (36%). Grade 3 nonhematologic adverse events included 4 patients (15%) with renal failure associated with tumor lysis syndrome, 1 patient (4%) with peripheral sensory neuropathy and motor neuropathy that improved with VT dose reductions, and 1 patient (4%) with hypotension. One patient (4%) experienced Grade 4 thrombocytopenia. One patient (4%) died due to acute renal failure. No deep vein thromboses occurred in this study, compared with a reported incidence of thromboembolic events between 15–20% with TD-containing regimens. Conclusions: VT produced very high ORR and CR in the treatment of newly diagnosed MM patients. No DVTs occurred with this steroid-free combination without any use of anticoagulant drugs. The rate of peripheral neuropathy was lower than expected. This is a very effective regimen with manageable toxicity. Table 1. Response of Newly Diagnosed MM to Bortezomib 1.3mg/m2 and Thalidomide 100mg completed cycles N ORR n (%) CR n (%) nCR n (%) PR n (%) SD n (%) 2 cycles 26 25 (96) 12 (46) 4 (15) 9 (35) 1 (4) 4 cycles 21 20 (95) 6 (29) 7 (33) 7 (33) 0 (0) 8 cycles 18 16 (89) 5 (28) 4 (22) 7 (39) 2 (11)

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Retrospective Analysis of the Efficacy and Safety of Modified Bortezomib-Lenalidomide-Dexamethasonelite (modified RVD-lite) Therapy for Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-112294 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1961-1961

Author(s):

Kiyoshi Okazuka ◽

Tadao Ishida ◽

Junichiro Nashimoto ◽

Takao Yogo ◽

Kanji Miyazaki ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Adverse Events ◽

Staging System ◽

Median Number ◽

Al Amyloidosis ◽

Fish Analysis ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Grade 3

Abstract [Background] Thecombination therapy consisting of bortezomib, lenalidomide and dexamethasone (RVD) for newly diagnosed multiple myeloma has been one of the standard induction therapies in recent years. However, 9-23 % of patients discontinued treatments because of severe adverse events in the previous reports (SWOG S077, IFM2009). Thus, it has not been clarified ifthe dosing schedule of RVD is appropriate. Here, we investigated the efficacy and safety of modified RVD-lite for 45 transplant eligible patients with newly diagnosed multiple myeloma (NDMM). [Patients and methods] We retrospectively analyzed 45 transplant eligible patients with NDMM who received modified RVD-lite for induction therapy between February 2016 and March 2018. The median age was 58 years old (range 36~66), and 6 (13.3%) patients were AL amyloidosisassociated with multiple myeloma. Patients received bortezomib 1.3 mg/m2once weekly subcutaneous (SC) on days 1, 8, 15, 22, lenalidomide 15 mg/day on days 2-7, 9-14, 16-21 and dexamethasone 40mg on days 1, 8, 15, 22. The Revised International Staging System (R-ISS) wereI in 13 (28.9%), II in 30 (66.7%) and III in 2 (4.4%). High-risk cytogenetics, defined as the presence of deletion 17, t(4;14) and t(14;16) by FISH analysis, were identified in 5 (11.1%) patients. After 4 cycles of modifiedVRd-lite, we evaluated the efficacy and adverse events. [Results] The overall response rate (ORR) after four 28-day cycles of modifiedRVD-lite was obtained in 41 (91.1%), including sCR in 6 (13.3%) and CR in 5 (11.1%). SD and PD were observed in 2 patients (4.4%) and 1 patient (2.2%), respectively. One patient was not evaluated efficacy, because a patient changed modifiedRVD-lite to ixazomib, lenalidomideand dexamethasone therapy for grade 3 peripheral neuropathy. Thirty-eight of 45 patients (84.4%) received autologous stem cell transplantation (ASCT) after at least 4 courses of modifiedVRd-lite. The median number of CD34+cells/kg collected was 4.83 x 106(range, 1.1-11.9). All patients received melphalan at doses of 200 mg/m2. In these patients, response after ASCT were sCR in 15(41.7%), CR in 2 (5.6%), VGPR in 8 (22.2%) and PR in 8 (22.2%). Three of seven patients who did not received ASCT will receive ASCT ina few months. Among other 4 patients who did not receive ASCT, 2 patients chose other therapies without ASCT, and 2 patients could not receiveASCT because they showed no improvement in cardiac AL amyloidosis. Grade 3 or higher adverse events (AEs) were observed in 17 (37.8%). Most frequent grade 3 or higher AE was neutropenia (grade 3:17.8%, grade 4:6.7%). Only one patient (2.2 %) discontinued modifiedRVD-lite because of grade 3 peripheral neuropathy. [Conclusions] The ORR after 4 cycles ofmodifiedRVD-lite was high (91.1%). These results might be related to low rate of discontinuation of treatment. Also, the ORR after ASCT was comparable to the results previously published (N Engl J Med .2017 Apr 6:376(14):1311). AEs in modified RVD-lite were feasible and manageable in most patients. Our results suggest that modifiedRVD-lite is very feasible and effective treatment for patients with transplant eligible NDMM. Disclosures Suzuki: Sanofi Aventis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ono: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; SRL.Inc: Employment.

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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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Bortezomib in Combination with Dexamethasone and Subsequent Thalidomide for Newly-Diagnosed Multiple Myeloma in Chinese Patients.

Blood ◽

10.1182/blood.v110.11.4827.4827 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4827-4827

Author(s):

Zhen Cai ◽

Weiyan Zheng ◽

Guoqing Wei ◽

Xiujin Ye ◽

Jingsong He ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Response Rate ◽

Response Rate ◽

Staging System ◽

Primary Treatment ◽

Chinese Patients ◽

Newly Diagnosed ◽

Overall Response ◽

International Staging System ◽

Grade 3

Abstract Background: Bortezomib-dexamethasone-thalidomide has been reported to be effective in newly-diagnosed multiple myeloma (MM) with an overall response rate of 92% and a CR rate of 18% (Alexanian et al, Hematology12(3):235–239, 2007), but this regimen has not been reported in Chinese patients. We now report our experience with this combination. Objectives: To investigate the efficacy and safety of bortezomib in combination of dexamethasone plus subsequent thalidomide as primary treatment for MM. Patients and Method: Between June 2006 and August 2007, 11 consecutive newly-diagnosed patients with symptomatic MM were treated with bortezomib at 1.3 mg/m2 IV on days 1, 4, 8 and 11, dexamethasone at 20 mg/m2 IV daily on the day of bortezomib and the day after. All patients received daily oral thalidomide that was escalated from 100 mg to 200 mg. Seven of 11 patients were male and 4 were female. Median age was 57 years (range 47–86). Seven of 11 patients were stage 2 according to the International Staging System, 4 out of 11 patients were stage 3. Eleven patients received a median of 2 cycles of therapy (range 1–6). The Blade criteria were used for response evaluation. Toxicities were evaluated according to the NCI Common Toxicity Criteria version 3. Results: Nine out of 11 patients (82%) achieved PR and 2 (18%) achieved CR; therefore the overall response rate was 100%. With a median follow-up duration of 5 months (1– 14 months), no patients died. Grade 3–4 toxicities included fatigue (3/11), thrombocytopenia (3/11), diarrhea (3/11) and orthostatic hypotension (2/11). Grade 2 neuropathy occurred in 3 out of 11 patients, herpes zoster occurred in 3 out of 11 patients. Routine anticoagulation or anti-thrombosis was not used. There was no DVT/PE in 11 patients. Conclusion: Our preliminary experience indicated that bortezomib-dexamethasone-thalidomide is highly effective in newly-diagnosed MM. Grade 3 and 4 toxicities were rare after median 2 cycles of therapy. The relative lower rates of neuropathy and DVT/PE in this report with Chinese MM patients are being cautiously observed.

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Phase II clinical trial of ixabepilone in metastatic breast cancer (MBC) patients previously untreated with taxanes

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.651 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 651-651 ◽

Cited By ~ 2

Author(s):

N. Denduluri ◽

J. J. Lee ◽

J. M. Walshe ◽

S. X. Yang ◽

U. Vatas ◽

...

Keyword(s):

Imaging System ◽

Metastatic Breast ◽

Sensory Neuropathy ◽

Hematologic Toxicity ◽

Motor Neuropathy ◽

P53 Expression ◽

P53 Antibodies ◽

Best Response ◽

Duration Of Response ◽

Grade 3

651 Background: Ixabepilone, an epothilone B analog, stabilizes microtubules by binding to tubulin. The response rate (RR) in taxane-pretreated patients at our institution was 22%. Methods: Patients (pts) were eligible if they had MBC previously untreated with taxanes and measurable disease by RECIST criteria. Ixabepilone was given at 6mg/m2/d intravenously days 1–5 every 3 weeks until unacceptable toxicity or disease progression. Primary objectives included RR and toxicity. Pts underwent pre and/or post treatment tumor biopsies for correlative studies. Acetylated α-tubulin, Tau-1, and p53 were stained with anti-acetylated α-tubulin, anti-Tau-1, and anti-p53 antibodies in samples from 13 pts. Staining was scored quantitatively using the Automated Cellular Imaging System. Results: Twenty-three pts received 197 cycles (C). Median of 7C (range 2–22) per pt were administered. Median age was 55 (range 22–79). Seven pts received 1 prior metastatic chemotherapy regimen. Ten of 23 or 43% (exact 95% confidence interval: 23.2% to 65.5%) pts had partial responses (PR), 9 (39%) stable disease (SD) (2 unconfirmed PRs), and 4 (17%) progressive disease (PD). Median time to progression was 5.3 months; median duration of response was 5.4 months from date of best response. Four pts required dose reductions for neutropenia, neuropathy or fatigue. Grade 3/4 toxicities included neutropenia (22%), fatigue (13%), anorexia (9%), infection without neutropenia (9%), motor neuropathy (4%), and muscle weakness (4%). No grade 3/4 sensory neuropathy was seen, but 35% and 13% of pts had grades 1 and 2 neuropathy respectively. Median acetylated α-tubulin at baseline was 0.2 in responders and 17.6 in non-responders (p=0.069). There were no differences in response according to Tau-1 or p53 expression at baseline. Conclusion: Ixabepilone is an effective treatment for MBC with a 43% RR in 23 pts previously untreated with taxanes. There was minimal hematologic toxicity and no grade 3 sensory neuropathy. The use of baseline level of acetylated α-tubulin to predict response may warrant further study. No significant financial relationships to disclose.

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A 28 Day Schedule for Lenalidomide, Bortezomib, and Dexamethasone in Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.2949.2949 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2949-2949

Author(s):

Ajai Chari ◽

Nitin Roper ◽

Sundar Jagannath

Keyword(s):

Multiple Myeloma ◽

Neuropathic Pain ◽

Partial Response ◽

Board Of Directors ◽

Sensory Neuropathy ◽

Treatment Schedule ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3 ◽

D 20

Abstract Abstract 2949 Background: The treatment of patients with newly diagnosed multiple myeloma (MM) with a 3 week cycle of lenalidomide (R), bortezomib (V), and dexamethasone (D) (R 25 mg days 1–14, V 1.3 mg/m2 day 1, 4, 8, 11, and D 20 mg day 1, 2, 4, 5, 8, 9, 11, 12) is associated with unprecedented response rates (Richardson et al. Blood 2010) (see Table 1). Partial response (PR) was 100% and 74% of patients achieved a very good partial response (VGPR) or better with RVD treatment. However, these responses come at the expense of an 80% rate of sensory neuropathy (27% grade 2 and 2% grade 3) and 32% with neuropathic pain (11% grade 2, 3% grade 3). As a result, only 59% of patients received all 3 agents and at least 1 dose modification of bortezomib was required in 44% of patients including 15% for neuropathic pain, 14% for sensory neuropathy, and 8% for fatigue Recent data confirm that a decrease in the dose intensity of bortezomib (for example with weekly dosing) is associated with significantly less toxicity, but importantly (at least in the context of combination chemotherapy) without a decrease in efficacy (Bringhen et al., Blood 2010). In this retrospective study, we examine the efficacy and toxicity of a 28 day RVD treatment schedule for patients with newly diagnosed MM. Methods: All patients with newly diagnosed, symptomatic MM who received front-line RVD on a 28 day schedule where R 25 mg was given days 1–21, V 1.3 mg/m2 was given on day 1, 4, 11, 18 and D 20 or 40 mg was given on day 1, 4, 11, 18 (see Table 2) were selected for this analysis. Patients were excluded if they had received any previous systemic anti-MM therapy (except prior corticosteroids for hypercalcemia or spinal cord compression). Patients who were empirically dose reduced for comorbidities were not excluded. All patients received prophylaxis for venous thromboembolism and VZV. Results: A total of 38 patients met the inclusion criteria for analysis. The median age at start of treatment was 59.5 years. The ISS distribution was Stage I 73% of patients, Stage II 16%, and Stage III 11%. Median treatment length was 4.5 cycles (range 3–12). After four cycles of treatment with VRD, the overall response rate was 97%, which included 63% VGPR or better (24/38) and 34% PR (13/38). 1 remaining patient had an MR (49% reduction in m spike). 32% of patients (n=12/38) went on to stem cell transplantation after four cycles of treatment while the rest were placed on maintenance therapy. With a median follow up of 9 months, no patients have had disease progression. Impressively, the rate of all grades of neuropathy at four cycles was 37% (n=14/38) with 21% (n=8/38) grade 1 sensory neuropathy, 11% (n=4/38) grade 2 neuropathy with pain and 5% grade 3 (n=2/38). There were no other hematologic or non-hematologic grade 3 or 4 toxicities. Conclusion: Despite a decrease in the dose density of bortezomib and dexamethasone, the continued synergy of these agents with a full 21 day course of lenalidomide provides excellent efficacy with reduced rates of toxicity. The 28 day schedule of RVD is an efficacious, convenient, and well tolerated treatment regimen for patients with newly diagnosed symptomatic MM. The subcutaneous administration of bortezomib on this 28 day schedule may allow even further reductions in toxicity without sacrificing efficacy. Disclosures: Chari: Millenium Takeda: speakers bureau (terminated May 2010); Celgene: lecturer. Jagannath:Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

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A Phase II Trial of Combined Bendamustine, Bortezomib and Dexamethasone in Newly Diagnosed Multiple Myeloma (MM) Patients Who Are Not Candidates for High-Dose Chemotherapy: Results of a Planned Interim Safety Analysis

Blood ◽

10.1182/blood.v118.21.2943.2943 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2943-2943 ◽

Cited By ~ 1

Author(s):

Jesus G. Berdeja ◽

Daniel R. Couriel ◽

Patrick Murphy ◽

Ralph V. Boccia ◽

Victor Priego ◽

...

Keyword(s):

Multiple Myeloma ◽

Interim Analysis ◽

Sensory Neuropathy ◽

Response Rates ◽

High Dose Chemotherapy ◽

High Dose ◽

Fish Analysis ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Grade 3

Abstract Abstract 2943 Background Despite significant advances, multiple myeloma is an incurable plasma cell disorder with an eventual fatal outcome. In newly diagnosed MM, combinations of bortezomib, steroids and alkylating agents, such as melphalan and prednisone, have achieved response rates in excess of 70% and have been established as a standard of care in patients (pts) who are ineligible for high dose chemotherapy. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective as single agent and in combination with steroids, thalidomide and bortezomib for the treatment of MM. Pönisch et al reported an overall response of 61% and CR of 15% in pts with relapsed/refractory MM using the combination of bendamustine, bortezomib and prednisone. In this study, the combination of bendamustine, bortezomib and dexamethasone (BVD) was tested for efficacy and safety in newly diagnosed pts with active MM who are not candidates for high-dose chemotherapy. Methods Patients with newly diagnosed active multiple myeloma who were not candidates for high-dose chemotherapy and met standard eligibility criteria with regards to renal, hepatic and hematologic function were enrolled. Pts were treated with bendamustine 80 mg/m2 on days 1, 4, bortezomib 1.3 mg/m2 on days 1, 4, 8, 11 and dexamethasone 40 mg on days 1, 2, 3, 4 every 28 days for a total of 8 cycles or 2 cycles beyond documented CR, whichever occurred first. Responses were assessed using the IMWG criteria. We report on the preliminary efficacy and safety results of a planned interim analysis of the BVD combination. Results Between May 2010 and February 2011, 18 pts were enrolled, all evaluable for toxicity. The median age was 75 (range 56–82); nine (50%) pts were DS stage III; seven (39%) pts had a B2M ≥ 5mg/L. Cytogenetics and FISH analysis for 13 del, t4;14, t14;16, and 17p del were available for all but 1 pt; 8 (44%) pts had at least 1 chromosomal abnormality, while 9 (50%) pts had none. At the time of data cut off, pts completed a median of 5.5 cycles (range 1–8); with 11 (61 %) receiving at least 4 cycles; and 5 (28%) receiving 8 cycles. Seven (39%) pts remain on study and 10 have discontinued therapy (1 disease progression and 3 deaths on study [2 cardiac arrest, 1 pulmonary emboli; all 3 determined to be unrelated to treatment], 1 MD discretion, 1 non-compliance, 1 pt request, 2 poor tolerance, 1 intercurrent illness) and 1 completed treatment. The most common grade 3/4 adverse events, occurring in more than 10% of pts, were leucopenia (17%), neutropenia (11%), myalgia (17%) and sensory neuropathy (11%). Twelve pts had treatment emergent sensory neuropathy: 5 (28%) grade 1, 5 (28%) grade 2 and 2 (11%) grade 3. Of the 17 patients evaluable for response, 15 had at least a PR for an ORR of 88% (9 (53%) VGPR, 6 (35%) PR, 2 (12%) SD). The presence of cytogenetic abnormalities did not seem to have a strong impact on response rates, with 88% of pts with 1 or more abnormalities responding compared to 88% with none. The median time to best response was 9 weeks. Conclusions In this planned interim analysis, the combination of BVD produced a high ORR, however the current schedule is relatively toxic in this pt population. The majority of the non-hematological toxicities appear to be related to bortezomib and dexamethasone. For this reason, the protocol was amended where bortezomib and dexamethasone are now dosed weekly (days 1, 8, and 15). The amended trial is currently accruing. Disclosures: Off Label Use: Bendamustine in myeloma. Flinn:Cephalon and Millenium: Research Funding.

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Successful Treatment with Bortezomib in Combination with Bendamustine and Prednisone of Patients with Newly Diagnosed/Untreated Multiple Myeloma and Light Chain Induced Renal Failure

Blood ◽

10.1182/blood.v118.21.2938.2938 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2938-2938

Author(s):

Wolfram Pönisch ◽

Marc Andrea ◽

Ina Wagner ◽

Doreen Hammerschmidt ◽

Ute Kreibich ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Failure ◽

Renal Impairment ◽

Creatinine Clearance ◽

Research Funding ◽

Cross Resistance ◽

Newly Diagnosed ◽

Myeloma Protein ◽

Increased Risk ◽

Grade 3

Abstract Abstract 2938 Introduction: Renal impairment is one of the most severe complications of Multiple Myeloma (MM) at diagnosis. These patients are at increased risk for infections and have a significantly worse prognosis. Small phase I/II studies suggest that treatment with chemotherapy and/or new substances results in recovery of renal function in up to 25%. The window of opportunity to reverse renal impairment is rather small, making an immediate and highly active treatment strategy mandatory. Bortezomib as well as Bendamustine have turned out to be effective, rapid action drugs in the treatment of MM. Bendamustine is a bifunctional alkylating agent with low toxicity that produces both single- and double-strand breaks of DNA, and shows only partial cross resistance with other alkylating drugs. Methods: Between June 2006 and May 2011, 18 patients (median age 69; range 43 – 86 years) with newly diagnosed/untreated MM and renal insufficiency (creatinine clearance < 35 ml/min) were treated with Bendamustine 60 mg/qm day 1 and 2, Prednisone 100 mg on day 1, 2, 4, 8 and 11, and Bortezomib 1.3 mg/qm on day 1, 4, 8 and 11 (BPV). Cycles were repeated every 21 days up to the stage of maximum response or disease progression. MM response was assessed using IMWG criteria modified to include near complete response (nCR) and minimal response (MR). Eight patients were on dialysis at the time of diagnosis. Results: Fifteen patients (83%) responded after at least one cycle of chemotherapy with three sCR, five nCR, five VGPR, and two PR. With a median follow up of 17 months, PFS at 12 months was 57 % and OS was 61 %. The median number of the BPV-treatment cycles was 2 (1–5) cycles. The myeloma protein decreased rapidly, reaching the best response after the first cycle in 4 patients and after the second cycle in a further 7. Six patients showed a complete remission of the kidney function (creatinine clearance > 60 ml/min) and in seven patients a partial remission (creatinine clearance > 30 ml/min) was attained. Transient grade 3 – 4 neutropenia was reported in one patient, and grade 3 – 4 thrombocytopenia occurred in 6 patients. One patient experienced a new grade 3 polyneuropathy. Summary: These results indicate that the combination of Bortezomib, Bendamustine and Prednisone is effective and tolerated in patients with newly diagnosed/untreated MM and renal failure. Disclosures: Pönisch: Mundipharma: Honoraria, Research Funding. Niederwieser:Mundipharma: Research Funding.

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Clinical Outcomes of Non-Traditional Lenalidomide, Bortezomib, and Dexamethasone Regimens in Multiple Myeloma

Blood ◽

10.1182/blood-2020-143385 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 25-26

Author(s):

Shawn O. Streeter ◽

Omar Nadeem ◽

Paul G. Richardson ◽

Jacob P. Laubach ◽

Clifton C. Mo ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Descriptive Analysis ◽

Dose Intensity ◽

Progression Free Survival ◽

Staging System ◽

Newly Diagnosed ◽

Cutaneous Toxicity ◽

Free Survival ◽

Significant Difference

Introduction Lenalidomide, bortezomib, and dexamethasone (RVD) is a standard first-line regimen for patients with newly diagnosed multiple myeloma and is associated with high response rates and improvement in progression-free survival and overall survival compared to traditional chemotherapy regimens. Traditional (RVD Classic, RVD Lite) and non-traditional (RVD Premium Lite, RVD Ultra Lite) variations of the RVD regimen are utilized at Dana-Farber Cancer Institute (DFCI) and have not been fully evaluated in terms of safety and tolerability. RVD Premium Lite is administered in a 28-day cycle with weekly bortezomib; whereas, RVD Ultra Lite administers three weekly doses of bortezomib instead of four (Table 1). These two regimens have not been fully evaluated in terms of safety, tolerability, and efficacy. Selection is based on provider preference in addition to flexibility of dosing schedule. The regimens also allow for convenience of weekly dosing while keeping dose intensity. This retrospective, descriptive analysis is the first study to explore the safety, tolerability, and efficacy of four different RVD regimens used at DFCI. Methods This single-center, retrospective, descriptive analysis identified 90 newly diagnosed patients with multiple myeloma treated at DFCI main campus for >2 cycles of an RVD-based regimen in the front-line setting. We reviewed patients started on treatment from January 2017 to December 2019. Patients were excluded if treated primarily at an outside institution or satellite campus. Results A total of 90 patients were included between January 2017 to December 2019, and median age was 69.5 years (range 44-87). Most patients had either standard-risk or unknown cytogenetics. Of the 44 patients with available International Staging System (ISS) information, the majority were R-ISS/ISS I or II. The most common M-protein type at diagnosis was IgG (56.7%), followed by light chain restricted disease (25.6%). In terms of traditional and non-traditional RVD regimens, most patients received RVD Classic (33.3%) or RVD Ultra Lite (32.2%), followed by RVD Lite (23.3%) and RVD Premium Lite (11.1%). Patients in RVD Lite and RVD Ultra Lite groups were of older age when compared to the RVD Classic group (P<0.001). Lenalidomide dosing delays and reductions trended higher in the RVD Classic regimen at 14.3%, followed by RVD Ultra Lite at 12.3%. Bortezomib dosing delays and reductions were similar between the RVD Lite and RVD Classic regimens at 11.8% and 11.2%, respectively. Overall, combined lenalidomide and bortezomib dosing delays/reductions trended higher in the RVD Classic (14.3%/11.2%) and RVD Lite (11.0%/11.8%) compared to RVD Ultra Lite (12.3%/9%) and RVD Premium Lite (10.8%/9.6%). The most common toxicities noted with all variations of the RVD regimen were peripheral neuropathy, cutaneous toxicity, infection, diarrhea, and constipation. The highest rates of adverse events among all RVD regimens were infection and peripheral neuropathy. Peripheral neuropathy was slightly higher in the RVD Premium Lite and RVD Classic regimen at 8.43% and 8.70%, respectively, compared to RVD Lite and RVD Ultra Lite at 7.1% and 7.7%, respectively. No significant difference in toxicities were seen when regimens were compared (p=0.1369). Intolerance leading to therapy change trended higher in the RVD Lite group at 23.8%, followed by RVD Classic and RVD Ultra Lite at 16.7% and 10.3%, respectively. Nineteen percent of patients in the RVD Lite group had minimal response or progression leading to therapy change, which was highest among all RVD regimens. Rate of transplant was highest in the RVD Classic group at 36.7%, followed by RVD Premium Lite at 20%. There was no significant difference in intolerance, minimal response or progression, maintenance, continued induction or planned change, transplant, and death between regimens (p=0.089). In terms of progression-free survival, no differences were seen between the groups (p=0.36). Conclusion In conclusion, the current investigation allowed us to assess the safety, tolerability, and efficacy of traditional and non-traditional variations of the RVD regimen in multiple myeloma used at our institution. There are minimal differences between each regimen when toxicities are managed appropriately. Disclosures Richardson: Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Mo:Celgene/BMS: Membership on an entity's Board of Directors or advisory committees.

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Bortezomib and Thalidomide Treatment of Newly Diagnosed Patients with Multiple Myeloma - Efficacy and Neurotoxicity.

Blood ◽

10.1182/blood.v108.11.3528.3528 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3528-3528 ◽

Cited By ~ 11

Author(s):

Ivan Borrello ◽

Anna Ferguson ◽

Carol Ann Huff ◽

Shirley George ◽

Barbara Biedryzcki ◽

...

Keyword(s):

Multiple Myeloma ◽

Performance Status ◽

Newly Diagnosed ◽

Ecog Performance Status ◽

Best Response ◽

Similar Disease ◽

Skin Biopsies ◽

Grade 3 ◽

Deep Vein ◽

Thalidomide Treatment

Abstract Introduction: As single agents, Bortezomib (V) and thalidomide (T) have activity in less than 50% of newly diagnosed myeloma (MM) patients whereas combinations with dexamethasone (D) with T (TD) and V (VD) demonstrated response rates of 63% and 85%, respectively. We sought to examine the anti-myeloma activity of VT, a steroid-free regimen. Considering the neurotoxicity of both agents, we examined the baseline neuropathy and progression of neurotoxicity post-VT. Methods: Eligible patients had untreated Salmon-Durie Stage II/III MM and an ECOG performance status ≤2. V was given 1.3mg/m2 i.v. on days 1, 4, 8, 11 every 21 days. T was started at 50mg daily and increased weekly to 150mg. Patients were treated for a minimum of 4 (evaluable), but to a maximum of 8 cycles. The neurologic evaluation utilized the reduced Total Neuropathy Score (rTNS), a validated scoring system combining symptoms, signs and nerve conduction studies. The rTNS was measured at baseline and after every 2 cycles. rTNS scores range between 0 to 32. Results: 30 patients have been enrolled and 27 are evaluable for response. Median age is 59 (37–83), b2-microglobulin 3.3 (1.2–36.9), and albumin 3.6 (2.3–5.2). The mean dose of V was 1.11mg/m2 and of T 110 mg/d. A dose reduction for ≥1 agent was required in all patients. Treatment was discontinued in 5 patients due to neurotoxicity, and 1 due to disease progression. A ≥ 50% reduction in M-spikes was observed in 82% of patients with 31% achieving undetectable levels. Median time to best response was 5 cycles (range 2–8). Clinical evidence of baseline peripheral neuropathy (PN) was noted in 15%, whereas 67% had abnormal baseline skin biopsies. By cycle 5 all patients developed PN: rTNS 2–8, (grade 1) 50%; rTNS 9–16 (grade 2) 31%; rTNS 17–24 (grade 3) 15%; and rTNS 25–32 (grade 4) 4%. There was no correlation between severity of PN and the cumulative V/T doses. Neuropathic symptoms improved with T/V dose reductions. Additional common adverse events (≥ grade 2) included fatigue 57%, constipation 52%, generalized pain 44%, and leg cramps 23%. Although the incidence of thromboembolic events with steroid-containing regimens ranges between 15–20%, no deep vein thromboses occurred in this study. Conclusions: The VT combination achieved an 82% response rate in previously untreated multiple myeloma patients. No DVTs occurred with this steroid-free combination. This study established the baseline PN in newly diagnosed, untreated myeloma patients and demonstrated progression of neuropathy post-VT therapy. Future studies utilizing neuropathic preventive agents, lower doses of VT, or V in combination with other agents may yield similar disease responses with reduced neuropathic toxicities.

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Prospective Canadian Trial In Newly Diagnosed Multiple Myeloma Patients with t(4;14): Bortezomib-Based Therapy without ASCT

Blood ◽

10.1182/blood.v116.21.1968.1968 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1968-1968

Author(s):

Donna E. Reece ◽

Giovanni Piza Rodriguez ◽

Andrew Belch ◽

David Szwajcer ◽

Michael J. Kovacs ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Peripheral Neuropathy ◽

Pegylated Liposomal Doxorubicin ◽

Progression Free Survival ◽

Marrow Transplant ◽

Newly Diagnosed ◽

Post Induction ◽

Grade 3

Abstract Abstract 1968 Two previous studies have reported that multiple myeloma (MM) patients (pts) with t(4;14), identified by FISH cytogenetics, experience a median progression-free survival (PFS) of only 8–9 mos and median overall survival (OS) of 18 mos when treated with a single ASCT (Chang H, et al. Bone Marrow Transplant 2005; 36: 793; Gertz M, et al. Blood 2005; 106: 2837). On the other hand, the novel agent bortezomib is efficacious in relapsed myeloma pts with t(4;14). Based on these observations, we designed a phase II protocol for newly diagnosed MM pts with t(4;14) that consists of induction with pegylated liposomal doxorubicin, bortezomib and dexamethasone (DBD) × 4 cycles, followed by post-induction therapy with oral cyclophosphamide 300 mg/m2 days 1,8 15, 22 with bortezomib 1.5 mg/m2 days 1,8,15 and prednisone 100 mg q 2 days of a 28-day cycle (CyBor-P) × 8 additional cycles. Maintenance therapy with dexamethasone (dex) 40 mg/month was then administered until progression. Although elective stem cell collection was recommended after induction, routine ASCT was not performed in the absence of disease progression. Between February 2008-July 2010, the bone marrows of 201 newly diagnosed MM pts were screened for t(4;14) in 7 Canadian centers, and 31 (15.4%) were found to be positive by FISH. Five pts did not meet the criteria for symptomatic MM, 4 had received ≥ 2 mos of prior therapy, 1 refused treatment and 2 were ineligible due to peripheral neuropathy or renal failure. Nineteen pts have been entered onto study. One of these was later determined to have a variant abnormality of chromosome 4 but not t(4;14) and underwent ASCT after induction; this pt is included in the safety analysis only. The median age was 60 yrs (45-69) and 53% were male. The median percent nuclei positive for t(4;14) was 26% (3-44%), serum β2-microglobulin was 318 nmol/L (43-1695) and albumin was 36 g/L (28-48); 6 pts had ISS stage 1, 6 had stage 2 and 5 had stage 3 MM. Immunoglobulin subtype included IgGκ (5), IgGλ (4), IgAκ (3), IgAλ (4), λ LC (1) and nonsecretory (1). To date, 15 pts have commenced DBD induction (57 total cycles administered), 12 have started post-induction CyBor-P (67 total cycles) and 6 are on maintenance dex (35 total cycles). Using modified Uniform criteria, the best response in 15 evaluable pts includes: sCR in 3 (20%), CR in 3 (20%), VGPR in 6 (40%), PR in 1 (6.7%) and stable disease in 2 (13.3%). Four have progressed a median of 3 mos (1-11) after commencing induction; one who progressed through DBD remains in nCR 1.5 yrs after salvage D-PACE followed by ASCT and lenalidomide maintenance. Fourteen SAEs occurred, of which 11 were grade 3 and 0 were grade 4; 5 pts developed grade 2 peripheral neuropathy (numbness and tingling) during induction with DBD. Grade 3/4 neutropenia was seen in 2/0 pts, and grade 3/4 thrombocytopenia in 2/1 pts, respectively. Two pts have died, due to MM progression in 1 and complex medical problems including syringomyelia with progressive weakness/ruptured diverticuli/depression in another who withdrew consent despite achieving VGPR with induction. Median follow-up (F/U) is 9.4 mos (1-23). Actuarial PFS is 66% (95% CI 42–100%) and overall survival is 92% (95%CI 79–100%) at 1 year. We conclude: 1) the incidence of t(4;14) by FISH in newly diagnosed MM pts is 15.4% as expected; 2) 26% of newly diagnosed pts with this entity have asymptomatic MM; 3) this bortezomib-based regimen is well-tolerated; 4) the overall response rate (sCR + CR + VGPR + PR) is 87%; 5) preliminarily, the 1-year PFS and OS with this approach compare favorably with reports of single ASCT in t(4;14) positive MM, although longer follow-up is required. Disclosures: Reece: Ortho Biotech: Honoraria, Research Funding. Off Label Use: Bortezomib as first line therapy in myeloma. Chen:Ortho Biotech: Honoraria. Kukreti:Ortho Biotech: Honoraria. Anglin:Ortho Biotech: Honoraria. Trudel:Ortho Biotech: Honoraria.

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