Efficacy and Safety Of Melphalan and Prednisone In Combination With Thalidomide, Bortezomib Or Lenalidomide In Newly Diagnosed Transplant-Ineligible Multiple Myeloma Patients: A Single Center Experience

Abstract Background The introduction of new agents has substantially changed the management of patients with multiple myeloma (MM). PATIENTS AND METHODS: We evaluated retrospectively 69 symptomatic newly diagnosed transplant-ineligible MM patients treated at our Institute, between 2004 and 2012, with Melphalan and Prednisone (MP) plus Thalidomide (MPT; 23 patients) or plus Bortezomib (MPV; 30 patients) or plus Lenalidomide (MPR; 16 patients). There were 37 men and 32 woman, median age was 73 years (range 65-84) with 20 patients >75 years, 19 (27.5%) were in stage III according to ISS, 12 (17%) had renal failure (creatinine >1.5 mg/dl at baseline), 7 (10%) an underlying diabetes mellitus and 36 (52%) a cardiovascular disease. Melphalan was given at 9 mg/m2 and Prednisone at 60 mg/m2 orally on days 1-4; Bortezomib at 1.3 mg/m2 intravenously on days 1, 4, 8, 11, 22, 25, 29, 32 for the first 4 cycles and thereafter on days 1, 8, 15, 22; Lenalidomide at 10 mg on days 1-21 and Thalidomide 100 mg/daily were administered orally. All patients received antibacterial prophylaxis; thromboprophylaxis and antiviral prophylaxis were administered to patients treated with IMIDs and Bortezomib, respectively. Aims To evaluate the safety and efficacy within the MPT-, MPV- and MPR-treated groups. Results The overall response rates ( ≥ partial response), according to the IMWG criteria, were 20/23 (87%) in the MPT group, 26/30 (87%) in the MPV group, 11/16 (68%) in the MPR group (including 3, 9, 2 very good partial response and 2, 3, 2 complete response/near complete response, respectively). The median PFS was 29 months (95% CI: 18-NA months) for patients who received MPT, 24 months (95% CI: 20-32 months) with MPV and 21.5 months (95% CI: 17-NA months) with MPR, with no significant differences between the three regimens. Among the 69 patients, the overall grade 3-4 hematologic and non-hematologic toxicities were 36% and 43%, respectively. The most common non-hematologic toxicities included all grades of peripheral neuropathy (14% with MPV, 7.2% with MPT and none with MPR), grade 3-4 infections (7.2% with MPV, 4.3% with MPT and 2.9 with MPR) and grade 3-4 cardiovascular disease (4.3% with MPT, 1.4% with MPV and none with MPR). With the use of thromboprophylaxis in all IMID-treated patients, we observed only one deep vein thrombosis in one patient treated with MPT. Conclusions MPT, MPV and MPR are highly active and well tolerated regimens for previously untreated MM patients. The rates of treatment-associated thrombocytopenia and neutropenia were similar between the 3 different regimens and proved transient, predictable and manageable; few patients required supportive care. The results obtained using MP plus one of the recently developed drugs confirm that MPT, MPV and MPR should be considered the standard of care in the frontline treatment of newly diagnosed transplant-ineligible MM patients. Disclosures: Petrucci: Janssen and Celgene: Honoraria; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees.

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Daratumumab (DARA) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in patients (pts) with newly diagnosed multiple myeloma (MMY1001): An open-label, phase 1b study.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.8000 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 8000-8000 ◽

Cited By ~ 21

Author(s):

Andrzej J. Jakubowiak ◽

Ajai Chari ◽

Sagar Lonial ◽

Brendan M. Weiss ◽

Raymond L. Comenzo ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Safety Profile ◽

Standard Of Care ◽

Complete Response ◽

Newly Diagnosed ◽

Open Label ◽

Frontline Treatment ◽

Grade 3

8000 Background: DARA in combination with established standard of care regimens prolongs PFS, deepens responses, and demonstrates a favorable safety profile in relapsed or refractory multiple myeloma (MM). The tolerability and efficacy of DARA-KRd in newly diagnosed MM pts was examined. Methods: Newly diagnosed pts regardless of transplantation eligibility were enrolled. Pts received DARA 16 mg/kg QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter. All pts received the 1st dose of DARA split over 2 days. Carfilzomib (K) was administered on Days 1, 8 and 15 of each 28-day cycle (20 mg/m2 on C1D1, 36 or 70 mg/m2 subsequently based on tolerability of first dose) for ≤13 cycles or elective discontinuation for ASCT. Lenalidomide 25 mg was given on Days 1-21 and dexamethasone 20-40 mg per week. The primary endpoint was tolerability. Results: Twenty-two pts (median [range] age, 60 [34-74] y) were enrolled and received a median of 8 (1-10) treatment cycles. Nineteen pts escalated K dose to 70 mg/m2 by C1D15. Median (range) duration of follow-up was 7.4 (4.0-9.3) months. Six (27%) pts discontinued treatment (1 AE [pulmonary embolism]; 1 PD; 4 other [ASCT]). Serious AEs occurred in 46% of pts, and 14% were possibly related to DARA; 18 (82%) experienced a grade 3/4 TEAE. The most common grade 3/4 TEAEs (>10%) were lymphopenia (50%) and neutropenia (23%); 1 (5%) cardiac grade 3 TEAE was observed (congestive heart failure) which resolved; pt quickly resumed study treatment with reduced K dose. No grade 5 TEAE was reported. All DARA-associated infusion reactions (27% of pts) were grade ≤2. Treatment with DARA-KRd yielded an ORR (≥partial response) of 100% (5% complete response, 86% ≥very good partial response) in 21 response-evaluable pts. The 6-month PFS rate was 100%. Conclusions: The addition of DARA to KRd was well tolerated; the overall safety profile was consistent with that previously reported for KRd, with no additional toxicity observed with the addition of DARA. Deep and durable responses were observed. These data support further investigation of DARA-KRd as a frontline treatment regimen. Updated data will be presented based on longer follow up. Clinical trial information: NCT01998971.

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Melphalan, Prednisone, and Lenalidomide Treatment for Newly Diagnosed Myeloma: A Report From the GIMEMA—Italian Multiple Myeloma Network

Journal of Clinical Oncology ◽

10.1200/jco.2007.12.3463 ◽

2007 ◽

Vol 25 (28) ◽

pp. 4459-4465 ◽

Cited By ~ 236

Author(s):

Antonio Palumbo ◽

Patrizia Falco ◽

Paolo Corradini ◽

Antonietta Falcone ◽

Francesco Di Raimondo ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Adverse Events ◽

Survival Rates ◽

Standard Of Care ◽

Maximum Tolerated Dose ◽

Treatment Schedule ◽

Newly Diagnosed ◽

Low Incidence ◽

Grade 3

PurposeLenalidomide has shown significant antimyeloma activity in clinical studies. Oral melphalan, prednisone, and thalidomide have been regarded as the standard of care in elderly multiple myeloma patients. We assessed dosing, efficacy, and safety of melphalan, prednisone, and lenalidomide (MPR) in newly diagnosed elderly myeloma patients.Patients and MethodsOral melphalan was administered in doses ranging from 0.18 to 0.25 mg/kg on days 1 to 4, prednisone at a 2-mg/kg dose on days 1 to 4, and lenalidomide at doses ranging from 5 to 10 mg on days 1 to 21, every 28 days for nine cycles, followed by maintenance therapy with lenalidomide alone. Aspirin was given as a prophylaxis for thrombosis.ResultsFifty-four patients were enrolled and evaluated after completing the assigned treatment schedule. The maximum tolerated dose was defined as 0.18 mg/kg melphalan and 10 mg lenalidomide. With these doses, 81% of patients achieved at least a partial response, 47.6% achieved a very good partial response, and 23.8% achieved a complete immunofixation-negative response. In all patients, 1-year event-free and overall survival rates were 92% and 100%, respectively. At the maximum tolerated dose, grade 3 adverse events included neutropenia (38.1%), thrombocytopenia (14.2%), febrile neutropenia (9.5%), vasculitis (9.5%), and thromboembolism (4.8%); grade 4 adverse events were neutropenia (14.2%) and thrombocytopenia (9.5%).ConclusionOral MPR therapy is a promising first-line treatment for elderly myeloma patients. Hematologic adverse events were frequent but manageable. A low incidence of nonhematologic adverse events was noted. Aspirin appears to provide adequate antithrombosis prophylaxis.

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Combination Therapy Based on Bortezomib for Newly Diagnosed Multiple Myeloma Patients

Blood ◽

10.1182/blood.v120.21.5048.5048 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5048-5048

Author(s):

Jingsong He ◽

Li Yang ◽

Dian Jin ◽

Xuanru Lin ◽

Qianqian Yang ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Combination Therapy ◽

Conflicts Of Interest ◽

Complete Response ◽

Chinese Patients ◽

Newly Diagnosed ◽

Serious Adverse Events ◽

Novel Drugs ◽

Grade 3

Abstract Abstract 5048 Introduction: Novel drugs, such as bortezomib, have significantly improved the response rates in multiple myeloma (MM), but little has been reported on bortezomib-based therapies in Chinese patients. Methods: In the initial eight 28-day cycles, newly diagnosed ymptomatic patients were treated with combination therapy including bortezomib plus dexamethasone (PD) and the triplet combinations of PD with adriamycin (PAD), cyclophosphamide (PCD), thalidomide (PDT) between February 1, 2006 and May 31, 2012. Among the above regimens, bortezomib (1. 3 mg/m2) was given intravenously on days 1, 4, 8, 11, while dexamethasone (20 mg/m2/day) was given intravenously on days 1–2, 4–5, 8–9, 11–12, adriamycin (10 mg/m2) was given intravenously on days 1–4, cyclophosphamide (200 mg/m2) was given intravenously on days 1–4 and thalidomide (100 mg) was administered orally each day. Results: The overall response rate (¡Ý partial response, PR) of all the 151 eligible patients was 88. 7% (including 29. 8% very good partial response (VGPR) and 25. 8% complete response/near complete response (CR/nCR). The responses per IMWG criteria for patients are shown in Table 2. The median PFS was 20. 3 months (95% CI: 14. 8–25. 8 months) in the patients who received PDT, 24. 8 months (95% CI: 20. 0–30. 0 months) in the patients who received PCD, 22. 9 months (95% CI: 17. 6–28. 2 months) in patients who received PAD and 21. 8 months (95% CI: 15. 3–28. 3 months) in the patients who received PD with no significant differences between the groups. The median OS for PD arm was 42. 0(95% CI: 20. 1–63. 9 months) months while other arms were not reached, but the median OS for PDT, PCD and PAD was significant longer than PD (P=0. 042, 0. 039, 0. 010). PFS and OS for patients with favorable cytogenetics were significantly longer than those with unfavorable cytogenetics by FISH. The frequently observed hematologic toxicities (Grade 3/4) were: thrombocytopenia (17. 00%), neutropenia (15. 00%) and anemia (8. 61%). The most common non-hematologic toxicities included (all Grades) peripheral neuropathy(57. 61%), fatigue(27. 15%), infection(23. 84%), constipation(22. 52%), herpes zoster(17. 22%) and diarrhea(15. 23%). Conclusions: Our experience indicated that bortezomib-based regimens were active and well-tolerated for MM patients, and triplet combinations were superior to PD. Serious Adverse events were rare in the Chinese patients with MM who received bortezomib-based chemotherapy. Disclosures: No relevant conflicts of interest to declare.

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Upfront Carfilzomib, Lenalidomide, Dexamethasone with Transplant in Multiple Myeloma Patients, the IFM KRd final results

Blood ◽

10.1182/blood.2021010744 ◽

2021 ◽

Author(s):

Murielle Roussel ◽

Valerie Lauwers-Cances ◽

Soraya Wuilleme ◽

Karim Belhadj ◽

Salomon Manier ◽

...

Keyword(s):

Multiple Myeloma ◽

Residual Disease ◽

Standard Of Care ◽

Complete Response ◽

Primary Objective ◽

Vein Thrombosis ◽

Common Grade ◽

Grade 3 ◽

D 20 ◽

Deep Vein

Bortezomib, lenalidomide, dexamethasone plus transplant is a standard of care for eligible Multiple Myeloma patients. As responses can deepen with time, regimens with longer and more potent induction/consolidation phases are needed. In this phase II study, patients received eight 28-day cycles of carfilzomib (K) 20/36mg/m2 (D1-2,8-9,15-16), lenalidomide (R) 25 mg (D1-21), and dexamethasone (d) 20 mg (D1-2,8-9,15-16,22-23). All patients proceeded to transplant after 4 cycles and received 1-year lenalidomide maintenance (10 mg, D1-21). The primary objective was stringent complete response (sCR) at the completion of consolidation. Overall, 48 patients were screened and 46 enrolled; 21% had adverse cytogenetics. Among 42 evaluable patients after consolidation, 26 were in sCR (61.9%), 27 in ≥CR (64.3%): 92.6% had undetectable Minimal Residual Disease by flow cytometry (≥2.5 x10-5) and 63.0% by next generation sequencing (10-6). Median time to CR was 10.6 months. By MFC and NGS, 69.0% and 66.7% patients, respectively had undetectable MRD at some point. With a median follow-up of 60.5 months, 21 patients progressed and 10 died (7 from MM). Median PFS was 56.4 months. There was no KRd related death. Four patients discontinued the program due to toxicities; 56 serious AEs were reported in 31 patients including 8 cardiovascular events (2 heart failures, 5 pulmonary embolisms or deep vein thrombosis). Common grade 3/4 AEs were hematological (74%) and infectious (22%). In conclusion, 8 cycles of KRd produce fast and deep responses in transplant eligible NDMM patients. Safety profile is acceptable but cardiovascular AEs should be closely monitored.

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Safety and Efficacy of Four Drug Versus Three Drug Regimens Among Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood-2020-143379 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-3

Author(s):

Saad Ullah Malik ◽

Nazma Hanif ◽

Priyanka Kumari ◽

Khadija Noor Sami ◽

Chase Warner ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Adverse Events ◽

Randomized Clinical Trials ◽

Standard Of Care ◽

Drug Regimen ◽

P Value ◽

Newly Diagnosed ◽

Drug Regimens ◽

Grade 3

Introduction: During recent years there has been a boom in the availability of treatments for multiple myeloma (MM). Based on the status of disease (newly diagnosed or relapsed/refractory), several regimens have successfully improved progression free survival (PFS) and overall survival (OS) in these two types of patients. Triple drug regimen is considered the current standard of care for newly diagnosed MM patients. However, with the advent of four drug regimens, some studies demonstrated a significant improvement in PFS and OS compared to standard of care where as others showed marginal to no difference. Also, it remains unclear whether the benefits of using four drug regimen outweigh the risks. Thus, the aim of our meta-analysis was to compare the efficacy and safety of four drug versus three drug regimens among newly diagnosed multiple myeloma patients. Methods: We built a PICO based search strategy using keywords like "multiple myeloma", "randomized clinical trials" and ran literature search on PubMed, Embase, Wiley Cochrane Library, Web of Science and ClinicalTrials.gov ranging from the date of inception till 16th July, 2020. A pre-validated data extraction sheet was used to extract data on PFS, OS and ≥Grade 3 hematologic adverse events at the longest follow-up. We included only randomized clinical trials (RCTs) comparing four versus three drug regimen in newly diagnosed MM patients. We excluded studies other than RCTs, studies conducted on relapsed refractory MM patients or other plasma cell dyscrasias. A generic variance weighted random effects model (DerSimonian and Laird) was used to derive hazard ratio estimates along with their 95% confidence intervals (CIs) for PFS and OS. Risk ratio along with its 95% CIs was estimated for Grade ≥3 hematologic adverse events. Heterogeneity was assessed with Cochrane Q -statistic and was quantified with I2 test (I2 >50% was consistent with a high degree of heterogeneity). A pre-specified sensitivity analysis was also performed for risk of adverse events. Cochrane Collaboration's tool was used to assess the quality of included RCTs and GRADE was used to rate the quality of evidence. Results: Initial search retrieved 7622 titles. After duplicate removal, 4880 articles were left. Following initial screening, 58 articles were considered for full text review. Of these only 3 studies (n=2277) met inclusion criteria. Four drug regimens included daratumumab, bortezomib, melphalan-prednisone (D-VMP), daratumumab, bortezomib, thalidomide-dexamethasone (D-VTd) and bortezomib and melphalan prednisone and thalidomide (VMPT-VT) respectively. Whereas, three drug regimens were bortezomib, melphalan-prednisone (VMP), bortezomib, thalidomide-dexamethasone (VTd) and bortezomib, melphalan and prednisone (VMP) respectively. There was a significant improvement in PFS when 4 vs 3 drug regimens were compared in patients with newly diagnosed MM (HR: 0.53, 95% CI: 0.46-0.62, p-value:<0.001, I2: 0%). Also, OS improved significantly in four drug regimen group (HR: 0.62, 95% CI: 0.51-0.76, p-value:<0.001, I2: 3.5%). There was no statistically significant difference in any grade ≥3 hematologic adverse events when 4 vs 3 drug regimens were compared (RR: 1.26, 95% CI: 0.93-1.73, p-value:0.14, I2: 93%). Sensitivity analysis after removing D-VTd regimen from any grade ≥3 hematologic adverse events revealed similar results (RR: 1.05, 95% CI: 0.97-1.13, p-value:0.23, I2: 23%) confirming the robustness of analysis. When each hematologic adverse event was looked at separately, there was no difference between 4 vs 3 drug regimen in rates of anemia (RR: 0.99, 95% CI: 0.76-1.28, p-value:0.92, I2: 0%), neutropenia (RR: 1.39, 95% CI: 1.00-1.94, p-value:0.05, I2: 85%) and thrombocytopenia (RR: 1.13, 95% CI: 0.92-1.39, p-value:0.24, I2: 33%). There was low risk of bias and strength of evidence was of moderate. Conclusion: Using four drug regimens, compared to three drug regimens, significantly improves PFS and OS among newly diagnosed multiple myeloma patients without any difference in the risk of ≥3 grade hematologic adverse events. Further randomized clinical trials are required to establish four drug regimen as standard of care for patients with newly diagnosed multiple myeloma. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

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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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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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Melphalan, Prednisone and Lenalidomide Followed by Lenalidomide Maintenance Displays Treatment Characteristics Favourable to Global Quality of Life in Newly Diagnosed Multiple Myeloma (NDMM) Patients ≥ 65 Years,

Blood ◽

10.1182/blood.v118.21.3988.3988 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3988-3988 ◽

Cited By ~ 2

Author(s):

Meletios Athanasios Dimopoulos ◽

Antonio Palumbo ◽

Roman Hajek ◽

Martin Kropff ◽

Maria Teresa Petrucci ◽

...

Keyword(s):

Quality Of Life ◽

Multiple Myeloma ◽

Partial Response ◽

Progressive Disease ◽

Newly Diagnosed ◽

Employment Equity ◽

Risk Of Disease ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 3988 Background: Melphalan, prednisone and lenalidomide followed by lenalidomide maintenance (MPR-R) demonstrated higher response rates (ORR; 77% vs. 50%, p <.001; VGPR or better: 32% vs. 12%, p <.001) and significantly reduced the risk of disease progression (hazard ratio [HR] = 0.423, p <.001) vs. MP alone [Palumbo, 2010]. Alongside efficacy considerations, analyses on health-related quality of life (HRQoL) may help more fully establish a regimen's overall treatment profile. HRQoL improvements with MPR-R were observed during MPR induction as well as lenalidomide maintenance, documenting a well-balanced profile in terms of efficacy, tolerability and HRQoL [Dimopoulos, 2011]. Alternative findings on novel NDMM treatment have shown efficacy of melphalan, prednisone and bortezomib (VMP) treatment to be associated with an intermittent deterioration in patients' HRQoL [Dhawan, 2009]. Methods: A mixed effects model was developed based on parameters pre-selected as potentially clinically relevant in impacting HRQoL. Models were run on six domains pre-selected based on clinical relevance: Global QoL, Physical Functioning, Fatigue and Pain (from EORTC QLQ-C30), and Disease Symptoms and Side Effects of Treatment (from EORTC MY20). Cycle 16 was determined as the last observation time point with a statistically meaningful sample size at time of follow-up (May 2010). Following explanatory variables were included: time-dependant covariates at individual HRQoL measurement time points (i.e. cycle 4, 7, 10, 13 and 16), treatment group (MPR-R vs. MP), gender (Female vs. Male), age, baseline QoL, Partial Response (PR) vs. Stable Disease (SD) and Very Good Partial Response or better (≥VGPR) vs. SD, Progressive Disease (PD) and Discontinuation (DC). Neutropenia and anemia, both Grade 3 or 4, were considered the clinically most relevant safety parameters. Main results for Global QoL are reported, with results from other domains found to be comparable. Results: Across all time-dependant covariates, a statistically significant reduction on Global QoL (−4.63; p=.004) was observed at Cycle 4. Being female vs. male significantly reduced Global QoL by -−.07 (p=.026). Each additional life year was found to lower Global QoL b− −0.40 points (p=.034). Baseline Global QoL was also significant, each additional score point leading to +0.30 (p <.001). A response level of ≥VGPR vs. SD increased Global QoL by 9.11 (p=.023); Progressive Disease (PD) reduced Global QoL by -−.34 score points (p <.001). All other pre-defined variables did not significantly impact Global QoL. Clinically meaningful changes for Global QoL in the underlying patient population have been determined to constitute at least a 7-point change [Dimopoulos, 2011]. Progressive disease (reducing Global QoL), respectively ≥VGPR (increasing Global QoL) exerted clinically meaningful changes, as did anemia grade 3–4, which had a clinically meaningful, but not statistically significant negative impact (−9.85; p=.057). Although no significant direct effect of MPR-R over MP on Global QoL was detected in the underlying model, MPR-R displays properties which favor an improved HRQoL profile, including a stronger delay in PD and higher % of VGPR vs. MP patients. Furthermore, certain properties more frequently observed with MPR-R than MP (neutropenia grade 3 or 4 and discontinuation, DC) were shown not to have a significant impact on HRQoL. Anemia grade 3 or 4, exerted a clinically meaningful negative effect but was not significantly more often observed with MPR-R compared to MP (24% vs. 17%, p= 0.091). Conclusions: More patients achieved ≥VGPR when receiving continuous MPR-R treatment than those receiving MP. In the above pooled analysis, ≥VGPR was shown to improve Global QoL in a clinically meaningful and statistically significant way. Furthermore, progression was also shown to negatively impact Global QoL (−8.34; p <.001), with MPR-R significantly reducing the risk of disease progression over MP. Delaying progression with continuous MPR-R therefore helps to maintain a high Global QoL. Disclosures: Dimopoulos: Celgene: Consultancy, Honoraria. Off Label Use: Lenalidomide in newly diagnosed multiple myeloma. Palumbo:Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Ortho-Biotech: Honoraria. Hajek:Celgene: Honoraria; Janssen-Cilag: Honoraria; Merck: Honoraria. Petrucci:Celgene: Honoraria. Lewis:Celgene: Employment, Equity Ownership. Millar:Celgene: Consultancy. Zhang:Celgene: Employment, Equity Ownership. Mei:Celgene: Employment, Equity Ownership. Delforge:Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Speakers Bureau.

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Phase 2 Trial of Concurrent Monosialotetrahexosylganglioside in the Prophylactic Treatment of Bortezomib-Induced Peripheral Neuropathy in Patients of Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.5399.5399 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5399-5399

Author(s):

Liang Wang ◽

Zhongjun Xia ◽

Xiaoqin Chen

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Partial Response ◽

Subcutaneous Injection ◽

Complete Response ◽

Phase 2 ◽

Newly Diagnosed ◽

Female Ratio ◽

Phase 2 Trial

Abstract Backgrounds Bortezomib is an important drug in the treatment of multiple myeloma (MM), and peripheral neuropathy (PN) is a significant dose-limiting toxicity of bortezomib. No effective prophylaxis has been defined for PN. Monosialotetrahexosylganglioside (GM), a nerve-protecting drug, is often used to promote growth of nerve and function restoration of damaged nerve. The role of GM in the prophylaxis of bortezomib-induced PN in MM patients has never been investigated. Methods A phase 2 clinical trial was conducted in newly diagnosed MM patients to evaluate the value of GM in the prophylaxis of bortezomib-induced PN. All eligible patients were treated with VD (bortezomib 1.3mg/㎡,subcutaneous injection, d1 ,8,15,22, and dexamethasone 40mg, po,d1 ,8,15,22, 4 weeks a cycle) or CyBorD (cyclophosphamide 300mg/㎡,po,d1 ,8,15, bortezomib 1.3mg/㎡,subcutaneous injection, d1 ,8,1 5,22, and dexamethasone 40mg, po,d1 ,8,15,22, 4 weeks a cycle) for at least 4 cycles. GM was used at a dosage of 100mg/day intravenously at d1 -2, 8-9, 15-16, 22-23. No other nerve-protective drugs or thalidomide-containing regimens were allowed. The primary endpoint was overall incidence rate of PN (the grade of PN was recorded according to CTCAE v3.0). The secondary endpoints included duration of PN, complete response rate after 4 cycles of treatment, 1-year PFS and OS rate. (This trial was registered in ClinicalTrial.gov, NCT02093910). Results From February 2014 to February 2015, 25 patients of newly diagnosed MM were enrolled. The median age was 55 years old (37-75), and male to female ratio was 19:6. 5 patients had ISS stage I disease, 6 patients with stage II, and the remaining 14 patients with stage III. All patients received a median of 4 cycles (range 2-9) of Bortezomibcontaining regimens. At the time of data analysis, 84% of patients had at least partial response, 48% had at least very good partial response, and 24% had complete response. 7 patients experienced PN after a median of 2 cycles (range 1-4) of treatment, resulting in the overall PN rate of 28%. Among these 7 patients, only 1 patient (4%) had grade 2 PN, leading to dose reduction of bortezomib, and all other patients had grade 1 PN. During treatment, 1 patient (4%) had grade 2 diarrhea, and another 1 patient (4%) had herpes zoster infection. The concurrent use of GM did not introduce new side effects and seemed not compromise the efficacy of bortezomib. At a median follow up time of 8 months, 1-year PFS rate and OS rate were speculated to be 69.8% and 100%, respectively. Conclusions The early-term analysis of this phase 2 trial found it feasible to concurrently use GM and bortezomib-containing regimens, and GM had the potential role of reducing bortezomib-induced PN rate and severity without compromising efficacy. This needs to be validated in future phase 3 randomized clinical trials. Disclosures No relevant conflicts of interest to declare.

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Targeting Complete Response with Upfront Bortezomib Followed By Autologous Transplantation and Consolidation Therapy for Untreated Multiple Myeloma (TUBA study)

Blood ◽

10.1182/blood.v128.22.3463.3463 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3463-3463

Author(s):

Hideki Nakasone ◽

Kiriko Terasako-Saito ◽

Teiichi Hirano ◽

Atsushi Wake ◽

Seiichi Shimizu ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Progression Free Survival ◽

Complete Response ◽

Induction Treatment ◽

High Dose ◽

Induction Phase ◽

Consolidation Therapy ◽

Newly Diagnosed ◽

Free Survival

Abstract [Background] Multiple myeloma (MM) is generally considered incurable. Recently, novel drugs, including bortezomib, have demonstrated a survival benefit for newly diagnosed MM patients compared with classical treatments. Complete response (CR) after treatment is known to be associated with superior progression-free survival. Thus, we prospectively evaluated the efficacy and safety of boretezomib + dexamethasone (BD) for patients with newly diagnosed MM, followed by autologous hematopoietic stem cell transplantation (ASCT). We added BD consolidation therapy to aim CR if CR was not achieved after ASCT. [Patients and methods] This clinical study prospectively recruited newly diagnosed MM patients eligible for ASCT between 2010 and 2012. Due to health insurance issues in Japan, two courses of high-dose dexamethasone (HD-DX) had been administrated prior to BD induction treatment until Nov. 2011, while BD was administrated as an initial induction treatment since Dec. 2011. BD induction treatment included 1.3 mg/m2 of bortezomib on days 1, 4, 8, and 11 with 20mg of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. This BD induction cycle was repeated every 3 weeks for 4 courses. Thereafter, filgrastim-based mobilization and ASCT following high-dose melphalan administration was performed. If patients did not achieve CR after ASCT, BD consolidation therapy (bortezomib: 1.3 mg/m2 on days 1, 8, and 15; dexamethasone 20 mg/day on days 1-2, 8-9, and 15-16) every 4 weeks was added to target CR (Figure 1) (UMIN-CTR: UMIN000002442). [Results] The median observational duration among survivors was 1536 days (range: 464-2023) at this analysis. Of the 47 enrolled MM patients, 46 (male 27; female 19) were eligible for BD induction treatment, while the remaining one achieved CR before BD induction. The median age of the patients was 59 (range: 35-67) years. Of the 44 patients whose karyotype analyses were available, normal karyotype was observed in 35. Abnormal karyotype included complex type in 4, diploid in 1, and other abnormalities in 4. FISH revealed deletion of p53 in 5 of 39 patients whose information was available; deletion of 13-chromosome in 16 of 42, IgH-MAF fusion in 1 of 40; IgH-FGFR3 fusion in 5 of 41; IgH-BCL1 fusion in 9 of 39. Of the 46 MM patients, 19 received HD-DX prior to BD induction, and 34 received ASCT after BD induction treatment (Figure 1). During the BD induction phase, 3 patients experienced disease progression, and BD treatment was discontinued in 9 patients because of their consent withdrawal (n=2) and adverse events (n=7) including interstitial pneumonia in 2, persistent neuropathy in 1, CMV enterocolitis in 1, heart failure in 1, diabetes mellitus in 1, and liver dysfunction in 1. After BD induction phase (n=46), their response was >= CR in 4 (8%), very good partial response (VGPR) in 10 (22%), partial response (PR) in 18 (39%), stable disease (SD) in 2 (4%), and progression or withdrawal in 12 (26%). After ASCT, their response was >=CR in 9 (20%), VGPR in 11 (24%), PR in 12 (26%), SD in 1 (2%), and additional progression or withdrawal in 1 (2%). Of the 24 patients who received ASCT and whose response was less than CR, 21 received BD consolidation therapy for a median of 4 courses (range: 1- 8). BD consolidation was discontinued in 4 patients due to persistent neuropathy or cytopenia. Finally, maximum response after ASCT with or without BD consolidation was >= CR in 19 (41%), VGPR in 7 (15%), PR in 6 (13%), < SD in 2 (2%, Figure 2). Through BD consolidation, CR was achieved in 8 of 11 patients with post-ASCT VGPR and 2 of 12 patients with post-ASCT PR. In total, 4-year progression-free survival (PFS) and overall survival (OS) was 43% (95%CI: 28-57%) and 80 % (95%CI: 64-90%), respectively. Focusing on CR patients after ASCT and those who actually received BD consolidation, PFS adjusted for karyotype and age were not different between CR patients after ASCT and after BD consolidation, while patients with VGPR or less after consolidation had significantly lower PFS (Figure 3). [Conclusion] BD induction and ASCT provided CR rate of 27% among ASCT patients, although BD induction may expectedly cause adverse events including persistent neuropathy and viral infections. Patients who achieved CR after ASCT showed good PFS, and targeting CR through BD consolidation might improve CR rate. It is worthwhile to prospectively compare the efficacy of BD consolidation only for patients who failed to achieve CR or universal consolidation strategy. Disclosures Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding.

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