Phase 2 Clinical Trial of Oral Lenalidomide, Cyclophosphamide, and Prednisone (RCP) for Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1970-1970
Author(s):  
Attaya Suvannasankha ◽  
Sherif Farag ◽  
Robin Obryant ◽  
Lisa l Wood ◽  
Nicole Porter ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Conflicts Of Interest ◽  
Treatment Protocol ◽  
Sensory Neuropathy ◽  
Hematological Toxicity ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Post Transplant

Abstract Abstract 1970 Background: An effective and convenient regimen is appealing for Multiple Myeloma (MM) therapy. Lenalidomide and dexamethasone combination is highly effective in MM. However, at the FDA approved dose, dexamethasone related toxicity remains challenging. We report the efficacy and side effect profile of an all oral, dexamethasone-sparing combination of lenalidomide, cyclophosphamide and prednisone in newly diagnosed MM. Methods: The treatment protocol consisted of lenalidomide (Revlimid®) given orally at a dose of 25 mg daily on days 1–21 of a 28-day cycle, cyclophosphamide at a dose of 50 mg b.i.d. days 1–21 of a 28-day cycle, and prednisone 50 mg q.o.d (RCP). Responses were assessed on intent-to-treat basis based on the International Uniform Response Criteria. Treatment was planned for 6 cycles. Responding patients proceeded to observation, or transplantation, based on patient's preferred choices. All patients received, unless contraindicated, aspirin prophylaxis (81 or 325 mg daily) for prevention of deep-vein thrombosis, acyclovir for herpes zoster prevention, and bisphosphonates. Results: Forty six patients were enrolled from October 2007 to August 2010. Median follow up duration was 5.6 months. At this time, 38 of 46 patients are evaluable for confirmed responses (i.e., off-study or completed at least 4 cycles of therapy). The median age was 63 years (range, 41–76). 16 patients had ISS stage II (42%) and 8 (21%) had stage III disease. The median number of cycles was 6 (range: 1 – 6). Among the 38 evaluable patients, the overall response rate was 95%, consisting of CR: 1 (3%), VGPR: 9 (24%) and PR: 26 (68%). One patient had stable disease (1%) after the first cycle and treatment is ongoing. One patient had progression (3%). Thirty twoof 38 patients have discontinued study treatment. Reasons for treatment discontinuation are: completed study per protocol (24), disease progression (3), adverse event (2), non compliance (1), alternate treatment (1) and withdrawal of consent unrelated to toxicity (1). The most common toxicity was sensory neuropathy (24%): 8 (21%) grade I and 1 (3%) grade II. Other common toxicity included constipation (21%), pruritus (21%) and edema of limbs (18%). The most common hematologic toxicity was neutropenia (18%); 4 grade III and 2 grade IV. Infections were seen in 4 patients (2 febrile neutropenia and 2 with normal ANC). Five patients had grade 4 metabolic abnormalities (2 renal failure attributed to dehydration and tumor lysis, 2 hyperglycemia. and 1 hypokalemia). Thirteen patients had dose adjustments or interruption, most commonly due to hematological toxicity attributed to lenalidomide or cyclophosphamide. Twenty-five patients had stem cell collection. In all, sufficient numbers of stem cells (CD34+ cells ≥ 4.0 × 106 cells/kg) were collected for the transplantation use. To date, fifteen have undergone high dose chemotherapy and stem cell transplantation. Of eight patients with PR on RCP, seven achieved VGPR and one achieved CR post transplant. Of four patients with VGPR on RCP, 2 achieved CR and 2 remained in VGPR post transplant. Post-transplant response is not yet evaluable in the 3 remaining patients. Conclusions: The combination of lenalidomide, cyclophosphamide, and prednisone (RCP) has excellent activity in the setting of newly diagnosed myeloma. Overall toxicities were manageable. The study is still ongoing with the total accrual goal of up to 48 patients. The updated data for response and toxicities will be presented at the ASH Annual Meeting. Disclosures: No relevant conflicts of interest to declare.

Phase 2 Clinical Trial of Oral Lenalidomide, Cyclophosphamide, and Prednisone (RCP) for Newly Diagnosed Multiple Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2882-2882 ◽  
Author(s):  
Attaya Suvannasankha ◽  
Sherif Farag ◽  
Robin A O'Bryant ◽  
Lisa L Wood ◽  
Rafat Abonour
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Treatment Protocol ◽  
Median Number ◽  
High Dose Chemotherapy ◽  
M Protein ◽  
Hematological Toxicity ◽  
High Dose ◽  
Newly Diagnosed ◽  
Intent To Treat

Abstract Abstract 2882 Poster Board II-858 Background: Effective and convenient regimen is appealing for Multiple Myeloma (MM) therapy. Lenalidomide and dexamethasone combination is highly effective in MM. However, at the FDA approved dose, dexamethasone related toxicity remains problematic. We previously reported that oral cyclophosphamide and prednisone, when combined with thalidomide, was active and well tolerated in relapsed MM (Oncologist Jan, 2007). Using the similar approach, we now explore the efficacy of all oral, dexamethasone-sparing combination of lenalidomide, cyclophosphamide and prednisone in newly diagnosed MM. Methods: The treatment protocol consisted of lenalidomide given orally at a dose of 25 mg daily on days 1–21 of a 28-day cycle, cyclophosphamide at a dose of 50 mg b.i.d. days 1–21 of a 28-day cycle, and prednisone 50 mg q.o.d. Patients also received an aspirin once daily as thromboprophylaxis. Response was defined as a decrease in serum monoclonal (M) protein by 50% or higher and a decrease in urine M protein by at least 90% or to a level less than 200 mg/24 hours. Responses were assessed on intent to treat basis. Results: Twenty-one patients were enrolled from October 2007 to July 2009. The median age was 67 years (range, 41-76). 7 patients (33%) had ISS stage II and 3 (14%) had stage III disease. The median number of cycles was 6 (range: 1 – 6). The response is not evaluable in 4 patients who are still undergoing the first cycle of therapy. Among the remaining 17 patients, the over all response rate was 94%. The best response based on intent to treat basis was 83%, including CR: 1 (6%), nCR: 1 (6%), VGPR: 3 (18%), PR: 11 (65%) and less than PR: 1 (6%). Overall, 14 of the 21 enrolled patients have discontinued study treatment. Reasons for treatment discontinuation are: completed study per protocol (10), disease progression (1), and adverse event (1) and alternate treatment (1). Hematologic toxicities were the most common with grade 3 neutropenia seen in 10 patients. Infections were seen in 10 patients (5, febrile neutropenia and 5, with normal ANC). Non hematologic toxicities were fatigue, gastrointestinal side effects, neuropathy and mood swings. Specifically, neuropathy was reported in 5 patients. All were grade I. Five patients had grade 4 metabolic abnormalities (2 renal failure attributed to dehydration and tumor lysis, 2 hyperglycemia. and 1 hypokalemia). Five patients had dose adjustments, most commonly due to hematological toxicity attributed to lenalidomide or cyclophosphamide. Seven patients had stem cell collection. In all, sufficient numbers of stem cells were collected for the transplantation use. To date, five have undergone high dose chemotherapy and stem cell transplantation. Three patients with PR on RCP achieved VGPR. Response is not yet evaluable in the 2 remaining patients. Conclusions: The combination of lenalidomide, cyclophosphamide, and prednisone (RCP) has excellent activity in the setting of newly diagnosed myeloma. Overall toxicities were manageable. Myelosuppression was a significant toxicity and attenuated with dose reductions. The study is still ongoing with the total accrual goal of up to 48 patients. The updated data for response and toxicities will be presented at the ASH Annual Meeting. Disclosures: Abonour: Celgene: Honoraria; Millennium: Honoraria.

Sequential VAD (Vincristine, Adriamycin, Dexamethasone) and VTD (VELCADE®, Thalidomide, Dexamethasone) Induction Followed by High-Dose Therapy with Autologous Stem Cell Transplantation and Maintenance Treatment with VELCADE for Newly Diagnosed Multiple Myeloma: Interim Results of Phase II Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 952-952 ◽  
Author(s):  
Sung-Soo Yoon ◽  
Hye Jin Kim ◽  
Dong Soon Lee ◽  
Hyeon Seok Eom ◽  
Jun Ho Jang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Maintenance Treatment ◽  
Response Rate ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Newly Diagnosed

Abstract Introduction Effective reduction of myeloma before autologous stem cell transplantation (ASCT) prolongs survival in multiple myeloma patients. Recently, incorporation of novel agents resulted in improved response rate and reduced side effect in newly diagnosed multiple myeloma. Method: Patients are planned to receive 2 cycles of VAD (vincristine 0.4mg D1-4, adriamycin 9mg/m2 D1-4, dexamethasone 40mg D1-4, 9–12 every 3 weeks), and VTD (bortezomib 1.3mg/m2 D1, 4, 8, 11, thalidomide 100mg daily, dexamethasone 40mg D1-4, 9–12 every 3 weeks). High dose melphalan (200mg/m2) is used as a conditioning regimen for ASCT. Bortezomib (1.3mg/m2) as a maintenance treatment is administered weekly x 4 times every 6 weeks for 4 cycles after ASCT. Response was assessed by EBMT criteria, with additional category of nCR. Adverse events were graded by the NCI-CTCAE, Version 3.0. Result: At this interim analysis, 60 patients have been entered into the ongoing trial, and efficacy could be assessed in 53 patients. After 2 cycles of VAD, response rate was 70%. After VTD, two patients showed further improvement with additional CR, and an overall response was 97% with 14% CR. Especially, patients with poor prognostic cytogenetics (n=6) all responded after VTD. So far, autologous stem cells were successfully collected in all 28 patients with a median CD34+ count of 7.8 x 106/kg (range, 2.17–44.7 x 106/kg). In 24 patients who underwent autologous stem cell transplantation, five patients gained additional CR. There was no progression in patients completed bortezomib maintenance (n=9, CR 77%). The median follow-up duration was 6 months, median time to response was 1.4 months, and median overall survival was not reached. Grade 3,4 hematologic toxicity was more frequently observed after VAD than VTD (anemia 15.8%, 4.6%, neutropenia 7.9%, 3.5%), and incidence of grade 2,3 peripheral neuropathy was low (VAD 3.5%, VTD 7%). Conclusion: Sequential VAD and VTD induction therapy in newly diagnosed multiple myeloma was highly effective, even in patients with poor prognostic cytogenetics, and did not prejudice stem cell collection. VTD could have contributed to increased RR and minimized side effects. An updated results will be presented at the ASH meeting. *Protocol Number: KMM51-NCT00378755.

Cybord Is An Active, Well Tolerated, Cost-Effective Induction Regimen In Newly Diagnosed Multiple Myeloma – a Single Centre Experience

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5396-5396 ◽  
Author(s):  
Janusz Krawczyk ◽  
Sahar Khan ◽  
Bushra Ahsan ◽  
Larissa Higgins ◽  
Enda McGowan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Dose Reduction ◽  
Conflicts Of Interest ◽  
Haematological Toxicity ◽  
Cost Effective ◽  
Newly Diagnosed ◽  
Phase Ii Trials ◽  
Post Transplant ◽  
Drug Regimens

Abstract Background Based on evidence from clinical trials there is a growing consensus that a three drug regimen involving at least one novel agent (proteasome inhibitor or immunomodulatory drug) should be used as initial induction in patients with newly diagnosed multiple myeloma (NDMM), usually for 3-4 cycles, prior to harvesting stem cells and proceeding to autologous stem cell transplantation (ASCT). Three drug regimens achieve deeper responses both before and after ASCT and this has been shown to translate into superior progression free survival (PFS). CR rates with the three drug regimens prior to ASCT are reported to be in the range of 20-30% with correspondingly high rates of very good partial response (VGPR) (50-60%).  One such regimen is the combination of bortezomib with cyclophosphamide and dexamethasone (CyBorD). The published overall response rates (ORR) from phase II trials with CyBorD are approximately 90%, with at least 60% of patients achieving VGPR. At our center, CyBorD has been used as front line therapy since 2008. In this report we present our experience using this regimen as initial therapy in transplant eligible patients. Methods We retrospectively analysed clinical and laboratory records for 31 NDMM patients treated with CyBorD at our institution between 2008 and 2013, all of whom subsequently proceeded to ASCT. The standard protocol consisted of bortezomib 1.3 mg/m2 i.v. twice a week, cyclophosphamide orally at a dose of 300 mg/m2weekly, and dexamethasone orally of 40 mg daily given in 4 days long blocks weekly. Since November 2009 we have also used weekly CyBorD. Results The median age was 57 years (range from 45 to 65), including 24 males and 7 females. According to ISS, 45% patients were classified as stage I, 5% stage II, and 50% as stage III. The ORR was 90% post cycle I and increased to 96% post cycle IV. At least VGPR was observed in 13% of patients after cycle 1 and 56% after cycle IV. Transplantation had improved the responses and 79% had at least VGPR post transplant versus 63% prior, and 24% patients achieved CR post ASCT in comparison to 16% prior ASCT (Fig. 1). The therapy was well tolerated. Haematological adverse events were acceptable and no patient required significant dose reduction or experienced treatment delay due to haematological toxicity. Importantly, no patients developed > grade 3 peripheral neuropathy and no patients required dose reduction or discontinuation of bortezomib due to neurological complications. Stem cell mobilisation was performed using a combination of cyclophosphamide 1.5g/m2 and G-CSF. All patients mobilized successfully without requirement for plerixafor.  The medium CD34+ yield after 2 collection days was 8.2 x106/kg (range 1.8 -19.4). The PFS at 2 years was 75% and 64% at three years of follow up. At 2 years post transplant, the patients achieving at least a VGPR had a longer median PFS in comparison to patients with PR (91% vs 76%, p=NS) (Fig. 2). The cost analysis has shown that on average, the drug only cost of 4 cycles of CyBorD was 18 000€. This compares to 38 000€ for 4 cycles of bortezomib, lenalidomide, dexamethasone (VRD). Conclusions Our data confirm the safety and efficacy of the CyBorD protocol and its applicability to routine clinical practice outside of large academic myeloma centres. CyBorD is an active, well tolerated and cost effective option for patients with NDMM, which could be an ideal backbone for the incorporation of new modalities, such as monoclonal antibodies in induction therapy. A randomized comparison with other triple drug regimens are required to fully establish its place in the treatment of newly diagnosed multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

Lenalidomide, Bortezomib, and Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma: Encouraging Efficacy in High Risk Groups with Updated Results of a Phase I/II Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 92-92 ◽  
Author(s):  
Paul Richardson ◽  
Sagar Lonial ◽  
Andrzej Jakubowiak ◽  
Sundar Jagannath ◽  
Noopur S Raje ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Dose Level ◽  
Safety Data ◽  
Maximum Tolerated Dose ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Dose Levels

Abstract Background: Bortezomib (VELCADE®, Bz) is approved for the treatment of patients (pts) with multiple myeloma (MM). Lenalidomide (Revlimid®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed MM pts following ≥1 prior therapy. Len/Bz±Dex is active and well tolerated in relapsed/refractory MM, and Len/Dex and Bz/Dex are active in front-line MM. The aims of this phase l/ll study were to determine the maximum tolerated dose of Len/Bz/Dex (RVD) and to assess safety and efficacy in previously untreated MM pts. Methods: Pts received Len 15–25 mg on days 1–14, Bz 1.0–1.3 mg/m2 on days 1, 4, 8, 11, and Dex 40/20 mg (cycles 1–4/5–8) on days 1, 2, 4, 5, 8, 9, 11, 12, for up to eight 21-day cycles, initially at four planned dose levels (Len/Bz: 15/1.0, 15/1.3, 20/1.3, 25/1.3). Dose-escalation proceeded (three-pt cohorts) depending on dose-limiting toxicities (DLTs; Grade (G) ≥3 non-hematologic toxicity; G4 thrombocytopenia with platelets <10,000/mm3 on >1 occasion despite transfusion support; G4 neutropenia for >5 days and/or resulting in neutropenic fever; inability to receive cycle 2/day 1 dose due to drug-related toxicity). Based on safety data, dose level 4M (Len/Bz 25/1.3) was added with a reduced Dex (20/10 mg) starting dose. Pts with G≥2 peripheral neuropathy (PNY) were excluded. Responses were assessed by modified European Group for Blood and Marrow Transplantation (EBMT) and Uniform Criteria. Pts with at least partial response (≥PR) could proceed to autologous stem cell transplant (ASCT) after ≥4 cycles. Results: 68 pts have been enrolled to date: 33 in phase l, including 17 pts at the maximum planned dose (MPD, dose level 4M) and 35 in phase ll (at MPD). Data are available for 66 pts (median age 58 yrs, 55% men, 67% IgG MM, 50% with ISS stage II/III). Pts have received a median of 10 cycles; 46 have completed all 8 cycles, 39 have discontinued/completed therapy. Two DLTs of G3 hyperglycemia due to high-dose Dex were seen at dose level 4. Dose reductions in cycle 2 and beyond have occurred in overall/dose levels 1–4 for: Len 16/8 pts, Bz 23/8 pts, and Dex 19/15 pts. Toxicities to date have been manageable, including all G3/4 hematological toxicities (3–15%), G3 hypophosphatemia (8%) and deep vein thrombosis/pulmonary embolism (5%, with daily aspirin), with no G4 PNY, and no treatment-related mortality. The overall response rate (ORR; ≥ PR) is 98%, including 71% ≥ VGPR and 36% CR/nCR; at MPD, ORR is 100%. Efficacy was independent of baseline cytogenetics or ISS stage (Table). ORR and ≥ VGPR rates were similar regardless of the absence or presence of deletion 13q or translocation 4;14; ORR rates ranged from 86% to 100% and ≥ VGPR rates ranged from 57% to 75%. Pts from all three ISS categories achieved ORR ranging from 97% to 100% and ≥ VGPR ranging from 51% to 80%; of note, the 10 pts with ISS stage III disease had an ORR of 100% and ≥ VGPR rate of 80%. Median stem cell collection in 21/23 pts was 6.2 × 106 CD34+ cells/kg after a median of 6 cycles of therapy; 15 pts have proceeded to ASCT, with the transplant course in each case reported as unremarkable. Two of 23 pts (9%) have had difficulty with mobilization. After a median follow-up of 8 months, median time to progression, progression-free survival, and overall survival have not been reached. Conclusions: RVD produces high quality responses and is well tolerated in newly diagnosed MM pts, regardless of their cytogenetic status or ISS stage. MPD has been reached at Len 25 mg, Bz 1.3 mg/m2, and Dex 20 mg, with phase ll enrollment now complete and 100% ORR reported at the MPD. Stem cell mobilization has been successful in almost all pts, with transplant course in pts otherwise unremarkable. Updated efficacy and ASCT data will be presented at the meeting. Responses by cytogenetic status (normal, abnormal [deletion 13q or t(4;14)]), and ISS stage Normal Abnormal No Del 13q With Del 13q No t(4;14) With t(4;14) * pts with available data n* (63) 39 24 52 7 49 10 ≥ PR 100% 96% 100% 86% 98% 100% P 0.381 0.119 1.00 ≥ VGPR 69% 79% 75% 57% 73% 70% P 0.560 0.375 1.00 ISS I ISS II ISS III n* (64) 33 21 10 ≥ PR 97% 100% 100% P 0.385 ≥ VGPR 51% 57% 80% P 0.421

scholarly journals Utilization of Autologous Stem Cell Transplantation in Older Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5701-5701
Author(s):  
Justin King ◽  
Mark A. Fiala ◽  
Scott R. Goldsmith ◽  
Keith E. Stockerl-Goldstein ◽  
Mark A. Schroeder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Older Patients ◽  
Research Funding ◽  
Small Sample ◽  
Poor Performance Status ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Equity Ownership

Historically, high-dose therapy in combination with autologous stem cell transplants (ASCT) for multiple myeloma (MM) was reserved for younger patients. In more recent years, the use of ASCT has expanded in the older population. However, there is still limited data on the utilization and efficacy of ASCT in older patients, particularly those over the age of 75. To further evaluate this issue, we retrospectively analyzed all patients with newly diagnosed MM between the ages of 75-78, the institutional cutoff for ASCT eligibility, that were referred to the stem cell transplant unit at our institution for consultation from the years 2012-2018. Baseline characteristics, anti-myeloma treatments, and patient outcomes were abstracted through chart review. Seventy-five patients were referred to our institution. 71% were male, 29% female. 39% patients were considered ineligible for ASCT by the consulting transplant physician. Most patients were considered transplant ineligible due to comorbidities or poor performance status. Of the 46 patients eligible for ASCT, 52% underwent the procedure during their first-line therapy. The majority of those patients received reduced intensity melphalan (140 mg/m2) while 2 patients received conventional dosing (200 mg/m2). The other 22 patients eligible for ASCT declined or elected to defer the procedure and to be treated with conventional therapy. The characteristics of these three groups were similar and are detailed in Table 1. After a median follow-up of 30 months, 25% of the patients had expired. Estimated median overall survival (OS) was 71.3 months (unable to quantitate 95% CI) for all patients. Compared to transplant eligible patients, regardless of transplant receipt, those who were transplant ineligible had a 186% increase risk for death (HR 2.86; 95% CI 1.12-7.35; p = 0.029). There was also a notable trend for longer OS in those who underwent ASCT compared to those who were eligible but declined the procedure, but it was not statistically significant (HR 0.36; 95% CI 0.10-1.28; p = 0.114). At a transplant center, two-thirds of patients referred for newly diagnosed MM between the ages 75-78 were considered eligible for ASCT and one-third underwent the procedure. Outcomes were better for patients eligible for ASCT, regardless of whether they underwent the procedure. There was also a trend for better OS in patients who underwent the procedure compared to those who declined. While small sample sizes and the retrospective nature of the study limit our ability to draw conclusions, it appears that ASCT has an OS benefit among patients age 75-78. Disclosures Fiala: Incyte: Research Funding. Stockerl-Goldstein:AbbVie: Equity Ownership; Abbott: Equity Ownership. Vij:Genentech: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wildes:Janssen: Research Funding; Carevive: Consultancy.

Bortezomib-Thalidomide-Dexamethasone as Primary Induction Therapy for Newly Diagnosed Multiple Myeloma Significantly Decreases Bone Resorption While Sparing Bone Formation as Compared to Thalidomide-Dexamethasone

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5117-5117 ◽  
Author(s):  
Patrizia Tosi ◽  
Elena Zamagni ◽  
Paola Tacchetti ◽  
Giulia Perrone ◽  
Michela Ceccolini ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Bone Resorption ◽  
Bone Formation ◽  
Induction Therapy ◽  
Phase Iii ◽  
High Dose ◽  
Newly Diagnosed ◽  
Bone Formation Markers

Abstract Bone disease occurs in approximately 80% of patients with newly diagnosed multiple myeloma (MM) and is caused by the interaction of the neoplastic clone with bone marrow microenvironment, ultimately resulting in an altered balance between bone resorption and bone formation. It has been previously reported that therapies aimed at eradicating the myeloma clone could contribute to decrease bone resorption, even though bone formation remains impaired even in responding patients, due to the use of high-dose steroids. It has been recently demonstrated, both in vitro and in animal models, that Bortezomib improves bone formation by stimulating osteoblasts. In order to test whether this activity was retained also in vivo, we evaluated markers of bone resorption (serum crosslaps) and bone formation (serum osteocalcin-OC and bone alkaline phosphatase - BAP) in a series of patients who were enrolled in the “Bologna 2005” phase III clinical trial at our Center. By study design, after registration patients were randomized to receive three 21-days courses of induction therapy with either VTD (Bortezomib, 1.3 mg/sqm on d 1, 4, 8, and 11, plus Dexamethasone, 40 mg on each day of and after Bortezomib administration plus Thalidomide 200 mg/d from d 1 to 63.) or TD (Thalidomide as in VTD and Dexamethasone 40 mg/d on d 1–4 and 9–12 of every 21-d cycle), prior to stem cell collection and double autologous stem cell transplantation. As of January 2008, 27 patients (19 male and 8 female, median age = 57.5 yrs) entered the sub-study; of these, 15 and 12 patients were randomized in the VTD and TD arm, respectively. At diagnosis, both groups of patients showed a marked increase in serum crosslaps as compared to upper baseline limit (7321±1445pmol/L in the VTD arm and 11140±2576pmol/L in the TD arm) while both OC and BAP were reduced as compared to lower baseline limits. After completion of the induction therapy, serum crosslaps were significantly decreased in both treatment groups (2747±319pmol/L in VTD arm, p=0.007; 3686±1084pmol/L in the TD arm, p=0.0015). In the TD group a significant further reduction in bone formation markers was also observed (42% reduction in serum OC and 30% in BAP, p=0.03 and 0.04 as compared to pre-treatment values); on the contrary, in the VTD arm both OC and BAP were not significantly decreased as compared to baseline values (15% and 11% for OC and BAP, respectively). These data suggest that incorporation of Bortezomib into induction therapy counteracts the inhibitory effects of high-dose steroids on osteoblastogenesis, thus sparing bone formation.

Sequential High-Dose Dexamethasone and Response Adapted PAD (Bortezomib, Adriamycin, Dexamethasone) or VAD (Vincristine, Adriamycin, Dexamethasone) Induction Chemotherapy Followed by High-Dose Chemotherapy with Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma; Open-Labelled, Multicenter Phase 2 Study (KMM-94 Study)-Interim Analysis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2044-2044
Author(s):  
Jin Seok Kim ◽  
Cheolwon Suh ◽  
June-Won Cheong ◽  
Kihyun Kim ◽  
Yang Soo Kim ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Induction Chemotherapy ◽  
Induction Treatment ◽  
High Dose ◽  
Newly Diagnosed ◽  
Younger Patients ◽  
High Dose Dexamethasone

Abstract Abstract 2044 Background: Induction treatment followed by autologous stem cell transplantation (ASCT) is the standard therapy for the newly diagnosed younger patients with multiple myeloma (MM). Although new drugs such as lenalidomide or bortezomib have been shown the promising results as induction treatment, many different type of induction treatment regimens still have been used. We evaluate the efficacy and safety of the short course of high dose dexamethasone (HD dexa) and the response adapted PAD (Bortezomib, Adriamycin, Dexamethasone) or VAD (Vincristine, Adriamycin, Dexamethasone) induction chemotherapy in the newly diagnosed younger patients with MM. Methods: 107 newly diagnosed patients with MM from 21 institutions received 2nd cycles of HD dexa followed by PAD or VAD chemotherapy according to the response to the initial high dose dexamethasone. The primary endpoint was complete response (CR) + near CR rate after ASCT. Among 107 patents enrolled this study from November 2009, 25 patients (23%) have been dropped out. This trial will be continued until total 210 patients will be enrolled. The trial is registered on National Cancer Institute website, number NCT01255514. Results: One hundred seven patients (58 male, 49 female) were enrolled (median age; 56). 26 (24%) light chain disease were included. 31 (29%) patients were D-S stage II and 67 (63%) were stage III. According to the ISS, 23 (22%) patients had stage I, 51 (48%) had stage II and 33 (31%) had stage III. 26 (24%) patients had abnormal cytogenetics. There were 31% del13, 7% del17, 19% t(4;14), 15% t(14;16) and 28% t(11;14) in FISH analysis. Among the 82 evaluable patients, CR + PR rate was 48% (39/82) after 2nd cycles of HD dexa therapy. 39 patients (48%) received subsequent VAD chemotherapy and 43 patients (52%) received PAD chemotherapy. Among the 64 patients finished VAD or PAD chemotherapy, CR + PR rate was 83% (79%, 26/33 in VAD group vs. 87%, 27/31 in PAD group). 56 patients were finished ASCT until now. CR + near CR rate after ASCT were 61% (58% in VAD group vs 63% in PAD group). Mortality rate of this trial was 13% (11/82). The cause of death was disease progression (n=3), bleeding (n=1) and infections (n=7). Among 82 patients in whom VAD or PAD chemotherapy was actually performed, 1 year overall survival (OS) rate was 84.7%. 1 year survival rate was 93.8% versus 77.2% (P=0.049) with VAD versus PAD (median follow-up; 9.1 months). Conclusion: Risk adapted approach using initial steroid response showed good response results after ASCT compared with previous trial (CR + near CR rate of IFM 2005-01trial-Bortezomib+dexa induction & ASCT was 35%, J Clin Oncol. 2010;28:4621–9) The MM patients who had poor response to HD dexa also showed similar good response rate after ASCT compared with the patients who had good response to HD dexa treatment in this trial. PAD re-induction therapy after failure of initial steroid induction treatment might overcome the inferior results in the high risk MM patients. Therefore, initial steroid response adapted strategy might be the more cost-effective approach in the newly diagnosed ASCT eligible MM patients. Disclosures: No relevant conflicts of interest to declare.

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