Bortezomib and Thalidomide, a Steroid Free Regimen in Newly Diagnosed Patients with Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2867-2867
Author(s):  
Nilanjan Ghosh ◽  
Anna Ferguson ◽  
Xiaobu Ye ◽  
Carol A. Huff ◽  
Ivan M. Borrello
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Peripheral Neuropathy ◽  
Median Time ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Overall Response ◽  
Venous Thromboembolic Events ◽  
Grade 3

Abstract Abstract 2867 Poster Board II-843 Corticosteroids have historically been the backbone of most myeloma targeted therapies. However, they are often the major cause of toxicities, especially in elderly patients. In recent years, novel agents such as bortezomib and thalidomide have demonstrated significant anti-myeloma activity with increased overall response rates. We thus designed a study combining these two agents in a steroid-free regimen. Bortezomib (B) and thalidomide (T) were examined as first line treatment in 27 patients with symptomatic multiple myeloma between September 2004 and September 2006. Patients received B 1.3 mg/m2 on days 1, 4, 8 and 11 every 21 days and T 150 mg daily for a maximum of 8 cycles. The overall response rate was 81.5%, with a near CR or greater of 25.8% and a CR (immunofixation negative) of 11%. A major response identified by greater than 90% reduction in the paraprotein was seen in 33% of the patients. Responses were rapid: median time to first response was 36.5 days (range, 14-101 days) and median time to best response was 61 days (range, 16-171 days). The most common grade 3 toxicities were peripheral neuropathy (22%), pneumonia (15%) and fatigue (7%). The only grade 3 hematologic toxicity was anemia (7%). No grade 4 toxicities were seen. 3 patients had mild peripheral neuropathy (PN) at baseline. PN was the most common reason for dose reduction with an average B dose of 1.1mg/m2 and T of 110mg daily. The major cause of discontinuation of treatment was PN. The PN completely resolved in 80% of the patients upon completion of therapy. No venous thromboembolic events (VTE) were observed even in the absence of prophylactic anticoagulation. It should be noted that upon completion of the study all patients received either B or T maintenance and no patients proceeded onto stem cell transplant immediately. The median progression free survival (PFS) was 16.8 months (95% CI 8.7-21.6 months). Median overall survival has not yet been reached at a median follow up of 39 months. The 3 year overall survival is 74%. This study demonstrates: 1) the excellent efficacy of a steroid-free regimen; 2) good PFS in the absence of stem cell transplantation; and 3) that most treatment-related PN resolves. Disclosures: Huff: Celgene: Consultancy. Borrello:Celgene: Speakers Bureau; Mellenium: Consultancy.

A Phase II Study of Sequential Velcade/Thalidomide/ Dexamethasone (VTD) as Maintenance Therapy Post Single Autologous Peripheral Stem Cell (PSCT) in Patients with Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3403-3403
Author(s):  
Firoozeh Sahebi ◽  
Amrita Krishnan ◽  
George Somlo ◽  
Leslie Popplewell ◽  
P. Parker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Peripheral Neuropathy ◽  
Maintenance Therapy ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Disease Stage ◽  
Cell Transplant ◽  
Grade Iii

Abstract Abstract 3403 Poster Board III-291 Autologous PSCT remains standard treatment in younger patients (pts) with multiple myeloma. However, relapse is the major cause of treatment failure. Several studies have reported improved progression-free survival (PFS) and possibly overall survival with thalidomide alone or in combination with steroid and chemotherapy as maintenance/consolidation therapy post autologous PSCT. We performed a phase II study investigating the role of sequential velcade/thalidomide/dexamethasone (VTD) as maintenance therapy post single PSCT. The objectives were to examine the toxicities of prolonged course of sequential VTD, CR rate, PFS and overall survival following single autologous PSCT. Within 4-8 weeks of autologous PSCT using melphalan 200mg/m2, pts received weekly velcade (vel) at 1.3mg/m2 /wk x 3 weeks with 1 week rest and dexamethasone (dex) at 40mg/d x 4 d for 6 months, followed by thalidomide (thal) at 50 -200mg/d and dexamethasone (dex) at 40mg/dx4 d for 6 more months. Single agent thalidomide was then continued until disease progression. Twenty-eight pts have been enrolled. Median age is 54 years (29-66). Median time from diagnosis is 7.9 mo. (4.2 – 145). Disease stage at diagnosis; by Salmon-Durie (II/III 6/22) and by ISS (I/II/III 11/9/7/missing data in 1 pt). Pts received induction treatment with thal/dex (14), velcade based (15) and revlimid based regimens (7). Median B2M at enrollment is 1.75 mg/L (1.14 -5.3). Disease status at enrollment; CR (7) VGPR (9), PR (11), SD (1). Three pts have chromosome 13 abnormalities (1 pt by karyotype and 2 pts by FISH). Results: All pts have undergone transplant. Four pts were unable to start planned maintenance therapy due to development of grade II or more neuro toxicities (3), and persistent thrombocytopenia (1) after PSCT. Twenty-four pts started maintenance vel/dex within 4-8 weeks of PSCT. Nine pts have completed 6 months of vel/dex. Two pts stopped vel/dex because of low WBC (1) or PN (1). With a median F/U of 5.2 mo. (1.2 -17.3) nine of 28 pts (33%) have achieved CR post PSCT and six out of 11 evaluable pts (55%) have achieved CR after vel/dex. Six out of 9 pts (66%) who have completed 6 mo. of vel/dex achieved CR. Two out of 9 pts (22%) have upgraded their response with vel/dex. Four pts have completed 6 month of thal/dex and are beyond 1 year post PSCT. Two out of 4 pts remain in CR at one year post PSCT. One pt is in PR and 1 pt has progressed. Two pts could not complete thal/dex phase of therapy because of relapse (1) and grade III GI toxicity (1). Three pts have relapsed of whom 1 pt died of relapsed myeloma (leptomeningeal disease). No grade IV toxicity has been noted. Grade III toxicities have occurred in 4 pts; low platelet (1), fatigue (1), mood alteration (1), GI (severe constipation) (1). Thirteen pts have peripheral neuropathy (PN). Ten pts had PN grade I at enrollment. Only 3 pts have developed PN on the study and all are grade I - II. Median velcade dose is 1.3 mg /m2/wk and thalidomide dose is 100mg /d. Conclusion: Prolonged sequential velcade/thalidomide/dexamethasone maintenance therapy post single autologous PSCT is well tolerated with no severe peripheral neuropathy. Fifty-five percent of pts have achieved CR and 22% have upgraded their response after six months of velcade/dexamethasone therapy suggesting this is an active and well tolerated maintenance strategy post PSCT. Disclosures: Sahebi: Celgene: Honoraria; Millennium Pharmaceutical: Research Funding. Off Label Use: The use of bortezomib(Velcade)in combination with thalidomide and dexamethasone is investigated as maintenance therapy post autologuous stem cell transplant in patients with multiple myeloma.

Third Autologous Stem Cell Transplantation for Relapsed Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4548-4548
Author(s):  
Catherine Garnett ◽  
Chrissy Giles ◽  
Maialen Lasa ◽  
Osman Ahmed ◽  
Marco Bua ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Disease Progression ◽  
Cell Transplantation ◽  
Median Time ◽  
Autologous Stem Cell Transplantation ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant

Abstract Abstract 4548 High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is currently standard treatment for younger patients with multiple myeloma (MM). In the face of almost inevitable disease relapse, there is growing evidence for second ASCT as salvage therapy in certain patient groups. However, few published data exist regarding efficacy and safety of third ASCT in relapsed disease. We retrospectively analysed the results of eight patients treated at a single UK institution who each received three separate autologous stem cell transplants for relapsed MM between May 1997 and April 2012. There were four men and four women. Median age at diagnosis was 48 years (range, 25–64 years). Paraprotein isotype was IgA in two patients and IgG in the remaining six patients. At the time of 1st transplant, seven patients were in partial response (PR) and one in complete response (CR). Conditioning melphalan dose was 200mg/m2 in all but two patients who received 140mg/m2. Three patients entered CR following 1st transplant and four patients showed PR. Median time to disease progression was 31 months (range, 11.8–52.9 months). Prior to 2nd transplant, five patients achieved very good partial response (VGPR) and three PR with induction chemotherapy. Melphalan dose was 200mg/m2 in five patients and 140mg/m2 in the remaining three. Median time to disease progression was 22.3 months (range, 10.1– 39.6 months). At the time of 3rd transplant, two patients had achieved VGPR following induction chemotherapy, one showed PR, two stable disease (SD) and three evidence of disease progression. For the 3rd transplant, melphalan dose was reduced in most cases. Median follow up post 3rd transplant was 8.3 months (range 1.1–29.3 months). One patient died of overwhelming sepsis within one month of transplantation (treatment related mortality). At the time of analysis, five patients had relapsed following 3rd ASCT, with median time to disease progression of 10.4 months (range, 2.7–23.7 months). Three of these patients died at 3.5, 17.6 and 27.1 months post 3rd transplant. The remaining two patients are alive with no evidence of disease relapse (progression free survival (PFS) time of 3.3 and 1.3 months). Overall survival (OS) for the group from diagnosis is 62% at 10 years with a median OS from diagnosis of 149 months (range 68.5 – 189.2 months) (Figure 1). Median OS for the group from 3rd transplant is 17.6 months (range, 1.1–29.3 months) (Figure 2). Median PFS is 10.4 months (range 1.1–23.7 months). These results demonstrate that third ASCT is a possible treatment strategy for patients with relapsed MM and may prolong patient survival. Figure 1: Overall survival from diagnosis for patients receiving 3rd autologous stem cell transplantation for relapsed multiple myeloma Figure 1:. Overall survival from diagnosis for patients receiving 3rd autologous stem cell transplantation for relapsed multiple myeloma Figure 2: Overall survival from time of 3rd autologous stem cell transplant Figure 2:. Overall survival from time of 3rd autologous stem cell transplant Disclosures: No relevant conflicts of interest to declare.

Phase I Trial of CCI-779 (Temsirolimus) and Weekly Bortezomib in Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3696-3696 ◽  
Author(s):  
Irene M. Ghobrial ◽  
Nikhil Munshi ◽  
Robert Schlossman ◽  
Stacey Chuma ◽  
Renee Leduc ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Phase I ◽  
Median Time ◽  
Single Agent ◽  
Mtor Inhibitors ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Dose Escalation Study ◽  
Progression Of Disease

Abstract BACKGROUND: Preclinical studies have demonstrated activity of the combination of mTOR inhibitors and bortezomib in Multiple Myeloma (MM). Single agent mTOR inhibitors (including CCI-779) have shown modest activity in MM. The objective of this phase I dose-escalation study was aimed to determine the maximum tolerated dose (MTD) as well as the activity of the combination of CCI-779 (Wyeth Pharmaceutical, PA) and bortezomib (Millennium Pharmaceutical, MA) in patients with relapsed and/or relapsed, refractory MM. METHODS: Four cohorts (3 patients each) were planned, with dosing of bortezomib 1.3 or 1.6mg/m2 (days 1, 8, 15 and 22) every 35 days (1 cycle) and CCI-779 15 or 25 mg IV (days 1, 8, 15, 22 and 29) every cycle. Dexamethasone was not permitted during therapy. NCI CTCAE v3.0 was used for toxicity assessment; Dose limiting toxicity (DLT) was defined as any grade (G) 3 or greater non-hematologic toxicity related to therapy, G4 neutropenia for 7 d and/or neutropenic fever, or platelets <10,000/mm3 on >1 occasion despite transfusion, inability to receive day 1 dose for cycle 2 due to toxicity. Response was assessed by modified EBMT criteria. Prior therapy with bortezomib or CCI-779 was allowed. Patients remained on therapy until progression of disease or intolerance. RESULTS: Twenty patients (13 men and 7 women) have been treated to date, of these 5 were on cohort 3 and 9 on cohort 4. The median age was 58 yrs (range: 48–81), and median number of prior therapies was 5 (range: 1–10), including prior stem cell transplant with autologous, or allogeneic transplant, bortezomib, lenalidomide, thalidomide, and combination chemotherapy. All of the patients had received prior bortezomib therapy except for one patient. One DLT was observed in cohort 4 (death due to sepsis and septic shock grade 5, possibly related to therapy and underlying myeloma). Cohort 4 was expanded and no further DLTs were observed. MTD was therefore declared at CCI-779 of 25 mg and bortezomib of 1.6mg/m2. Grade (G) 3 and 4 related toxicities included thrombocytopenia (G3 in 35%, G4 in 25%) leucopenia and neutropenia G3 in 25% with no G4 toxicity, G3 anemia in 15%, and nausea, vomiting, viral infection, hyponatremia, pneumonia, hyperglycemia, mucositis, fatigue, and renal insufficiency in 2% of patients. No significant (G2 to G4) peripheral neuropathy has been seen thus far. No anticoagulant prophylaxis has been required, and no DVTs have occurred. The median time of follow up is 6 months (1–13 months). Response was assessed after completion of 2 cycles of therapy. In 15 evaluable patients, the overall response rate (CR+PR+MR) was 33% (5 patients), including 1nCR and 4 MR. The median time of therapy of patients who achieved response was 8 months (2–12 months). All responses occurred in patients who have received prior bortezomib. Six patients had stable disease for a median of 7 months (6–11 months), and 4 patients showed progression of disease (at 3–5 months post initiation of therapy). Responses occurred in the early cohorts indicating activity of these agents even at lower doses. Conclusions: The combination of CCI-779 25 mg and weekly bortezomib 1.6mg/m2 weekly is active and well tolerated, and minimal peripheral neuropathy to date. The ORR of 33% in heavily pretreated patients with MM, including prior bortezomib therapy, is encouraging. The phase II trial using the MTD of this combination is currently being initiated and enrollment is ongoing.

High Rate of Complete Remission (CR) and Upgraded Response with Weekly Maintenance Bortezomib Post Single Autologous Peripheral Stem Cell Transplant (PSCT) In Patients with Multiple Myeloma. Results of a Phase II Prospective Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2399-2399 ◽  
Author(s):  
Firoozeh Sahebi ◽  
Amrita Krishnan ◽  
Leonardo Farol ◽  
Ji-Lian Cai ◽  
George Somlo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Peripheral Neuropathy ◽  
Complete Remission ◽  
Partial Response ◽  
Maintenance Therapy ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Grade Iii

Abstract Abstract 2399 The quality and depth of response particularly achievement of complete remission (CR) have been associated with significant improvement in progression free survival (PFS) and overall survival in multiple myeloma patients undergoing autologous stem cell transplant. Achievement of CR is considered a valid surrogate endpoint for survival in clinical trials for patients with multiple myeloma. We performed a phase II study investigating the role of sequential bortezomib/dexamethasone followed by thalidomide/dexamethasone as maintenance therapy post single autologous PSCT. The objectives were to examine the feasibility, toxicities, CR, PFS and overall survival rates. Within 4–8 weeks of autologous PSCT using melphalan 200mg/m2, pts received weekly bortezomib (bor) at 1.3mg/m2 /wk × 3 weeks with 1 week rest and dexamethasone (dex) at 40mg/d × 4 d for 6 months, followed by thalidomide (thal) at 50 –200mg/d and dexamethasone (dex) at 40mg/dx4 d for 6 more months. Single agent thalidomide was then continued until disease progression. Between March 2008 and June 2010, forty-five pts were enrolled. Median age was 54 years (29-71). Median time from diagnosis was 6.1 mo. (3.5 – 145.9). Disease stage at diagnosis; by Salmon-Durie (I/II/III 2/8/34/1 not available) and by ISS (I/II/III 18/14/8/ 5 not available). Pts received prior induction treatment with thal/dex (15), bortezomib based (27) and lenalidomide based regimens (10). Median B2M at enrollment was 1.8 mg/L (1.05 -5.3). Disease status at enrollment included complete remission (CR) (11), very good partial response (VGPR) (11), partial response (PR) (23). Six pts had chromosome 13 abnormalities (1 pt by karyotype and 5 pts by FISH), 2 pts had t 4;14 (one with concurrent ch 17 p del) and 3 pts had complex cytogenetic abnormalities. Results: Forty-five pts have been enrolled and undergone transplant. Five pts were unable to start planned maintenance therapy due to development of grade II or more neuro toxicities (4), and persistent thrombocytopenia (1) after PSCT. Thirty nine pts started maintenance bor/dex within 4–8 weeks of PSCT. One pt is too early for maintenance therapy. Twenty-five pts have completed the planned 6 months of bor/dex. Ten pts stopped bor/dex because of low WBC (2), PN (4), diagnosis of adrenal cancer (1), myocardial infarction (MI) (1), and relapse (2). Six pts are still receiving maintenance bortezomib. With a median F/U of 8.5 mo. (0.2 -24.0) twelve of 44 evaluable pts (27%) have achieved CR post PSCT and 17 of 33 evaluable pts (51%) have achieved CR after bor/dex on an intention to treat (ITT) analysis. Fifteen of 25 pts (60%) who have completed 6 months of bor/dex have achieved CR. Nine of 25 pts (36%) have upgraded their response with bor/dex. Eight pts (24%) could not complete bortezomib due to toxicities. At one year post PSCT fourteen of 28 evaluable pts (50%) remain in CR. Six pts have relapsed of whom 2 died of relapsed myeloma (leptomeningeal disease 1 pt). One pt experienced MI while receiving bortezomib (grade IV). Grade III toxicities have occurred in 17 pts; low platelet (1), asthenia (2), mood alteration (1), GI (severe constipation due to partial bowel obstruction on thalidomide) (1), skin rash (1), hyperglycemia (1), lymphopenia (10), sinus bradycardia (1), elevated triglyceride (1), DVT (1), low phosphate (3), leukopenia (1), edema (1). Sixteen pts had peripheral neuropathy (PN) grade I prior to start of bortezomib. Only 8 pts have developed new PN on the study and all are grade I-II. No patient has experienced grade III-IV PN. Median bortezomib dose is 1.3 mg /m2 per week. Conclusion: Prolonged weekly bortezomib maintenance therapy is well tolerated and can upgrade response post single autologous PSCT with no severe peripheral neuropathy. Fifty one percent of pts have achieved CR and 36% have upgraded their response after six months of bortezomib/dexamethasone therapy suggesting this is an active maintenance strategy post PSCT. Disclosures: No relevant conflicts of interest to declare.

Comparison of Early and Late Autologous Stem Cell Transplants for Multiple Myeloma: A Single Institution Experience.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 928-928
Author(s):  
Shaji Kumar ◽  
Martha Q. Lacy ◽  
Angela Dispenzieri ◽  
Suzanne R. Hayman ◽  
S. Vincent Rajkumar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Plasma Cell ◽  
Complete Response ◽  
High Dose ◽  
Cell Transplant ◽  
Plateau Phase ◽  
Overall Response ◽  
Delayed Group

Background: High dose chemotherapy and autologous stem cell transplant (SCT) remains the preferred therapy for eligible patients with multiple myeloma (MM). Several studies have demonstrated an improvement in median survival with use of SCT. Patients with myeloma may undergo SCT immediately following 4–6 cycles of ‘induction’ therapy or at the time of relapse from the initial plateau phase. Available evidence does not suggest a survival difference between the two approaches. Methods: We retrospectively evaluated our experience with autologous single SCT for MM to compare the results of delayed SCT to early SCT. We identified from our transplant database, 202 patients with MM, who underwent SCT between October 1992 and November 2002. 101 patients, who responded to induction chemotherapy, had stem cells collected in plateau phase, received maintenance chemotherapy and had SCT at the time of first relapse (delayed SCT group). The remaining 101 patients, after initially achieving a response underwent upfront SCT (early SCT group). Patients refractory to initial therapy were excluded from this study. Most of the early transplants were done in the recent years and hence this group has a shorter follow up. Results: The study cohort had a median age of 55 years (range 29 – 72) at diagnosis consisting of 126 males (62%), with no significant demographic difference between the two groups. As expected measures of tumor burden (M protein, B2M and marrow plasma cell percentage) were significantly higher in the delayed group. Plasma cell labeling indices and presence of abnormal cytogenetics were higher in the delayed SCT group as well at transplant. TBI containing regimens were used more often in the delayed group reflecting a difference in the time periods of transplant. There was no difference between the groups in terms of overall response to transplant though complete response rate was higher for the early transplants. (Table). There was no difference in the time to overall response between the groups (P=0.13, Kaplan Meier estimate). Though the median progression free survival (PFS) from transplant was shorter for the delyaed SCT group, the overall survival (OS) from diagnosis of MM was comparable for the two groups (Table). The overall survival estimate at 5 year from diagnosis was 60% for both groups. Conclusions: Review of our experience demonstrates comparable overall survival for an early SCT compared to SCT at the time of relapse. Although there is an advantage for early SCT in terms of more chemosensitive disease as shown by a longer PFS from SCT, there is no benefit in OS from time of diagnosis. Patient preference and other co-morbidities should play a role in the decision regarding timing of transplant. This study has the disadvantage of being retrospective in nature and the two groups being spread over different periods in time. Early (n=101) Delayed (n=101) P Overall Response 100 (99%) 94 (94%) 0.07 Complete Response 43 (42%) 28 (27%) 0.04 Median PFS (From Transplant) 26.7 months 14.8 months <0.0001 Median OS (From diagnosis) 67 months 70 months 0.1

scholarly journals Phase 2 Trial of LDE225 and Lenalidomide Maintenance Post Autologous Stem Cell Transplant for Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1905-1905
Author(s):  
Francis K. Buadi ◽  
Martha Q. Lacy ◽  
Angela Dispenzieri ◽  
Gabriela Perez ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Grade 3

Background: Lenalidomide maintenance therapy post-autologous stem cell transplantation (ASCT) is associated with improved progression-free survival (PFS) and possibly overall survival in multiple myeloma (MM). However, almost all patients do relapse as a result of residual multiple myeloma cells that remain after the high-dose chemotherapy. In the myeloma setting it has been found that the hedgehog (Hh) pathway is essential for maintaining a subset of tumor causing stem cells. LDE 225 (Sonidegib) is a potent selective oral bioavailable antagonist of Smoothened (SMO), a component of the Hh signaling pathway. In in vitro experiments, LDE225 treatment of myeloma cell lines resulted in a modest inhibition of cell proliferation at increasing doses. When LDE225 was combined with lenalidomide, a more than additive effect was observed in terms of cell proliferation, an effect that was more pronounced in the context of myeloma cell lines growing in co-culture with marrow derived stromal cells. These findings form the basis of evaluation of LDE 225 as a strategy to enhance the activity of lenalidomide in the post-transplant maintenance setting. The minimal residual state post SCT provides the most optimal situation for evaluation of a drug that is likely to work by inhibiting the tumor cells that escaped high dose therapy. Methods: Multiple myeloma patients without evidence of progression, who were 60 - 120 days after a single autologous stem cell transplant (SCT), performed within 1 year of diagnosis were eligible for the study. Maintenance therapy was started approximately 3 months after SCT. Treatment consisted of lenalidomide 10 mg days 1-21 and LDE225 400 mg days 1-28 in 28-day cycles for a total of 18 cycles. The goal of the study was to assess toxicity of this combination, complete response rate (CR) progression free survival (PFS) at 1 and 2 year and overall survival (OS). CR and PFS were estimated using an exact binomial distribution and Kaplan Meier curves respectively. Results: A total of 28 patients were accrued from Jan 2014 to Aug 2016, 1 patient canceled prior to treatment and 1 patient was deemed ineligible resulting in 26 evaluable pts for CR and PFS. The median age of all pts (n=26) was 60 years (range 43-69) and 50% were males. Seventy-three percent of patients reported one treatment regimen prior to SCT, while 27% reported 2 or more prior regimens. The other characteristics of the patient are summarized in Table 1. Twenty seven pts received at least one cycle of treatment and are evaluable for toxicities (AE). Patients were treated for a median of 12.5 (range 1-18) cycles. While 10 pts (38.5%) completed protocol treatment (18 cycles), the remaining 16 pts went off treatment due to AEs (6, 23%), disease progression (3, 11.5%), refusal of further treatment (3, 11.5%) and other reasons (4, 15.4%). A grade 3 or higher AE at least possibly attributed to either drug was seen in 63%. Grade 3+ hematologic toxicities were noted in 30%, with 7% neutropenia and 4% thrombocytopenia. Notable grade 2+ non-hematologic toxicities with more than 5% incidence were dysgeusia 22%, alopecia 11%, and anorexia 7%. Grade 3+ non-hematologic toxicities were fatigue, myalgia and arthralgia each at 7%. The CR rate in evaluable patients was 46% (5 CRs and 7 sCRs) with a 95% CI of 27% - 66%. CR rate improved from 31% to 46%. VGPR or better improved from 42% to 85%. The 24-month PFS (time from SCT to progression or death due to any cause) was 73% (95% CI: 57.9 - 92.3%) with a median time to censoring of 38 months. Conclusion: Lenalidomide in combination with LDE225 as posttransplant maintenance therapy was associated with some toxicity but manageable. The combination improved the depth of response after autologous stem cell transplant. Long-term follow-up is needed to determine overall survival. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Spectrum: Honoraria, Research Funding; Janssen: Honoraria. Kapoor:Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Celgene: Honoraria; Sanofi: Consultancy, Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Russell:Imanis: Equity Ownership. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. OffLabel Disclosure: Sonidegib (LDE 225) is a selective oral bioavailable antagonist of Smoothened (SMO), a component of the hedgehog signaling pathway.

Lenalidomide maintenance after second autologous stem cell transplant improves overall survival in multiple myeloma

2020 ◽  
Vol 61 (8) ◽  
pp. 1877-1884 ◽  
Author(s):  
Dipenkumar Modi ◽  
Jie Chi ◽  
Seongho Kim ◽  
Lois Ayash ◽  
Asif Alavi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant

Weekly Cyclophosphamide and Alternate Day Prednisone: An Effective, Convenient and Well Tolerated Treatment for Relapsed Multiple Myeloma Following Autologous Stem Cell Transplant.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4917-4917
Author(s):  
A. Keith Stewart ◽  
Young Trieu ◽  
Suzanne Trudel ◽  
Greg Pond ◽  
Joseph Mikhael ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Median Time ◽  
Stem Cell Transplant ◽  
Alkylating Agents ◽  
Progression Free Survival ◽  
Median Number ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Protein Reduction

Abstract Alkylating agents remain among the most potent therapies available for treatment of Multiple Myeloma (MM). Their use prior to, or following, autologous stem cell transplant (ASCT) is, however, compromised by concerns about stem cell quality and by myelosuppression limiting effective dose delivered. To address this concern we have studied a combination of cyclophosphamide 500 mg p.o. once weekly and prednisone 100 mg p.o. on alternate days in 66 patients requiring salvage therapy post-ASCT. Dose reductions were allowed for toxicity beginning at cycle 2. On an intent to treat basis, 66 patients received this regimen, however, 7 of these patients were not fully evaluable for response due to non-secretory disease. Of the 59 patients evaluable for response, the median time from transplant to treatment was 26.4 months (range, 6.0 to 66.6). The median time from post-transplant relapse to start of cyclophosphamide and prednisone (C/P) therapy was 1.4 months. The median number of therapies from time of diagnosis to C/P initiation was 2 (range, 1.0 to 5.0). At the date of analysis, treatment with C/P is ongoing in 12 (20.3%) patients, with a median duration of 3.6 months (range, 1.9 to 11.6). The 47 patients who have completed C/P therapy were treated for a median time of 5.5 months (range, 0.5 to 21.7). The reason for discontinuation among these 47 patients included disease progression (42.6% of patients discontinued), plateau disease (21.3%), receiving a second transplant (17.0%), toxicity (10.6%), or switched to another regimen (8.5%). A partial response (&gt;50% protein reduction) was obtained in 37.3% of patients, 18.6% attained minimal response (25–50% protein reduction), 33.8% patients stable disease, while 10.2% patients had progressed on treatment. The estimated median (95% CI) months of progression-free survival after start of C/P treatment is 14.9 (8.7, 21.7). Twenty-three (38.9%) of patients have relapsed after C/P treatment, a median (range) of 8.7 (0.5–65.7) months after start of C/P treatment. At 6 months 74.3% (95% C.I. 61.9% – 89.1%) of patients were progression-free with 28% (95% CI: 16.1–49.2%) progression free at two years. At time of analysis, 44 (74.6%) patients are still alive, with a median follow up of 10.6 months (range, 1.2 to 65.7) since the start of C/P therapy. Fifteen patients have died at a median 13.0 months (range, 1.4 to 61.7) since the time of C/P initiation. The median overall survival (95% C.I.) is estimated to be 35.9 months (24.2, NA). These results demonstrate that the combination of oral cyclophosphamide and prednisone is an effective (56% MR or PR), very well tolerated (10% discontinued due to toxicity) and convenient treatment as salvage MM therapy post-ASCT. The relative lack of myelosuppression allows for re-collection of stem cells and salvage transplant while retaining other active second line agents for later relapse. This regimen thus compares favorably with recent salvage therapeutics introduced in MM and is now being studied in combination with these newer active agents and in induction therapy.

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 ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2546-2546 ◽  
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.

Dose Intensive Induction Chemotherapy Does Not Decrease Tumor Contamination of Autograft or Improve Survival for Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplant.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2932-2932
Author(s):  
Farzana A. Sayani ◽  
Nizar J. Bahlis ◽  
Peter Faris ◽  
Mary Lynn Savoie ◽  
Ahsan Chaudhry ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Small Sample ◽  
Cell Transplant ◽  
Intensive Chemotherapy ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Time To Relapse

Abstract Multiple dose intensive chemotherapy regimens have been used for induction/mobilization of stem cells for autologous stem cell transplantation (ASCT) in multiple myeloma. However, the exact role and regimens of such dose intensive chemotherapy has not been clearly defined. We therefore did a retrospective study to determine if dose intensive cyclophosphamide (Cyclo) 5.25 g/m2, etoposide 1.05 g/m2 and cisplatin 105 mg/m2 (DICEP) results in improved relapse rate and survival compared to standard mobilization with only Cyclo 2 g/m2. Between January 1998 and March 2004, a consecutive series of 57 newly diagnosed multiple myeloma patients receiving DICEP (38) or Cyclo (19) for in-vivo purging/mobilization were analyzed. Both groups were similar in regards to age and sex. There were no significant differences in IPI score, Durie-Salmon stage, B2 microglobulin, calcium, creatinine and albumin levels between treatment groups. Outcomes included time to relapse and time to death. Median follow up time was 799 days. Kaplan-Meier plots for time to relapse showed no significant difference (p=0.0992). Median relapse time in the DICEP group was 905 days (95% CI 580–1604) compared to 1112 days (95% CI 742-infinity) in the Cyclo group. Kaplan-Meier plots for overall survival showed no significant difference between both groups (p=0.8664). The median survival times have not yet been reached in either group and are not reported. Analysis revealed no discernable confounding risk factors. Effects of treatment on outcomes were not altered after adjusting for IPI score and Durie-Salmon staging using the stratified log-rank test. Small sample size and short duration of followup are potential limiting factors for this study, however, preliminary analysis of a larger sample of 91 multiple myeloma patients receiving either DICEP or a less intense induction/mobilization regimen, also revealed no significant difference in disease free or overall survival. Monoclonal plasma cell contamination of stem cell products was not significantly different between both groups (DICEP 42.9%, Cyclo 56.3%, p=0.5573). This study therefore suggests that the very intense DICEP induction/mobilization regimen results in no significant difference in survival outcomes. The more intense regimen does not significantly decrease tumor contamination of autograft stem cells. Overall, our experience suggests that novel induction therapies such as bortezomib, lenolidomide etc. should be pursued in preference to any further study of high dose cytotoxic chemotherapy induction. Figure Figure

Sign in / Sign up

Export Citation Format

Share Document