Treatment of Newly Diagnosed, Inner-City Multiple Myeloma Patients with Zoledronate, Dexamethasone, and Low-Dose Thalidomide: A Phase II Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5124-5124
Author(s):  
Uwe Klueppelberg ◽  
Eric L.P. Smith ◽  
Marc J. Braunstein ◽  
David Kahn ◽  
Olcay A. Batuman
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Inner City ◽  
Phase Ii ◽  
Low Dose ◽  
Phase Ii Trial ◽  
Newly Diagnosed ◽  
Hiv Patients ◽  
Long Term Treatment

Abstract Background: This Phase II trial was designed to assess the long-term effectiveness and safety of low-dose thalidomide with dexamethasone and zoledronate (TDZ) in newly diagnosed multiple myeloma (MM) in an inner-city population in which AIDS is the third-leading cause of death. Although the incidence of MM is increased in HIV+ patients, guidelines for treatment of MM in this population are not yet known. The TDZ regimen was intended to be non-myelotoxic and compatible with HAART. Because zoledronate mitigates tumor growth and angiogenesis as well as bone resorption, it was expected to boost the therapeutic effect of thalidomide and dexamethasone. Method:Of 45 consecutive enrollees, 38 (27F/11M; median age = 60.4 years) were evaluable. All patients had skeletal involvement of varying severity; baseline levels of *2-microglobulin (4.3 mg/dL; SE = 0.68) and serum albumin (3.3 mg/dL; S.E.= 0.38) indicated advanced disease. Eight evaluable patients (21%) were HIV+ (7F/1M; median age = 47 years). Patients with HIV were younger (P < .001), with marginally higher *2-microglobulin levels (P = .076). Seven of the HIV+ patients were on HAART at the time of treatment. The TDZ regimen, given for 24 months or until progression, consisted of: thalidomide, 100 mg daily; dexamethasone, 10–40 mg for 4 days/week for 3 weeks each month for 6 months, then reduced to 4 days each month; zoledronate, 4 mg IV monthly; and ASA, 81 mg daily. Response was stratified by reduction of M protein levels: > 75% (very good partial response [VPR]), > 50–75% (partial response [PR]), or 25–50% (minor response [MR]). Results: Age-adjusted one-year survival was 74.4%, and is identical to NCI SEER data (73.7%). Mean duration of TDZ treatment was 21.4 months (range = 13–24). VPR was achieved in 32% (n = 12), PR in 39% (n = 15), and MR in 18% (n = 7). Three patients had stable disease, and one progressed. Median time to maximum response was 3.0 months. Overall cumulative survival at 24 months was 68% by Kaplan-Meier analysis, and was not affected by HIV status, age, or sex. Baseline creatinine clearance both for HIV+ and HIV− patients was within normal limits, and was not adversely affected by monthly treatment with zoledronate (P > .2 for both). Despite prophylactic ASA, thromboembolism occurred in 6 patients (16%), all of whom were successfully treated with full anticoagulation. Other toxicities ≥ Grade 2, were not observed. Skeletal events occurred in 8% of patients; osteonecrosis of the jaw was not encountered. Death occurred in 10 patients, 9 of whom were evaluable; 6 deaths were due to progression or complications of MM, and 4 were from unrelated causes. Seven patients were dropped from the study (5 moved from the area and 2 patients declined to continue). Conclusion: Thalidomide administered at less than half the standard sage in combination with zoledronate and dexamethasone provided safe and effective long-term treatment of MM both in HIV− and HIV+ patients. The modest frequency of toxicity and skeletal events under this regimen indicates improvement in quality of life as well as survival.

Treatment of Newly Diagnosed, Inner-City Multiple Myeloma Patients with Low-Dose Thalidomide in Combination with Dexamethasone and Zoledronate: A Phase II Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5180-5180 ◽  
Author(s):  
Uwe Klueppelberg ◽  
Iuliana Shapira ◽  
Eric Smith ◽  
Marc Braunstein ◽  
David Kahn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Inner City ◽  
Phase Ii ◽  
Low Dose ◽  
Phase Ii Trial ◽  
Therapeutic Effects ◽  
Newly Diagnosed ◽  
Hiv Patients ◽  
Β2 Microglobulin

Abstract Background: Although the incidence of multiple myeloma (MM) is increased in HIV+ patients, optimal treatment of MM in the HIV setting remains unknown. This Phase II trial was designed to assess the long-term effectiveness and safety of low-dose thalidomide in combination with dexamethasone and zoledronate (TDZ) in newly diagnosed MM in an inner-city population, in which the HIV infection rate is high. The TDZ regimen was thus intended to be non-myelotoxic and compatible with HAART. Because it mitigates tumor growth and angiogenesis as well as bone resorption, zoledronate was expected to boost the therapeutic effects of thalidomide and dexamethasone. Methods: Of 45 consecutive enrollees, 38 (22F/16M; median age = 61 years) were evaluable. All patients had bone disease, and baseline levels of β2-microglobulin (4.9 mg/dL; SE = 0.76) and serum albumin (3.3 mg/dL; SE = 0.11) indicated advanced disease. Eight evaluable patients (21%) were HIV+ (7F/1M; median age = 47 years). Patients with HIV were younger (P <.001) and had higher β2-microglobulin levels (P =.003), and 6 were receiving HAART. The TDZ regimen consisted of thalidomide, 100 mg daily; dexamethasone, 10–40 mg for 4 days/week for 3 weeks each month for 6 months, then reduced to 4 days each month; zoledronate, 4 mg IV monthly; and ASA, 81 mg daily. Patients were treated for 24 months or until disease progression. Response was stratified by reduction of M protein levels: > 90% (near-complete response [N-CR]), > 50–90% (partial response [PR]), or 25–50% (minor response [MR]). Results: Mean duration of TDZ treatment was 18 months (range = 3–24). Age-adjusted one-year survival was 74.4%, and was identical to SEER data (73.7%). N-CR was achieved in 30% (n = 11, [7 HIV−/4 HIV+]) and PR in 68% (n = 26, [22 HIV−/3 HIV+] of evaluable patients. One patient did not respond. Median time to maximum response was 4.5 months in HIV− patients and 2.5 months in HIV+ patients (P <.05). Overall cumulative survival at 24 months was 68% by Kaplan-Meier analysis, and was not affected by HIV status, age, or sex. Baseline creatinine clearance both for HIV+ and HIV− patients was within normal limits, and was unaffected by TDZ. Even with prophylactic ASA, thromboembolism occurred in 6 patients (13%), necessitating additional anticoagulation with warfarin. No other significant toxicity was observed. Of the 10 patients who died, 9 were HIV− and 1 was HIV+; deaths were due to progression of MM (n = 3), complications of MM (n = 3), and causes unrelated to MM (n = 4). Seven patients were dropped from the study (5 moved from the area and 2 patients declined to continue). Conclusions: Thalidomide administered at less than half the standard dosage and in combination with zoledronate and dexamethasone is a safe and effective treatment in the long-term management of MM both in HIV− and HIV+ patients. The potential synergy of thalidomide and zoledronate in the treatment of MM should be evaluated in a larger randomized study. In addition, the faster response to TDZ in HIV+ MM patients on HAART suggests a cooperative interaction between the two regimens that should be further evaluated.

scholarly journals Three Drug Regimens for Newly Diagnosed Multiple Myeloma Transplant-Ineligible Elderly Patients - a Systematic Review

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5574-5574
Author(s):  
Abdul Aziz Siddiqui ◽  
Kazi Najamus-saqib Khan ◽  
Arafat Ali Farooqui ◽  
Muhammad Saad Farooqi ◽  
Muhammad Junaid Tariq ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Elderly Patients ◽  
Phase Ii ◽  
Low Dose ◽  
Phase Ii Trial ◽  
Alkylating Agents ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Great Efficacy ◽  
Drug Regimens

Introduction: Patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplant (ASCT) tend to have comorbidities and/or advanced age that make this subset of patients difficult to manage with current drug regimens. Methods: A comprehensive literature search of PubMed, Embase, Clinicaltrials.gov and Web of Science was performed from inception and completed on 07/17/2019. Studies focusing on efficacy and tolerability of 3-drug regimens in patients with NDMM were included for the review. Results: Out of 3579 studies, a total of 10 (08 phase II and 03 phase III) clinical trials in last ten years (2010-2019) using 3-drug regimens in NDMM elderly pts (893M/807F) ineligible for ASCT (determined by investigators) were selected. A total of 1703/1740 NDMM pts were evaluated. Proteasome inhibitors (PIs) such as carfilzomib (C), bortezomib (V) and ixazomib (I) showed promising results in elderly transplant-ineligible NDMM pts. CLARION trial (phase III, n=955) compared two PIs (C and V) with melphalan (M) and prednisone. There was no statistically significant difference in progression-free survival (PFS) between two groups (median: 22.3 vs 22.1 months; HR: 0.91; 95% CI, 0.75-1.10, p = 0.159) as well as overall survival (OS) (HR: 1.08; 95% CI: 0.82-1.43). Difference in the least square means of the HR-QoL (Health related- quality of life) was 4.99 (p<.0001) favoring C-group. M may not be an ideal drug to combine with carfilzomib in this setting given more AEs.(Facon et al 2019). V as 3-drug regimen in combination with lenalidomide (L) in 242 pts achieved statistically significant prolonged PFS (median 43 mo) and OS (median 75 mo) with great efficacy and acceptable risk-benefit profile. (Durie et al 2017; phase III). Multinational phase II trial (n=70) by Dimopoulos et al (2019) evaluated I, with different fixed doses of cyclophosphamide (Cy). Median duration was 19 cycles, indicating the long-term tolerability of regimen. With favorable toxicity profile and maintained QoL scores, trial concluded that this therapy is tolerable in elderly transplant-ineligible NDMM pts. Tuchman et al (2017) in phase II trial (n=14) investigated (V-Cy-d) and achieved ORR of 64%, with ≥VGPR of 57%. Low dose V showed great efficacy with M yielding ORR of 86% and VGPR or better of 49% in phase II trial (n=101) that also evaluated Cy as 3-drug combination but results were more productive with M with longer PFS and OS which reduced when impact of frailty was examined on outcomes. Since toxicity was higher with M, trial suggested that 2-drug combination should be preferred in elderly frail patients. (Larocca et al 2015). Efficacy was quite promising when Bringhen et al (2014) trialed C with Cy-d; 87% OS and 76% PFS at 1 y in phase II trial (n=58) with much favorable safety profile. Monoclonal antibodies (mAb) such as elotuzumab (E) and pembrolizumab (Pe) are also tested in elderly. First study conducted on NDMM pts using humanized mAb; E, in phase II trial (n=40) by Takezako et al (2017) attained primary endpoint of the study (ORR) of (88%) and VGPR or better of 45% in Japanese pts with tolerable toxicities in elderly. No subjects on this study experienced severe peripheral neuropathy. KEYNOTE-185; a phase III multinational trial by Usmani et al (2019) evaluated Pe with Ld in 151 pts. FDA halted this study due to unfavorable benefit-risk profile; 19 deaths, 6 due to disease progression (PD), and 13 due to treatment-related AEs. Median PFS and median OS were not reached in either group. Immunomodulators such as L achieved one of the longest PFS reported in a trial of transplant ineligible patients (35 mo) by using LVd regimen in phase II multicenter trial (n=50). (O'Donnell et al 2018) Alkylating agents like bendamustine (ben) and M have been tested in different novel regimens. Decreasing intensity and increasing duration of ben resulted in better outcomes in phase II trial (n=59) by Berdeja et al (2016) and can be given as first line treatment. Ben yielded great results with low dose dexa as compared to high dose achieving 92% ORR. Original regimen was effective but relatively more toxic. Incidence of herpes and neuropathy decreased dramatically with the treatment modifications. Conclusion: Three-drug regimens having PIs, mABs, immunomodulators and alkylating agents have shown desirable results in NDMM transplant (ASCT)-ineligible elderly patients and are likely the emerging standard of care for NDMM. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Long-term treatment of newly-diagnosed multiple myeloma with low-dose thalidomide, dexamethasone and zoledronate (TDZ)

2005 ◽  
Vol 23 (16_suppl) ◽  
pp. 6697-6697 ◽  
Author(s):  
U. Klueppelberg ◽  
I. Shapira ◽  
L. Chen ◽  
M. C. Aloba ◽  
E. Smith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Low Dose ◽  
Term Treatment ◽  
Newly Diagnosed ◽  
Long Term Treatment

scholarly journals Efficacy of Elotuzumab Based Combinations in Patients with Multiple Myeloma - a Systematic Review

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5548-5548
Author(s):  
Arafat Ali Farooqui ◽  
Ahmad Anjum ◽  
Muhammad Saad Farooqi ◽  
Talha Bin Farooq ◽  
Tanveer Shaukat ◽  
...  
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Partial Response ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Entire Study ◽  
Tract Infections

Introduction Multiple myeloma afflicted cells express signaling lymphocytic activation molecule family member 7 (SLAMF7). Elotuzumab; a monoclonal antibody (mAb), targets SLAMF7 and fights myeloma cells by stimulating phagocytic action of natural killer (NK) cells and via antibody‐dependent cell‐mediated cytotoxicity (ADCC) pathway. This study focuses on the clinical utility and tolerability of elotuzumab based combinations in patients (pts) with multiple myeloma (MM). Methods Literature search of PubMed, Embase, Clinicaltrials.gov, Cochrane and Web of Science was performed from inception to June 12, 2019 for elotuzumab based combinations in MM patients. Total of 06 phase II and phase III clinical trials were selected for systematic review out of 292 studies. Results Elotuzumab (E) based combinations were evaluated in 1075 patients (pts) out of 1115 enrolled pts. 119 were newly diagnosed (ND) and 956 were relapsed/refractory (RR) patients. Newly Diagnosed MM patients: Takezako et al. 2017; in phase II trial, showed overall response rate (ORR) of 88% (complete response [CR] 3% + stringent CR [sCR] 5% + partial response [PR] 43% + very good partial response [VGPR] 38%) with ELd (E-Lenalidomide-dexamethasone) arm vs 74% in Ld arm in 82 ND pts. Progression free survival (PFS) at 1 year (y) was 93% versus (vs) 91%. Grade (G) ≥3 adverse events (AEs) included neutropenia (18%) and leukopenia (15%). Relapsed/Refractory MM patients: E-Bortezomib(B)-d arm in a phase II trial by Jakubowiak et al. (2016) showed 1 y PFS of 39% vs 33% in Bd arm in 152 RR pts (Hazard ratio [HR]: 0.72; p = .09) with 28% decrease in progression or death with EBd vs Bd arm. Objective response rate (ORR) was 66% (4% CR+ 33% VGPR + 30% PR) vs 63%. OS (overall survival) at 1 y was 85% (EBd) and 74% (Bd) (HR: 0.6). G≥3 AEs were infections (21%), thrombocytopenia and peripheral neuropathy (9% each). Mateos et al. (2016) in phase II trial (n=40) evaluated E-T (thalidomide)-d with or without Cy (cyclophosphamide) in heavily pre-treated RR pts. Pts received Cy if they failed to achieve PR by the 5th cycle or because of progressive disease (PD). Responses were better with ETd vs ETdCy. ORR was 38% (95% CI: 23-54) in ETd vs 9% (95% CI: 0-41) in ETdCy. Entire study yielded median PFS (mPFS) of 3.9 months (mo) (95% CI: 2.79%-9.43%) with 1-y PFS of 30% and mOS of 16.3 mo (95% Cl: 8.87%-25.66%) with 1-y survival rate of 63%. G≥3 AEs were lymphopenia (50%), anemia (20%), leucopenia (20%) and respiratory tract infections (RTI) (8%). Dimopoulos et al. 2018 studied E + pomalidomide (P) + d (EPd) for RR pts with ≥2 prior therapies in phase II ELOQUENT-3 trial (n=117). EPd arm yielded mPFS of 10.2 mo vs 4.6 mo in Pd arm [HR: 0.54 (95% CI: 0.34-0.86; p=0.008)], i.e. 46% lower risk of progression or death in EPd vs Pd arm. ORR was 53% (CR 5% + sCR 3% + PR 33% + VGPR 12%) in EPd vs 26% in Pd arm (odds ratio [OR]: 3.25 (1.49-7.11). G≥3 AEs were anemia (10%), neutropenia and infections (13% each). Phase III ELOQUENT-2 trial randomized 646 RR pts. PFS at 4 y was 21% vs 14% (HR: 0.71, 95% CI: 0.59-0.86; p= .0004), favoring ELd with 29% reduction in myeloma progression or death. With VGPR of 30%, ORR was 79% vs 66 % (ELd vs Ld) with HR: 0.77; 95% CI: 0.62-0.95; p = 0.0176. OS at 4 y was 50% vs 43% (HR: 0.78; 95% CI: 0.63-0.96). G≥3 AEs included lymphocytopenia (79%), neutropenia (36%), anemia (20%) and thrombocytopenia (21%). (Dimopoulos et al, 2018). Newly Diagnosed & Relapsed/Refractory MM patients: Phase II trial (n=70) by Berenson et al. (2017) studied G≥3 infusion reactions (IRs) using ELd in ND (n=37) and RR (n=33) pts. ORR was 78% (95% CI: 62%‐90%) for ND and 61% (95% CI: 42%‐77%) for RR pts. Other response rates were CR 6%, VGPR 27% and PR 37% in all patients. G3 AEs included anemia in 10% pts (no G3 IRs were seen). Conclusion: Elotuzumab based combinations showing promising outcomes in terms of ORR, PFS and OS for ND and RR MM patients with tolerable toxicity profile. More clinical studies with elotuzumab in unique and newer combinations need to be tested in prospective trials. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

First-Line Treatment of Multiple Myeloma with a Combination of Thalidomide, Dexamethasone, and Zoledronate (TDZ) in an Inner-City Population with High HIV Prevalence.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4932-4932
Author(s):  
Uwe Klueppelberg ◽  
Eric Smith ◽  
Laurie Chen ◽  
Chona M. Aloba ◽  
Iuliana Shapira ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Hiv Infection ◽  
Inner City ◽  
Antiretroviral Treatment ◽  
M Protein ◽  
Newly Diagnosed ◽  
Hiv Status ◽  
Hiv Patients ◽  
Β2 Microglobulin

Abstract Background: The combination of thalidomide and dexamethasone is a rescue regimen for multiple myeloma (MM) in relapse, and for pretransplant in newly diagnosed patients. The bisphosphonate zoledronate mitigates bone resorption and possibly tumor growth and angiogenesis. The long-term utility of this combination in a newly diagnosed inner-city MM population with high prevalence of HIV-infection is addressed in this phase II trial. MM is reported with increased frequency in patients with HIV infection, and optimal treatment of MM in these patients is unknown. Methods: Of 30 consecutive enrollees, 22 (16F/6M) were evaluable. Mean age was 61 years (range = 43–82); all had skeletal lesions, and 27% (n = 6) were HIV+ (mean age = 47, range 46–50, all female). Patients received thalidomide 100 mg QD, dexamethasone 10–40 mg PO on Days 1–4, 9–12, and 17–20 monthly for six months, then on Days 1–4 monthly; and zoledronate 4 mg IV monthly, until progression or relapse. Baseline β2-microglobulin indicated high risk for all patients (mean = 6.2 μg/ml, SD = 3.8). At enrollment, 4 patients had AIDS, and 3 were on HAART. Results: Overall response rate (> 50% decrease in M protein) was 72% (n = 13), and 83% (n = 5) in HIV+ patients. In 27% (n = 6), M protein levels were < 0.3 g/dL, including 3 HIV+ patients on HAART. In 23% (n = 5), M protein was reduced by < 50%. Median time to response was 2 months, and mean time on TDZ was 11 months. TDZ treatment decreased serum β2-microglobulin (P <.001). Two patients relapsed, and one patient with HIV and concomitant plasmacytoma did not respond. All three eventually died. Response to treatment was unaffected by HIV status or antiretroviral treatment. Side effects of TDZ were reversible by anticoagulant therapy or dexamethasone reduction. Conclusions: TDZ had significant activity against newly diagnosed MM, suggesting that zoledronate may facilitate response with lower doses of thalidomide. HIV status did not affect response, indicating that this regimen is compatible with concomitant antiretroviral treatment and is equally effective in HIV+ patients. These findings underscore the potential effectiveness of this combination of anti-myeloma agents as a long-term alternative, particularly in patients for whom transplant therapy is not feasible.

scholarly journals Phase II trial of pre-irradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligoastrocytomas: long term results of RTOG BR0131

2015 ◽  
Vol 124 (3) ◽  
pp. 413-420 ◽  
Author(s):  
Michael A. Vogelbaum ◽  
Chen Hu ◽  
David M. Peereboom ◽  
David R. Macdonald ◽  
Caterina Giannini ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Long Term Results ◽  
Newly Diagnosed

scholarly journals Phase II study of carfilzomib, thalidomide, and low-dose dexamethasone as induction and consolidation in newly diagnosed, transplant eligible patients with multiple myeloma; the Carthadex trial

Haematologica ◽  
2019 ◽  
Vol 104 (11) ◽  
pp. 2265-2273 ◽  
Author(s):  
Ruth Wester ◽  
Bronno van der Holt ◽  
Emelie Asselbergs ◽  
Sonja Zweegman ◽  
Marie Jose Kersten ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Low Dose ◽  
Phase Ii Study ◽  
Newly Diagnosed

Pomalidomide Plus Low-Dose Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma and Renal Impairment: Results From a Phase II Trial

2018 ◽  
Vol 36 (20) ◽  
pp. 2035-2043 ◽  
Author(s):  
Meletios Dimopoulos ◽  
Katja Weisel ◽  
Niels W.C.J. van de Donk ◽  
Karthik Ramasamy ◽  
Barbara Gamberi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Glomerular Filtration Rate ◽  
Adverse Events ◽  
Renal Impairment ◽  
Glomerular Filtration ◽  
Phase Ii ◽  
Filtration Rate ◽  
Low Dose ◽  
Estimated Glomerular Filtration Rate ◽  
Phase Ii Trial

Purpose Renal impairment (RI) limits treatment options in patients with relapsed/refractory multiple myeloma (RRMM). Here, we prospectively studied pomalidomide plus low-dose dexamethasone (LoDEX) in patients with RRMM and moderate or severe RI, including those receiving hemodialysis. Patients and Methods MM-013, a noncomparative, European phase II trial, enrolled three patient cohorts: moderate RI (cohort A; estimated glomerular filtration rate, 30 to < 45 mL/min/1.73 m2); severe RI (cohort B; estimated glomerular filtration rate, < 30 mL/min/1.73 m2); and severe RI that requires hemodialysis (cohort C). Patients received pomalidomide 4 mg/d on days 1 to 21 and LoDEX 20 or 40 mg once per week in 28-day cycles. The primary end point was overall response rate. Results Of 81 enrolled patients (33, 34, and 14 patients in cohorts A, B, and C, respectively), 13 were still receiving treatment at data cutoff (January 28, 2017). Overall response rates were 39.4%, 32.4%, and 14.3%, with a median duration of response of 14.7 months, 4.6 months, and not estimable, respectively. Of importance, 100%, 79.4%, and 78.6% of patients, respectively, achieved disease control. With a median follow-up of 8.6 months, median overall survival was 16.4 months, 11.8 months, and 5.2 months, respectively. Complete renal responses were observed only in cohort A (18.2%), and no patients in cohort C became hemodialysis independent. Grade 3 and 4 hematologic treatment-emergent adverse events and pomalidomide discontinuations as a result of treatment-emergent adverse events occurred more frequently in cohort C. Pomalidomide pharmacokinetics were comparable among the three renal cohorts. Conclusion Pomalidomide 4 mg/d plus LoDEX is efficacious in patients with RRMM with moderate or severe RI, including those who had more advanced disease and required hemodialysis. The safety profile was acceptable among the three groups, and no new safety signals were observed.

Results From the Phase II Dose Expansion of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 445-445 ◽  
Author(s):  
Joseph R. Mikhael ◽  
Craig B. Reeder ◽  
Edward N. Libby ◽  
Luciano J. Costa ◽  
P. Leif Bergsagel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Phase Ii ◽  
Initial Phase ◽  
Stem Cell Transplant ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Abstract 445 Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its target and has a favorable toxicity profile that has shown significant activity in relapsed multiple myeloma (MM), leading to recent FDA accelerated approval. To achieve rapid and deep response in patients eligible for stem cell transplant, we combined carfilzomib with the regimen of cyclophosphamide-thalidomide-dexamethasone (CTD). We recently reported the results of the Phase I component of the trial (in which no MTD was reached) followed by the initial Phase II trial; however, with increasing evidence for the safe and effective use of higher doses of carfilzomib, we now report results from dose escalation extension of the Phase II trial. Methods: Newly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with Carfilzomib IV Days 1,2,8,9,15,16 (see Table 1 below for dosing per cohort) along with Cyclophosphamide 300 mg/m2 PO Days 1,8,15, Thalidomide 100 mg PO Days 1–28 and Dexamethasone 40 mg PO Days 1,8,15,22. We initially conducted a Phase I run in trial of 6 patients with no DLT observed before expanding to the Phase II portion of the study. The initial phase II regimen is shown below – as no DLTs were observed, we have now fully accrued to the Phase II dose level +1. Treatment was for 4 cycles with expected SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results: A total of 38 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II, and the remaining at dose escalated cohorts. We are reporting the 27 patients who have completed therapy and will update with the dose escalated cohorts. Median age was 65 (range 27–74) and 52% were female. ISS Stage was advanced (II-III) in 56%. Best overall response rate during 4 cycles of CYCLONE at dose level 0 is 96%: CR 29%, VGPR 46%, PR 21% (1 pt achieved MR). Adverse events of grade 3 or higher at least possibly related to CYCLONE occurred in 12 (44%). Most commonly reported non hematological toxicities (all grades) included fatigue (67%), constipation (56%), lethargy (41%) somnolence (37%), malaise (30%) depressed level of consciousness (22%); however, grade 3/4 toxicities occurring in >5% were uncommon: thromboembolic event 11%) and muscle weakness (7%). Two cases of pneumonia required hospitalization. Eight patients (30%) developed grade 1 sensory neuropathy; no higher grade or painful neuropathy was evident. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included neutropenia (15%) and lymphopenia (7%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. Conclusion: The 4 drug CYCLONE regimen is highly efficaceous with a response rate after only 4 cycles of 96% (75% ≥VGPR, 29% CR) at the current dosing level of carfilzomib IV 20/27 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. Increasing the dose of carfilzomib is feasible and updated results of dose escalated cohorts will be reported at 20/36 and 20/45 mg/m2. Disclosures: Bergsagel: onyx: Membership on an entity's Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

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