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.

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.

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 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.

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.

scholarly journals Phase II Trial of In Vivo Purging with Daratumumab in Newly Diagnosed Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Shebli Atrash ◽  
Myra Robinson ◽  
Barry Paul ◽  
Sarah Norek ◽  
David M. Foureau ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
T Cell ◽  
Clinical Response ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Newly Diagnosed ◽  
Post Induction

Background: In multiple myeloma, induction therapy (IT) before hematopoietic progenitor cells (HPC) collection reduces the tumor burden, improves the quality of the collection, and diminishes end-organ damage. The data concerning the impact of the response to IT on progression-free survival (PFS) after autologous stem cell transplant (ASCT) remains limited. IFM 2005-01 reported better PFS in patients who achieved at least a very good partial response (VGPR) after IT (PFS post-ASCT 41 vs. 31 months, p= 0.01). Also, studies have consistently shown that minimal residual disease (MRD) negativity impacted PFS/ overall survival (OS). Currently, rates of CR and MRD-negativity post-ASCT are sub-optimal. Given the clinical activity and the safety profile of daratumumab (Dara), evaluation of this novel agent pre- and post-ASCT is warranted, as it may improve the post-ASCT ≥ CR and MRD-negativity rates. Study Design and Methods: This study is a single-arm, two-stage phase II trial to estimate the CR rate post-ASCT in newly diagnosed MM (NDMM). Transplant eligible (TE) NDMM subjects who did not achieve at least a VGPR post initial IT are eligible for the trial. Enrollment will be planned post-induction and before HPC mobilization. Subjects will receive four weekly doses of Dara prior to HPC mobilization, then another four weekly doses of Dara after HPC engraftment post-ASCT. The primary objective is to evaluate the ≥ CR rate post-ASCT in NDMM subjects who did not achieve at least a VGPR post-induction. The secondary objectives are to estimate: ≥VGPR rate, time to first response (TTFR), time to best response (TTBR), duration of response (DoR), PFS, time to progression (TTP), time to next treatment (TTNT), and OS. Also, the study will evaluate toxicities related to Dara and ASCT outcomes (HPC collection and engraftment parameters). The exploratory objectives are to explore: MRD rates of bone marrow and HPC product using Euro-flow criteria and DNA-PCR.The correlation between systemic immune profiling and the clinical response using cytokine profiling by multiplex protein assay and Blood immunotyping [including NK, NK-T, and T cell subsets distribution and activation analyses by flow cytometry.The correlation between circulating T cell receptor (TCR) repertoire immuno-sequencing by next-generation sequencing (NGS) with clinical response parameters.The changes in BM and BM plasma cells' biology before and after treatment by Whole Exome Sequencing, andThe correlation between PET/CT responses and endpoint. The main eligibility criteria are age ≥ 18 years, ECOG PS 0-2, measurable disease at the time of diagnosis, &lt; VGPR per IMWG 2016 criteria following a 3-drug IT regimen for TE-NDMM. However, patients must have achieved at least a minimal response, and treatment plan includes ASCT post-induction. Statistical methods: Post-ASCT ≥CR response is the primary endpoint for this study. For NDMM, standard therapy strategies provide ≥CR rates of approximately 50%. For this population of subjects treated with Dara-based in vivo purging, the aim is to achieve a post-ASCT ≥ CR rate of 70%. A minimax 2-stage design will be used to test the hypothesis that the ≥ CR rate post-ASCT is less than or equal to 50%. Twenty-three subjects will be enrolled in the first stage, and if at least 12 of the 23 subjects have ≥CR after ASCT, an additional 16 subjects will be enrolled (total of 39 subjects). If at least 24 of 39 subjects have ≥CR after ASCT, the null hypothesis will be rejected. Based on a one-sided, α = 0.10 significance level, this sample size will provide 90% power to reject the null, assuming the true ≥CR rate post-ASCT is 70%. The treatment schedule: Pre-mobilization Dara on days 1,8,15,22. Four weeks after the Day 22 dose of Dara, all subjects will undergo HPC mobilization with the hematopoietic growth factor G-CSF with or without the chemokine receptor type 4 (CXCR4) antagonist. Post-ASCT and after engraftment is complete, Dara will be restarted days +49, +56, +63, +70. ClinicalTrials.gov Identifier: NCT04230031 Figure 1 Disclosures Atrash: Amgen, GSK, Karyopharm.: Research Funding; Takeda, Amgen, Karyopharm, BMS, Sanofi, Cellactar, Janssen and Celgene: Honoraria; BMS, Jansen oncology, Sanofi: Speakers Bureau. Paul:Regeneron: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Other: Stock Ownership (prior employee). Symanowski:Casgen: Consultancy; Eli Lilly: Consultancy; Immatics: Consultancy; Novartis: Consultancy. Bhutani:Janssen: Other: Clinical Trial Funding to Institute; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; Prothena: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Takeda: Other: Clinical trial funding to institute, Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute. Voorhees:Bristol-Myers Squibb: Other: Personal fees; Celgene: Other: Personal fees; Janssen: Other: Personal fees; Novartis: Other: Personal fees; Oncopeptides: Other: Personal fees; TeneoBio: Other: Personal fees; Levine Cancer Institute, Atrium Health: Current Employment; Adaptive Biotechnologies: Other: Personal fees. Usmani:Merck: Consultancy, Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Research Funding; GSK: Consultancy, Research Funding; Celgene: Other; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Abbvie: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding.

Phase II Trial of Lenalidomide (Revlimid™) with Cyclophosphamide and Dexamethasone (RCd) for Newly Diagnosed Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 91-91 ◽  
Author(s):  
Shaji Kumar ◽  
Suzanne Hayman ◽  
Francis Buadi ◽  
Martha Lacy ◽  
Keith Stewart ◽  
...  
Keyword(s):  
Phase Ii ◽  
Low Dose ◽  
Phase Ii Trial ◽  
Initial Therapy ◽  
Phase Iii ◽  
M Protein ◽  
Hematological Toxicity ◽  
Newly Diagnosed ◽  
Intent To Treat ◽  
Dose Reductions

Abstract Background: The combination of lenalidomide and dexamethasone (RD) has been shown to be highly effective as initial therapy for multiple myeloma. More recently, a phase III trial demonstrated improved survival with use of lenalidomide and low dose dexamethasone (Rd). Further improvements by incorporating other active agents may increase the depth of response and may improve long-term outcome. We report the results from a phase II trial combining lenalidomide and low dose dexamethasone with cyclophosphamide (RCd) as initial therapy for newly diagnosed MM. Methods: The trial was initiated in July 2006 and completed the initial target accrual of 33 patients by July 2007 (Cohort 1). Due to high rate of dose reductions in cohort 1, between July 2007 and May 2008 an additional 20 patients were enrolled with lower doses of cyclophosphamide (Cohort 2). The treatment protocol consisted of lenalidomide given orally at a dose of 25 mg daily on days 1–21 of a 28-day cycle. Dex was given orally at a dose of 40 mg on days 1, 8, 15, and 22 of each cycle. Cyclophosphamide at a dose of 300 mg/m2 was given on days 1, 8, and 15 of each cycle in cohort 1 and 300 mg on days 1, 8, and 15 of each cycle in cohort 2. 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: 53 patients were enrolled. The median age was 64 years (range, 37–82). 14 patients (29%) had ISS stage III disease. The median number of cycles was 4 (range: 1 – 20). The best response based on all enrolled patients on an intent to treat basis was 83%, including CR:1 (2%), VGPR: 20 (38%), PR: 23 (43%), and less than PR: 9 (17%). The CR plus VGPR rate was 40%. Among the 20 patients in cohort 2 who were enrolled after optimization of the cyclophosphamide dosing, 16 (80%) have already achieved a partial response or better with 17 patients in this cohort still receiving study treatment. Overall, 25 of the 53 enrolled patients have discontinued study treatment. Reasons for ending treatment are: completed study per protocol (14), disease progression (5), adverse event (3) and alternate treatment (3). This includes 3 patients from cohort 2, one completed treatment per protocol, one went to alternate therapy and one patient went off for progression. Hematological toxicity was the most common with grade 4 toxicity seen in 8 patients (only 1 from cohort 2). Non-hematological toxicities included neuropathy, diarrhea, cystitis, and thrombosis. There were 6 patients with grade 4 non-hematological toxicities (none from cohort 2) attributed to the drug (thrombosis, confusion, depression and sepsis). Thirteen patients had dose adjustments, most commonly due to hematological toxicity attributed to lenalidomide or cyclophosphamide. One patient has died off study, of intracranial hemorrhage. The median follow-up for the remaining patients is 7.8 months. Conclusions: The combination of lenalidomide, cyclophosphamide, and dexamethasone (RCd) has excellent activity in the setting of newly diagnosed myeloma. Seventeen patients continue on study and the response rates are likely to be higher with additional followup. Myelosuppression was a significant toxicity leading to dose reductions and cycle delays, and is lower with decreased dose of CTX in cohort 2 without any apparent loss of responses.

Sign in / Sign up

Export Citation Format

Share Document