Pembrolizumab in Combination with Pomalidomide and Dexamethasone (PEMBRO/POM/DEX) for Pomalidomide Exposed Relapsed or Refractory Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2119-2119 ◽  
Author(s):  
Lilly Wilson ◽  
Adam D. Cohen ◽  
Brendan M. Weiss ◽  
Dan T. Vogl ◽  
Alfred L. Garfall ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Renal Insufficiency ◽  
Patient Population ◽  
Research Funding ◽  
Alkylating Agents ◽  
Proteasome Inhibitors ◽  
High Dose ◽  
Infectious Colitis ◽  
Refractory Multiple Myeloma

Abstract Introduction: Modern therapy for multiple myeloma including generations of thalidomide analogues, proteasome inhibitors and alkylating agents has substantially improved the survival for this disease. Patients who have progressed through these agents have limited options and a very poor prognosis. Programmed death ligand 1 (PD-L1) is expressed by myeloma cells and associated cells in the microenvironment. Blockade of the PD1-PDL1 axis enhances anti-myeloma activity in pre-clinical models. Pembrolizumab, a monoclonal antibody that blocks PD1-PD-L1 signaling, has shown clinical activity when combined with pomalidomide and dexamethasone in pomalidomide naïve patients with relapsed or refractory multiple myeloma (Badros et al, ASH 2015). Here we report the clinical experience of a previously pomalidomide exposed patient population receiving PEMBRO/POM/DEX. Methods: We retrospectively analyzed the efficacy of PEMBRO/POM/DEX in 9 heavily, pre-treated pomalidomide exposed patients with relapsed or refractory multiple myeloma between February 2016 and July 2016. All patients had been treated with ≥ 5 prior lines of therapy, including proteasome inhibitors, immunomodulatory drugs, and alkylating agents including high dose melphalan and autologous stem cell transplantation. The PEMBRO/POM/DEX regimen included pembrolizumab 2 mg/kg administered intravenously over 30 minutes every 2 or 3 weeks with pomalidomide 4 mg (range 2-4 mg) orally daily 21/28 days and dexamethasone 40 mg (range 4-40 mg) weekly until evidence of progression (PD) or unacceptable toxicity. Adverse events were captured via chart review. Responses were assessed as per IMWG criteria. Results: The median age of the patients was 65 years (range 51-77) with 66% females. The patients had a median of 8 prior lines of therapy (range 5-14). The majority of subjects (78%) had cytogenetic abnormalities: 33% were gain of 1q21, 44% monosomy 17, and 11% t(11;14). Prior to therapy, 89% had significant anemia, 78% lytic bone lesions and 2 with significant renal insufficiency (creatinine 2.32 and 3.32 mg/dl respectively) though no one was on dialysis. Isotype included 5 IgA, 2 IgG, 2 lambda light chain. All patients progressed after prior lenalidomide and 8 of 9 patients progressed on previous pomalidomide the other one having stable disease. Patients received a median 3 cycles (range 2-7) of PEMBRO/POM/DEX, with modifications of pomalidomide and dexamethasone dosage dependent on toxicity. Seven patients received aspirin DVT prophylaxis. The overall response rate of PEMBRO/POM/DEX was 33%. Eighty-nine percent of patients achieved clinical benefit (3 PR, 2 MR, 3 SD). Median PFS was 57 days (0-85 days). There were no observed discontinuations of treatment or deaths attributed to drug toxicity and no pneumonitis was seen. However, adverse events consistent with previous reports from pembrolizumab as well as pomalidomide and dexamethasone were observed across all 9 patients. These AEs included: fatigue (n=9), anemia (n=9), thrombocytopenia (n=7), neutropenia (n=5), diarrhea (n=5), fevers (n= 4), shortness of breath (n=4), lower extremity edema (n=4), nausea/ vomiting (n=3), and renal insufficiency (n=3). Two patients experienced non-infectious colitis that responded to prednisone. Overall survival at 6 months for the 9 patients was 56%. 4 patients have died from progressive disease. Conclusion: PEMBRO/POM/DEX is an active regimen for relapsed and refractory multiple myeloma with acceptable toxicity even in a heavily treated pomalidomide exposed patient population. Further investigation of this combination earlier in the course of the disease is warranted. Disclosures Cohen: Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy, Research Funding. Weiss:Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy; Prothena: Other: Travel, accommodations, Research Funding; Millennium: Consultancy, Other: Travel, accommodations; GlaxoSmithKline: Consultancy. Vogl:Constellation: Research Funding; Karyopharm: Consultancy; Teva: Consultancy; Calithera: Research Funding; GSK: Research Funding; Acetylon: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy. Garfall:Medimmune: Consultancy; Bioinvent: Research Funding; Novartis: Consultancy, Research Funding. Mangan:Novartis: Speakers Bureau. Stadtmauer:Janssen: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Teva: Consultancy.

Comparison of Two Alkylating Agents Among Refractory Multiple Myeloma: Published and Our Retrospective Bendamustine Combination Experience with Melflufen As Single Agent

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-14
Author(s):  
Ekin Kircali ◽  
Guldane Cengiz ◽  
Sevgi Çolak ◽  
Mehmet Gunduz ◽  
Pinar Ataca Atilla ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Research Funding ◽  
Alkylating Agents ◽  
Phase 1 ◽  
Single Agent ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Refractory Multiple Myeloma ◽  
Support Research

Introduction: Bendamustine is a synthetic alkylating agent made of both mustard and benzimidazole groups. It is used mainly in myeloma patients who have run out of classical treatment options and yet, have eligible performance status. Although data is still accumulating, there is not enough information to recommend a certain standard bendamustine dose or regimen in multiple myeloma. Melflufen is also an alkylator that is activated once metabolized by peptidases [1]. The logic this molecule selects and exterminates myeloma tumor cells by is that, myeloma cells overexpress aminopeptidases. Here, we have compared our and published bendamustine combination with melfufen data. Methods: We retrospectively analyzed our relapsed or refractory multiple myeloma patients who received bendamustine between 2002 and 2020 at Ankara University Medical School. All statistical analyses were performed via SPSS statistics version 20.0 software. After Pubmed search, all published bendamustine combination and melflufen clinical data among relapse refractory myeloma patients were included in the analysis. Results: Female/ male ratio was 14/ 18 (43.7 % / 56.3 %). Median age was 62 (36- 77) years. 22 (68.7 %) patients had Ig G myeloma, 6 (18.7 %) had Ig A myeloma and 4 (12.6 %) had light chain myeloma. ISS scores were as follows: I/ II/ III: 8 (25 %)/ 17 (53.1 %)/ 7 (21.9 %). FISH defined cytogenetics were available for 18 patients; 8 of them had normal chromosome analysis, 3 had only del13q, 1 had tri7. High risk cytogenetics was observed among 6 (33.3 %). R-ISS scores were as follows: I/ II/ III: 4 (22.2 %)/ 12 (66.7 %)/ 2 (11.1 %). Median prior lines of therapy was 3 (1- 6). 30 (93.8 %) patients had a history of bortezomib, 21 (65.6 %) had lenalidomide, 9 (28.1 %) had thalidomide. 21 (65.6 %) patients had undergone high-dose chemotherapy supported by autologous stem cell transplantation before bendamustine. 15 (46.9 %) patients were in treatment- refractory status at bendamustin initiation while 17 (53.1 %) used it for disease progression. Bendamustin was given either with Dexa (n= 13, 40.6 %) Bortezomib+ Dexa (n=6, 18.8 %), Lenalidomide+ Dexa (n=6, 18.8 %), Pomalidomide+ Dexa (n=5, 15.6 %) or Thalidomide+ Dexa (n= 2, 6.3 %). Bendamustine dose was 100- 120 mg/ m2/ day, 2 days monthly. 32 patients were followed up for median 26 months. Response to bendamustine treatment were as follows: Complete remission 4 (12.5 %), very good partial response 12 (37.5 %), partial response 8 (25 %), unresponsive 8 (25 %). Median progression free survival (PFS) was 5.6 (1- 40.6) months and overall survival (OS) was 17.3 (2- 79) months with bendamustine based treatment protocols. 15 (46.9 %) patients suffered grade ≥3 myelosuppression. Febrile neutropenia was experienced by 7 (21.9 %) patients, and 6 (18.7 %) had CMV reactivation during bendamustine treatment. There was no drug related mortality. Conclusion: Although bendamustine is effective among highly refractory myeloma patients, toxicity profile and immune plus myelosuppression prevents long term use. Bendamustine in our experience in combination has provided efficacy comparable to earlier publications. Current single agent Melflufen data in advanced stages may be even more promising if combined with proteasome inhibitors or IMIDs. References 1. Richardson, P.G., et al., Melflufen plus dexamethasone in relapsed and refractory multiple myeloma (O-12-M1): a multicentre, international, open-label, phase 1-2 study. The Lancet Haematology, 2020. 2. Knop, S., et al., The efficacy and toxicity of bendamustine in recurrent multiple myeloma after high-dose chemotherapy. haematologica, 2005. 90(9): p. 1287-1288. 3. Grey-Davies, E., et al., Bendamustine, thalidomide and dexamethasone is an effective salvage regimen for advanced stage multiple myeloma. British journal of haematology, 2012. 156(4): p. 552-555. 4. Damaj, G., et al., Efficacy of bendamustine in relapsed/refractory myeloma patients: results from the French compassionate use program. Leukemia & lymphoma, 2012. 53(4): p. 632-634. 5. Ludwig, H., et al., Bendamustine-bortezomib-dexamethasone is an active and well-tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood, The Journal of the American Society of Hematology, 2014. 123(7): p. 985-991. Disclosures Ozcan: Abdi Ibrahim: Other; Archigen Biotech: Research Funding; Amgen: Honoraria, Other: Travel support; Bristol Myers Squibb: Other: Travel support; Jazz Pharmaceuticals: Other; Sanofi: Other; F. Hoffmann-La Roche Ltd: Other: Travel support, Research Funding; Celgene: Research Funding; MSD: Research Funding; Janssen: Other: Travel support, Research Funding; AbbVie: Other: Travel support, Research Funding; Bayer: Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding.

scholarly journals Novel Non-Immunologic Agents for Relapsed and Refractory Multiple Myeloma: A Review Article

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5210
Author(s):  
Arthur Bobin ◽  
Cécile Gruchet ◽  
Stéphanie Guidez ◽  
Hélène Gardeney ◽  
Laly Nsiala Makunza ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Alkylating Agents ◽  
Treatment Options ◽  
Hdac Inhibitors ◽  
Proteasome Inhibitors ◽  
Curative Therapy ◽  
Refractory Multiple Myeloma ◽  
Novel Treatments ◽  
Treatment Regimens ◽  
Drug Classes

Novel treatments are needed to address the lack of options for patients with relapsed or refractory multiple myeloma. Even though immunotherapy-based treatments have revolutionized the field in recent years, offering new opportunities for patients, there is still no curative therapy. Thus, non-immunologic agents, which have proven effective for decades, are still central to the treatment of multiple myeloma, especially for advanced disease. Building on their efficacy in myeloma, the development of proteasome inhibitors and immunomodulatory drugs has been pursued, and has led to the emergence of a novel generation of agents (e.g., carfilzomib, ixazomib, pomalidomide). The use of alkylating agents is decreasing in most treatment regimens, but melflufen, a peptide-conjugated alkylator with a completely new mechanism of action, offers interesting opportunities. Moreover, with the identification of novel targets, new drug classes have entered the myeloma armamentarium, such as XPO1 inhibitors (selinexor), HDAC inhibitors (panobinostat), and anti-BCL-2 agents (venetoclax). New pathways are still being explored, especially the possibility of a mutation-driven strategy, as biomarkers and targeted treatments are increasing. Though multiple myeloma is still considered incurable, the treatment options are expanding and are progressively becoming more diverse, largely because of the continuous development of non-immunologic agents.

An Open-Label Phase I Study of the Safety and Efficacy of RAD001 in Combination with Lenalidomide in the Treatment of Patients with Relapsed and Relapsed/Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3856-3856 ◽  
Author(s):  
Noopur Raje ◽  
Paul Richardson ◽  
Parameswaran N Hari ◽  
Anuj Mahindra ◽  
Sarah Kaster ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Oral Steroid ◽  
High Dose ◽  
Advisory Committees ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 3856 Poster Board III-792 Background Lenalidomide (Revlimid®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (MM) patients following ≥1 prior therapy. mTOR inhibitor RAD001 has been studied as a single agent in MM, and although well tolerated, did not have single agent activity. Given the increased toxicity noted with pulsed high dose steroids, we sought to study a non-steroid containing oral regimen for the treatment of relapsed MM predicated upon our previous studies which demonstrated synergistic anti-MM activity of mTOR inhibitors when combined with len. Here, we extended our in vitro observations to a phase I clinical trial combining RAD001 with len in patients with relapsed or refractory MM. The primary objective was to assess toxicity of this combination and to determine the maximum tolerated dose (MTD). The secondary objective was to determine the activity of this combination. Methods Patients with relapsed and refractory MM were assigned to len and RAD001 to be taken for 21 days of a 28 day cycle. Dose escalation followed a modified Fibonacci design. Patients were allowed to continue therapy until disease progression or unacceptable toxicity. Patients received concomitant anti-thrombotic (aspirin 81 or 325 mg/day) therapy. Response was assessed according to modified EBMT and Uniform Criteria, and toxicities were assessed using NCI CTCAE v3.0. Results Eighteen MM patients have been enrolled to date. One patient in cohort 1 (Len: 10mg and RAD001: 5 mg x 21 days) developed grade 3 neutropenia requiring expansion of the cohort. Cohort 2 (Len: 15mg and RAD001: 5 mg x 21 days) also required expansion because of grade 4 thrombocytopenia noted in 1 patient. Dose limiting toxicities included grade 4 neutropenia and thrombocytopenia in 2/3 patients in cohort 3 (Len: 20mg and RAD001: 5 mg x 21 days). The MTD for patients with MM was therefore declared at 15 mg of len and 5mg of RAD001 for 21 days with a 7 day rest period. Apart from the hematological toxicities expected with the combination, patients otherwise tolerated the regimen well. Most common (≥10%) grade 1 / 2 events included nausea, fatigue, dyspnea, diarrhea, constipation, neuropathy and muscle cramps, all of which were manageable with supportive care. No thromboembolic events were noted. Grade 3 / 4 adverse events ≥ 5% included thrombocytopenia (11%) and neutropenia (22%). Fifteen patients have finished at least 2 cycles of therapy: 8 of 15 patients have either stable disease (SD: 1), minimal response (MR: 5) or a partial response (PR: 2), including 7 of 9 patients treated at the recommended MTD for an overall response rate (MR or better) of 50% (90% CI: [30.76%]). One patient with SD continued therapy for a total of 10 cycles, without significant toxicities. Conclusions The combination of Len plus RAD001 is a well tolerated regimen with predictable hematological toxicities. Promising responses were noted in this heavily pretreated patient population. This combination provides an oral steroid free combination alternative strategy which warrants future evaluation in phase II studies. Disclosures: Raje: Astrazeneca : Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: RAD001 not labelled for use in myeloma. Richardson:Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hari:Celgene: Research Funding, Speakers Bureau. Laubach:Novartis:. Ghobrial:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Adams:Novartis: Employment. Makrides:Celgene: Employment.

scholarly journals Lenalidomide Compared to Ixazomib Maintenance in Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3776-3776
Author(s):  
Eunice Lai ◽  
Yu Yang Soon ◽  
Ainsley Ryan Yan Bin Lee ◽  
Shi Yin Wong ◽  
Cinnie Yentia Soekojo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Meta Analysis ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Risk Of Bias ◽  
Newly Diagnosed ◽  
Maintenance Strategies

Abstract Background Maintenance therapy is considered a standard of care in transplant eligible (TE) and non transplant eligible (NTE) patients with newly diagnosed multiple myeloma (NDMM). While immunomodulators (IMID) and proteasome inhibitors (PI) have been proposed as maintenance therapy options, there are no randomised trials (RCTs) directly comparing these agents in the maintenance setting. The IMID lenalidomide (Len) and the PI ixazomib (Ixa) have been compared against placebo as maintenance strategies in NDMM. We present a network meta-analysis (NMA) of RCTs comparing the efficacy and safety of Len and Ixa maintenance therapies in NDMM. Methods We searched various biomedical databases for eligible studies evaluating Len or Ixa against placebo/ observation as maintenance therapy in patients with NDMM from date of inception through November 2020. The primary outcome was progression-free survival (PFS). Secondary outcomes include overall survival (OS) and adverse events (AE). The Cochrane risk of bias tool version 2.0 was used to assess trial quality. A Bayesian NMA model was used to assess the relative effects of competing treatments on PFS and OS outcomes. Adverse events were assessed using the synthesis without meta-analysis (SWIM) approach due to variability in the toxicity scoring criteria. The GRADE approach was used to rate the certainty of the evidence. This study is registered with PROSPERO, CRD42021226157. Results We identified eight studies including 3229 transplant eligible (TE) and 1689 non transplant eligible (NTE) patients. All studies were judged to have low risk of bias. Len but not Ixa was associated with statistically significant improvement in PFS when compared to placebo in TE (Len: Hazard Ratio (HR) 0.46, 95% Credible Interval (CrI) 0.35-0.56, high certainty; Ixa: HR 0.72, 95% CrI 0.46-1.13, moderate certainty) and NTE (Len: HR 0.46, 95% CrI 0.29-0.75, high certainty; Ixa: HR 0.69, 95% CrI 0.43-1.18, moderate certainty). Bayesian modelling demonstrated a 97% and 93% probability that Len resulted in superior PFS compared to Ixa in TE and NTE patients respectively. Both Len and Ixa were not associated with statistically significant improvement in OS compared to placebo in TE and NTE patients. There was no significant effect modification on the effect of Len vs placebo and Ixa vs placebo by cytogenetics status, use of proteasome inhibitors for induction or duration of maintenance therapies for PFS and/or OS outcomes. Len were judged to have a higher incidence of second malignancies and grade 3 or 4 neutropenia than Ixa while Ixa was judged to have a higher incidence of thrombocytopenia than Len. Conclusions Maintenance therapy with Len may provide a larger PFS benefit than Ixa regardless of type of induction therapy and cytogenetic risk in patients with NDDM. The differing toxicity profile of these agents is also an important consideration for treatment decisions. RCTs directly comparing these maintenance strategies are warranted. Figure 1 Figure 1. Disclosures Ooi: Jansen: Honoraria; Teva Pharmaceuticals: Honoraria; GSK: Honoraria; Abbvie: Honoraria; Amgen: Honoraria. Chng: Sanofi: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Amgen: Honoraria; BMS/Celgene: Honoraria, Research Funding; Johnson and Johnson: Honoraria, Research Funding; Pfizer: Honoraria.

Incidence and Characteristics of Secondary Myelodysplastic Syndrome Developing During Lenalidomide-Based Regimens In Relapsed and/or Refractory Multiple Myeloma Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1877-1877 ◽  
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Rashmi S. Goswami ◽  
Sharon Fung ◽  
David Barth ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Myelodysplastic Syndrome ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Alkylating Agents ◽  
Survival Rates ◽  
Myelogenous Leukemia ◽  
Cytotoxic Agents ◽  
High Dose ◽  
Secondary Myelodysplastic Syndrome

Abstract Abstract 1877 Secondary myelodysplastic syndrome and acute myelogenous leukemia (2° MDS/AML) are well-known complications that can occur after alkylating agent therapy for multiple myeloma (MM) or other cancers. However, until recently, the survival of MM pts was relatively short, a feature which may have contributed to a relatively low reported incidence of this complication in MM. The introduction of novel agents has improved survival rates of MM pts; lenalidomide (len) + dexamethasone–currently approved for MM after one prior therapy– is one of the main regimens that has contributed to this finding. Since alkylating agents—either given orally or as part of high-dose melphalan + ASCT—still remain an important component of myeloma therapy, more pts may survive to be at risk for 2° MDS/AML. Using the MM database at PMH, we retrospectively reviewed the charts of pts with relapsed/refractory (rel/ref) MM treated with len-based regimens to determine the incidence and characteristics of 2° MDS/AML that developed during this therapy. Between 06/2006—11/2009, 230 pts with rel/ref MM received ≥ 1 cycle of len + corticosteroids (195 pts), len alone (3 pts) or cyclophosphamide + len + prednisone (CPR) (32 pts). 2° MDS/AML developed in 6 (2.6%) at a median of 76 months (range 43–190) from the time of diagnosis of MM and 61 (21-168) months from the time of initiation of len regimens. The cytogenetic changes were variable, but 4 pts had deletions of all or part of chromosome 5. The characteristics of pts, at the time of starting len, in those who later developed (+) or did not develop (-) 2° MDS/AML during therapy, are shown in Table 1. The median number of len cycles given was 21 (9-35) versus 9 (1-50) and Grade 3–4 neutropenia occurred during len in 50% versus 54% in those with and without 2° MDS/AML, respectively. G-CSF was used in 50% of pts who developed MDS compared with 54% who did not. The cumulative incidence of 2° MDS/AML (95% CI) was 1% (0-5 %) at 1 yr, 3% (1-9 %) at 8 yrs and 7% (2-19 %) at 12 yrs from the time of diagnosis of MM, while the cumulative incidence was 1% (0-5 %) at 1 yr, 4% (1-9 %) at 2 yr and 9% (4-12%) at 3 yrs after commencing len-based regimens. We conclude: 1) pts developing MDS/AML while on len regimens were slightly older and had less often received prior ASCT, thalidomide and bortezomib; 2) the pattern of MDS development is consistent with the hypothesis that extensive exposure to cytotoxic agents, particularly oral alkylating agents (which had been given to 5/6 [83%] of affected pts), increases the risk of 2° MDS/AML; 3) although len is effective therapy in some pts with MDS, its use does not protect heavily pre-treated MM pts from this complication. Disclosures: Reece: Celgene: Honoraria, Research Funding. Off Label Use: Combination of lenalidomide and cylophosphamide plus prednisone in relapsed and refractory myeloma patients. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria. Trudel:Celgene: Honoraria.

Thalidomide Based Regimens for Treatment of Unfit Patients with Relapsed and Refractory Multiple Myeloma: a Monocentric Experience

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5048-5048
Author(s):  
Alessandro Moscetti ◽  
Francesca Saltarelli ◽  
Maria Paola Bianchi ◽  
Bruno Monarca ◽  
Giacinto La Verde
Keyword(s):  
Multiple Myeloma ◽  
Side Effects ◽  
Response Rate ◽  
Conflicts Of Interest ◽  
Therapeutic Option ◽  
Alkylating Agents ◽  
High Dose ◽  
Refractory Multiple Myeloma ◽  
Unfit Patients

Abstract Abstract 5048 Thalidomide, an immunomodulating drug with antiangiogenic activity, is an efficacious therapeutic option for unfit patients with multiple myeloma. Its efficacy may be increased by the addiction of steroids or other cytotoxic drugs such melphalan or cyclophosphamide. In this study we assessed the efficacy and toxicity of thalidomide based regimens as savage therapy in a series of elderly patients with relapsed/refractory multiple myeloma. Previous treatments included at least one therapy (range 1–4), such as high dose dexamethasone, alkylating agents, anthracyclines, IFN-α and autologous graft. Thalidomide 50–200 mg/die was administered orally in a total of 16 patients (median age 73.8 years, range 59–84) with relapsed/refractory multiple myeloma observed in our Hematology Department between May 2004 and January 2010. Oral dexamethasone or prednisone was added to the treatment. All patients continued therapy until relapse or progression and were prospectively followed-up including accurate monitoring of side effects. Response to thalidomide was assessed according to the European Group for Blood and Marrow Transplantation criteria. The median follow-up time was 25.6 months (range 8 – 68). Overall response rate was 81.2% (13/16 patients) with a median duration of response of 26.7 months (range 7 – 67): 3 patients showed a very good partial remission, 10 partial response, 1 stable disease and 2 progression of disease. During follow-up, 6 patients died (3 due to progression, 2 due to other neoplasm, 1 due to heart failure), 10 patients are still alive (2 VGPR and 7 PR in continuous therapy, 1 PD in third line therapy). No response was observed in 3/16 patients (18.7%). Despite the following side effects, mild to moderate bradycardia (25%, 1 needed PMK positioning and 1 dose reduction), peripheral sensitive polyneuropathy (18.7%) and constipation (6%), no patient discontinued therapy. This study shows that thalidomide based regimens are an effective therapy with a high response rate and manageable side effects when used in patient with multiple myeloma with relapsed/refractory disease. Disclosures: No relevant conflicts of interest to declare.

Phase II Study of Infusional Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 947-947 ◽  
Author(s):  
Nikoletta Lendvai ◽  
Heather Landau ◽  
Alexander Lesokhin ◽  
Ioanna Tsakos ◽  
Guenther Koehne ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Cell Transplant ◽  
Phase 2 ◽  
Advisory Committees ◽  
Refractory Multiple Myeloma ◽  
Higher Doses

Abstract Abstract 947 Background: Carfilzomib (CFZ) is a selective, irreversible epoxyketone inhibitor of the chymotrypsin-like activity of both the constitutive proteasome and the immunoproteasome. In patients with multiple myeloma single-agent CFZ is active and well tolerated at doses up to 27 mg/m2 when administered intravenously over 2–10 minutes. Based on preclinical safety data showing that a slower infusion was better tolerated and permitted administration of higher doses than a 2–10 minute infusion, the phase1b/2 PX-171-007 (NCT00531284) study evaluated the administration of CFZ as a 30-minute infusion. That study found the maximally tolerated dose of CFZ given as a 30 minutes infusion to be 56mg/m2. We designed a single institution, phase 2 study of high dose, infusional CFZ in patients with relapsed and/or refractory multiple myeloma. Methods: CFZ was given as a 30-minute IV infusion on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle1 Day1–2 doses were 20 mg/m2, followed by escalation to 56mg/m2. Dexamethasone 8 mg was given prior to infusion as premedication to mitigate infusion-related reactions. Patients who did not achieve a partial response (PR) after two cycles of CFZ or initially responded to single agent CFZ, but later showed evidence of progression of disease (POD) had dexamethasone (40mg/week) added to their regimen. Overall response rate (ORR; [sCR + CR + VGPR + PR]) was determined according to International Myeloma Working Group Uniform Response Criteria. Subjects were evaluated for adverse events according to the Common Terminology Criteria for Adverse Events v 4.0. Results: Thirty-four patients have been enrolled. Patients had received a median of 5 (range 1–11) prior treatment regimens and included 7 patients who relapsed following allogeneic stem cell transplant. Seventy eight percent of patients were bortezomib-refractory. ORR among patients who completed 4 cycles of therapy or experienced POD prior to completing 4 cycles of therapy was 58% with 1 CR, 7 VGPRs, and 6 PRs. ORR after 4 cycles of therapy was 57% in bortezomib-refractory patients. By intention to treat analysis the ORR in all comers was 50%. Median progression free survival was 4.6 months, median overall survival has not been reached with a median follow-up among survivors of 9.6 months (range: 0.3–14.3 months). The average time to best response was two cycles. Three out of the 11 patients that had dexamethasone 40mg/week added to their regimen obtained an improved response. Twelve patients (35%) were dose reduced. Treatment emergent, non-hematologic Grade 3/4 adverse events for which contribution of CFZ cannot be excluded were: HTN (n = 7), lung infection (n = 6), pulmonary edema (n = 3), reduced ejection fraction (n=1), sepsis (n=2), febrile neutropenia (n=1), bacteremia (n = 1), protothecosis (n = 1), fatigue (n=1), neuropathy (n=1), microangiopathic hemolytic anemia(n=1), nausea/vomiting/+/− diarrhea (n = 2), gastrointestinal bleed in the setting of Grade 4 thrombocytopenia (n = 1), hyperkalemia (n = 1). Conclusions: The 20/56 mg/m2 dose for CFZ administered as a 30-minute IV infusion was associated with 58% ORR, in a heavily pretreated patient population, including 21% of patients w/ prior allogeneic transplant, where the majority of patients were bortezomib-refractory. The ORR from this study is consistent with the one previously reported at the similar dose. Higher doses of carfilzomib continue to be explored in ongoing Phase 2 and Phase 3 studies. Disclosures: Landau: Onyx: Research Funding; Milleneum: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hassoun:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Giralt:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Milleneum: Membership on an entity's Board of Directors or advisory committees.

A Phase I Study of Ixazomib in Combination with Panobinostat and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4221-4221 ◽  
Author(s):  
Frederic J. Reu ◽  
Jason Valent ◽  
Ehsan Malek ◽  
Ronald M. Sobecks ◽  
Beth M Faiman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Response Criteria ◽  
Additional Patient ◽  
Cardiac Events ◽  
Minor Response ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Background: In a pivotal trial addition of panobinostat at 20mg three times a week, two weeks on, one week off, to bortezomib and dexamethasone increased progression-free survival of relapsed or relapsed and refractory multiple myeloma (MM) but clinically significant adverse events, including severe diarrhea and unexpected cardiac events limited enthusiasm. Here we describe safety and preliminary efficacy data for an all-oral regimen that uses ixazomib as proteasome inhibitor and every other week dosing of panobinostat. Methods: Two dose levels (DL) of ixazomib (3mg, 4mg) given on day 1, 8, 15 every 28 days were evaluated in combination with panobinostat 20mg on day 1, 3, 5, 15, 17, 19 and dexamethasone 20mg day 1, 2, 8, 9, 15, 16 using a classical 3 x 3 design. Inclusion criteria included at least two prior regimens, previous therapy with a proteasome inhibitor and IMiD, measurable disease according to uniform response criteria, and adequate organ function with QTcF < 450msec and estimated creatinine clearance of at least 30ml/min. Results: Eleven patients (pts) of median age 65 (range 50-73), all with MM refractory to their last regimen, were enrolled after a median of 5 prior regimens (range 2-10). Their disease was refractory to lennalidomide (n=11), bortezomib (n=10), proteasome inhibititor with IMiD (n=9), carfilzomib (n=7), and alkylating chemotherapy (n=7). The target dose level 2 was reached without dose limiting toxicity (DLT). Median time on therapy as of July 21, 2015 is 54 days (range 21-183) including three pts who remain on study. No serious adverse event was observed and no dose reductions of panobinostat or ixazomib were required. No non-hematologic CTCAE v. 4.03 grade 3/4 toxicities were seen but 3 pts developed grade 3 hematologic toxicities (2 neutropenia, 1 thrombocytopenia). Worst diarrhea was grade 1 (n=6), worst nausea grade 2 (n=1) and 4 additional pts developed transient grade 1 nausea. Other possibly panobinostat or ixazomib related grade 1/2 adverse events included thrombocytopenia (n=5), neutropenia (n=3), fatigue (n=2), anemia (n=2), anorexia (n=1) and arthralgia (n=1). Median QTcF before treatment start was 405 msec (range 378-430) and increased on average by 4.3% (maximally by 13%). One patient developed transient grade 1 QTcF prolongation to 552 msec. No other cardiac adverse events were observed. Best response according to uniform response criteria with adapted EBMT criteria for minor response (MR) was MR in 3 pts, of whom two had disease progressive on proteasome/IMiD combinations at study entry. One MR is ongoing; the other two each lasted 6 months. One additional patient had stable disease for 6 months. Conclusions: Addition of panobinostat at 20mg three times a week every other week to ixazomib at target 4mg weekly, three weeks on, one week off, with dexamethasone 20mg on the day of and after ixazomib was very well tolerated and demonstrated activity in extensively pretreated multiple myeloma patients with progressive disease on proteasome/IMiD combinations. We therefore propose this regimen for phase 2 evaluation. Disclosures Reu: Celgene: Research Funding; Takeda/Millennium: Research Funding; Novartis: Research Funding. Off Label Use: Panobinostat and Ixazomib combined in myeloma. Valent:Takeda/Millennium: Speakers Bureau; Celgene: Speakers Bureau. Faiman:Celgene: Consultancy, Speakers Bureau; Amgen/Onyx: Consultancy; Takeda/Millennium: Consultancy. Hamilton:Takeda/Millennium: Speakers Bureau. Smith:celegene, spectrum, genentech: Honoraria.

scholarly journals How I treat relapsed and/or refractory multiple myeloma

2020 ◽  
Vol 12 (s1) ◽  
Author(s):  
Hans C. Lee ◽  
Claudio Cerchione
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Export ◽  
Histone Deacetylase Inhibitors ◽  
Alkylating Agents ◽  
Treatment Options ◽  
Unmet Need ◽  
Proteasome Inhibitors ◽  
Antibody Drug Conjugate ◽  
Refractory Multiple Myeloma ◽  
Therapeutic Landscape

The expanding therapeutic landscape of relapsed and/or refractory multiple myeloma (RRMM) has contributed to significant improvements in patient outcomes. These have included combinations of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), histone deacetylase inhibitors, and/or alkylating agents. More recently, the approval of the first-in-class nuclear export inhibitor selinexor and the first-in-class B-cell maturation antigen (BCMA) antibody-drug conjugate (ADC) belantamab mafodotin has helped address the current unmet need in patients refractory to PI, IMiD, and anti-CD38 mAb directed therapy, otherwise known as triple class refractory myeloma. With the growing number of treatment options in the RRMM therapeutic landscape, the choice and sequencing of drugs and combinations has become increasingly complex. In this review we discuss our approach and considerations in the treatment of both early and late RRRM based on best available data and our clinical experience.

scholarly journals Lower Dose Lenalidomide and Dexamethasone for Patients with Relapsed/Refractory Multiple Myeloma Who Are Aged 60 Years or over and/or at Risk of Myelosuppression: Final Analysis of the Revlite Trial and Matched Comparison to the MM009 and MM010 Trials

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4236-4236 ◽  
Author(s):  
Hang Quach ◽  
Simon Harrison ◽  
Liam J. Fernyhough ◽  
Ross Alistair Henderson ◽  
Gillian Corbett ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Standard Dose ◽  
Survival Outcome ◽  
Phase Iii ◽  
High Dose ◽  
Matched Cohort ◽  
Pivotal Phase ◽  
Multicentre Phase ◽  
Refractory Multiple Myeloma

Abstract Background: The pivotal phase III MM009 and MM010 trials have established standard dose lenalidomide (len; 25mg daily, days 1-21 of 28 day cycle) and high-dose dexamethasone (dex; 40mg daily, days 1-4,9-12,17-20) [RD] as effective treatment for patients with relapsed/refractory multiple myeloma (RRMM). However, moderate toxicities were seen with RD that necessitated dose reduction in 76% and treatment cessation in 20% of patients. We prospectively investigated lower dose len-dex (rd) in a group of patients who were deemed at higher risk of myelosuppression and compared this to a matched cohort of patients who received RD in the MM009 and MM010 trials. Methods: RevLite was a multicentre phase II single-arm study across 12 centres in Australia and New Zealand of patients with RRMM, who were aged ≥60 years and/or with CrCL 20-59ml/min and/or platelets ≤75x109/L. Patients received rd (len 15mg daily, day 1-21 of a 28 day cycle and dex 20mg daily, days 1-4,9-12,17-20) until disease progression. The primary end point was overall response rate (ORR) and secondary endpoints were progression free survival (PFS) and adverse events (AE). A matched cohort of patients who received RD was extracted from the MM009/010 trials. Toxicities and survival outcome were compared between the cohort of patients receiving rd and RD. Results: A total of 149 patients (median age 69 years; male 60%) received rd in the RevLite trial. 65% of patients had prior thalidomide and 49% had at least 3 prior lines of treatment. ORR was 69.1% with CR 14.1%. With a median follow up of 28.4 months (0.2-63.5), median PFS was 8.9 months (95% confidence interval (CI): 6.9-11.5) and median OS was 30.5 months (20.0-36.2). Data of a total of 255 patients were extracted from the RD cohort in the MM009 and MM010 trials. Patients from the rd vs. RD cohort were similar in age, sex, ISS stage and CrCL. There was a higher prior exposure to thalidomide in the rd cohort (65% vs. 36% (RD)). ORR was similar between rd (69%; CR 14.1%) and RD (60%; CR 13.7%). No difference was seen in PFS (p=0.34) and OS (p=0.21). On multivariate analysis, after adjusting for other baseline prognostic factors, there was a trend for better OS with RD (HR 0.76 (95%CI 0.57-1.01), p=0.058). Grade 3-4 toxicities were lower with rd, mainly lower neutropenia (29 vs. 41%), infections (23.3 vs. 31.4%), and VTE (3 vs. 13%). Patients who were still on treatment after 3 years were on an average daily dose of 15mg in both groups. Conclusion: Lower dose len-dex is less toxic but remains efficacious in patients with RRMM who are at higher risk of myelosuppression. While this trial was not powered to detect non-inferiority of rd vs RD with respect to PFS and OS, rd was shown to induce a meaningful depth of response and PFS that was comparable to that seen with standard dose len-dex in patients who are aged ≥60 years and/or with renal impairment and/or with thrombocytopenia. These results reinforce the growing recognition of treatment attenuation in elderly or frail patients, and confirm that such practice with len-dex will not likely compromise patient response or survival outcome. Disclosures Quach: Celgene Corp, ONYX, Janssen, Takeda, Novartis, BMS: Honoraria, Research Funding. Harrison:Celgene: Honoraria, Research Funding. Li:Celgene Corp: Employment, Equity Ownership. Dimopoulos:Amgen: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Prince:Celgene Corp, Amgen, Janssen: Honoraria, Research Funding.

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