scholarly journals Management of multiple myeloma in the relapsed/refractory patient

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 508-517 ◽  
Author(s):  
Pieter Sonneveld
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Proteasome Inhibitor ◽  
Systematic Approach ◽  
Drug Combinations ◽  
New Drugs ◽  
Careful Evaluation ◽  
Prior Therapy ◽  
Relapsed Disease ◽  
The Right

Abstract The approach to the patient with relapsed or relapsed/refractory multiple myeloma requires a careful evaluation of the results of previous treatments, the toxicities associated with it, and an assessment of prognostic factors. The majority of patients will have received prior therapy with drug combinations, including a proteasome inhibitor and an immune-modulatory agent. It is the physician’s task to choose the right moment for the start of therapy and decide with the patient which goals need to be achieved. The choice of regimen is usually based on prior response, drugs already received, adverse effects, comorbidities of the patient, and expected efficacy and tolerability. Many double and triple drug combinations are available. In addition, promising new drugs such as pomalidomide, carfilzomib, and monoclonal antibodies are or will be available shortly, and other options can be explored in clinical trials. Finally, supportive care and palliative options need to be considered in later relapsed disease. Increasingly, it becomes important to consider the therapeutic options for the whole duration of the disease and integrate a systematic approach for the patient.

Minimal residual disease in multiple myeloma: an important tool in clinical trials

2021 ◽  
Vol 16 ◽  
Author(s):  
Alessandro Gozzetti ◽  
Monica Bocchia
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
New Drugs ◽  
Next Generation ◽  
Depth Of Response ◽  
Next Generation Sequencing Ngs ◽  
Future Therapy ◽  
Minimal Residual

: Minimal residual disease (MRD) detection represents a great advancement in multiple myeloma. New drugs are now available that increase depth of response. The International Myeloma Working Group recommends the use of next-generation flow cytometry (NGF) or next-generation sequencing (NGS) to search for MRD in clinical trials. Best sensitivity thresholds have to be confirmed, as well as timing to detect it. MRD has proven as the best prognosticator in many trials and promises to enter also in clinical practice to guide future therapy.

Global Approaches in Myeloma: Critical Trials That May Change Practice

2018 ◽  
pp. 656-661 ◽  
Author(s):  
Philippe Moreau ◽  
Cyrille Touzeau
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Therapeutic Strategies ◽  
New Drugs ◽  
High Dose ◽  
High Dose Therapy ◽  
The Past ◽  
Induced Changes ◽  
The Impact ◽  
Specific Section

The treatment of multiple myeloma (MM) has changed dramatically in the past decade with the introduction of new drugs into therapeutic strategies both in the frontline and relapse settings. With the availability of at least six different classes of agents that can be combined in doublet, triplet, or even quadruplet regimens and used together with high-dose therapy and autologous stem cell transplantation, the choice of the optimal strategy at diagnosis and at relapse represents a challenge for physicians. Also problematic is the lack of trials addressing questions, such as sequencing or the duration of maintenance. This review will focus on the results of recent clinical trials both in the frontline and relapse settings that have induced changes in clinical practice and will discuss the impact of important ongoing trials. A specific section will discuss therapeutic strategies when new drugs are not available.

scholarly journals Recent advances in understanding multiple myeloma

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2053 ◽  
Author(s):  
Binod Dhakal ◽  
Saulius Girnius ◽  
Parameswaran Hari
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Single Agent ◽  
Progression Free Survival ◽  
Response Rates ◽  
New Drugs ◽  
High Dose ◽  
Disease Biology ◽  
Oral Agents ◽  
Ultra High Risk

There have been major recent advancements in the understanding and management of multiple myeloma. Diagnostic criteria have been revised and former ultra-high-risk smoldering multiple myeloma is now considered multiple myeloma in need of treatment. Understanding clonal progression, evolution, and tides not only has helped elucidate the disease behavior but might help expand therapeutic choices in order to select appropriate treatment for patients. Unprecedented response rates with modern triplet induction therapies containing proteasome inhibitor and immunomodulators have made this approach standard for initial treatment. The US Food and Drug Administration approved four new drugs (two targeted antibodies and two oral agents) in 2015 in relapsed/refractory multiple myeloma and these drugs along with the other already-available drugs have now increased the choices of regimens. Even drugs without single-agent activity, such as panobinostat and elotuzumab, have an important role, especially in the proteasome inhibitor refractory setting. Recent studies done in the context of novel agent induction suggest that high-dose therapy followed by autologous transplant continues to improve response rates and progression-free survival, thus underscoring their role in transplant-eligible patients. Evolving paradigms in the treatment of multiple myeloma include newer promising immune approaches, such as adoptive cellular therapies, vaccines, or antibody-based immune manipulations. Though multiple myeloma is still considered incurable, it is clear that with the improved understanding of disease biology and clonal architecture of relapse combined with the availability of multi-targeted approaches, we are ever closer to a lasting cure or transformation into indolent and long-lasting disease courses or both.

Evaluation of the Revised International Staging System (R-ISS) in an Independent Cohort of Unselected Patients with Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3045-3045
Author(s):  
Efstathios Kastritis ◽  
Evangelos Terpos ◽  
Maria Gavriatopoulou ◽  
Magdalini Migkou ◽  
Evangelos Eleutherakis-Papaiakovou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
High Risk ◽  
Board Of Directors ◽  
Staging System ◽  
New Drugs ◽  
Primary Therapy ◽  
Advisory Committees ◽  
International Staging System ◽  
Independent Cohort

Abstract The International Staging System (ISS), which is based on beta2-microblobulin (β2M) and serum albumin, has been widely used for the risk stratification of multiple myeloma (MM) patients, since 2003. Chromosomal abnormalities (CA) detected by iFISH have been also recognized as strong prognostic factors, while elevated serum lactate dehydrogenase (LDH) has been consistently associated with poor prognosis. In order to improve the prognostic power of ISS, IMWG has revised ISS (R-ISS) by adding high risk cytogenetics by iFISH and serum LDH: R-ISS-1 includes patients with ISS-1 (serum β2M level <3.5 mg/L and serum albumin level ≥3.5 g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)] and normal LDH levels (below the upper limit of normal (UNL)); R-ISS-3 includes patients with ISS-3 (serum β2M level >5.5 mg/L) and either high-risk CA or high LDH level; and R-ISS-2 includes all the other possible combinations. R-ISS was based on the data of 3,060 patients who had participated in clinical trials. However, it has not been validated in an independent cohort of unselected patients. Our aim was to evaluate R-ISS in consecutive, unselected patients, treated in a single center. Our study included 475 patients with available data for cytogenetics [t(4;14) and del17p by iFISH], LDH and ISS. Median age was 67 years (range 27-91); 53% were >65 years and 25% >75 years of age. Only 8.6% did not receive new drugs as primary therapy; 42% received IMiDs (19% thalidomide-based, 23% lenalidomide-based) and 49% bortezomib-based primary therapy, while 36% received ASCT. In the IMWG cohort, 65% had received ASCT, 6% no new drugs, 44% proteasome inhibitors and 66% IMiDs. Per ISS, 24% were ISS-1, 34% ISS-2 and 42% ISS-3. High risk cytogenetics (either t(4;14) or del17p) were present in 23.5% and elevated LDH in 15%. In the IMWG cohort used for the formulation of R-ISS, 38% were ISS-1, 38% ISS-2 and 24% ISS-3; thus, our patients had more often ISS-3 and less often ISS-1 disease. High risk CAs and elevated LDH were not different compared to our cohort of patients (24% and 13%, respectively). The difference in ISS disposition between the two cohorts probably reflects the unselected nature of our population, which also included patients with severe renal impairment who often are excluded from clinical trials. Per R-ISS, 85 (18%) patients had R-ISS-1, 83 (17.5%) had R-ISS-3 and 306 (64.5%) had R-ISS-2. The disposition in the original cohort was 28% for R-ISS-1, 62% for R-ISS-2 and 10% for R-ISS-3. This difference was due to the higher proportion of patients with ISS-3 disease in our cohort. The R-ISS disposition in those ≤65 years, was 21%, 60% and 19% for R-ISS-1, -2 and -3; among patients 66-75 years it was 19%, 63% and 18%, and among those >75 years it was 11%, 74% and 15%, respectively (p=0.128). The median follow up was 40 months; 57% of patients progressed or died and 63% have remained alive. Median PFS was 27 months and estimated median OS was 63 months. Median PFS for R-ISS-1, -2 and -3 was 34, 28 and 17 months, respectively (p<0.001). According to R-ISS, the probability of 3-year OS was 83%, 69% and 45% and of 5-year OS 77%, 53% and 19% for R-ISS-1, -2 and -3, respectively (p<0.001). In patients treated with ASCT, the probability for 5-year OS per R-ISS stage was 93%, 77% and 32%, respectively (p<0.001), while for patients not treated with HDM it was 64%, 41% and 13% (p<0.001). The probability for 5-year OS for patients treated with bortezomib was 95%, 69% and 18% for R-ISS-1, -2 and -3 (p<0.001) and for those treated with IMiDs, it was 68%, 41% and 23%, respectively (p=0.002). We evaluated the performance of R-ISS in patients ≤65, 66-75 and >75 years. In patients ≤65 years, the probability for 5-year OS was 84%, 71% and 29%, for R-ISS-1, -2 and -3 (p<0.001); for patients 66-75 years, it was 73%, 43% and 18% (p=0.001), while in patients >75 years, the median OS was >5 years, 35 and 29 month, respectively (p=0.122). Thus, R-ISS identified a group of patients >75 with favorable prognosis, although there was no significant difference in the OS for R-ISS-2 vs -3, probably due to the impact of other comorbidities and performance status of the very elderly. In conclusion, our data in consecutive, unselected patients, with differences in the characteristics and treatment approaches compared to the original IMWG cohort, verified that R-ISS provides significant prognostic information and it allows the identification of three different patient groups with clearly different outcome. Disclosures Terpos: Novartis: Honoraria; Celgene: Honoraria, Other: travel expenses; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Novartis: Honoraria; Celgene: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria.

scholarly journals Identification of Novel Therapeutic Targets in the Clinically Predictive Vk*MYC Mouse Model of Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 415-415 ◽  
Author(s):  
Marta Chesi ◽  
Victoria Garbitt ◽  
P. Leif Bergsagel
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Mouse Model ◽  
Nuclear Export ◽  
Research Funding ◽  
Histone Deacetylase Inhibitors ◽  
Single Agent ◽  
New Drugs ◽  
Common Mutation ◽  
Activating Mutations

Abstract A genetic rearrangement of the MYC locus, resulting in dysregulated expression of MYC, is the most common mutation in human multiple myeloma (MM). The genetically engineered Vk*MYC mouse model is based on dysregulation of MYC, and has been extensively validated as a clinically and biologically faithful model of untreated MM. We previously reported 9 drugs or classes of drugs (DNA alkylators, glucocorticoids, proteasome inhibitors, IMiDs, nab-paclitaxel, histone deacetylase inhibitors, TACI-Ig, perifosine and SNS-032, a CDK2,7,9 inhibitor) with more than 20% partial response (PR) rate in Vk*MYC MM. Among those, the first 5 also have more than 20% PR in patients with MM for a positive predictive value of 56%. Although the HDACi did not show single agent activity in relapsed/refractory MM patients, the PANORAMA phase 3 study of panobinostat in combination with bor+dex has shown superior PFS compared to bor+dex, suggesting the possibility that HDACi may have shown single agent activity if tested in a less advanced clinical setting. In contrast, 11/12 drugs that have less than 20% PR in Vk*MYC MM also have less than 20% PR in patients with MM for a NPV of 92%. Confident that drugs with activity in Vk*MYC mice will likely be effective in the treatment of MM, we have used this model to study novel drugs for prioritization in clinical trials. Pim kinases are constitutively active serine/threonine kinases identified using retroviral mutagenesis as potent suppressors of MYC induced apoptosis and can be inhibited by the pan-PIM kinase inhibitor LGH447. KPT-276 is a selective inhibitor of nuclear export CRM1/XPO1 inhibitor. Both drugs are active in Vk*MYC MM and are showing early evidence of promising clinical activity, increasing the PPV of the Vk*MYC model of MM to 64% (or 73% if HDACi are considered clinically active). Also active in the Vk*MYC model were the bromodomain inhibitors GSK I-BET151, CPI-203, CPI-456, OTX-015, which, like JQ1, compete with acetylated histones for the binding to BRD4, inhibiting super-enhancer activity and MYC transcription. The histone methyltransferase enhancer of Zeste homolog 2 (EZH2) induces transcriptional repression through histone H3 lysine 27 trimethylation (H3K27me3) at the promoter of silenced genes. Activating mutations in the SET domain of EZH2 are prevalent in germinal center DLBCL and follicular lymphoma but have not been identified in MM, where the frequent dysregulation of MMSET by t(4;14) translocation or biallelic deletion of UTX are thought to play a tumorigenic role equivalent to EZH2 activation. EZH2 inhibitors have demonstrated activity against lymphoma with EZH2 activating mutations. Interestingly, we found the EZH2 inhibitor CPI-169 active against Vk*MYC MM, identifying EZH2 as a promising new epigenetic target in MM. EDO-S101 is a novel drug resulting from the fusion of a molecule of bendamustine with a molecule of vorinostat, with the aim of increasing the efficacy of the alkylator through the HDACi-mediated chromatin relaxation that would make DNA more accessible to the damaging effect of bendamustine. It induced a high rate of response in Vk*MYC MM that was sustained for more than 3 months in mice receiving only 2 doses, one week apart. Remarkably EDO-S101 is the only drug we have identified with single agent activity in the very aggressive, multi-drug resistant Vk12653 transplant model of relapsed/refractory MM. Finally, 2 agents (anti-murine PD-L1 and LCL161) that primarily modulate the immune microenvironment, with little to no direct anti-MM activity, also induced responses. Anti-PD-L1 blocks immunosuppressive signaling from MM cells to PD1 on T cells. LCL161 is an IAP antagonist that leads to constitutive activation of the alternative NFkB pathway with direct stimulation of the innate and adaptive immune systems. Although antibodies to CD38 are among the most exciting new agents for the treatment of MM, they cannot be evaluated in Vk*MYC MM since murine normal or malignant plasma cells do not express CD38. In contrast while SLAMF7 is expressed in Vk*MYC MM, there is no murine equivalent of elotuzumab. In summary, we report 7 new drugs with single agent activity in Vk*MYC MM, nearly doubling the number of drugs or classes of drugs with promising anti-MM activity. Two (LGH447 and KPT-330) are already beginning to demonstrate clinical efficacy in MM. All of these agents should be prioritized for rapid evaluation in clinical trials of patients with MM. Disclosures Bergsagel: Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding.

scholarly journals Antibody Based Three-Drug Regimens for Multiple Myeloma - a Systematic Review of Phase II and Phase III Clinical Trials

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5546-5546
Author(s):  
Arafat Ali Farooqui ◽  
Humaira Sarfraz ◽  
Zunairah Shah ◽  
Muhammad Saad Farooqi ◽  
Maimoona Khan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Partial Response ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Residual Disease ◽  
Drug Regimen ◽  
Drug Combinations ◽  
Phase Iii ◽  
Myeloma Cells

Introduction Elotuzumab is monoclonal antibody (mAb) that specifically targets signaling lymphocytic activation molecule family member 7 (SLAMF7) that is present on myeloma cells. It fights myeloma cells by stimulating phagocytic action of NK cells and via ADCC (antibody‐dependent cell‐mediated cytotoxicity) pathway. Daratumumab is an anti-CD38 mAb with dual mechanisms of action i.e. tumoricidal and immunomodulation. The aim of this study is to review the efficacy and toxicity of elotuzumab and daratumumab based 3-drug combinations in patients (pts) with multiple myeloma (MM). Methods A systematic search of PubMed, Embase, Clinicaltrials.gov, Cochrane and Web of Science was performed for elotuzumab and daratumumab based regimen in MM patients from inception to June 12, 2019. Out of 604 studies, 08 phase II and III clinical trials based on 3-drug regimen were finalized. Results Total 2809 patients (pts) were evaluated out of 2879 enrolled pts. 856 were newly diagnosed (ND) and 1953 were relapsed/refractory (R/R). Elotuzumab (E) based 3-drug regimen were evaluated in 560 whereas daratumumab (D) based 3-drug regimen were analyzed in 889 pts. ELOQUENT-3 trial (n=117) in phase II used E + pomalidomide (P) and dexamethasone (d) (EPd) for R/R pts with ≥2 prior therapies. Median (m) progression free survival (PFS) was 10.2 months (mo) in EPd versus (vs) 4.6 mo in Pd arm [Hazard ratio (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 (overall response rate) was 53% (complete response [CR] 5% + stringent CR [sCR] 3% + partial response [PR] 33% + very good partial response [VGPR] 12%) in EPd vs 26% in Pd arm (odds ratio [OR]: 3.25 (1.49-7.11). Grade (G) ≥3 adverse events (AEs) were anemia (10%), neutropenia and infections (13% each). (Dimopoulos et al. 2018). Phase II trial by Jakubowiak et al. (2016) observed 1 year (y) PFS of 39% in E-Bortezomib(B)-d vs 33% in Bd arm in 152 R/R pts (HR: 0.72; p = .09) with 28% decrease in progression or death with EBd vs Bd. 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). In phase II trial, ELd (E-Lenalidomide-d) arm yielded ORR of 88% (CR 3% + sCR 5% + PR 43% + VGPR 38%) vs 74% in Ld arm in 82 ND pts. PFS at 1 yr was 93% vs 91%. G≥3 AEs included neutropenia (18%) and leukopenia (15%). (Takezako et al. 2017). Berenson et al. (2017) in phase II trial (n=70) studied G≥3 infusion reactions (IRs) using ELd in ND and R/R pts. ORR was 70% (CR 6% + VGPR 27% + PR 37%). G3 AEs included anemia in 10% pts (no G3 IRs). ELOQUENT-2 trial randomized 646 R/R pts in phase III. PFS at 4 y is 21% vs 14% (HR: 0.71, 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; 0.62-0.95; p = 0.0176. OS at 4 y was 50% vs 43% (HR: 0.78; 0.63-0.96). G≥3 AEs included lymphocytopenia (79%), neutropenia (36%), anemia (20%) and thrombocytopenia (21%). (Dimopoulos et al, 2018). POLLUX trial used daratumumab (D)-Ld regimen in 569 R/R patients in phase III. PFS at 3 y was 55% vs 27% (DLd vs Ld) in pts with 1-3 prior therapies. With 56% CR and 80% VGPR; ORR was 93% vs 76%. DLd arm achieved 30% minimal residual disease (MRD)-negative status compared to 5% in Ld arm (p<0.001). OS at 3-yr was 34% vs 42%. G≥3 AEs were neutropenia (55%), anemia (18%), thrombocytopenia (15%) and pneumonia (14%). (Bahlis et al. 2018). CASTOR trial in phase III (n=498) showed 18-mo PFS of 48% vs 7.9% in DBd vs Bd arm in R/R pts (HR: 0.31 (0.24-0.39); p<0.0001). ORR was 83.8% (CR 28.8%+ sCR 8.8% + VGPR 62.1%) vs 63.2% (p<0.001). DBd-treatment led to 11.6% MRD-negative status vs 2.4% in Bd-treated pts (p=0.000034). Thrombocytopenia (45.7%), anemia (15.2%) and neutropenia (13.6%) were G≥3 AEs. (Spencer et al. 2018). A Phase III trial (n=737) observed 30 mo PFS of (66 vs 52) % in ≥75 y old pts [HR 0.63 (0.44-0.92)] with DLd vs Ld arms in ND transplant ineligible pts with ORR of (90 vs 81) % (≥CR 41% + ≥VGPR 77%). MRD- negative rate was (19 vs 8) % in DLd vs Ld arms respectively. G≥3 AEs were neutropenia (60%), lymphopenia (19%), anemia (16%), pneumonia (15%) and leukopenia (12%). <75 y old showed ORR of (95 vs 82) % with 30 mo PFS of (75 vs 58) % in both arms. (Usmani et al 2019). Conclusion: Elotuzumab and daratumumab based 3-drug combinations showing great improvements in ORR, PFS and OS of ND and RR MM patients with favorable toxicity profile. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Choosing the Right Therapy for Patients with Relapsed/Refractory Multiple Myeloma (RRMM) in Consideration of Patient-, Disease- and Treatment-Related Factors

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4320
Author(s):  
Laura Gengenbach ◽  
Giulia Graziani ◽  
Heike Reinhardt ◽  
Amelie Rösner ◽  
Magdalena Braun ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Health Status ◽  
Treatment Options ◽  
Treatment Decision ◽  
Bone Lesions ◽  
Related Factors ◽  
Refractory Multiple Myeloma ◽  
Prior Therapy ◽  
Symptomatic Relapse ◽  
The Right

Treatment of relapsed/refractory multiple myeloma (RRMM) is more complex today due to the availability of novel therapeutic options, mostly applied as combination regimens. immunotherapy options have especially increased substantially, likewise the understanding that patient-, disease- and treatment-related factors should be considered at all stages of the disease. RRMM is based on definitions of the international myeloma working group (IMWG) and includes biochemical progression, such as paraprotein increase, or symptomatic relapse with CRAB criteria (hypercalcemia, renal impairment, anemia, bone lesions). When choosing RRMM-treatment, the biochemical markers for progression and severity of the disease, dynamic of disease relapse, type and number of prior therapy lines, including toxicity and underlying health status, need to be considered, and shared decision making should be pursued. Objectively characterizing health status via geriatric assessment (GA) at each multiple myeloma (MM) treatment decision point has been shown to be a better estimate than via age and comorbidities alone. The well-established national comprehensive cancer network, IMWG, European myeloma network and other national treatment algorithms consider these issues. Ideally, GA-based clinical trials should be supported in the future to choose wisely and efficaciously from available intervention and treatment options in often-older MM adults in order to further improve morbidity and mortality.

The HIV Protease Inhibitor Nelfinavir in Combination with Bortezomib and Dexamethasone (NVd) Has Excellent Activity in Patients with Advanced, Proteasome Inhibitor-Refractory Multiple Myeloma: A Multicenter Phase II Trial (SAKK 39/13)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 487-487 ◽  
Author(s):  
Christoph Driessen ◽  
Rouven Müller ◽  
Urban Novak ◽  
Nathan Cantoni ◽  
Daniel Betticher ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Proteasome Inhibitor ◽  
Poor Prognosis ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Hiv Protease ◽  
Refractory Multiple Myeloma ◽  
Prior Therapy ◽  
Multicenter Phase

Abstract Rationale: Proteasome inhibitor-refractory multiple myeloma (MM) patients are a difficult to treat population with a very poor prognosis. The activity of registered, current or next generation MM drugs (pomalidomide, carfilzomib, daratumumab) in heavily pretreated, proteasome inhibitor-refractory MM is in the range of 30%. The biology of proteasome inhibitor resistance is driven by adaptive downregulation of the unfolded protein response (UPR), which regulates plasma cell maturation and sensitivity to proteasome inhibitor treatment (Leung-HagesteijnC. et al., Cancer Cell 2013 Sep 9;24(3):289-304). The oral HIV protease inhibitor nelfinavir (NFV) has anti-MM activity in vivo, triggers UPR activation, sensitizes MM to proteasome inhibitors and overcomes proteasome inhibitor resistance in vitro. Combination therapy with NFV and bortezomib (BTZ) showed UPR activation in vivo and strong signals of activity in bortezomib-refractory MM in the SAKK 65/08 phase I trial (Driessen C. et al.,Haematologica 2016 Mar;101(3):346-55). Objective: We performed a prospective, multicenter phase II trial to assess the activity ofnelfinavir,bortezomiband dexamethasone (NVd) in proteasome inhibitor-refractory MM. Methods: Patients with progressing, measurable, proteasome inhibitor-refractory MM (IMWG criteria) were included in this multicenter phase II trial. Further selection criteria included WHO performance status ≤ 3, platelets ≥ 50 x 109/L, hemoglobin ≥ 80 g/L (both may be achieved by transfusion) and adequate hepatic function. Concomitant use of other anti-cancer medication or radiotherapy, except for local pain control, was excluded. Patient age or prior number or types of therapy were not limited. Simon's two stage design was used to differentiate a promising activity (best response at any time point, partial response (PR) or better, ≥ 35 %) from an uninteresting activity (≤ 15% PR; power 80%, alpha 5%). Results: 34 patients were treated with oral nelfinavir 2500 mg days 1-14 b.i.d. in combination with bortezomib + dexamethasone (BTZ 1.3 mg/m2 days 1, 4, 8, 11, dexamethasone 20 mg p.o. days 1-2, 4-5, 8-9, 11-12) for a maximum of 6 21-day cycles at 9 SAKK trial sites throughout Switzerland. Patients (median age 67.5 years, range 42-82 years) had a median of 5 (range 2-12) prior therapy lines, 26 (76%) patients had prior high dose chemotherapy, and 13 (39%) had known poor prognosis cytogenetic abnormalities. All treated patients had proteasome inhibitor refractory MM according to IMWG criteria, i.e. they had progressed during or within 60 days after adequately dosed proteasome inhibitor-containing therapy. Moreover, 26 (76%) patients werelenalidomide-refractory by IMWG criteria (double refractory). Trial therapy is still ongoing in 2 patients. The median number of treatment cycles delivered per patient is 4. 22 patients achieved an objective response with a PR or better, resulting in an overall response rate (OR) of 65% (90% CI 49.2%-75.7%) to date. VGPR was reached in 5 patients, PR in 17 patients, MR in 3 patients, SD in 4 patients and PD in 3. Inpatients double-refractory for proteasome inhibitors andlenalidomide, the OR was 69%, in patients with poor prognosis cytogenetic abnormalities it was 77%. The OR was independent from the number of prior therapy lines (OR rate 69% with < 5 prior therapy lines, OR rate 61% with ≥ 5 prior lines). Most frequent > grade (G) 2 adverse events to date were anemia (G3 29%), thrombocytopenia (G3 24%, G4 18%), infections (G3 24%, G4 9%, G5 3%), hyperglycemia (G3 18%, G4 3%) and fatigue (G3 12%). Six patients maintained their PR or better for the full 6 cycles per protocol while on study. Four patients continuedNVd therapy on a compassionate use basis after completing the study. Updated final data will be provided at the meeting. Conclusion: Nelfinavir in combination with bortezomib and dexamethasone (NVd) is a reasonable, active, safe and widely available treatment option for patients with proteasome inhibitor-refractory multiple myeloma. The objective response rate of 65% observed in this very advanced, heavily pretreated, mostly dual-refractory patient population is exceptional. Our results warrant further development of nelfinavir as a sensitizing drug for proteasome inhibitor-based treatments and promising new agent for MM therapy. Figure Maximum relative change in serum M-protein or serum free light chain concentration in individual evaluable patients. Figure. Maximum relative change in serum M-protein or serum free light chain concentration in individual evaluable patients. Disclosures Driessen: Mundipharma-EDO: Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy; janssen: Consultancy. Samaras:Celgene (Adboard, educational talk), Amgen (adboard), Takeda (Adboard), Roche (Adboard), Sanofi (Adboard), Novartis (Adboard): Consultancy, Honoraria. Zander:Bristol Myers, Celgene, Amgen, Mundipharma, Janssen-Cilag, Takeda Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Efficacy of Subcutaneous Bortezomib in the Management of Patients with Multiple Myeloma or Relapsed Mantle Cell Lymphoma

2014 ◽  
Vol 6 ◽  
pp. CMT.S9308 ◽  
Author(s):  
Klaus Podar
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Mantle Cell Lymphoma ◽  
Safety Profile ◽  
Cell Lymphoma ◽  
Drug Application ◽  
Local Tolerance ◽  
Prior Therapy ◽  
Mantle Cell ◽  
Remission Rates

The identification of the ubiquitin–proteasome system as a new therapeutic target has been one of the most recent successes in cancer treatment. The development and clinical approval of the first-in-class proteasome inhibitor, bortezomib has revolutionized the treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL). In MM, bortezomib is now integrated in induction, conditioning, consolidation, maintenance, and salvage treatment protocols. Bortezomib-based regimens provide high remission rates and confer significant survival advantage compared to conventional chemotherapy in both the bone marrow transplant and non-transplant setting. In MCL, overall response rates in patients who have received at least one prior therapy range from 30 to 45%, even in chemotherapy resistant patients. Clinical trials to further improve the sequencing of bortezomib-containing combination therapies are ongoing. Until recently, intravenous injection was the standard route of bortezomib administration. However, severe adverse side effects, peripheral neuropathy in particular, were observed in up to 16% of MM patients and up to 54% of MCL patients treated with intravenous bortezomib, with grade 3 and 4 in 11 and 12% of patients, respectively. Moreover, complete remission rates, if at all, are low and duration of response is short both in MM and MCL. These limitations may be overcome by changing the method of bortezomib administration as well as by rationally combining bortezomib with other therapeutic agents. Indeed, recent data demonstrate that subcutaneous bortezomib administration is non-inferior to intravenous administration, with an improved systemic safety profile, good local tolerance, and a more convenient route of administration. Based on these data, subcutaneous bortezomib injection was approved as a supplemental new drug application for all approved indications in MM and MCL after at least one prior therapy. More than 30 clinical trials in MM and MCL are currently ongoing to evaluate the efficacy and safety profile of subcutaneous bortezomib also in induction, maintenance, and salvage therapy.

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