The MYRACLE protocol study: a multicentric observational prospective cohort study of patients with multiple myeloma.

BACKGROUND: Despite recent advances in the treatment of multiple myeloma, the disease constantly relapses and is still considered as incurable. The current knowledge about the biological mechanisms underlying resistance to the different class of drugs in multiple myeloma remains poor. The primary objective of the MYRACLE (Myeloma Resistance And Clonal Evolution) cohort, a multicenter prospective cohort of patients with multiple myeloma, is to address this limitation. We here describe the study background, design and methods used for this cohort. METHODS/DESIGN: All patients (> 18 year old) diagnosed with de novo or relapsed multiple myeloma and treated in two hematology department from west of France are included in the MYRACLE cohort. Patients provide a signed informed to be included in the study. All subjects are followed until refusal to participate in the study or death. The MYRACLE cohort prospectively collects data on socio-economic status, medical status, imaging, prognosis factors, MM therapies and associated events (resistance, safety issues). Patients also complete standardized quality of life questionnaires. In addition, bone marrow samples will be collected at time of diagnosis and relapses to perform biomarkers analysis and functional assays exploring mechanisms underlying drug resistance. DISCUSSION: The "real-life" MYRACLE cohort offers the opportunity to prospectively collect epidemiological, medical, QoL and biological data from MM patients during the course of the disease (at time of diagnosis and subsequent relapses). At mid-tem, this integrative cohort will be unique at producing a large variety of data that can be used to conceive the most effective personalized therapy for MM patients. Additionally, the MYRACLE cohort will allow integrating the medical care of MM patients in a health and pharmacoeconomic perspective.

Pomalidomide, cyclophosphamide, and dexamethasone for relapsed/refractory multiple myeloma patients in a real-life setting: a single-center retrospective study.

Pomalidomide dexamethasone is a standard of care for relapsed multiple myeloma (MM) patients who received at least two prior lines of therapy, including both lenalidomide and proteasome inhibitors (PI). We report here a real-life single-center series of 49 consecutive patients with relapsed and refractory MM treated with the triplet pomalidomide cyclophosphamide dexamethasone (PCD) combination. The median of prior lines of therapy was 3 and all patients were previously exposed to proteasome inhibitors and lenalidomide. The overall response rate was 76%, including 27% very good partial response or better. With a median follow-up of 16 months, the median progression-free survival (PFS) was 7.3 months and the median overall survival was not reached. Regarding safety, most frequent toxicity was hematologic, including 37% grade 3-4 cytopenias. Nine patients (18%) discontinued therapy due to adverse event. Our study confirms that PCD combination is feasible and results in favorable response rate and PFS in comparison with pomalidomide dexamethasone alone.

Single-agent daratumumab in very advanced relapsed and refractory multiple myeloma patients: a real-life single-center retrospective study.

The anti-CD38 monoclonal antibody daratumumab is approved as a single agent for the treatment of patients with relapsed and refractory multiple myeloma (RRMM) who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMID), or who are double refractory to a PI and an IMID. To date, no real-life data on the efficacy and tolerance of daratumumab in this setting are available. We report here the results of a single-center series of 41 RRMM patients treated with single-agent daratumumab outside clinical trials. Patients received a median number of 4 prior therapies. All patients were previously exposed to PI and IMID and all patients were refractory to the last line of therapy. Most patients presented with high-risk characteristics, including 24% adverse cytogenetics (del17p/t(4,14)), 31% extramedullary disease and 12% circulating plasmacytosis at time of daratumumab therapy. The overall response rate was 24%, including 5% very good partial response or better. After a median follow-up of 6.5 months, all patients experienced disease relapse. The median progression-free survival was 1.9 months. At the time of disease progression, 44% of patients did not receive subsequent therapy. The median overall survival was 6.5 months. No new safety signal was identified. These real-life results revealed modest efficacy of single-agent daratumumab in advanced patients with RRMM in comparison with data from clinical trials.

Poor outcome despite modern treatments: A retrospective study of 99 patients with primary and secondary plasma cell leukemia.

BACKGROUND: Plasma cell leukemia (PCL) is a rare monoclonal gammopathy, associated with short survival. Because of its very low incidence, only a few cohorts have been reported and thus, information on this disease is scarce. The goal of this study was to better understand the clinical features, prognostic factors, and efficacy of modern treatments in both primary PCL (pPCL) and secondary PCL (sPCL). METHODS: We performed a retrospective, multicenter study of patients diagnosed with PCL, defined as circulating plasma cells ≥20% of total leukocytes and/or ≥2 × 109/L. RESULTS: We identified 99 eligible PCL patients, of whom 33 were pPCL and 66 were sPCL. The median progression-free survival (PFS) to frontline treatment and overall survival (OS) were, respectively, 4.8 (95% CI, 0.4-9.2) and 18.3 months (95% CI, 0.0-39.0) for pPCL and 0.8 (95% CI, 0.5-1.1) and 1.2 months (95% CI, 0.9-1.5) for sPCL (both p < 0.001). We observed no improvement in OS over time (2005-2012 vs. 2013-2020, p = 0.629 for pPCL and p = 0.329 for sPCL). Finally, our data suggested that sPCL originates from a high-risk multiple myeloma (MM) population with a short OS (median 30.2 months), early relapse after stem cell transplant (median 11.9 months) and a high proportion of patients with multiple cytogenetic abnormalities (36% with ≥2 abnormalities). CONCLUSIONS: This study is one of the largest PCL cohorts reported. We are also the first to investigate characteristics of MM before its transformation into sPCL and demonstrate that high-risk biologic features already present at the time of MM diagnosis. Moreover, our data highlights the lack of improvement in PCL survival in recent years and the urgent need for better treatment options.

Update on elotuzumab for the treatment of relapsed/refractory multiple myeloma: patients' selection and perspective.

Monoclonal antibodies (mAbs) targeting antigens expressed by plasma cells demonstrated major clinical activity in multiple myeloma patients and therefore became a new major class of drug for these patients. Elotuzumab is a humanized mAb targeting the cell surface signaling lymphocytic activation molecule family member 7, a glycoprotein highly expressed on plasma cells, that is the second mAb approved for the treatment of myeloma patients. The mechanism of action of elotuzumab includes natural killer cell (NK) mediated antibody-dependent cellular cytotoxicity and direct activation of NK-cells. Elotuzumab has been approved in combination with lenalidomide and dexamethasone (Elo-Rd) and pomalidomide and dexamethasone (Elo-Pd) for the treatment of relapsed myeloma patients. The present review will focus on elotuzumab, providing a summary of the mechanism of action, efficacy and safety and taking into consideration patients' selection.