Clinical development of chimeric antigen receptor (CAR)-T-cell therapy has been enabled by advances in synthetic biology, genetic engineering, clinical-grade manufacturing, and complex logistics to distribute the drug product to treatment sites. A key ambition of the CARAMBA project is to provide clinical proof-of-concept for virus-free CAR gene transfer using advanced Sleeping Beauty (SB) transposon technology. SB transposition in CAR-T engineering is attractive due to the high rate of stable CAR gene transfer enabled by optimized hyperactive SB100X transposase and transposon combinations, encoded by mRNA and minicircle DNA, respectively, as preferred vector embodiments. This approach bears the potential to facilitate and expedite vector procurement, CAR-T manufacturing and distribution, and the promise to provide a safe, effective, and economically sustainable treatment. As an exemplary and novel target for SB-based CAR-T cells, the CARAMBA consortium has selected the SLAMF7 antigen in multiple myeloma. SLAMF7 CAR-T cells confer potent and consistent anti-myeloma activity in preclinical assays in vitro and in vivo. The CARAMBA clinical trial (Phase-I/IIA; EudraCT: 2019-001264-30) investigates the feasibility, safety, and anti-myeloma efficacy of autologous SLAMF7 CAR-T cells. CARAMBA is the first clinical trial with virus-free CAR-T cells in Europe, and the first clinical trial that uses advanced SB technology worldwide.

/pdf/caramba-a-first-in-human-clinical-trial-with-slamf7-car-t-2ib33tjyk5.pdf

CARAMBA: a first-in-human clinical trial with SLAMF7 CAR-T cells prepared by virus-free Sleeping Beauty gene transfer to treat multiple myeloma.

The current strategies for the treatment of multiple myeloma (MM) have improved, thanks to effective drug classes and combination therapies, for both the upfront and relapsed settings. Clinical trials for newly diagnosed transplant-ineligible patients led to the approval of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) in combination with anti-CD38 monoclonal antibodies (mAbs), to be administered during the induction phase before transplantation and during maintenance treatment, with lenalidomide recommended until relapse. In relapsed/refractory patients, the complex treatment scenario currently includes several options, such as triplets with anti-CD38 mAbs plus IMiDs or PIs, and novel targeted molecules. Comparisons among clinical trials and real-world data showed a good degree of reproducibility of some important results, particularly in terms of overall response rate, progression-free survival, and overall survival. This may help clinicians towards a proper selection of the best treatment options, particularly in real-world settings. However, as compared with the management of real-world settings, clinical trials have some pitfalls in terms of outcome and especially in terms of safety and quality of life. In fact, trials include younger and presumably healthier patients, excluding those with worst clinical conditions due to MM features (e.g., renal insufficiency or bone disease, which can impair the performance status) and comorbidities (e.g., cardiac and pulmonary disease), thus resulting in a possible lack of representativeness of data about the patients enrolled. In this review, we analyze comparable and discrepant results from clinical trials vs. real-world settings published in the last 10 years, focusing on different drugs and combinations for the treatment of MM and providing an overview of treatment choices.

/pdf/beyond-clinical-trials-in-patients-with-multiple-myeloma-a-fjev8xot.pdf

Beyond Clinical Trials in Patients With Multiple Myeloma: A Critical Review of Real-World Results

Background: Renal insufficiency is one of the most frequent complications in multiple myeloma. The incidence of renal insufficiency in patients with multiple myeloma ranges from 20% to 50%. Renal impairment in patients with multiple myeloma results primarily from the toxic effects of monoclonal light chains on the kidneys. Dehydration, hypercalcemia, hyperuricemia, the application of nephrotoxic NSARs, antibiotics, contrast agents, etc., all play a major role in the deterioration of renal function in patients with multiple myeloma. The diagnosis and treatment of these patients use an interdisciplinary approach in consultation with hematologist–oncologists, radiologists, nephrologists and intensive care specialists. Using new drugs in the treatment of patients with refractory/relapsed multiple myeloma and renal insufficiency markedly improves progression-free survival and overall survival in these patients. Conclusions: New drugs have helped to widen the treatment options available for patients with renal impairment and refractory/relapsed multiple myeloma, since dose adjustments are unnecessary with carfilzomib as well as with panobinostat, elotuzumab, pomalidomide or daratumumab in patients with renal impairment. Several new substances for the treatment of refractory/relapsed multiple myeloma have been approved in the meantime, including belantamab mafodotin, selinexor, melflufen, venetoclax, CAR T-cell therapy and checkpoint inhibitors. Ongoing studies are investigating their administration in patients with renal impairment.

Advances in the Treatment of Relapsed and Refractory Multiple Myeloma in Patients with Renal Insufficiency: Novel Agents, Immunotherapies and Beyond.

Multiple myeloma (MM) treatment has changed over the years, doubling the patients’ life expectancy. This result is predominantly related to the extensive use of proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs), representing myeloma therapy milestones. However, the outcome of patient refractory to PI and IMiDs remains poor [1]. In this scenario, several monoclonal antibodies (mAbs) have been developed. Elotuzumab (formerly HuLuc63) is a humanized IgG1 antibody targeting signaling lymphocytic-activation molecule F7 (SLAMF7), a homotypic adhesion molecule highly expressed on MM plasma cells [2].

Elotuzumab in multiple myeloma

Study on the Relationship Between the Expression of B Cell Mature Antigen and the Classification, Stage, and Prognostic Factors of Multiple Myeloma

Treatment of patients with Mayo stage IIIb light chain (AL) amyloidosis remains challenging, and prognosis remains very poor. Mayo IIIb patients were excluded from the pivotal trial leading to the approval of daratumumab in combination with bortezomib-cyclophosphamide-dexamethasone. This retrospective, multicenter study evaluates the addition of daratumumab to the first-line therapy in patients with newly diagnosed stage IIIb AL amyloidosis. In total, data from 119 consecutive patients were analyzed, 27 patients received an upfront treatment including daratumumab, 63 a bortezomib-based regimen without daratumumab, 8 received therapies other than daratumumab or bortezomib and 21 pretreated patients or deceased prior to treatment were excluded. In the daratumumab group, median overall survival was not reached after a median follow-up time of 14.5 months, while it was significantly worse in the bortezomib- and the otherwise treated group (6.6 and 2.2 months, respectively) (p=0.002). Overall hematologic response rate at 2 and 6 months was better in the daratumumab compared to the bortezomib group (59% vs. 37%, p=0.12, 67% vs. 41%, p=0.04, respectively). Landmark survival analyses revealed a significantly improved overall survival in patients with partial hematologic response or better, compared to non-responders. Cardiac response at 6 months was in the daratumumab-, bortezomib- and otherwise treated group 46%, 21%, 0%, respectively (p=0.04). A landmark survival analysis revealed markedly improved overall survival in patients with cardiac very good partial response vs. cardiac non-responders (p=0.002). This study demonstrates for the first time the superiority of an upfront treatment with daratumumab over standard-of-care in stage IIIb AL amyloidosis.

Daratumumab in first-line treatment of patients with light chain amyloidosis and Mayo stage IIIb improves treatment response and overall survival.

The anti-SLAMF7 monoclonal antibody, elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) is approved for relapsed/refractory MM in the U.S. and Europe. Recently, a small phase 2 study demonstrated an advantage in progression-free survival (PFS) for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited. To analyze the efficacy and safety of elo/pom/dex in a “real world” cohort of patients with advanced MM, we queried the databases of the university hospitals of Wurzburg and Vienna. We identified 22 patients with a median number of five prior lines of therapy who received elo/pom/dex prior to licensing within an early access program. Patients received a median number of 5 four-week treatment cycles. Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35% and 28%, respectively. The overall response rate was 50% and 64% of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy. Objective responses were also seen in five patients who had been pretreated with pomalidomide. Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry v 6.4 months for ISS III), although this difference did not reach statistical significance. No infusion-related reactions were reported. The most frequent grade 3/4 adverse events were neutropenia and pneumonia. Elo/pom/dex is an active and well-tolerated regimen in highly advanced MM even after pretreatment with pomalidomide.

/pdf/elotuzumab-pomalidomide-and-dexamethasone-is-a-very-well-4suw05a4ev.pdf

Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers.

Open-Label, Prospective, Multicentre, Phase I/II Study of AOP2014, a Novel PEG-Proline-Interferon Alpha-2b in Patients with Polycythemia Vera: Update from an Ongoing Study

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Papers

Daratumumab in first-line treatment of patients with light chain amyloidosis and Mayo stage IIIb improves treatment response and overall survival.

Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers.

Open-Label, Prospective, Multicentre, Phase I/II Study of AOP2014, a Novel PEG-Proline-Interferon Alpha-2b in Patients with Polycythemia Vera: Update from an Ongoing Study