The prognosis for patients with cardiac impairment due to AL-amyloid deposition and severe cardiac insufficiency is poor, with a survival median in the order of months. The classical treatment of AL-amyloidosis in combination with cardiac insufficiency is very poorly tolerated and the treatment of such patients is associated with considerably higher mortality than among other patients with AL-amyloidosis. If, however, patients with an isolated or another dominating cardiac impairment, without severe damage to other organs and tissues, have a heart transplant performed, their cardiovascular condition will significantly improve as a result, along with their ability to tolerate any kind of treatment for AL-amyloidosis including that using high-dose chemotherapy with a transplant of autologous hematopoietic stem cells. The achievement of complete remission of AL-amyloidosis is a precondition for long-term survival, since when not achieved, amyloid deposition also arises in the transplanted heart. At the Centre for Cardiovascular and Transplantation Surgery, Brno, the first heart transplant due to its impairment by AL-amyloidosis was performed in 2010. By the year 2017 the number of patients with AL-amyloidosis, who had first undergone a heart transplant with subsequent treatment for AL-amyloidosis, increased to 5. The median age at which a heart transplant was performed is 60 (48-65) years. Four patients were men, one was a woman. The median monitoring equals 65 (88-15) months. Complete remission of AL-amyloidosis was achieved in all the patients. There were 5 lines of treatment needed for the first patient to attain it, of that twice high-dose melphalan with autologous stem cell transplantation, for the second patient a second-line treatment, high-dose melphalan and bortezomib-based therapy. No specific therapy was needed for the third patient, as immunosuppressive therapy following the heart transplant containing prednison led to complete remission of AL-amyloidosis. In the fourth case, sustainable complete remission was reached by high-dose melphalan and in the fifth case by one line of bortezomib-based therapy. The aforementioned data illustrate that a heart transplant is the first step which makes the patients with a severe heart failure, not tolerating any efficient therapy of AL-amyloidosis, capable of undergoing intense treatment of AL-amyloidosis. Sometimes one high-dose chemotherapy is sufficient, while at other times multiple treatment lines are needed to reach complete remission of AL-amyloidosis.Key words: AL-amyloidosis - autologous hematopoietic stem cells transplantation - bortezomib - cardiomyopathy - lenalidomide - thalidomide - heart transplantation.

Allogeneic hematopoietic stem cell transplantation (AlloHCT) is offered increasingly to elderly patients with hematologic malignancies. However, outcome data in those who are 70 years or older are limited, and no standard conditioning regimen has been established for this population. In this retrospective study, we evaluated the outcome of 53 consecutive patients aged 70 years and older who underwent AlloHCT with melphalan (Mel)-based reduced-intensity conditioning (RIC) at City of Hope. Engraftment was prompt, with median time to neutrophil engraftment of 15 days. More than 95% of patients achieved complete donor chimerism within 6 weeks from HCT, consistent with "semi-ablative" nature of this regimen. With a median follow up of 31.1 months, the 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) were 68.9%, 63.8%, and 17.0%, respectively. Cumulative Incidence (CI) of relapse at 1- and 2-years were 17.0% and 19.3%, respectively. 100-day CI of grade II-IV acute GVHD was 37.7% (grade III-IV: 18.9%), and 2-year CI of chronic GVHD was 61.9% (45.9% extensive). The only significant predictor for poor OS was high/very high disease risk index (DRI). Transplant-related complication/morbidities observed here did not differ from the commonly expected in younger patients treated with RIC. In conclusion; AlloHCT with Mel-based conditioning regimen is associated with acceptable toxicities and NRM, lower incidence of relapse and favorable OS and PFS in patients with 70 years of age or older.

High dose melphalan followed by autologous stem cell transplant (ASCT) is standard of care for eligible patients with multiple myeloma (MM). EVOMELAR (propylene glycol-free melphalan HCl, PG-Free Mel) was approved by the FDA as conditioning therapy for ASCT in MM in two daily 100 mg/m2 doses for a total dose of 200 mg/m2. In this phase II, open-label study; PG-Free Mel (EvomelaR) conditioning was given at single dose of 200 mg/m2 on day -2 pre-ASCT in order to establish pharmacokinetic (PK) parameters and safety. Twenty-four patients (median age 64 years) were enrolled between August 2016 and February 2017. Myeloablation followed by successful neutrophil engraftment occurred at a median of 10 days in all patients. Peak melphalan concentration was observed at 10-minute post-infusion while there was considerable variation in the maximum plasma concentration (Cmax) and area under concentration time curve (AUC). Median Cmax was 7380 ng/ml with an interquartile range (IQR) 6522 to 8027 ng/ml. Similarly, median AUC was 53,3552 ng/ml*min (IQR 45,0850 to 66,2936 ng/ml*min). PG-Free Mel had an acceptable safety profile regardless of the exposure with no mortality and an overall response rate of 96% and a very good partial response rate (>VGPR) of 75%. In conclusion, while PG-Free Mel at a single dose of 200mg/m2 was safe, considerable PK variability was observed with highest quartile having ~ 3-fold higher AUC than the first quartile suggesting that strategies for higher targeted exposure could be explored in future trials to optimize clinical benefit.

An 80-year-old man presented to our hospital with a thoracic vertebrae compression fracture. He was diagnosed with IgG-λ myeloma (International Staging System stage II, Durie-Salmon stage IIIA). Since melphalan-prednisolone (MP) was not effective, we treated him with lenalidomide and low-dose dexamethasone (DEX) (Ld), achieving a partial response. As DEX provoked edema and psychiatric symptoms, the patient disagreed with its use, and pomalidomide (POM) monotherapy was initiated. Although the POM dosage was reduced to 1-2 mg/day due to somnolence, which was reported as an adverse event, stringent complete response (sCR) was achieved and sustained for 10 months following 11 cycles of low-dose POM monotherapy. It is assumed that sCR was achieved with low-dose POM monotherapy due to its early introduction as well as there being no high-risk chromosomal abnormalities. Even though adverse events develop with a standard dose, a continuation of low-dose POM is considered more important than discontinuation.

Multiple myeloma (MM) is a debilitating neoplasm of terminally differentiated plasma B-cells that has resulted in over 13,000 deaths in 2017 alone. Combination therapies involving melphalan, a small molecule DNA alkylating agent, are commonly prescribed to patients with relapsed/refractory MM, which necessitates the stratification of responding patients to minimize toxicities and improve quality of life. Here, we evaluated the use of 18F-FDOPA, a clinically available positron emission tomography (PET) radiotracer with specificity to the L-type amino acid transporter-1 (LAT1), which also mediates melphalan uptake, for imaging melphalan therapy response in a preclinical immunocompetent model of MM. Methods: C57Bl/KaLwRij mice were implanted subcutaneously with unilateral murine 5TGM1-GFP tumors, and divided into three independent groups: untreated, treated beginning week 2, and treated beginning week 3 post tumor implantation. The untreated and week 2 therapy cohorts were imaged with preclinical magnetic resonance imaging (MRI) and dynamic 18F-FDG and 18F-FDOPA-PET/computed tomography (PET/CT) at week 4 on separate, contiguous days, while the week 3 therapy cohort was longitudinally imaged weekly for 2 weeks. Metabolic tumor volume, lesion avidity, maximum standard uptake value, and total uptake metrics were calculated for both tracers. Immunohistochemistry was performed on representative tissue from all groups for LAT1 and glucose transporter-1 (GLUT1) expression. Results: Melphalan therapy induced a statistically significant reduction in lesion avidity and uptake metrics for both 18F-FDG and 18F-FDOPA. There was no visible effect on GLUT1 expression, but LAT1 density was increased in the week 2 therapy cohort. Longitudinal imaging of the week 3 group showed variable changes in 18F-FDG and 18F-FDOPA uptake, with increase in 18F-FDOPA lesion avidity in the 2nd week relative to baseline. LAT1 and GLUT1 surface density in the untreated tumor and week 3 treatment group were qualitatively similar. Conclusion: 18F-FDOPA-PET/CT served as a complementary method to 18F-FDG-PET/CT in imaging melphalan therapy response in extramedullary preclinical MM. 18F-FDOPA uptake was linked to LAT1 expression and melphalan response, with longitudinal imaging suggesting stabilization of LAT1 levels and melphalan tumor cytotoxicity. Future work will explore additional MM cell lines with heterogeneous LAT1 expression and response to melphalan therapy.  .