Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) can be late complications following mutagenic treatment. Limited data is available on the outcome of patients developing therapy-related MDS and AML after treatment for multiple myeloma (MM). We identified 250 patients with therapy-associated MDS or AML in the Duesseldorf MDS registry. Of those, 50 patients were previously diagnosed with multiple myeloma (mm-MDS/AML). We compared them to patients with de novo MDS (n = 4862) and to patients with MDS following other underlying diseases (tMDS) (n = 200). mm-MDS patients and tMDS patients showed similar karyotypes and degrees of cytopenia. However, mm-MDS patients had significantly higher blast counts and more often belonged to the high-risk group according to the International Prognostic Scoring System (IPSS) (bothp < 0.05). Although the rate of progression to AML was similar in mm-MDS and tMDS, both transformed significantly more often than de novo MDS (p < 0.05). Median overall survival of patients with mm-MDS (13 months; range: 1–99) and tMDS (13 months; range 0–160) was also similar yet significantly shorter than patients with de novo MDS (32 months; range 0–345 months; p < 0.05). Furthermore, survival of mm-MDS patients was not affected by myeloma activity. Despite significantly more high-risk disease and higher blast cell counts, myeloma-associated MDS-patients show features akin to other tMDS. Survival is similar to other tMDS and irrespective of myeloma remission status or transformation to AML. Thus, patient outcome is not determined by competing clones but rather by MDS governing the stem cell niche.

Randomized controlled trials (RCT) are the driver of therapeutic innovations. However, it has been frequently shown that less than 5% of adult cancer patients enroll in clinical trials, although 70% of patients are considered as being willing to participate. Barriers to trial participation have been extensively studied. Although there is evidence that trial participation correlates with improved survival and reduced mortality, the rate of participation has not changed substantially. We provide retrospective data from a single-center analysis of 411 patients with multiple myeloma (MM) who were treated at the University Hospital Duesseldorf in Germany between January 2014 and December 2016. Each patient was analyzed for the real-world possibility of participating in a clinical study, based on the inclusion and exclusion (I/E) criteria and the recruiting period of open studies. The overall rate of study participation was 19%. A total of 53% of NDMM patients were eligible for first-line studies (GMMG-HD6, LenaMain). Of these, 80% consented to enrolment (42% of all). In contrast, only 38% of the RRMM population was eligible (GMMG-Relapse, Castor, Tourmaline, Admyre). Of these, only 22% (7% of all) consented. This was confirmed by virtual analysis, showing that only 29% of all RRMM patients would have been eligible for six internationally recruiting trials leading to later drug approval. The majority of cases were rendered ineligible by only one I/E criterion. The most common criteria were study-specific (prior therapies or refractory disease to a specific drug), kidney disease, and previous malignancy, followed by internal, neurologic, and infectious disease. In summary, this single-center analysis showed that I/E criteria permit study participation for most NNDM patients, with a dramatic decrease in the RRMM population. This is aggravated by the fact that the willingness for study participation also significantly declines in RRMM. Thus, addressing patient expectations and priorities seems to be the most promising approach to increasing patient enrollment in clinical trials.

Purpose: For multiple myeloma, high-dose chemotherapy and autologous blood stem-cell transplantation (ASCT) followed by lenalidomide maintenance (LenMT) at 10–15 mg/day is considered standard of care. However, dose reductions due to side effects are common and median LenMT doses achieved over time may remain lower. Dose response during LenMT has never been investigated. Patients and Methods: In a multicenter, randomized, open-label trial, patients with multiple myeloma after ASCT and high-dose lenalidomide consolidation therapy (CT) at 25 mg/day were randomized to receive LenMT at either 25 or 5 mg/day. Primary endpoint was progression-free survival (PFS). Results: Ninety-four patients (median age, 58 years) were randomized to either arm, with 22% having International Staging System (ISS) stage 3 and 22% being in complete remission (CR). After median follow-up of 46.7 months, median doses of 14.5 and 5 mg/day were achieved in the two arms; 53% of dose reductions occurring during CT. In the high- and the low-dose arm, median PFS was 44.8 and 33.0 months (HR, 0.65; 95% CI, 0.44–0.97; P = 0.032), 36% and 23% of patients had stringent CR as best response (P = 0.08), and 4-year OS was 79% and 67% (P = 0.16), respectively. Hematologic toxicity, grade ≥3 neutropenia, and infections were initially more common with LenMT 25 mg, but decreased after dose adjustments. SPM incidence and quality-of-life (QoL) scores in both arms were similar. Conclusions: LenMT dose correlated with efficacy and toxicity. High rates of dose reductions during CT argue against a high starting dose. However, continuous up- and down-titration for each patient to the current maximum tolerated dose is prudent.

The deposition of immunoglobulin light chains (IgLCs) in the form of amorphous aggregates or amyloid fibrils in different tissues of patients can lead to severe and potentially fatal organ damage, requiring transplantation in some cases. There has been great interest in recent years to elucidate the origin of the very different in vivo solubilities of IgLCs, as well as the molecular determinants that drive either the formation of ordered amyloid fibrils or disordered amorphous aggregates. It is commonly thought that the reason of this differential aggregation behaviour is to be found in the amino acid sequences of the respective IgLCs, i.e. that some sequences display higher intrinsic tendencies to form amyloid fibrils. Here we perform in depth Thermodynamic and Aggregation Fingerprinting (ThAgg-Fip) of 9 multiple myeloma patient-derived IgLCs, the amino acid sequences of all of which we have solved by de novo protein sequencing with mass spectrometry. The latter technique was also used for one IgLc from a patient with AL amyloidosis. We find that all samples also contain proteases that fragment the proteins under physiologically relevant mildly acidic pH conditions, leading to amyloid fibril formation in all cases. Our results suggest that while every pathogenic IgLC has a unique ThAgg fingerprint, all sequences have comparable amyloidogenic potential. Therefore, extrinsic factors, in particular presence of, and susceptibility to, proteolytic cleavage is likely to be a strong determinant of in vivo aggregation behaviour. The important conclusion, which is corroborated by systematic analysis of our sequences, as well as many sequences of IgLCs from amyloidosis patients reported in the literature, challenges the current paradigm of the link between sequence and amyloid fibril formation of pathogenic light chains.

Introduction: The LenaMain trial (NCT00891384) reported increased progression-free survival with 25 mg of lenalidomide maintenance compared to 5 mg. Here, we report the patient-reported outcomes. Materials and Methods: Scores obtained from the EORTC Quality of Life Questionnaire C30 were analyzed for longitudinal changes from baseline within the groups as well as cross-sectional scores. Results: Compliance rates were high, with 95.7% at baseline and 70% during maintenance. At study entry, scores were high for functioning and low for symptoms. During maintenance, the median global health status/quality of life (GHS/QoL) was constant, without significant differences over time (median GHS/QoL: 68 at baseline and 58 for Len high and 68 for Len low at 2 years) and between treatment arms (mean change < 2). Similarly, most functional scale domains were constant. Notably, diarrhea increased consistently for both treatment arms (baseline: −1.905 (range: −5.78–1.97); end of year 2: 16.071 (range: 5.72–26.42); p < 0.05). The subgroup analysis showed that neither disease activity, duration of treatment, nor adverse events affected the health-related quality of life (HR-QoL) or utility. Conclusion: High baseline scores were maintained throughout the trial without significant differences between the Len dosages, which supports continuous treatment with a dose tailored to patients’ HR-QoL.