Risk of multiple myeloma and other malignancies among first- and second-degree relatives of patients with multiple myeloma: A population-based study.

OBJECTIVES: We conducted a population-based study to assess the risk for multiple myeloma (MM) and other cancers in first- and second-degree relatives of MM patients, and to investigate whether evidence of anticipation is present in familial MM. METHODS: We retrieved 24 845 first-degree relatives and 41 008 second-degree relatives of 7847 MM patients, and 86 984 first-degree relatives, and 138 660 second-degree relatives of 26 511 matched controls. A Cox model was used to assess the risk for MM and other cancers in relatives of MM patients. Anticipation was assessed by a Cox model, where all parents and offspring of MM patients were included in the risk set. RESULTS: In second-degree relatives of MM patients, no overall significant association with an MM diagnosis was observed (HR 1.99; 95%CI:0.86-4.57). In parents and offspring of MM patients, we found no significant difference in the ages at onset of MM (HR 1.28;95% CI:0.50-3.28). In affected parent-offspring pairs, we observed no statistically significant difference in overall survival between the generations (HR 0.74; 95%CI:0.20-2.69). CONCLUSIONS: Overall, second-degree relatives of MM patients were not associated with an increased risk for MM. Our study supports that genetic anticipation is not present in familial MM.

Patterns of previous and secondary malignancies in patients with multiple myeloma.

OBJECTIVES: In contrast to secondary primary malignancies (SPM) following multiple myeloma (MM), less is known about previous malignancies. We therefore conducted a population-based study to assess the patterns of previous malignancies in MM patients as well as the risk for SPM. METHODS: Using data from the Cancer Registry of Norway, we included 9574 MM patients and 37 810 matched control subjects. The association between previous malignancies and a subsequent diagnosis of MM was analysed by a logistic regression model and the risk for SPM by a Cox model. RESULTS: A previous diagnosis of myeloproliferative neoplasia (MPN) (OR 3.57; 95% CI:1.45-8.80) and Hodgkin lymphoma (HL) (OR 3.66; 95% CI: 1.40-9.55) was associated with the subsequent development of MM. For MPN, the association with MM was explained by an excess of primary myelofibrosis (PMF) in the MM group. The overall incidence of a previous malignancy was not different between MM patients and the control subjects (OR 0.93; 95% CI: 0.87-1.00). MM patients had an increased risk for secondary acute myelogenous leukaemia/myelodysplastic syndromes (HR 6.1, 95% CI: 3.9-9.5). CONCLUSIONS: A previous diagnosis of HL and PMF was associated with a subsequent diagnosis of MM, whereas the overall incidence of previous cancers was not increased for MM patients.

Incidence and survival of multiple myeloma: a population-based study of 10 524 patients diagnosed 1982-2017.

Population-based studies from high-quality nationwide cancer registries provide an important alternative to clinical trials in the assessment of the impact of modern myeloma treatment. Based on data from the Cancer Registry of Norway, we investigated trends in incidence and relative survival (RS) for 10 524 patients in three age groups diagnosed between 1982 and 2017. Nationwide myeloma drug consumption statistics were obtained from the Norwegian Institute of Public Health. Patients aged <65 years had a steady increase in both 5- and 10-year RS across all calendar periods from 1982. For patients aged 65-79 years, RS was stable until the calendar period 1998-2002, followed by an improvement in both 5- and 10-year RS. The 5-year RS for patients aged ≥80 years also increased significantly between the first and the last calendar period. In conclusion, we demonstrate a significant improvement in 5-year RS in all age groups. Improved RS in patients aged ≥80 years at the time of diagnosis is only rarely described in other population-based studies. For patients aged ≥65 years, the improvement in RS coincides with the introduction of modern drugs, whereas patients aged <65 years had an ongoing improvement before the introduction of autologous stem-cell transplant.

Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial.

The Nordic Myeloma Study Group conducted an open randomized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation (ASCT) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma. Overall, 370 patients were centrally randomly assigned 3 months after ASCT to receive 20 doses of bortezomib given during 21 weeks or no consolidation. The hypothesis was that consolidation therapy would prolong progression-free survival (PFS). The PFS after randomization was 27 months for the bortezomib group compared with 20 months for the control group (P = .05). Fifty-one of 90 patients in the treatment group compared with 32 of 90 controls improved their response after randomization (P = .007). No difference in overall survival was seen. Fatigue was reported more commonly by the bortezomib-treated patients in self-reported quality-of-life (QOL) questionnaires, whereas no other major differences in QOL were recorded between the groups. Consolidation therapy seemed to be beneficial for patients not achieving at least a very good partial response (VGPR) but not for patients in the ≥ VGPR category at randomization. Consolidation with bortezomib after ASCT in bortezomib-naive patients improves PFS without interfering with QOL. This trial was registered at www.clinicaltrials.gov as #NCT00417911.

Serotonin in blood: assessment of its origin by concomitant determination of ß-thromboglobulin (platelets) and chromogranin A (enterochromaffin cells).

BACKGROUND: Serotonin is produced in enterochromaffin (EC) cells, taken up and stored in platelets and released during platelet activation. Measurement of platelet-poor plasma serotonin is difficult, mainly due to platelet activation during blood sampling. We aimed to establish a method to assess the influence of platelet release upon platelet-poor plasma serotonin measurement by concomitant determination of serotonin, ß-thromboglobulin (ß-TG) and chromogranin A (CgA). METHODS: Blood samples from patients with thrombocytosis, thrombocytopenia and small intestinal neuroendocrine (EC-cell) tumors (SI-NETs) as well as healthy volunteers were analyzed. We also measured serotonin in venous and arterial samples from patients undergoing coronary angiography to evaluate peripheral serotonin metabolism. RESULTS: Serotonin and CgA were significantly higher in patients with SI-NETs compared to all other groups implying EC cell origin of serotonin in patients with SI-NETs. We found that the serotonin concentration was similar in patients with thrombocytosis and thrombocytopenia, whereas plasma ß-TG was higher and lower respectively. A high EDTA concentration in the sampling tubes gave significantly lower serotonin concentrations. Serotonin concentrations did not differ between arterial and venous blood. CONCLUSIONS: Our methodology to measure platelet-poor plasma serotonin was appropriate. Blood platelet numbers did not affect the level of serotonin in contrast to ß-TG.

Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study.

OBJECTIVES: Thalidomide and bortezomib have been frequently used for second-line therapy in patients with myeloma relapsing after or refractory to initial melphalan-based treatment, but no randomized trials have been published comparing these two treatment alternatives. METHODS: Thalidomide- and bortezomib-naïve patients with melphalan refractory myeloma were randomly assigned to low-dose thalidomide + dexamethasone (Thal-Dex) or bortezomib + dexamethasone (Bort-Dex). At progression on either therapy, the patients were offered crossover to the alternative drug combination. An estimated 300 patients would be needed for the trial to detect a 50% difference in median PFS between the treatment arms. RESULTS: After inclusion of 131 patients, the trial was prematurely closed because of low accrual. Sixty-seven patients were randomized to Thal-Dex and 64 to Bort-Dex. Progression-free survival was similar (median, 9.0 months for Thal-Dex and 7.2 for Bort-Dex). Response rate was similar (55% for Thal-Dex and 63% for Bort-Dex), but time to response was shorter (P < 0.05) and the VGPR rate higher (P < 0.01) for Bort-Dex. Time-to-other treatment after crossover was similar (median, 13.2 months for Thal-Dex and 11.2 months for Bort-Dex), as was overall survival (22.8 months for Thal-Dex and 19.0 for Bort-Dex). Venous thromboembolism was seen in seven patients and cerebrovascular events in four patients in the Thal-Dex group. Severe neuropathy, reactivation of herpes virus infections, and mental depression were more frequently observed in the Bort-Dex group. In the quality-of-life analysis, no difference was noted for physical function, pain, and global quality of life. Fatigue and sleep disturbances were significantly more prevalent in the Bort-Dex group. CONCLUSIONS: Thalidomide (50-100 mg daily) in combination with dexamethasone seems to have an efficacy comparable with that of bortezomib and dexamethasone in melphalan refractory myeloma. However, the statistical strength of the results in this study is limited by the low number of included patients.

Antiplatelet effect of clopidogrel is reduced in patients treated with therapeutic hypothermia after cardiac arrest.

BACKGROUND: The platelet inhibitor clopidogrel is administered to patients treated with therapeutic hypothermia following cardiac arrest due to acute coronary syndromes. Interactions with proton pump inhibitors and genetics are factors with a known potential to attenuate the platelet inhibition of clopidogrel. In patients treated with therapeutic hypothermia, reduced gastrointestinal function and hypothermia may also reduce the effect of clopidogrel. To investigate the net platelet inhibition of clopidogrel, we have measured the platelet reactivity index in patients treated with therapeutic hypothermia. METHODS AND RESULTS: Twenty-five Caucasian patients treated with clopidogrel and therapeutic hypothermia were prospectively included. Therapeutic hypothermia was defined as 33-34°C and delivered for 24h. Clopidogrel loading doses (300-600 mg) were administered enterally the day of admission and followed by 75 mg daily. Blood samples were collected on day 1 (n=25) and day 3 (n=16). The samples were analysed for inhibition by clopidogrel with a vasodilator stimulated phosphoprotein phosphorylation kit. On day 1 and day 3, platelet reactivity index was 0.77±0.09 and 0.57±0.16, respectively. The number of patients with a satisfactory antiplatelet effect (defined as platelet reactivity index <0.5) were 0 (0%) and 5 (31%), respectively. CONCLUSION: In patients treated with therapeutic hypothermia after cardiac arrest, the effect of clopidogrel on platelets was virtually nonexistent on day 1 after administration, with some improvement on day 3.

Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma.

In this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days every 6 weeks until plateau phase. The dose of thalidomide/placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7% in the MPT and MP arms, respectively (P < .001). There was no significant difference in progression-free or overall survival, with median survival being 29 months in the MPT arm and 32 months in the MP arm. Most quality of life outcomes improved equally in both arms, apart from constipation, which was markedly increased in the MPT arm. Constipation, neuropathy, nonneuropathy neurologic toxicity, and skin reactions were significantly more frequent in the MPT arm. The number of thromboembolic events was equal in the 2 treatment arms. In conclusion, MPT had a significant antimyeloma effect, but this did not translate into improved survival. This trial was registered at www.clinicaltrials.gov as #NCT00218855.

HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma.

The bone disease in multiple myeloma is caused by an uncoupling of bone formation from bone resorption. A key difference between patients with and patients without osteolytic lesion is that the latter have fewer and less active osteoblasts. Hepatocyte growth factor (HGF) is often produced by myeloma cells and is found at high concentrations in the bone marrow of patients with multiple myeloma. Here we show that HGF inhibited bone morphogenetic protein (BMP)-induced in vitro osteoblastogenesis. Thus, HGF inhibited BMP-induced expression of alkaline phosphatase in human mesenchymal stem cells (hMSCs) and the murine myoid cell line C2C12, as well as mineralization by hMSCs. Furthermore, the expression of the osteoblast-specific transcription factors Runx2 and Osterix was reduced by HGF treatment. HGF promoted proliferation of hMSCs, and the BMP-induced halt in proliferation was overridden by HGF, keeping the cells in a proliferative, undifferentiating state. BMP-induced nuclear translocation of receptor-activated Smads was inhibited by HGF, providing a possible explanation of how HGF inhibits BMP signaling. The in vitro data were supported by the observation of a negative correlation between HGF and a marker of osteoblast activity, bone-specific alkaline phosphatase (rho = -0.45, P = .008), in sera from 34 patients with myeloma. These observations suggest that HGF inhibits bone formation in multiple myeloma.

Bone disease in multiple myeloma.

A new understanding of the regulation of bone resorption developed with the discovery of receptor activator of nuclear factor-kappaB, receptor activator of nuclear factor-kappaB ligand, and osteoprotegerin in 1997-1998. The RANK signaling system is abnormally regulated in multiple myeloma, and this favors increased osteoclast function, which early in the disease is compensated by increased osteoblast function. Later in the disease osteoblast activity decreases, resulting in osteolytic lesions. We review the factors implicated in osteoclast and osteoblast function. Among these are receptor activator of nuclear factor-kappaB, receptor activator of nuclear factor-kappaB ligand, osteoprotegerin, hepatocyte growth factor, macrophage inflammatory protein-1alpha, bone morphogenetic proteins, and the Wnt system. Bisphosphonates are the only drugs used in routine clinical management; however, the complex regulation system of bone homeostasis offers a number of of possible targets for therapy, which are discussed.

Osteopontin is an adhesive factor for myeloma cells and is found in increased levels in plasma from patients with multiple myeloma.

BACKGROUND AND OBJECTIVES: Osteopontin (OPN) is a non-collagenous matrix protein produced by various cells including osteoblasts, osteoclasts and several types of tumor cells. It is involved in a number of physiologic and pathologic events including adhesion, angiogenesis, apoptosis, inflammation, wound healing and tumor metastasis. We wanted to investigate the potential role of OPN in multiple myeloma. DESIGN AND METHODS: Myeloma cells and stromal cells from myeloma patients were investigated as potential OPN-producers. Furthermore, OPN was tested in proliferation, migration and adhesion assays with myeloma cells. Serum and plasma OPN in myeloma patients were measured by enzyme-linked immunosorbent assay (ELISA). OPN levels were correlated to disease variables at diagnosis and to disease outcome. RESULTS: Myeloma cells produce OPN, and stromal cells from myeloma patients express higher levels of OPN than stromal cells from healthy controls. The myeloma cell lines ANBL-6 and INA-6 adhered to OPN. NOD/SCID mice inoculated with OPN-producing ANBL-6 cells had elevated levels of murine OPN in serum, whereas human OPN was not detectable. Plasma and serum levels of OPN were significantly higher in myeloma patients than in healthy individuals. Interpretation and Conclusions. Myeloma cell lines adhere to OPN, indicating that elevated stromal expression of OPN may be one of the factors responsible for the retention of myeloma cells in the bone marrow. The elevated plasma OPN levels in myeloma patients could be due to both production of OPN by the tumor cells and tumor-induced production of OPN by non-tumor cells.

Bone morphogenetic protein-5, -6 and -7 inhibit growth and induce apoptosis in human myeloma cells.

Previously, bone morphogenetic protein (BMP)-2 and -4 have been shown to inhibit proliferation and induce apoptosis in human myeloma cells. BMP-2 and -4 belong to a subgroup of BMPs using the BMP receptors Alk-3 or -6. In this study, we examined the effects on human myeloma cells of BMP-6 and -7, members of a different BMP subgroup, which mainly utilize Alk-2 as their receptor. All cell lines examined expressed mRNA for the BMP-6 and -7 receptor Alk-2. We did not detect transcripts for the BMP-2 and -4 receptors Alk-3 or Alk-6 in INA-6 and RPMI-8226 cells by RT-PCR. Accordingly, the intracellular signalling molecules Smad-1, -5 and -8 were not phosphorylated by BMP-4 in INA-6 and RPMI-8226 cells. The expression patterns of various BMP receptors in the myeloma cell lines explained the differences in responses to the various BMPs. Alk-2-expressing cell lines responded with growth inhibition and apoptosis to BMP-6 and -7, whereas cell lines lacking both Alk-3 and -6 were resistant to BMP-4. Soluble Alk-3 and -6 were able to neutralize the BMP-4 effects in BMP-4-responsive cell lines. All BMPs reduced viability in more than 70% of purified primary myeloma cell samples. BMPs have intriguing antitumor effects in vitro. Importantly, myeloma cells not responsive to BMP-2 and -4 may still be sensitive to BMP-6 or -7. It is possible that therapeutic use of BMP or BMP analogues could have an impact on both myeloma bone disease and myeloma cell growth.

Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells.

Multiple myeloma (MM) is a hematologic malignancy characterized by accumulation of plasma cells in the bone marrow (BM). Bone destruction is a complication of the disease and is usually associated with severe morbidity. The balance between receptor activator of nuclear factor-kappaB (NF-kappaB) ligand and osteoprotegerin (OPG) is of major importance in bone homeostasis. We have recently shown that serum OPG levels are lower in patients with myeloma than in healthy individuals. Here we show that myeloma cells can bind, internalize, and degrade OPG, thereby providing a possible explanation for the lower levels of OPG in the BM of patients with MM. This process is dependent on interaction of OPG with heparan sulfates on the myeloma cells. The results suggest a novel biologic mechanism for the bone disease associated with MM and that treatment of the bone disease with OPG lacking the heparin-binding domain should be considered.