Niels Abildgaard

Failure of oral pamidronate to reduce skeletal morbidity in multiple myeloma: a double‐blind placebo‐controlled trial

In order to study whether oral bisphosphonate therapy might prevent or reduce skeletal‐related morbidity in patients with newly diagnosed multiple myeloma who required chemotherapy, 300 patients were included in a randomized multi‐centre trial. Patients were given oral pamidronate at a dose of 300u2003mg daily, or placebo, in addition to conventional intermittent melphalan/prednisolone (and in some cases alpha‐interferon) treatment. With a median treatment duration of about 550u2003d, no statisticallly significant reduction in skeletal‐related morbidity (defined as bone fracture, related surgery, vertebral collapse, or increase in number and/or size of bone lesions) could be demonstrated. Pamidronate treatment also did not have any influence on patient survival or on the frequency of hypercalcaemia. However, in patients treated with pamidronate there were fewer episodes of severe pain (Pu2003=u20030.02) and a decreased reduction of body height of 1.5u2003cm (Pu2003=u20030.02). The overall negative result of the study is attributed to the very low absorption of orally administered bisphosphonates in general.

Prognostic evaluation in multiple myeloma: an analysis of the impact of new prognostic factors.

We have analysed the prognostic information for survival of presenting features in an unselected series of 394 myeloma patients. 15 variables with significant prognostic information were identified, among these were some not previously or only recently reported: serum levels of hepatocyte growth factor (HGF), interleukin‐6 (IL‐6), C‐terminal cross‐linked telopeptide of collagen I (ICTP) and soluble interleukin‐6 receptor (sIL‐6R). In a multivariate Cox analysis six variables were significantly and independently associated with poor survival: high age, low W.H.O.‐performance status (PS), high serum levels of calcium, β‐2‐microglobulin (β‐2M), IL‐6 and sIL‐6R. A risk score formed to predict survival for each percentile of the patient population allowed an efficient separation of prognostic groups. The discriminating power of the model compared favourably with three other previously published staging systems applied to the study population. Exclusion of IL‐6 and sIL‐6R from the model only marginally decreased the efficacy of the separation. The predictive value of some variables (sIL‐6R, β‐2M and W.H.O.‐PS) decreased significantly over time. We conclude that formation of a risk score based on independent variables is an efficient way to separate prognostic groups, that the contribution of new and not easily available parameters should be thoroughly evaluated before inclusion in prognostic models for clinical use and that the predictive value of parameters may decrease over time.

Serum markers of bone metabolism in multiple myeloma: prognostic value of the carboxy-terminal telopeptide of type I collagen (ICTP)

This study was performed to evaluate the prognostic significance of serum markers of bone and collagen metabolism in multiple myeloma. Serum C‐terminal telopeptide of type I collagen (ICTP) reflects degradation of bone, whereas serum osteocalcin, together with serum C‐terminal propeptide of procollagen type I (PICP) and serum bone‐specific alkaline phosphatase (bAP) reflect synthesis of bone matrix. The N‐terminal propeptide of procollagen type III (PIIINP) in serum reflects synthesis of type III collagen. We analysed frozen sera from 109 patients with newly diagnosed multiple myeloma. Serum ICTP was elevated (>5.0μg/l) in most patients (median 6.6u2003μg/l, range 1.4–29.4u2003μg/l). Serum PIIINP was elevated (>4.2μg/l) in 46% (median 4.0u2003μg/l, range 1.4–20.1u2003μg/l). Serum PICP was generally within the reference limits, whereas serum osteocalcin and serum bAP were elevated in 19% and 37%, respectively. Serum ICTP correlated with serum PIIINP, serum β2‐microglobulin (β2m), serum calcium, performance status, and stage. In univariate analysis, the test variables serum ICTP (P=0.026) and serum osteocalcin (P=0.036) were found to be of prognostic value, but PIIINP, PICP, or bAP in serum were not. Serum ICTP and serum β2m had a similar prognostic value. In multivariate analysis, serum calcium showed the highest prognostic significance, and serum β2m was the only other variable of independent prognostic value. However, in normocalcaemic patients, serum ICTP showed the highest prognostic significance, followed by serum osteocalcin. Thus, the serum levels of ICTP and osteocalcin seem related to bone turnover and calcium metabolism, and provide further information about myeloma activity, particularly in normocalcaemic patients.

Abnormal bone turnover in monoclonal gammopathy of undetermined significance: analyses of type I collagen telopeptide, osteocalcin, bone-specific alkaline phosphatase and propeptides of type I and type III procollagens

Abstract: The main difference between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) is the presence of lytic bone destructions in the latter. About 20% of MGUS patients develop MM, and histomorphometric studies have shown disturbed bone turnover rates in some of these patients. This study was performed in order to evaluate whether serum analyses of the C‐terminal telopeptide of type I collagen (ICTP), as a reflector of bone degradation, and of osteocalcin, bone‐specific alkaline phosphatase (bAP) and the C‐terminal propeptide of type I procollagen (PICP), as markers of bone formation, might give information on disturbancies of bone metabolism in MGUS. Furthermore, serum N‐terminal propeptide of procollagen III (PIIINP) might give information on disturbances in collagen III metabolism in the bone marrow. In the 35 patients examined, serum ICTP was elevated in 12 patients (34%), serum PIIINP elevated in 6 patients (17%), serum osteocalcin elevated in 11 patients (31%), serum bAP elevated in 6 patients (17%), and serum PICP elevated in 4 patients (11%). Serum ICTP correlated significantly with PIIINP (r=0.72, p<0.001), and with serum osteocalcin (r=0.57, p<0.001) and serum bAP (r=0.51, p=0.002). These findings indicate disturbancies of bone turnover and affected collagen metabolism in some MGUS patients. Follow‐up observation may reveal any prognostic value of these findings.

Assessment of bone involvement in patients with multiple myeloma using bone densitometry

Abstract:u2002 To evaluate the use of dual energy X‐ray absorptiometry (DXA) in multiple myeloma (MM) we performed a prospective study of 34 patients with newly diagnosed MM. Most patients had advanced disease and all but two patients had osteolytic bone destructions and/or pathological fractures. Bone mineral content (BMC) and bone mineral density (BMD) of the lumbar spine (L1–L4) and hip were measured using a Hologic QDR‐1000 scanner. Collapsed vertebrae were not excluded from analysis. Data from 289 healthy Danish volunteers aged 21–79 yr were used for calculation of Z‐scores. Lumbar spine BMC (Z‐score –0.46±0.23, p=0.05) and lumbar spine BMD (Z‐score –0.56±0.23, p=0.02) were significantly reduced in MM patients, whereas no reduction was seen in hip BMC or BMD. Collapsed vertebrae had marked reduced BMD (Z‐score –1.34±0.22, p<0.001), as had non‐fractured vertebrae in the same individuals (Z‐score –1.42±0.25, p<0.001). Lumbar spine BMD correlated with radiologically assessed bone morbidity (r –0.37, p=0.03) and stronger with the incidence of vertebral fractures (r –0.64, p<0.001). Thus, osteopenia of the back is common in multiple myeloma and correlates with an increased incidence of fractures. DXA may identify subjects with increased risk of vertebral fractures for more intensive chemotherapeutic or anti‐resorptive treatment.

Bone marrow fibrosis and disease activity in multiple myeloma monitored by the aminoterminal propeptide of procollagen III in serum.

Simple bone marrow fibrosis is seen in 10–30% of multiple myeloma (MM) patients. We investigated the incidence and characteristics of the bone marrow stromal alterations, in order to characterize the collagens involved by immunohistochemistry, and to evaluate the use of serum aminoterminal propeptide of type III procollagen (PIIINP) as a marker of marrow fibrogenesis and disease activity in MM. 34 consecutive patients with newly diagnosed MM were included prospectively, and followed for 12–30 months. Compared with the findings in 15 normal individuals we found increased interstitial deposits of collagen III in 48% of MM patients, whereas deposits of collagen I were not increased. Interstitial fibrosis appeared to be restricted to areas of severe plasma cell infiltration, but it could also have a more dispersed presentation in the severely infiltrated marrow. There was a high co‐distribution of collagen III fibrils and reticulin fibres. Serum PIIINP levels were elevated in most patients, and in the follow‐up study serum PIIINP showed a good correlation with the response to treatment. Patients with resistant or progressive disease had continually elevated levels of PIIINP. In most patients with responsive disease serum PIIINP normalized, and we observed no relapses in patients who had normal serum PIIINP levels. Other patients who responded to treatment by reduced M‐component level, but had persistently elevated serum levels of PIIINP, had either early relapses or developed progression of osteolytic lesions in spite of unchanged M‐component levels. Therefore an elevated serum PIIINP during treatment might indicate an active malignant clone. Serum PIIINP does not simply follow the M‐component, but gives further information of potential therapeutic value.

Pneumococcal Septicaemia and Meningitis in Vaccinated Splenectomized Adult Patients

A retrospective survey of the occurrence of pneumococcal septicaemia and meningitis in splenectomized adults was performed at a regional haematological centre after the introduction of pneumococcal vaccination in 1978. During this period 4 episodes of pneumococcal septicaemia were observed in 3 vaccinated, splenectomized patients. In all episodes the pathogenic strain was of an unusual serotype not included in the vaccine lending indirect evidence for the clinical efficacy of the pneumococcal vaccine, even in immunocompromised patients.

Nonfatal Total Expulsion of the Distal Oesophagus Due to Invasive Candida Oesophagitis

Invasive fungal infection is an increasing problem in severely immunocompromised patients. A 30-year-old man with profound pancytopenia due to acute myelogenous leukaemia acquired a severe invasive candida oesophagitis with total desquamation and expulsion of 90 mm of the distal oesophagus. The case report lends support to the concept of early recognition of fungal oesophagitis including species identification and possibly also antimycotic prophylaxis during immunosuppressive treatment.