Effects Of Dalteparin On The Heparanase/Syndecan-1 Axis In a Randomized Phase 2 Clinical Trial Of Patients With Treatment-Naive Multiple Myeloma

The role of the tumor microenvironment (TME), including the heparanase/syndecan-1 (H/S1) axis in the growth and progression of multiple myeloma (MM) has been studied principally in in vitroor animal models. Targeting the TME with anti-myeloma agents such as immunomodulatory drugs (IMiDs) is considered standard but the effect of anticoagulation on the H/S1 axis has not been reported in a clinical trial setting. We investigated the combination of lenalidomide (Len; IMiD) and low-dose dexamethasone (dex) with different doses of the low-molecular-weight heparin, dalteparin (DAL), in treatment-naïve MM patients and report the effects on the H/S1 axis.

A randomized phase 2 clinical trial of Len+Dex with prophylactic (5000IU) or therapeutic (200IU/Kg) doses of DAL in newly diagnosed MM patients was initiated. Patients were administered 14 days of respective DAL dose alone as a “run-in” and then Len+Dex were added for a maximum of 6, 28-day cycles. Peripheral blood collection was done on day (D)-14, D-7, D1, D7, D15 in cycle1 and then D1 of each subsequent cycle to measure D-dimer, Syndecan-1 and IL6 levels by ELISA. Log-transformed levels were used in a linear model to test for differences between the two doses of DAL overall, changes over time, as well as different change patterns between the two doses. Basic summary statistics and scatterplots were used to summarize the data, while untransformed data were used for non-parametric summary numbers (medians, ranges, Spearman correlation). Means and associated 95% confidence intervals (CI) were based on the log-transformed values and anti-log transformation was used to present the results in the original scale, with the result that differences between the two groups were reported as ratios.

Eleven patients (5 females, 6 males) have been enrolled in the ongoing trial (target accrual: 30), of which one was ineligible due to an acquired factor VIII inhibitor. Median age at study onset was 60.8 years (range 38.1-69.9 years). Disease stage included International Staging System (ISS) I in 5, II in 4 and III in 2 patients. Lytic lesions at diagnosis were present in 6 (55%) patients while plasmacytomas were noted in 5 (45%) patients. Median bone marrow plasmacytosis was 40% (range 10%-90%). One case of venous thrombosis was noted on treatment in the high-dose arm after 4 cycles of treatment. We did not find any correlations between baseline levels of D-dimer, IL6 or Syndecan with patient age, gender, ISS stage, presence of lytic lesions or plasmacytomas. No significant correlation was observed between the changes in these three parameters over time or related to DAL dose. However, observing shorter treatment periods showed that the D-dimer decreased significantly between C1D-14 and C1D1 for the low-dose group (mean 0.52; 95% CI 0.37, 0.72), high-dose group (mean 0.44; 95% CI 0.31, 0.65) and all patients taken together (mean 0.48; 95% CI 0.4, 0.59). We also noted a significant increase in Syndecan-1 between C1D-14 and C1D1 for the high-dose group (mean 2.06; 95% CI 1.3, 3.25) and for all patients taken together (mean 1.71; 95% CI 1.28, 2.27), but not for the low-dose group. No significant change was noted in IL6 for this period. However, a significant increase in IL6 was noted early on after the introduction of Len+Dex to DAL between C1D1 and C1D15 in the high-dose (mean 3.21; 95% CI 1.17, 8.8) and overall (mean 2.46; 95% CI 1.52, 3.99) patient groups. These changes did not persist in subsequent treatment periods.

In an ongoing phase 2 clinical trial focused on the modulation of H/S1 axis in response to treatment of MM with IMiDs and DAL, we noted a significant decrease in D-dimer when patients were treated with DAL alone prior to initiating Len+Dex. We observed a significant increase in Syndecan-1 in all patients as well as in the high-dose group in response to treatment with DAL alone. We also noted an IL6 flair phenomenon, with a significant increase in IL6 in all patients immediately after the initiation of Len+Dex. These initial findings suggest significant modulation of the MM microenvironment by LMWH.

Off Label Use: Use of lenalidomide for treatment-naive multiple myeloma patients, Use of dalteparin for prophylaxis of thromboembolism in multiple myeloma patients treated with immunomodulatory agent with dexamethasone. O'Connell:Celgene Corp.: Speakers Bureau.