Thalidomide-dexamethasone as up-front therapy for patients with newly diagnosed multiple myeloma: thrombophilic alterations, thrombotic complications, and thromboprophylaxis with low-dose warfarin

Abstract Thalidomide-containing regimens are currently being used as standard initial therapy for both younger and elderly pts with multiple myeloma (MM), but are associated with an increased risk of venous thromboembolism (VTE) which necessitates routine thromboprophylaxis. Controversies exist concerning the best thromboprophylactic regimen to be used in these pts. To address this issue, the Italian Myeloma Network GIMEMA designed a phase III sub-study aimed at prospectively investigating the efficacy and safety of low molecular weight heparin (LMWH) or fixed low-dose warfarin (WAR) or low-dose aspirin (ASA) as prophylaxis against VTE in newly diagnosed MM pts who were randomized to receive primary induction therapy with thalidomide-containing regimens in the context of 2 phase III studies conducted by the same group. In one of these studies, pts with ≤65 years of age were randomly assigned to receive Velcade-Thalidomide-Dexamethasone (VTD) or Thalidomide-Dexamethasone (TD) before autologous transplantation. In the other study, Velcade-Melphalan-Prednisone (VMP) was compared with VMP plus thalidomide (VMPT) for elderly patients aged >65 years. The daily dose of Thalidomide was 200 mg in both VTD and TD, and 50 mg in VMPT. Pts randomized to VTD or TD received a total Dexamethasone dose of 320 mg/cycle, while those assigned to VMP or VMPT were given a total Prednisone dose of 240 mg/m2/cycle. By sub-study design, pts treated on VTD or TD or VMPT were randomly assigned to receive thromboprophylaxis with LMWH (Enoxaparin, 40 mg/d) or WAR (1.25 mg/d) or ASA (100 mg/d) for the duration of induction therapy. At the opposite, pts randomized to VMP did not receive any prophylaxis and were used as controls. Sub-study end points included incidence of VTE, acute cardiovascular events, sudden death, bleeding and any other serious adverse events. At the time of the present analysis, 703 pts who received at least 3 cycles of induction therapy were evaluated. Of these pts, 164 treated on VMP were the control group, while the remaining 539 pts (of whom, 209 treated on VTD, 211 on TD and 119 on VMPT) were randomized to receive either LMWH (n=178) or WAR (n=180) or ASA (n=181). Baseline pts characteristics and risk factors for VTE were comparable in all sub-groups. Overall, the risk of VTE was 3.9% with WAR vs 4.5% with LMWH vs 5.5% with ASA (P values not significant for comparisons between different sub-groups), whereas it was 1.8% among the controls. Median times to onset of VTE for pts treated on LMWH or WAR or ASA were 2.66 vs 2.96 vs 2.10 months, respectively. Pts receiving Velcade-containing regimens (VTD or VMPT) had a VTE frequency in the range of approximately 3%, as compared to 5.8% for pts on TD (P value not significant). The rates of cardiovascular events were 0.6% in each of sub-groups including LMWH, WAR and controls, vs 1.1% for pts treated on ASA. No sudden deaths were reported. The incidence of all grades bleeding was 0.6% with LMWH vs 1.1% with WAR vs 3.3% with ASA (P values not significant for comparisons between different sub-groups), while it was 3.7% among the controls. In conclusion, results of the present analysis show that the overall risk of VTE among sub-groups of pts treated with different thalidomide-containing regimens was not superior to that expected during the natural course of MM. No significant relationship was found between the frequency of VTE and thromboprophylactic regimens, induction treatments (e.g. containing or not Velcade) and age of pts (e.g. young vs elderly). In comparison with LMWH and WAR, there was a higher, albeit marginal, risk of VTE and bleeding complications associated with ASA prophylaxis. Finally, a finding not previously well recognized, fixed low-dose WAR was not inferior to LMWH in reducing the risk of VTE among newly diagnosed MM pts receiving thalidomide-containing regimens. For these pts, LMWH, WAR and ASA are likely to be effective thromboprophylactic regimens.

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Baseline Thrombophilic Alterations and Risk of Venous Thromboembolism in 266 Multiple Myeloma Patients Primarily Treated with Thalidomide and High-Dose Dexamethasone.

Blood ◽

10.1182/blood.v110.11.3997.3997 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3997-3997

Author(s):

Elena Zamagni ◽

Lelia Valdre ◽

Michela Cini ◽

Cristina Legnani ◽

Patrizia Tosi ◽

...

Keyword(s):

Multiple Myeloma ◽

Venous Thromboembolism ◽

Protein C ◽

Low Dose ◽

Autologous Transplantation ◽

Phase Iii ◽

High Dose ◽

Induction Phase ◽

Newly Diagnosed ◽

Dose Warfarin

Abstract Venous thromboembolism (VTE) has emerged as a major adverse event of primary induction therapy with thalidomide (thal) and dexamethasone (dex) for newly diagnosed multiple myeloma (MM). Aim of the present study was to investigate the relationship between thrombophilic alterations and the risk of VTE in 266 patients who received four months of therapy with thal (200 mg/d) and pulsed high-dose dex in preparation for double autologous transplantation. The rate of VTE in the whole group of patients was 11.6%. The risk of VTE was 26.3% (86.2% patient-years) among the first 19 patients who entered the study and did not received any prophylaxis against thrombosis. The corresponding value among the remaining 247 patients who received thromboprophylaxis with fixed low-dose (1.25 mg/d) warfarin during the four months of thal-dex therapy was 10.6% (35.5% patient-years) (P=0.04). Episodes of VTE occurred at a median of 53 days from the start of thal therapy and, with the exception of 3 patients, were observed after at least a partial response to thal-dex was documented. No VTE events were recorded during the first two months after the end of the induction phase. After VTE occurrence, the majority of patients went on with thal treatment plus full anticoagulation, without evidence of progression of thrombosis. One hundred and ninety patients were evaluated for the presence of thrombophilic alterations at baseline and at the end of thal-dex therapy. The prevalence of factor V Leiden (3.2%) or g20210A prothrombin (2.1%) polymorphism in patients with MM was similar to that observed in 183 healthy controls (3.3%, P= 0.81; 3.8%, P= 0.50, respectively). The relative risk of VTE for patients carrying one of these thrombophilic alterations was 20% compared with 9.4% for patients who lacked both of them (P= 0.58). Reduced protein C and S activities or acquired activated protein C resistance (aAPCR) were recorded at baseline in 11% and 7.4% of MM patients, respectively. Abnormal values at baseline normalized almost completely at the end of treatment. Carriers of aAPCR and/or of reduced levels of natural anticoagulants at baseline did not have a significantly higher risk of VTE compared with normal patients (15.2% vs 9.3%; P=0.49). In conclusion, no significant relationship was found between baseline thrombophilic alterations, including aAPCR, and the risk of thal-related VTE. Prophylaxis with fixed low-dose warfarin was associated with an apparent decrease in the rate of VTE in comparison with a subgroup of patients who did not receive any thromboprophylaxis. A prospective phase III study comparing low molecular weight heparin with fixed low-dose warfarin with aspirin is currently ongoing in Italy to evaluate the best prophylaxis against the risk of thal-related VTE for patients with newly diagnosed MM.

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Three Drug Regimens for Newly Diagnosed Multiple Myeloma Transplant-Ineligible Elderly Patients - a Systematic Review

Blood ◽

10.1182/blood-2019-132095 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5574-5574

Author(s):

Abdul Aziz Siddiqui ◽

Kazi Najamus-saqib Khan ◽

Arafat Ali Farooqui ◽

Muhammad Saad Farooqi ◽

Muhammad Junaid Tariq ◽

...

Keyword(s):

Multiple Myeloma ◽

Elderly Patients ◽

Phase Ii ◽

Low Dose ◽

Phase Ii Trial ◽

Alkylating Agents ◽

Phase Iii ◽

Newly Diagnosed ◽

Great Efficacy ◽

Drug Regimens

Introduction: Patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplant (ASCT) tend to have comorbidities and/or advanced age that make this subset of patients difficult to manage with current drug regimens. Methods: A comprehensive literature search of PubMed, Embase, Clinicaltrials.gov and Web of Science was performed from inception and completed on 07/17/2019. Studies focusing on efficacy and tolerability of 3-drug regimens in patients with NDMM were included for the review. Results: Out of 3579 studies, a total of 10 (08 phase II and 03 phase III) clinical trials in last ten years (2010-2019) using 3-drug regimens in NDMM elderly pts (893M/807F) ineligible for ASCT (determined by investigators) were selected. A total of 1703/1740 NDMM pts were evaluated. Proteasome inhibitors (PIs) such as carfilzomib (C), bortezomib (V) and ixazomib (I) showed promising results in elderly transplant-ineligible NDMM pts. CLARION trial (phase III, n=955) compared two PIs (C and V) with melphalan (M) and prednisone. There was no statistically significant difference in progression-free survival (PFS) between two groups (median: 22.3 vs 22.1 months; HR: 0.91; 95% CI, 0.75-1.10, p = 0.159) as well as overall survival (OS) (HR: 1.08; 95% CI: 0.82-1.43). Difference in the least square means of the HR-QoL (Health related- quality of life) was 4.99 (p<.0001) favoring C-group. M may not be an ideal drug to combine with carfilzomib in this setting given more AEs.(Facon et al 2019). V as 3-drug regimen in combination with lenalidomide (L) in 242 pts achieved statistically significant prolonged PFS (median 43 mo) and OS (median 75 mo) with great efficacy and acceptable risk-benefit profile. (Durie et al 2017; phase III). Multinational phase II trial (n=70) by Dimopoulos et al (2019) evaluated I, with different fixed doses of cyclophosphamide (Cy). Median duration was 19 cycles, indicating the long-term tolerability of regimen. With favorable toxicity profile and maintained QoL scores, trial concluded that this therapy is tolerable in elderly transplant-ineligible NDMM pts. Tuchman et al (2017) in phase II trial (n=14) investigated (V-Cy-d) and achieved ORR of 64%, with ≥VGPR of 57%. Low dose V showed great efficacy with M yielding ORR of 86% and VGPR or better of 49% in phase II trial (n=101) that also evaluated Cy as 3-drug combination but results were more productive with M with longer PFS and OS which reduced when impact of frailty was examined on outcomes. Since toxicity was higher with M, trial suggested that 2-drug combination should be preferred in elderly frail patients. (Larocca et al 2015). Efficacy was quite promising when Bringhen et al (2014) trialed C with Cy-d; 87% OS and 76% PFS at 1 y in phase II trial (n=58) with much favorable safety profile. Monoclonal antibodies (mAb) such as elotuzumab (E) and pembrolizumab (Pe) are also tested in elderly. First study conducted on NDMM pts using humanized mAb; E, in phase II trial (n=40) by Takezako et al (2017) attained primary endpoint of the study (ORR) of (88%) and VGPR or better of 45% in Japanese pts with tolerable toxicities in elderly. No subjects on this study experienced severe peripheral neuropathy. KEYNOTE-185; a phase III multinational trial by Usmani et al (2019) evaluated Pe with Ld in 151 pts. FDA halted this study due to unfavorable benefit-risk profile; 19 deaths, 6 due to disease progression (PD), and 13 due to treatment-related AEs. Median PFS and median OS were not reached in either group. Immunomodulators such as L achieved one of the longest PFS reported in a trial of transplant ineligible patients (35 mo) by using LVd regimen in phase II multicenter trial (n=50). (O'Donnell et al 2018) Alkylating agents like bendamustine (ben) and M have been tested in different novel regimens. Decreasing intensity and increasing duration of ben resulted in better outcomes in phase II trial (n=59) by Berdeja et al (2016) and can be given as first line treatment. Ben yielded great results with low dose dexa as compared to high dose achieving 92% ORR. Original regimen was effective but relatively more toxic. Incidence of herpes and neuropathy decreased dramatically with the treatment modifications. Conclusion: Three-drug regimens having PIs, mABs, immunomodulators and alkylating agents have shown desirable results in NDMM transplant (ASCT)-ineligible elderly patients and are likely the emerging standard of care for NDMM. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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Whole-Body Low-Dose Multidetector-Row CT in Multiple Myeloma: Guidance in Performing, Observing, and Interpreting the Imaging Findings

Life ◽

10.3390/life11121320 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1320

Author(s):

Antonio Pierro ◽

Alessandro Posa ◽

Costanzo Astore ◽

Mariacarmela Sciandra ◽

Alessandro Tanzilli ◽

...

Keyword(s):

Multiple Myeloma ◽

Low Dose ◽

Plasma Cells ◽

Traditional Approach ◽

Response To Treatment ◽

Whole Body ◽

Newly Diagnosed ◽

Low Dose Ct ◽

Lytic Lesions ◽

Total Body

Multiple myeloma is a hematological malignancy of plasma cells usually detected due to various bone abnormalities on imaging and rare extraosseous abnormalities. The traditional approach for disease detection was based on plain radiographs, showing typical lytic lesions. Still, this technique has many limitations in terms of diagnosis and assessment of response to treatment. The new approach to assess osteolytic lesions in patients newly diagnosed with multiple myeloma is based on total-body low-dose CT. The purpose of this paper is to suggest a guide for radiologists in performing and evaluating a total-body low-dose CT in patients with multiple myeloma, both newly-diagnosed and in follow-up (pre and post treatment).

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Phase II study of carfilzomib, thalidomide, and low-dose dexamethasone as induction and consolidation in newly diagnosed, transplant eligible patients with multiple myeloma; the Carthadex trial

Haematologica ◽

10.3324/haematol.2018.205476 ◽

2019 ◽

Vol 104 (11) ◽

pp. 2265-2273 ◽

Cited By ~ 8

Author(s):

Ruth Wester ◽

Bronno van der Holt ◽

Emelie Asselbergs ◽

Sonja Zweegman ◽

Marie Jose Kersten ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase Ii ◽

Low Dose ◽

Phase Ii Study ◽

Newly Diagnosed

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Double Autologous Transplant Versus Tandem Autologus - Non Myeloablative Allogeneic Transplant for Newly Diagnosed Multiple Myeloma.

Blood ◽

10.1182/blood.v106.11.46.46 ◽

2005 ◽

Vol 106 (11) ◽

pp. 46-46 ◽

Cited By ~ 4

Author(s):

B. Bruno ◽

M. Rotta ◽

F. Patriarca ◽

N. Mordini ◽

B. Allione ◽

...

Keyword(s):

Multiple Myeloma ◽

Low Dose ◽

High Dose Chemotherapy ◽

High Dose ◽

Newly Diagnosed ◽

Allogeneic Hct ◽

Autologous Transplant ◽

Autologous Hct ◽

Beta 2 Microglobulin

Abstract Allogeneic approaches employing low dose TBI nonmyeloablative conditionings reported a dramatic reduction of transplant-related mortality (TRM) compared to conventional high dose regimens in newly diagnosed multiple myeloma (MM) (Maloney et al, Blood, 2003). The role of allografting, however, compared to autologous HCT remains to be determined. From September 1999 to July 2004, 241 consecutive MM patients, up to the age of 65, were diagnosed at five academic Italian Institutions. Overall, 194/241 had natural siblings (Table 1): 158/194 (81%) were HLA typed, while 36/194 (19%) were not typed for the following reasons: patients not eligible for high dose chemotherapy (n. 14); siblings not eligible for peripheral hematopoietic cell (PHC) donation (n.11); patient refusal to high dose chemotherapy (n. 9), unknown (n.2). Seventy-six/158 (48%) with a matched donor were offered a tandem autologous- nonmyeloablative allogeneic HCT approach. Eventually, 56/76 (73%), the “auto-allo group”, were enrolled while 20 did not enter the tandem program as 5 siblings (5/76, 7%) were not eligible for PHC donation, 5 patients refused an allogeneic HCT, and 10 patients preferred allografting as a possible salvage treatment. Of 102 patients without matched donors or after refusal to allografting, 73, “double-auto group”, underwent a standard double autologous transplant while 29 received less intense treatments because of clinical conditions or patient preference. Table 1 Newly diagnosed pts 241 With sibs/without sibs 194 /47 (total 241) HLA typed /not HLA typed 158 /36 (total 194) Matched sibs /No matched sibs 76 /82 (total 158) Auto-Allo”/“Double Auto”/Other”“ 56 /73 /29 (total 158) After induction chemotherapy, patients of both groups underwent G-CSF mobilised autografting with high dose melphalan (200 mg/m2). In the “auto-allo” group, the autologous HCT was followed, 2-4 months later, by low dose (2.0 Gy) TBI, allogeneic PHC infusion, and post transplant mycophenolate mofetil and cyclosporin. In the “double-auto group”, patients received a second autologous HCT. Patients characteristics were as follows: age: 54 (range 34–65) vs 53 (range 33–64) (p=ns); stage III myeloma: 77% vs 64% (p=0.03); beta 2 microglobulin > 2,5 mg/dl: 75% vs 59% (p=0.005), for the “auto-allo group” and for “the double-auto group”, respectively. At the time of this analysis, 56/56 of the “auto-allo group” and 55/73 of “the double-auto group” had completed the transplant programs. After median follow up of 3 years (range 11–80 months), TRM was 11% vs 4% (p=0.09); complete remission rates, defined as the disappearance of the monoclonal paraprotein by immunofixation, were 46% vs 16% (p=0.0001); overall survivals were 84% versus 62% (p=0.003); progression free survivals were 75% vs 41% (p=0.00008); event free survivals were 61% (34/56)% vs 38% (30/73) (p=0.006) in the “auto-allo group” and in the “double-auto” group, respectively. Longer follow up is needed, however data suggest that the “auto- non myeloablative allo” approach is not inferior to “double autologous” HCT in newly diagnosed MM.

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A Phase III Study of Enoxaparin vs Aspirin vs Low-Dose Warfarin as Thromboprophylaxis for Newly Diagnosed Myeloma Patients Treated with Thalidomide Based-Regimens.

Blood ◽

10.1182/blood.v114.22.492.492 ◽

2009 ◽

Vol 114 (22) ◽

pp. 492-492 ◽

Cited By ~ 8

Author(s):

Antonio Palumbo ◽

Michele Cavo ◽

Sara Bringhen ◽

Maide Cavalli ◽

Francesca Patriarca ◽

...

Keyword(s):

Cardiovascular Events ◽

Low Dose ◽

Conflicts Of Interest ◽

Final Analysis ◽

Phase Iii ◽

Fixed Dose ◽

Minor Bleeding ◽

Newly Diagnosed ◽

Dose Warfarin ◽

Anticoagulant Prophylaxis

Abstract Abstract 492 Background. The risk of venous thromboembolism (VTE) is high in newly diagnosed myeloma (MM) patients who receive thalidomide-based regimens. Anticoagulant prophylaxis is recommended. Controversies exist on the best thromboprophylactic regimen to adopt. Aims. In this prospective, multicenter phase III trial we evaluated the safety and the efficacy of low-molecular weight heparin (LMWH) or low-dose aspirin (ASA) or low-fixed dose warfarin (WAR) as anticoagulant prophylaxis. End-points were incidence of VTE, acute cardiovascular events, sudden death, major and minor bleeding. Methods. In a GIMEMA study, 991 newly diagnosed MM patients were randomized to VTD (Velcade 1.3 mg/m2 d 1,4,8,11; Thalidomide 200 mg/d; Dexamethasone 320 mg/21 d) or TD (Thalidomide 200 mg/d; Dexamethasone 320 mg/21 d) or VMPT (Velcade 1.3 mg/m2 d 1,8,15,22; Melphalan 9 mg/m2 d 1-4; Prednisone 60 mg/m2 d 1-4; Talidomide 50 mg/d) or VMP (Velcade 1.3 mg/m2 d 1,8,15,22; Melphalan 9 mg/m2 d 1-4; Prednisone 60 mg/m2 d 1-4). In a sub-study, patients treated with VTD or TD or VMPT were randomly assigned to receive LMWH (Enoxaparin 40 mg/d, N=223) or ASA (Aspirin 100 mg/d, N=227) or WAR (Warfarin 1.25 mg/d, N=223) for the duration of the induction therapy; 61 patients were excluded from sub-study because of indication for anticoagulant/antiplatelet therapy or high-risk of bleeding. Patients treated with VMP (N=257) did not receive any prophylaxis and were used as controls. Results. Patient characteristics and distribution of major risk factors were similar in all groups. The incidence of VTE was 5% in the LMWH group, 6% in the ASA group and 8% in the WAR group (p not significant). VTEs were 2% in the VMP group. Median time to onset of VTE for patients who received LMWH or ASA or WAR were 4.7, 2.4 and 2.4 months, respectively. Patients who received higher doses of both steroids and thalidomide (VTD and TD) had a higher VTE incidence (7%) in comparison with those who received lower doses (VMPT, 3%, p=0.06). Patients treated with bortezomib (VTD and VMPT) had a lower VTE incidence (5%) in comparison with patients on TD (8%, p=0.08). The rates of cardiovascular events were 2% in the LMWH group, 1% in the ASA group and 0.5% in the WAR group. The incidence of major and minor bleeding was 2% in the LMWH group, 3% in the ASA group and 1% in the WAR group (p not significant). The incidence of combined thrombosis, bleeding and cardiovascular events was 9% in the LMWH group, 10% in the ASA group and 9% in the WAR group (p not significant). Conclusion. The overall incidence of VTE was less than 10% in all groups and was not superior to that expected during the natural course of MM. The LMWH patients had lower risk of VTE, although no statistical difference was observed. LMWH, WAR and ASA are likely to be effective thromboprophylactic regimens. The final analysis on 991 patients will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

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Low-dose dexamethasone and thalidomide with higher frequency zoledronic acid (dtZ) for newly diagnosed multiple myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.18506 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 18506-18506

Author(s):

G. Teoh ◽

D. Tan ◽

C. Chuah ◽

W. Hwang ◽

R. Yiu ◽

...

Keyword(s):

Multiple Myeloma ◽

Zoledronic Acid ◽

Complete Remission ◽

Median Time ◽

Low Dose ◽

Dental Treatment ◽

Osteonecrosis Of The Jaw ◽

Newly Diagnosed ◽

Grade 3 ◽

The Individual

18506 Background: Although dexamethasone (Dex), thalidomide (Thal) and zoledronic acid (Zol) have frequently been combined for the treatment of multiple myeloma (MM), the ideal dosing schedule is unknown. We previously reported that lower doses of Dex and Thal can be effectively combined with high-frequency dosing of Zol (Haematologica 2005). Methods: This “dtZ” regimen - which comprises weekly Dex 20 mg OM for 4 days, Thal 50 mg ON, and 3-weekly Zol 4 mg - resulted in an impressive response rate (RR) of 61.6% and near complete remission (nCR)/complete remission (CR) rate of 7.7% in 26 patients with relapsed/refractory MM. Results: In this present study, we treated 22 newly diagnosed MM patients with “dtZ” and report an even more impressive RR of 100.0% and nCR/CR rate of 20–35%. The median time to response was 1.8 months and median time to maximum response was 2.2 months. The median time to progression (TTP) has not been achieved yet. As expected, low-dose Dex/Thal resulted in lower (18.1%) grade 3 or 4 toxicities. These were all infections; which lead to further dose-reduction of Dex. There were no thromboembolic events, despite the fact that aspirin was not routinely given. Of particular interest, 3- weekly Zol was not associated with any significant decrease in renal function, and none of our patients developed osteonecrosis of the jaw (ONJ). In fact, at the time of writing of this abstract, more than 1,000 doses of Zol had been administered in a 3-weekly fashion to these as well as other patients, and only 1 patient developed ONJ. This patient who had already received greater than 20 doses of Zol healed uneventfully after receiving appropriate outpatient dental treatment, and subsequently received another 8 doses of Zol with no recurrence of ONJ. Conclusion: In conclusion, the Zol-based “dtZ” regimen is potentially a highly-effective and safe frontline regimen for MM. Using Zol every 3 weeks with lower doses of Dex and Thal does not appear to increase the rate or severity of nephrotoxicity or ONJ. Although we do not know exactly why every patient responded to “dtZ”, we speculate that this could be due to a critical balance that has been achieved between the anti-MM, anti-osteoclastic and immunostimulatory effects of the individual drugs of the combination. No significant financial relationships to disclose.

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