Multiple myeloma patients experience high response rate with new three-drug combination

Abstract Background: The combination of DVd with Thalidomide (T) results in a high response rate (greater than 80% with about 50% of patients achieving a CR or NCR) in multiple myeloma. Revlimid, an immunomodulatory drug (IMiD) is active in patients with MM. We previously reported on a phase I trial of DVd-R in patients with MM, in which the maximum tolerated dose of R was 10mg daily. Methods: The DVd-R regimen was given as follows: on day 1 D was given at 40 mg/m2 IVPB; V at 2 mg IVP; d at 40 mg PO daily for 4 days, R was started at 10mg daily. R was given for 21 days consecutively. For the first cycle R was started 7 days prior to chemotherapy, while it was started on day 1 on subsequent cycles (cycle 1 was 35 days). DVd was planned every 28 days for 2 cycles after best response or a minimum of 4 cycles. Maintenance therapy consisted of R +/− Prednisone 50 mg Qod. All patients received amoxicillin, acyclovir and aspirin 81mg prophylactically. Responses were assessed based on the criteria set forth by SWOG. Patients: The study accrued 58 patients to date (36 refractory and 22 relapsed patients), 45 are evaluable for response. The median patient age at the start of the study is 62 years and 74% are males. The median number of prior chemotherapeutic regimen is 3 (range 1–7), 67% of patients had progressed after a Thalidomide containing regimen, 70% had received a VAD like regimen and 17% had received a prior autologous stem cell transplant. The median time from diagnosis to study entry is 39 month (range 5–182). Eighty six percent had Durie Salomon stage III. The mean serum B2microglobin was 6.6mg/dL (s.d.4.2). Results: The median number of cycles of DVd-R delivered was 4. Of evaluable patients, 6 patients had a CR (13%), 5 had a NCR (11%), 16 had a PR (35%), 11 had stable disease (24%), and 7 had progressive disease (15%) as their best response. The median time to best response was 38 days. After a median follow up of 7.3 month (range 0–24 months), 23 patients had progressive disease and 16 patients had died. Fifty two percent of refractory patients (19/36) had a response on DVd-R. Grade 3 and 4 leukopenia occurred in 24% and 15% respectively, however febrile neutropenia occurred in only 1 patient. Grade 3 and 4 infections occurred in 26% and 3% respectively (all but one were pneumonia). Grade 3 thrombocytopenia occurred in 20%. Venous thromboembolic events occurred in 5 patients (9%) (2 patients with pulmonary embolus and 4 with deep venous thrombosis). Grade 3 neuropathy occurred in 3 patients (no patients had grade 4 neuropathy). Two patients developed grade 3 tumor lysis syndrome. Conclusion: DVd-R is an effective chemotherapeutic regimen in patients with RMM who progressed or did not respond to VAD like regimens or to Thalidomide containing regimens, produces a high response rate among chemotherapy resistant patients, and has a manageable toxicity profile. The results will be updated at the time of the meeting.

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Doxorubicin and Dexamethasone Followed by Thalidomide and Dexamethasone (AD-TD) as Initial Therapy for Symptomatic Patients with Multiple Myeloma.

Blood ◽

10.1182/blood.v104.11.2409.2409 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2409-2409 ◽

Cited By ~ 1

Author(s):

Hani Hassoun ◽

Lilian Reich ◽

Virginia M. Klimek ◽

Tarun Kewalramani ◽

Madhav Dhodapkar ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Response Rate ◽

Response Rate ◽

High Response Rate ◽

High Response ◽

Stage Ii ◽

Thromboembolic Complications ◽

Overall Response ◽

Β2 Microglobulin ◽

Low Incidence

Abstract Several drug combinations have been designed for the initial treatment of multiple myeloma. Although none has been shown to be superior, a regimen that leads to a high response rate in association with low incidence of major adverse events is highly desirable. We report response rates and complications - specifically thromboembolic complications- with the combination of doxorubicin, thalidomide and dexamethasone for patients with Durie-Salmon stage II and III symptomatic multiple myeloma. Methods: In this regimen, the drugs are used in a sequential fashion with the intent to reduce the high incidence (up to 28%) of venous thromboembolic complications known to be associated with this combination of drugs (NEJM2001; 344:1951–2; Blood2001;98:1614–5; Blood2002;100:1168–71). Doxorubicin and dexamethasone (AD; A=9mg/m2/day, Days 1–4; D=40mg/day, Days 1–4, 9–12, 17–20) are given for 3 months followed by thalidomide and dexamethasone (TD; T=200mg nightly; D=as above) for 2 months with prophylactic antibiotics and daily aspirin (81 mg/day). At any point during therapy patients achieving a complete response (immunofixation negative) are permitted to forgo further induction therapy and proceed with autologous stem cell transplantation. Results: As of 8/04, we have enrolled 38 patients ( 22 men, 16 women) with a median age of 59 years (range, 35–82). Median β2 microglobulin level was 2.5 mg/L (ND-12.5) and median albumin level 3.95 g/dL. Fluorescent in situ hybridization (FISH) studies of baseline bone marrows, searching for abnormalities of chromosomes 11, 13 and 14, are available for 36 patients. Among those, 22 patients have abnormal findings. Three patients have been removed from study, one for a DVT that occurred during cycle 5, one for a myocardial infarction after cycle 1, and one for refusing further therapy. Five patients are currently receiving treatment. Therefore response data are available for 30 patients. Among those, 26 have responded to therapy (86.6 %), including 6 complete responses (20%), 8 very good partial responses (26.6%) and 12 partial responses (40%). Two patients (6.6 %) have stable disease while two patients (6.6 %) have progression of disease. When patients are stratified according to the International Staging System using β2 microglobulin and albumin levels, the response rate is not influenced by stage, as overall response rate is 81% for stage I (n=22), 100% for stage II (n=7) and 100 % for stage III (n=1). Likewise, the presence of Δ13 does not appear to affect overall response rate (82% for patients with no Δ13 and 100 % for patients with Δ13). Among patients who completed the treatment and those removed from study because of DVT, only three developed DVT (3/31; 9.6 %). All other patients tolerated the treatment well and completed therapy with no major adverse event. Conclusion: These results indicate that the regimen consisting of doxorubicin, dexamethasone, and thalidomide used in a schedule that allows sequential administration of the drugs as described and DVT prophylaxis with low dose aspirin is well tolerated and results in a high response rate with a low incidence of therapy-related thromboembolic complications.

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Reduced-Dosage of Three Drugs Combination of Cyclophosphamide, Bortezomib and Dexamethasone (reduced-CyBorD) Retains High Response Rate with Less Toxicities in Elderly Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.1865.1865 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1865-1865 ◽

Cited By ~ 1

Author(s):

Hideo Yagi ◽

Ryosuke Fujiwara ◽

Keigo Sano ◽

Fujita Mariko ◽

Takashi Iizuka ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Elderly Patients ◽

Response Rate ◽

Conflicts Of Interest ◽

High Response Rate ◽

High Response ◽

High Dose ◽

Weekly Schedule ◽

High Dose Dexamethasone

Abstract Abstract 1865 Background: The three drugs combination of cyclophosphamide, bortezomib and dexamethasone (CyBorD) has been proven to be a powerful regimen for the treatment of the patients with multiple myeloma (MM). However, twice-weekly schedule of bortezomib and high dose dexamethasone has been shown to cause significant toxicities, including severe peripheral neuropathy (PN). Recently, once-weekly bortezomib induction therapy with CyBorD (modified-CyBorD) has shown less toxicity with high response rate equal to original regimen (Reeder, CB et al. Leukemia 2009). However, more than half of the patients developed bortezomib induced PN (BiPN) in modified-CyBorD. Thus it was still concerned adverse event for the transplant ineligible patients, especially frail elderly patients because it often caused interruption or withdrawal of the treatments, resulting in fewer efficacies. Under these circumstances, we introduced the reduced-dosage of CyBorD regimen (reduced-CyBorD) in the transplant ineligible patients with multiple myeloma for continuation of the treatment. Methods: The protocol consisted of bortezomib given intravenously at a dose of 1.3 mg/m2once a week on days 1, 8, 15, cyclophosphamide orally at a dose of 50 mg daily on days 1–21, and dexamethasone orally or intravenously at a dose of 20 mg daily on days 1,2,8,9,15,16 in 4-week cycles. Total of 20 patients, including 12 newly diagnosed and 8 refractory, were treated with reduced-CyBorD and evaluated its efficacy and safety. Results: The median age was 72 years (range from 62 to 81). 14 patients were more than 70 year-old (70%). A half of the patients were female. According ISS, 3 patients were classified in stage I, 6 were in II, and 11 were in III. The overall response was 86.6 % with 26.7 % CR/nCR (1 CR, 3 nCR, 5 VGPR and 4 PR). Hematological adverse events were neutropenia (35%; G1/2 n=7), lymphocytopenia (35%; G1/2 n=1, G3/4, n=1), thrombocytopenia (10%; G1/2 n=2). Non-hematological adverse events were pneumonia (20%; G2 n=2, G3 n=2), VZV infection (15%; G2 n=3), cerebral infarction (5%; G2 n=1). Importantly, only three patients (15%) developed grade 1 PN, and no patient reduced or discontinued bortezomib due to PN. Conclusions: Reduced-CyBorD with three times once-weekly bortezomib retained high efficacy seen in standard and modified CyBorD (4 times bortezomib administration). Furthermore, it was found that this regimen obviously revealed less toxicity, especially BiPN compared with those previous regimens (See Table). Our results suggested that reduced-CyBorD might be safe and effective approach to the transplant ineligible patients, especially elderly frail patients with MM. Disclosures: No relevant conflicts of interest to declare.

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