Bendamustine-Based Regimens as Salvage Therapy in Refractory/Relapsed Multiple Myeloma Patients: A Retrospective Real-Life Analysis by the Polish Myeloma Group

Multiple myeloma (MM) is an incurable disease and patients become refractory to the treatment in the course of the disease. Bendamustine-based regimens containing steroids and other agents are among the therapeutic options offered to MM patients. Here, we investigated the safety and the efficacy of bendamustine used in patients with refractory/relapsed MM (RRMM). The patients were treated with bendamustine and steroids (n = 52) or bendamustine, steroids and immunomodulatory agents or proteasome inhibitors (n = 53). Response rates, progression-free survival (PFS), overall survival (OS) and frequency of adverse events were compared between both study groups. Most efficacy measurements were better in patients treated with three-drug regimens: overall response rate (55% versus 37%, p = 0.062), median PFS (9 months versus 4 months, p < 0.001), median OS survival (18 months versus 12 months, p = 0.679). The benefit from combining bendamustine and steroids with an additional agent was found in subgroups previously treated with both lenalidmide and bortezomib, with stem cell transplant and with more than two previous therapy lines. Toxicity was similar in both study groups and bendamustine-based therapies were generally well-tolerated. Our study suggests that bendamustine may be an effective treatment for patients with RRMM. Three-drug regimens containing bendamustine, steroids and novel agents produced better outcomes and had acceptable toxicity. The efficacy of bendamustine combined with steroids was limited.

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Effect of prior treatments on selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01071-9 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Maria V. Mateos ◽

Maria Gavriatopoulou ◽

Thierry Facon ◽

Holger W. Auner ◽

Xavier Leleu ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Adverse Events ◽

Randomized Study ◽

Progression Free Survival ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Prior Therapy ◽

Boston Study ◽

Previously Treated

AbstractTherapeutic regimens for previously treated multiple myeloma (MM) may not provide prolonged disease control and are often complicated by significant adverse events, including peripheral neuropathy. In patients with previously treated MM in the Phase 3 BOSTON study, once weekly selinexor, once weekly bortezomib, and 40 mg dexamethasone (XVd) demonstrated a significantly longer median progression-free survival (PFS), higher response rates, deeper responses, a trend to improved survival, and reduced incidence and severity of bortezomib-induced peripheral neuropathy when compared with standard twice weekly bortezomib and 80 mg dexamethasone (Vd). The pre-specified analyses described here evaluated the influence of the number of prior lines of therapy, prior treatment with lenalidomide, prior proteasome inhibitor (PI) therapy, prior immunomodulatory drug therapy, and prior autologous stem cell transplant (ASCT) on the efficacy and safety of XVd compared with Vd. In this 1:1 randomized study, enrolled patients were assigned to receive once weekly oral selinexor (100 mg) with once weekly subcutaneous bortezomib (1.3 mg/m2) and 40 mg per week dexamethasone (XVd) versus standard twice weekly bortezomib and 80 mg per week dexamethasone (Vd). XVd significantly improved PFS, overall response rate, time-to-next-treatment, and showed reduced all grade and grade ≥ 2 peripheral neuropathy compared with Vd regardless of prior treatments, but the benefits of XVd over Vd were more pronounced in patients treated earlier in their disease course who had either received only one prior therapy, had never been treated with a PI, or had prior ASCT. Treatment with XVd improved outcomes as compared to Vd regardless of prior therapies as well as manageable and generally reversible adverse events. XVd was associated with clinical benefit and reduced peripheral neuropathy compared to standard Vd in previously treated MM. These results suggest that the once weekly XVd regimen may be optimally administered to patients earlier in their course of disease, as their first bortezomib-containing regimen, and in those relapsing after ASCT.Trial registration: ClinicalTrials.gov (NCT03110562). Registered 12 April 2017. https://clinicaltrials.gov/ct2/show/NCT03110562.

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The evolution of stem-cell transplantation in multiple myeloma

Therapeutic Advances in Hematology ◽

10.1177/2040620718761776 ◽

2018 ◽

Vol 9 (5) ◽

pp. 123-133 ◽

Cited By ~ 20

Author(s):

Sarakshi Mahajan ◽

Nidhi Tandon ◽

Shaji Kumar

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Maintenance Therapy ◽

Cell Transplantation ◽

Proteasome Inhibitors ◽

Progression Free Survival ◽

Complete Response ◽

Cell Transplant ◽

First Relapse

Autologous stem-cell transplantation (ASCT) remains an integral part of treatment for previously untreated, and may have value in the treatment of relapsed patients with, multiple myeloma (MM). The addition of novel agents like immunomodulators and proteasome inhibitors as induction therapy before and as consolidation/maintenance therapy after ASCT has led to an improvement in complete response (CR) rates, progression-free survival (PFS) and overall survival (OS). With advances in supportive care, older patients and patients with renal insufficiency are now able to safely undergo the procedure. The data concerning the timing of ASCT (early in the disease course or at first relapse), single versus tandem (double) ASCT and the role and duration of consolidation and maintenance therapy post ASCT remain conflicting. This review aims to discuss the evolution of stem-cell transplant over the past 3 decades and its current role in the context of newer, safer and more effective therapeutic agents.

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Immunotherapy in Multiple Myeloma: Experience of the Multiple Myeloma Gimema Lazio Group

Blood ◽

10.1182/blood-2018-99-115463 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5634-5634

Author(s):

Federico Vozella ◽

Agostina Siniscalchi ◽

Manuela Rizzo ◽

Tommaso Za ◽

Giusy Antolino ◽

...

Keyword(s):

Multiple Myeloma ◽

Therapeutic Option ◽

Proteasome Inhibitors ◽

Progression Free Survival ◽

Response Duration ◽

Advisory Board ◽

Cell Transplant ◽

Line Of Therapy ◽

Almost All

Abstract Introduction .Treatment of multiple myeloma (MM) patients (pts) has radically changed over the last years following the introduction of next generation proteasome inhibitors (PI) and immunomodulatory derivatives (IMiDs). Despite the improvement of pts' outcome due to these drugs, MM remainsan incurable disease given its propensity for clonal heterogeneity and its complex interaction with the surrounding bone marrow microenvironment. Almost all pts eventually relapse despite their responses to PI, IMiDs or both. Recently, one further therapeutic option for MM patients is represented bydaratumumab, an anti-CD38 monoclonal antibody approved alsofor heavily pre-treated pts who have exhausted all other therapeutic options. Patients and Methods. We report the experience of the Multiple Myeloma GIMEMA Lazio Group in 50 relapsed/refractory MM pts treated with daratumumab as monotherapy. Twenty-nine pts (58%) were men and 21 (32%) women. According to the ISS,24 pts (48%) were ISS I, 11 (22%) ISS II, 7 (14%) ISS III and 8(16%)not evaluable. According toDurie& Salmon, 20 pts (40%) were 1 A, 2 (4%) 1 B, 12 (24%) II A, 1 (2%) II B,7 (14%) III A, 3 (6%) III B and 5 (10%) not evaluable. Isotype IgG-k was found in 21 pts (42%), IgG-λ in 13 (26%), IgA-k in 6 (12%), IgA-λ in 3 (6%), micromolecular k in 5 (10%) andmicromolecular λ in 2 (4%). Median age was 62.3 years (range, 43.1 - 85.7); 32 pts (64%) were refractory to the last line of therapy; 26 (52%) had previously received a stem cell transplant (13 single autologous, 12 tandem autologous and one an autologous followed by an allogeneic transplant). After a median follow-up from diagnosis of 54.5 months (range 1.0 - 203.0) and a median of 3 previous lines of therapy (range 2 - 8), pts received a median of 3 cycles (range 1 - 23) of daratumumab. Results.Forty-seven pts (94%) performed at least one cycle and were evaluable for response. The overall response rate was 74%; in particular, 2 pts obtained a CR (4.2%), 3 pts a VGPR (6.3%), 17 pts a PR (36.2%) and 15 pts a SD (32%), while 10 pts (21.3%) presented a PD. After a median follow-up of 5.3 months (range 1 - 31) ,24 pts(65%) were still in response and alive, one pt (5.8%) died in PR due to post-allograft GVHD and 12 (32%) experienced a PD (1 CR, 1 VGPR, 6 PR and 4 SD). Seven (19%) pts died and 30 (81%) are still alive. With regard to the 3 pts not evaluable for response, 2 died early and 1 has not yet completed the first cycle. The median time to response, duration of response, progression-free survival and overall survival were 1.5 months (range 1.0 - 6.0), 6.7 months (95% CI, 4.14 - 14.21), 5.7 months (95% CI, 3.26 - 13.75) and 22.5 months (95% CI, 11.6 - 36.1), respectively. Daratumumab was well tolerated; the most common adverse events, of any grade, were infections in 20 pts (42.0%) and anaemia in 21 pts (44.0%), which did not lead to treatment discontinuation. Infusion-related reactionswere observed in 7pts (14.8%), grade I-II (4 pts), grade III (3 pts). Conclusions.Daratumumab monotherapy is an effective strategy for heavily pre-treated and refractory pts with multiple myeloma, with a favorable safety profile. This treatment option needs to be considered for pts not eligible for combination therapy of daratumumab with bortezomib or lenalidomide, recently approved also in our country. Disclosures Vozella: Takeda Oncology; Amgen: Honoraria. Annibali:Celgene; Takeda; Amgen, Janssen Cilag: Honoraria. Caravita di Toritto:Johnson & Johnson: Other: Advisory Board, Travel and Accomodation EHA; Amgen: Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Travel and Accomodation EMN; Takeda: Other: Advisory Board; Celgene: Other: Advisory Board, Travel and Accomodation ASH, Research Funding. Foà:NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; AMGEN: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau. Petrucci:Takeda Oncology; Amgen; Celgene; BMS; Janssen Cilag: Honoraria, Other: Advisory Board.

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Antibody Therapies for Multiple Myeloma

10.5772/intechopen.98656 ◽

2021 ◽

Author(s):

Nikolaos Kanellias ◽

Maria Gavriatopoulou ◽

Evangelos Terpos

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibodies ◽

Plasma Cells ◽

Proteasome Inhibitors ◽

Progression Free Survival ◽

Check Point ◽

Incurable Disease ◽

Significant Prolongation ◽

Significant Toxicity ◽

Check Point Inhibitors

Multiple Myeloma (MM) is characterized by the abberant proliferation and expansion of plasma cells in the Bone marrow. Despite the broad use of proteasome inhibitors and IMiDs, Multiple Myeloma remains an incurable disease. The introduction of Monoclonal antibodies, along with bi-specific antibodies and check point inhibitors, has significantly enhanced the armamentarium of available therapeutic options in the relapsed setting. The incorporation of the above-mentioned novel agents in triplet or quadruplet therapeutic regimens has led to significant prolongation of overall survival (OS) and progression free survival (PFS), without adding significant toxicity. Anti-CD38 monoclonal antibodies has become the cornerstone of antimyeloma therapy in both the newly diagnosed and relapsed setting.

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Boosting Immunity against Multiple Myeloma

Cancers ◽

10.3390/cancers13061221 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1221

Author(s):

Raquel Lopes ◽

Bruna Velosa Ferreira ◽

Joana Caetano ◽

Filipa Barahona ◽

Emilie Arnault Carneiro ◽

...

Keyword(s):

Multiple Myeloma ◽

Residual Disease ◽

Proteasome Inhibitors ◽

Treatment Strategies ◽

Complete Response ◽

Drug Conjugates ◽

Incurable Disease ◽

Car T ◽

Patient’S Outcome ◽

The Impact

Despite the improvement of patient’s outcome obtained by the current use of immunomodulatory drugs, proteasome inhibitors or anti-CD38 monoclonal antibodies, multiple myeloma (MM) remains an incurable disease. More recently, the testing in clinical trials of novel drugs such as anti-BCMA CAR-T cells, antibody–drug conjugates or bispecific antibodies broadened the possibility of improving patients’ survival. However, thus far, these treatment strategies have not been able to steadily eliminate all malignant cells, and the aim has been to induce a long-term complete response with minimal residual disease (MRD)-negative status. In this sense, approaches that target not only myeloma cells but also the surrounding microenvironment are promising strategies to achieve a sustained MRD negativity with prolonged survival. This review provides an overview of current and future strategies used for immunomodulation of MM focusing on the impact on bone marrow (BM) immunome.

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Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure

Blood ◽

10.1182/blood-2008-02-141614 ◽

2008 ◽

Vol 112 (12) ◽

pp. 4445-4451 ◽

Cited By ~ 127

Author(s):

Michael Wang ◽

Meletios A. Dimopoulos ◽

Christine Chen ◽

M. Teresa Cibeira ◽

Michel Attal ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Response Rate ◽

Response Rate ◽

Progression Free Survival ◽

Efficacy And Safety ◽

Time To Progression ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Previously Treated ◽

Survival Studies

AbstractThis analysis assessed the efficacy and safety of lenalidomide + dexamethasone in patients with relapsed or refractory multiple myeloma (MM) previously treated with thalidomide. Of 704 patients, 39% were thalidomide exposed. Thalidomide-exposed patients had more prior lines of therapy and longer duration of myeloma than thalidomide-naive patients. Lenalidomide + dexamethasone led to higher overall response rate (ORR), longer time to progression (TTP), and progression-free survival (PFS) versus placebo + dexamethasone despite prior thalidomide exposure. Among lenalidomide + dexamethasone-treated patients, ORR was higher in thalidomide-naive versus thalidomide-exposed patients (P = .04), with longer median TTP (P = .04) and PFS (P = .02). Likewise for dexamethasone alone-treated patients (P = .03 for ORR, P = .03 for TTP, P = .06 for PFS). Prior thalidomide did not affect survival in lenalidomide + dexamethasone-treated patients (36.1 vs 33.3 months, P > .05). Thalidomide-naive and thalidomide-exposed patients had similar toxicities. Lenalidomide + dexamethasone resulted in higher rates of venous thromboembolism, myelosuppression, and infections versus placebo + dexamethasone, independent of prior thalidomide exposure. Lenalido-mide + dexamethasone was superior to placebo + dexamethasone, independent of prior thalidomide exposure. Although prior thalidomide may have contributed to inferior TTP and PFS compared with thalidomide-naive patients, these parameters remained superior compared with placebo + dexamethasone; similar benefits compared with placebo + dexamethasone were not evident for thalidomide-exposed patients in terms of overall survival. Studies were registered at http://www.clinicaltrials.gov under NCT00056160 and NCT00424047.

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Characterization of BCL-2 alternative proteins and outcome in patients with peripheral T-cell lymphoma (PTCL).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e19531 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e19531-e19531

Author(s):

Mario L. Marques-Piubelli ◽

Luisa Maren Solis ◽

Luis Malpica ◽

Sushant Gouni ◽

Ranjit Nair ◽

...

Keyword(s):

Treatment Strategies ◽

Stage Iv ◽

Progression Free Survival ◽

Response To Therapy ◽

Rank Test ◽

Cell Transplant ◽

Functional Studies ◽

Tissue Biopsy ◽

Previously Treated

e19531 Background: The outcome of patients with PTCL, NOS is generally very poor, and the identification of biologically rational targets, which may translate into effective and non-toxic treatment strategies, is a high priority. The pro-survival BCL-2 family members BCL-2, BCL-XL (BCL2L1), BCL-W (BCL2L2), BCL2A1 and MCL-1 contribute to tumor maintenance, progression, and chemo-resistance across a range of cancers, but their contributions in PTCL, NOS are poorly understood. Methods: Patients with PTCL, NOS treated between 09/2000 and 09/2019 and with available tissue biopsy were included in the study. Diagnosis was retrospectively confirmed by two expert hematopathologists. BCL-2, BCL-XL, BCL-W, BCL2A1 and MCL-1 expression was assessed by immunohistochemistry (IHC), and the percentage of positive tumor cells assessed by standard microscopy. The 2014 Lugano Classification was used to define response to therapy. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and were compared using log-rank test between patient groups. Results: Twenty-seven patients were included in the study: 67% were male, 52% ≥ 65 year old, and 48% had stage IV disease; 59% were previously treated and 41% received > 2 lines of therapy, including stem cell transplant (SCT) in 19%. The median expression of BCL-2, BCL-XL, BCL-W, BCL2A1 and MCL-1 by IHC was: 30% (range: 0-100%), 10% (range: 0-90%), 100% (range: 40-100%), 20% (range: 0-90%), and 70% (range: 1-100%), respectively. BCL-2A1 was significantly higher in previously treated patients (35% vs 5%, p = 0.02), and in those who had previously received > 2 lines of therapy (40% vs 5%, p = 0.02). Twenty-four (89%) patients were treated after tissue biopsy, 17 (63%) with chemotherapy, 7 (26%) with biological therapy, and 6 (22%) received subsequent SCT. Five (24%) patients achieved complete remission (CR); only BCL-W associated with response, a higher expression (quartiles 3 and 4) being observed among patients not achieving CR (median 100% vs 90%, p = 0.07). After a median follow-up of 28 months (95% CI, 14-42 months), 22 (81%) patients progressed or died, and median PFS was 4 months (95% CI, 2-6 months); only BCL-W associated with PFS, a shorter median PFS being observed for patients with higher expression (3 months vs 7 months, p = 0.001). At most recent follow-up, 17 (63%) patients died, and median OS was 6 months (95% CI, 1-12 months). only BCL-W associated with OS, a shorter median OS being observed for patients with higher expression (4 months vs not reached, p = 0.004). Conclusions: High expression of BCL-W associates with significantly worse outcome in patients with PTCL, NOS. While clinical trials investigating the safety and efficacy of BCL-2 inhibition in PTCL, NOS are ongoing, these results suggest that concomitant BCL-W inhibition may be beneficial, and functional studies aimed at confirming these findings are highly needed.

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Weekly Cyclophosphamide and Alternate Day Prednisone: An Effective, Convenient and Well Tolerated Treatment for Relapsed Multiple Myeloma Following Autologous Stem Cell Transplant.

Blood ◽

10.1182/blood.v104.11.4917.4917 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4917-4917

Author(s):

A. Keith Stewart ◽

Young Trieu ◽

Suzanne Trudel ◽

Greg Pond ◽

Joseph Mikhael ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Median Time ◽

Stem Cell Transplant ◽

Alkylating Agents ◽

Progression Free Survival ◽

Median Number ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Protein Reduction

Abstract Alkylating agents remain among the most potent therapies available for treatment of Multiple Myeloma (MM). Their use prior to, or following, autologous stem cell transplant (ASCT) is, however, compromised by concerns about stem cell quality and by myelosuppression limiting effective dose delivered. To address this concern we have studied a combination of cyclophosphamide 500 mg p.o. once weekly and prednisone 100 mg p.o. on alternate days in 66 patients requiring salvage therapy post-ASCT. Dose reductions were allowed for toxicity beginning at cycle 2. On an intent to treat basis, 66 patients received this regimen, however, 7 of these patients were not fully evaluable for response due to non-secretory disease. Of the 59 patients evaluable for response, the median time from transplant to treatment was 26.4 months (range, 6.0 to 66.6). The median time from post-transplant relapse to start of cyclophosphamide and prednisone (C/P) therapy was 1.4 months. The median number of therapies from time of diagnosis to C/P initiation was 2 (range, 1.0 to 5.0). At the date of analysis, treatment with C/P is ongoing in 12 (20.3%) patients, with a median duration of 3.6 months (range, 1.9 to 11.6). The 47 patients who have completed C/P therapy were treated for a median time of 5.5 months (range, 0.5 to 21.7). The reason for discontinuation among these 47 patients included disease progression (42.6% of patients discontinued), plateau disease (21.3%), receiving a second transplant (17.0%), toxicity (10.6%), or switched to another regimen (8.5%). A partial response (>50% protein reduction) was obtained in 37.3% of patients, 18.6% attained minimal response (25–50% protein reduction), 33.8% patients stable disease, while 10.2% patients had progressed on treatment. The estimated median (95% CI) months of progression-free survival after start of C/P treatment is 14.9 (8.7, 21.7). Twenty-three (38.9%) of patients have relapsed after C/P treatment, a median (range) of 8.7 (0.5–65.7) months after start of C/P treatment. At 6 months 74.3% (95% C.I. 61.9% – 89.1%) of patients were progression-free with 28% (95% CI: 16.1–49.2%) progression free at two years. At time of analysis, 44 (74.6%) patients are still alive, with a median follow up of 10.6 months (range, 1.2 to 65.7) since the start of C/P therapy. Fifteen patients have died at a median 13.0 months (range, 1.4 to 61.7) since the time of C/P initiation. The median overall survival (95% C.I.) is estimated to be 35.9 months (24.2, NA). These results demonstrate that the combination of oral cyclophosphamide and prednisone is an effective (56% MR or PR), very well tolerated (10% discontinued due to toxicity) and convenient treatment as salvage MM therapy post-ASCT. The relative lack of myelosuppression allows for re-collection of stem cells and salvage transplant while retaining other active second line agents for later relapse. This regimen thus compares favorably with recent salvage therapeutics introduced in MM and is now being studied in combination with these newer active agents and in induction therapy.

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Clarithromycin (Biaxin®), Low Dose Thalidomide and Dexamethasone (BLT-D) in Newly Diagnosed and Previously Treated African American Patients with Multiple Myeloma: A Retrospective, Single Institution Experience.

Blood ◽

10.1182/blood.v106.11.3501.3501 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3501-3501

Author(s):

Jack Jacoub ◽

Joao L. Ascensao ◽

Boyer James ◽

Thomas O’Connor ◽

Reema Batra ◽

...

Keyword(s):

Multiple Myeloma ◽

African American ◽

Partial Response ◽

Plasma Cells ◽

Progression Free Survival ◽

Staging System ◽

Stage I ◽

M Protein ◽

Duration Of Treatment ◽

Previously Treated

Abstract Introduction : African-Americans (AA) are twice as likely to develop multiple myeloma (MM) than Caucasians but are largely underrepresented in clinical trials. Thalidmode plus dexamethasone is an established therapy in MM. Biaxin® may augment the efficacy of this combination possibly via potentiating steroid activity (M. Coleman, et al. Leuk Lymphoma 2002, R. Niesvizky, et al. Blood 2003, Abs #832). Methods : We conducted a retrospective review of all AA patients (pts) with symptomatic MM treated with BLT-D from 2002-present. Treatment consisted of Thalidomide 50–200mg daily, Biaxin 500mg twice daily and dexamethasone 40mg weekly. All pts received monthly bisphosphonate therapy and aspirin 81–325mg daily. Response criteria was defined as follows: complete response (CR) = no detectable M-protein, marrow plasma cells <5%; very good partial response (VGPR) = decrease in M-protein by >90%; partial response (PR) = decrease in M-protein by >50%; stable disease (SD) = M-protein decrease by <50% without clinical progression; no response (NR)= progression with no change or increase in M-protein or response <4wks. Progression free survival (PFS) was defined from the start of BLT-D until discontinuation or change in therapy due to progressive disease as clinically indicated. Toxicity was graded according to WHO criteria. Results :15 pts received BLT-D and their characteristics were as follows: all were males; median age 66 (range 30–78); IgG=53%, IgA=20%, light chain only=27%; Durie-Salmon stage I=20%, II=33%, III=47%; International Staging System stage I=20%, II=47%, III=13%, undefined = 20%; 7 were previously treated (5 pts had 1 prior regimen, 2 pts had ≥2 prior regimens). In previously treated pts (n=7) responses were as follows: no CR, 2 VGPR (28%), 3 PR (43%), 1 SD (14%) and 1 NR (14%) for an overall response rate (ORR) of 87%. Their duration of treatment ranged from 4–32 mos and median PFS in responders (VGPR+PR+SD) was 29.5 mos (range 23–35). 3 pts had BLT-D discontinued after 12–15 months of therapy and remained in stable plateau phase off therapy for > 1 year; one was referred for ASCT after 14 mo; one continues stable at 15 mo and the third relapsed at 12 months but failed to respond again to BLT-D. Responses in treatment naive pts (n=8) were as follows: no CR, 3 VGPR (38%), 1 PR (13%) and 2 SD (25%), 2 NR (25%) for an ORR of 75%. Their duration of therapy ranged from 3–20 mos and median PFS in responding patients was 11 mos (range 7–20). The longest survivor in this group (37 mos) received an ASCT after 12 mos of therapy. 13 pts (87%) remain alive at a median follow-up of 24 mos (range 8–37). Grade 3–4 toxicity consisted of 3 DVTs + 1 PE (27%), 5 hypergycemias (33%), 2 infections (13%) and 1 peripheral neuropathy (7%). Additionally, 1 pt developed superficial thrombophlebitis; 1 QT prolongation resolving with Biaxin discontinuation; 5 others with neuropathy; and 2 others with hyperglycemia. Conclusion : BLT-D is feasible and effective therapy in African-American patients with MM and is capable of inducing durable responses. However, we encountered significant thrombotic and endocrine toxicity that appears out of proportion to what has been previously reported with thalidomide plus dexamethasone alone. Furthermore, aspirin thromboprophylaxis at daily doses of 81–325 mg appears suboptimal in preventing thromboembolic events in this group of patients when prescribed this regimen.

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Treatment of Relapsed and Refractory Multiple Myeloma in Patients with p53 Deletion.

Blood ◽

10.1182/blood.v112.11.1724.1724 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1724-1724

Author(s):

Donna E. Reece ◽

Young Trieu ◽

Hong Chang ◽

Wei Xu ◽

Peter Anglin ◽

...

Keyword(s):

Multiple Myeloma ◽

Alkylating Agents ◽

Progression Free Survival ◽

Autologous Stem Cell Transplant ◽

Novel Agents ◽

Cell Transplant ◽

Time Period ◽

Investigational Drugs ◽

Beta 2 Microglobulin

Abstract p53 deletion by fluorescence in situ hybridization (FISH) has been reported in about 10% of newly diagnosed patients (pts) with multiple myeloma (MM) and has been associated with a poor prognosis. Previous data from our centre has demonstrated that the progression-free survival (PFS) and overall survival (OS) of these pts after a single autologous stem cell transplant (ASCT) is only 16.9 and 48.2 months, respectively, compared to 24.4 and 76.6 mos, respectively, in all pts transplanted during the same time period (Mikhael et al, Blood2007; 110: abstract 953). Minimal information is available on the treatment (Tx) and course of these pts following disease progression. Therefore, we performed a retrospective review of all MM pts treated at our institution who were found to have p53 deletion. We identified 31 pts with relapsed/refractory (rel/ref) MM with this cytogenetic abnormality. At diagnosis, median age was 54 years (range, 31–70), hemoglobin 97 g/L (range, 67–149), creatinine 96 μmol/L (range, 28–1751), beta 2-microglobulin 314 nmol/L (range, 225–437), CRP 3 mg/L (range, 2–7) and LDH 205 U/L (range, 82–478); 58% were male. Immunoglobulin subtypes included: IgG (14 pts), IgA (8 pts), IgD (2 pts) and light chain only (7 pts). Concomitant cytogenetic abnormalities included 13q deletion in 68% and t(4;14) in 67% of pts evaluable. Thirty-nine percent developed plasma cell leukemia (PCL) at some point in the disease course, which was associated with a poor OS (p=0.005). All but 5 had undergone prior ASCT with a median time from diagnosis to ASCT of 8 (95% CI, 4–145) mos. Txs given for rel/ref MM consisted of the following regimens: thalidomide-based in 15, bortezomib-based in 12, lenalidomide-based in 11, alkylating agents in 9 and steroids only in 5 pts, and other regimens (D-PACE or investigational drugs) in 7 pts. The median follow-up from diagnosis in these pts is 45 (95% CI, 4–145) mos. The overall response rate (≥PR) (ORR), median PFS and median OS from the start of each regimen is shown below. Agent Median duration of Tx (mos) ORR(%) Median PFS (mos) Median OS (mos) Thalidomide 6.2 20% 5.0 11.9 Bortezomib 5.2 50% 5.6 36.1 Lenalidomide 10.6 60% 4.8 36.1 Alkylating agents 6.0 11% 5.1 30.0 Steroids 1.9 20% 1.9 33.4 Other 2.2 43% 6.3 33.4 We conclude: 1) Median PFS in pts with the p53 deletion is less than 6 months, with an OS of 2.5–3 yrs; 2) novel agents other than thalidomide produce the highest ORR in rel/ref MM with p53 deletion; 3) the short OS in the thalidomide group is likely related to the unavailability of other novel agents for subsequent relapses, as the majority of the pts were treated before 2004; 4) better strategies/drugs are required for these pts.

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