Bortezomib, Cyclophosphamide, Dexamethasone Versus Lenalidomide, Cyclophosphamide, Dexamethasone in Multiple Myeloma Patients at First Relapse

Abstract In multiple myeloma (MM), treatment selection and sequencing become increasingly complex with the increasing number of therapeutic options, including antibodies. Choice of treatment is dependent on various factors including patient- and tumor-related features. In addition, treatment-related factors, such as type and response to prior therapy, are also critical in terms of the selection of a new treatment regimen. Furthermore, approval status and reimbursement policies influence treatment choice. At the time of first relapse, patients who received a bortezomib-based regimen can switch to lenalidomide-based treatment, whereas patients who received lenalidomide until progression can switch to a proteasome inhibitor–based therapy. Alternatively, there is increasing evidence that pomalidomide-based triplets are also effective following the development of lenalidomide-refractory disease both in early and later relapse settings. Patients who become refractory to immunomodulatory drugs, proteasome inhibitors, and CD38 antibodies have a poor prognosis. These triple-class refractory patients may benefit from novel, recently approved agents such as XPO1 inhibitors or from participation in a clinical trial. Furthermore, retreatment with agents that were received in previous lines of therapy can also be considered in heavily pretreated patients, for example, in combination with classic cytotoxic drugs. Importantly, with the increasing use of CD38 antibodies in newly diagnosed and early relapsed/refractory MM, more information is needed on the potential value of retreatment with CD38 antibodies. With the introduction of new immunotherapies with novel modes of action, we also need a better understanding of sequencing of immunotherapeutic agents by taking into account the effect of prior therapy on immune function.

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Pros and cons of frontline autologous transplant in multiple myeloma: the debate over timing

Blood ◽

10.1182/blood-2018-08-825349 ◽

2019 ◽

Vol 133 (7) ◽

pp. 652-659 ◽

Cited By ~ 11

Author(s):

Shaji K. Kumar ◽

Francis K. Buadi ◽

S. Vincent Rajkumar

Keyword(s):

Multiple Myeloma ◽

The United States ◽

Initial Therapy ◽

Treatment Modalities ◽

Therapeutic Approaches ◽

Geographical Variations ◽

Maximum Benefit ◽

Recent Phase ◽

Pros And Cons ◽

First Relapse

Abstract The treatment landscape for multiple myeloma has dramatically changed over the past decade with the introduction of several new classes of drugs, which are very effective at controlling the disease for prolonged periods of time, especially when used in multidrug combinations. Prior to the advent of these new agents, peripheral blood autologous stem cell transplantation (ASCT) was the mainstay of therapy for patients who were eligible to undergo the procedure, with deep and durable responses in the majority of patients. Despite the introduction of more effective therapies, ASCT continues to play an important role in overall management of younger patients, where it has been integrated with the other therapeutic approaches to provide maximum benefit. Recent phase 3 trials have once again confirmed the survival benefit associated with ASCT in myeloma. Retrospective studies have also demonstrated the feasibility of using ASCT at the time of first relapse rather than as a component of the initial treatment. Significant geographical variations exist in the use of ASCT, especially between the United States and Europe in terms of its use as part of upfront therapy. Much of these differences are driven by the availability of drugs and drug combinations for initial therapy of myeloma as well as maintenance approaches post-ASCT. It is amply clear from these trials that ASCT will continue to play an important role in management of myeloma and is likely to be used as a platform for enhancing the efficacy of other treatment modalities that are currently in development.

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Risk Stratification and Targets in Multiple Myeloma: From Genomics to the Bedside

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_200879 ◽

2018 ◽

pp. 675-680 ◽

Cited By ~ 10

Author(s):

Aurore Perrot ◽

Jill Corre ◽

Hervé Avet-Loiseau

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Plasma Cells ◽

Mechanisms Of Action ◽

The Past ◽

Novel Drugs ◽

Genetic Abnormalities ◽

Frequent Mutations ◽

Risk Patients ◽

First Relapse

In the past 15 years, significant improvements in overall survival have been observed in multiple myeloma (MM), mainly due to the availability of novel drugs with variable mechanisms of action. However, these improvements do not benefit all patients, and some of them, defined as high risk, still display short survival. The most important risk factors are the genetic abnormalities present in the malignant plasma cells. The most important high-risk features are the del(17p), the del(1p32), the t(4;14), and 1q gains. Assessing these markers is mandatory at diagnosis and at least at first relapse, since it has been clearly shown that the lenalidomide-dexamethasone combination is not efficient in these high-risk patients. In contrast, a triplet combination adding a proteasome inhibitor or a monoclonal antibody to the lenalidomide-dexamethasone backbone clearly improves the survival. Another way to improve the outcome would be to specifically target genetic abnormalities with specific inhibitors. The sequencing of more than 1,000 MM exomes revealed again a huge heterogeneity. The most frequent mutations involve the KRAS and NRAS genes (20%–25% each). However, to date, no good RAS-inhibitors are clinically available, preventing targeted therapy. The only drugable target is the V600E BRAF mutation. Unfortunately, this specific mutation is present in only 3% of the patients. Finally, it has been recently reported a specific efficiency of the BCL2-inhibitor venetoclax in patients with the t(11;14) translocation, which is found in 20% of the patients.

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Natural History and Prognostic Factors at First Relapse in Multiple Myeloma

Cancers ◽

10.3390/cancers12071759 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1759

Author(s):

Chen Wang ◽

Cinnie Yentia Soekojo ◽

Sanjay de Mel ◽

Melissa Ooi ◽

Yunxin Chen ◽

...

Keyword(s):

Multiple Myeloma ◽

Natural History ◽

Great Majority ◽

Autologous Stem Cell Transplant ◽

Clinical Relapse ◽

Cell Transplant ◽

Treatment Sequence ◽

World Picture ◽

First Relapse ◽

Relapsed Myeloma

The prognosis of multiple myeloma has considerably improved due to the introduction of novel agents in the upfront setting. However, the great majority of patients ultimately relapse, and choosing a salvage treatment at first relapse remains challenging. The natural history of first relapsed disease in the current era is also not well described. We retrospectively studied 300 patients with first relapsed myeloma seen between 2004 and 2019 from two institutes in Singapore. The median duration from diagnosis to first relapse was 22.7 months (1.1–97.0 months). Most patients received novel agent-based induction therapy, and 41.3% underwent autologous stem cell transplant. A very good partial response (VGPR) or better was achieved in 48.6%. Regarding first relapse, 50.5% were symptomatic and 19.0% received newer agent-containing regimens. Nearly a third of patients (31.7%) had a VGPR or better response. The median progression free and overall survival from first relapse was 12.0 and 44.8 months, respectively. Based on a randomized sample splitting, we first identified non-hyperdiploid karyotype at diagnosis, clinical relapse, and treatment sequence as impacting survival independently from a testing cohort, and we then further demonstrated their significance in a validation cohort. This study provides a real-world picture of first relapsed myeloma and highlights the prognostic importance of the treatment sequence.

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Real world experience of bortezomib re-treatment for patients with multiple myeloma at first relapse

British Journal of Haematology ◽

10.1111/bjh.14086 ◽

2016 ◽

Vol 177 (3) ◽

pp. 495-497

Author(s):

Yasmin Reyal ◽

Rakesh Popat ◽

Simon Cheesman ◽

Ali Rismani ◽

Shirley D'Sa ◽

...

Keyword(s):

Multiple Myeloma ◽

Real World ◽

First Relapse

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Comparison of Autologous and Allogeneic Transplantation As Therapy of First Relapse in Patients with Multiple Myeloma - Long-Term Follow up Analysis,

Blood ◽

10.1182/blood.v118.21.4124.4124 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4124-4124

Author(s):

Ute Hegenbart ◽

Stefan O Schonland ◽

Axel Benner ◽

Christina Wunder ◽

Thomas M. Moehler ◽

...

Keyword(s):

Multiple Myeloma ◽

Multivariate Analysis ◽

Chronic Gvhd ◽

High Dose ◽

Two Stage ◽

Hematopoietic Stem ◽

Number Of Patients ◽

First Relapse ◽

First Diagnosis

Abstract Abstract 4124 BACKGROUND: Most patients (pts) undergoing high-dose therapy with melphalan 200 mg/m2 (HDM) and autologous transplant for multiple myeloma (MM) develop disease recurrence. The optimal salvage treatment including autologous (auto-) and allogeneic (allo-) hematopoietic stem cell transplantation (SCT) as consolidation therapy for these patients is not yet defined. METHODS: We performed a retrospective analysis of 116 pts with MM treated in our institution between 1999 and 2005. Inclusion criteria were relapse after auto-SCT (n=88) or failure of induction treatment (n=28) and age ≤ 65 years. Re-induction was performed with TCED (thalidomide, cyclophosphamide, etoposide and dexamethasone (Möhler et al, Blood 2001). Seventy-one pts (median age, 59 yrs) received auto-SCT (auto-group) after HDM followed by maintenance therapy with thalidomide or interferon-alpha in 42 pts. Forty-five pts (allo-group, median age, 53 yrs) underwent a reduced-intensity allo-SCT (related in 24 pts), mostly using conditioning with 2 Gy total body irradiation and fludarabine. Thirty-eight pts received an auto-allo-tandem-SCT (Maloney, Blood 2003) and 7 pts have been directly transplanted after TCED. Statistical analysis was done using the two-stage test of Qiu & Sheng (JRSS Ser. B 2008) to compare two possibly crossing survival curves. Extended Cox proportional hazards regression models were applied to allow for time-varying differences between the two SCT groups. RESULTS: Estimated median follow-up after start of TCED was 95 months. All pts received a median number of 3 TCED cycles for re-induction therapy. 64 of 116 pts (55%) showed at least a PR after TCED chemotherapy (CR in 3 pts). TRM was 17% after 2 years in the allo-group and differed significantly from the auto-group (3%, p=0.02). More CR were achieved after allo-SCT compared to auto-SCT (17 vs. 4 pts., p<0.001). Median overall survival (OS) was 26 months for the auto group and 23 months for the allo group (Figure 1, p=0.16). Median progression-free survival (PFS) was 12 months for both groups but crossing hazards were observed (Figure 2, p=0.03, two-stage test of Qiu & Sheng). The results of multivariate regression analysis for OS and PFS including age at relapse-SCT, response to TCED, time between first diagnosis until first relapse-SCT and primary progression are shown in table 1. In the allo group, there was no OS or PFS difference between related and unrelated donors (multivariate analysis). Cumulative incidence of chronic GvHD was 73% (53% extensive). Patients with chronic GvHD showed a better OS and PFS than pts without (univariate analysis, both p<0.01). CONCLUSIONS: To our knowledge, this is the first analysis in a large number of patients with a long follow-up comparing allo with auto SCT in 1st myeloma relapse which were treated uniformly with TCED therapy for re-induction. Main problem was MM recurrence. However, younger pts with disease response after TCED and longer time from first diagnosis to first SCT after relapse profit best from TCED and this transplant approach. Most interestingly, disease control is better after allo compared to auto SCT in univariate and multivariate analysis leading to a PFS of about 20% after 4 years. In our opinion, allo SCT is a valuable clinical option for patients with 1st relapse after HDM and auto SCT. Disclosures: No relevant conflicts of interest to declare.

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Escalated Dose Bortezomib Once Weekly Combined with Lenalidomide and Dexamethasone (eVRD) Followed by Lenalidomide Maintenance in First Relapse of Multiple Myeloma (MM). the HOVON 86 Phase 2 Trial

Blood ◽

10.1182/blood.v120.21.1853.1853 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1853-1853

Author(s):

Pieter Sonneveld ◽

Okke de Weerdt ◽

Mark-David Levin ◽

Wendimagegn Ghidey ◽

Edo Vellenga ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Dose Escalation ◽

Research Funding ◽

Phase 2 ◽

Level 3 ◽

First Relapse ◽

Grade 3 ◽

Dose Levels

Abstract Abstract 1853 Background: Bortezomib (1.3 mg/m2) combined with Lenalidomide (10–25 mg) and Dexamethasone (VRD) is effective in newly diagnosed and relapsed multiple myeloma (MM). Reported data on the effect of these drugs in relapse/refractory MM are available from the APEX and MM-009/MM-010 trials, respectively. These trials, however, were performed in patients with 2–8 prior regimens. Aim: This investigator sponsored two-step phase 2 HOVON trial was designed to evaluate escalated dosages of Bortezomib (B) given once weekly and daily Lenalidomide (L) combined with weekly Dexamethasone (D) (eVRD) followed by Lenalidomide maintenance in an homogenous group of patients with symptomatic MM in first relapse. The goal was to explore the maximum tolerated dose of this combination in order to achieve a durable second remission. Methods: Dose levels were B 1.3 mg/m2, L 10 mg, (level 1); B 1.6 mg/m2, L 10 mg (level 2); B 1.6 mg/m2, L 15 mg (level 3); B 1.6 mg/m2, L 20 mg (level 4). D dose was 20 mg days 1–2, 8–9, 15–16 in all dose levels. Inclusion criteria were symptomatic MM ISS stage 1–3, aged 18–80 in first relapse after initial treatment. The primary endpoint was response (complete response (CR) according to IMWG criteria, very good partial response (VGPR), partial response (PR), together overall response (ORR)) with Progression-free Survival (PFS), overall survival (OS) and toxicity as secondary endpoints. Results: Eighty-one patients were included, i.e. 15 patients in dose levels 1, 2 and 3, followed by 66 in the phase 2 part. This report is based on 12 patients in the dose escalation phase and the first 42 patients in the phase 2 part. Median age was 67 yrs, with ISS stages 1 (56%), 2 (40%) and 3 (5%). 37/54 patients had received HDM followed by stem cell transplant as part of first-line treatment. The MTD was reached at dose level 3 when the maximum of 3 SAEs in 5 patients was observed. After establishment of the MTD, the phase 2 part of the trial was performed with B 1.6 mg/m2 once weekly for 3 weeks, L 20 mg days 1–21 and D 20 mg days 1–2, 8–9, 15–16, for 8 cycles of 28 days followed by L maintenance 10 mg days 1–21 of a 28 days cycle. The median number of cycles was 6 in the dose-escalation phase and 7 cycles in phase 2. 7/12 (58%) patients in the dose-escalation phase and 23/42 (55%) patients in phase 2 started lenalidomide maintenance. Reasons for premature discontinuation of the protocol treatment were toxicity (14%), progression (24%), no response (5%) or other (14%). Polyneuropathy grade 3–4 occurred in 19% with a median time to maximum PNP of 123 days. Hematological toxicity grade 3 and 4 was observed in 29 % of patients In the phase 2 part including 42 patients the ORR was 92 %, ≥VGPR 64% and CR/nCR 30%. Median time to response was 1.1 cycles. At a median follow-up of 13.6 months PFS at 18 months was 52% and OS 76%. Among predetermined risk factors ISS stage, prior HDM/ASCT and achieved response on protocol, depth of response was the only significant factor which was associated with PFS (p<0.001) and OS (p<0.001), Eight patients died from progressive MM (n=4) or other causes (n=4). One second primary malignancy was observed in dose level 3. Conclusions: Escalated VRD followed by Lenalidomide maintenance is effective and feasible in patients with first relapse MM. We will present an updated follow-up at ASH This trial was registered as Eudract nr 2007–002533–37. Unrestricted grants and study drug were provided by Janssen and Celgene. Disclosures: Sonneveld: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding.

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Skeletal-Related Events In Patients With Multiple Myeloma In The Era Of Novel Agents: Low Incidence Of Pathological Fractures After Treatment

Blood ◽

10.1182/blood.v122.21.3090.3090 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3090-3090 ◽

Cited By ~ 1

Author(s):

Evangelos Terpos ◽

Nikolaos Kanellias ◽

Lia A Moulopoulos ◽

Dimitrios Christoulas ◽

Andreas Koureas ◽

...

Keyword(s):

Multiple Myeloma ◽

Rib Fractures ◽

Novel Agents ◽

First Line ◽

Pathological Fractures ◽

First Line Therapy ◽

Line Therapy ◽

Skeletal Related Events ◽

First Relapse ◽

Frontline Therapy

Abstract Skeletal-related events (SREs) which include pathological fractures, spinal cord compression (SCC) and a need for radiotherapy or surgery to bone are frequent complications of multiple myeloma (MM). Although, the frequency and characteristics of SREs in MM patients who received conventional chemotherapy (CC) or thalidomide-based regimens along with bisphosphonates (BPs) have been described, there are no data available in the era of proteasome inhibitors or novel IMiDs. Thus, we retrospectively evaluated the records of 400 consecutive patients with symptomatic MM (207M/193F, median age: 63 years) who were diagnosed, treated and followed in a single center. All patients had a whole body skeletal survey using conventional radiography at diagnosis and then at the time of relapse or whenever clinically indicated, while MRI of the spine and pelvis at diagnosis was available for 223 patients. Furthermore, we tested 125 patients for SNPs in genes that are involved in the biology of bone destruction: LRP5 (rs4988321), GC vitamin D (rs4588), TNFRSF11A (rs3018362), DKK1 (rs1569198), RANKL (rs9594759), OPG (rs6469804) and ERS1 (rs1038304). At diagnosis, the skeletal survey detected osteolytic disease in 284 (71%) patients. In MRI, 34.5% of the patients had focal, 40.5% diffuse, 21% normal, and 4% a variegated pattern of marrow involvement. SREs were observed in 167 (41.7%) patients at diagnosis: 104 (26%) patients presented with pathological fractures (87 with vertebral fractures, 18 with rib fractures and 17 with fractures of the long bones; 22 patients had both vertebral and long bone or rib fractures), while 22 (5.5%) patients required surgery to bone, 21 (5.2%) radiotherapy and 20 (5%) patients presented with SCC. The incidence of SREs was higher in patients with osteolytic lesions (49.5% vs. 24%, p<0.001) or abnormal MRI pattern (49.7% vs. 23.3%, p=0.001). However, we noted that approximately 1/4 patients without lytic lesions in plain X-rays or with normal MRI pattern presented with a SRE at diagnosis. Patients homozygous for RANKL polymorphism had lower incidence of osteolysis at diagnosis (14/28, 50%) versus all others (76%, p=0.009), suggesting that this polymorphism may protect bone loss in MM, as it has been suggested for normal population. Frontline therapy with IMiD-based regimens was given in 172 (43%) patients, while 80 (20%) patients received bortezomib-based regimens, 111 (27.7%) both IMiD and bortezomib (VTD or VRD) and 37 (9.2%) patients CC. BPs were given in all but 86 patients (21.5%) at diagnosis, mainly due to renal insufficiency; however, almost 60% of them (n=51) received BPs later in the course of their therapy. The vast majority (91%) of patients received zoledronic acid (ZA). Due to renal impairment, ZA was discontinued in 6 patients, while the dose was reduced in 44. During first line treatment, 7 (1.75%) patients developed a SRE: 2 on bortezomib- and 5 on IMiD-based regimens. The rate of SREs was higher in patients who did not receive upfront BPs (4.7% vs. 1%; p=0.021). The median follow-up was 39 months. At the time of first relapse (data available for 176 patients), 3 patients presented with fractures and 35 patients required local radiotherapy to bone (SRE incidence: 21.6%). Patients who had received only bortezomib-based regimens (VD or VCD, n=20) had lower SRE rate (2/20, 10%) vs. all others (36/156, 22%, p=0.173); the 3 patients with fractures had received MPT (n=2) or RD (n=1). In total, during the course of their disease, 52.8% of the patients presented with at least one SRE. Presentation with SREs at diagnosis did not predispose for SREs during the disease course, regardless of anti-myeloma treatment, possibly due to the low number of fractures and the higher number of radiation needed after frontline therapy. In summary, our data from the first systematic report on the incidence and characteristics of SREs in the era of novel agents indicate that SREs remain a significant complication in MM. Importantly, despite high response rates after first line therapy more than 20% of patients required radiotherapy at the time of relapse. The fracture rate was very low during first line therapy and at first relapse probably due to the extensive use of potent BPs and bortezomib, which has bone anabolic effects. The use of modern imaging techniques (i.e. PET/CT or LDWBCT) that can detect bone masses earlier and lead to earlier initiation of treatment may reduce the SRE incidence in the near future. Disclosures: No relevant conflicts of interest to declare.

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